Lifestyle Factors and Development and Natural Course of Gastroenteropancreatic Neuroendocrine Tumors: A Review of the Literature.

INTRODUCTION: The rarity of neuroendocrine tumors (NETs) and their heterogeneous presentation complicate the identification of risk factors for their development and natural course. Several tumor-specific prognostic factors have been identified, but less attention has been given to lifestyle factors as risk and prognostic factors. This review aimed to identify studies on smoking, alcohol use, physical activity, diet, body mass index (BMI), and diabetes and their association with the development and course of gastroenteropancreatic (GEP-) NETs. METHODS: The literature was systematically searched for articles on lifestyle factors and NETs available via PubMed and Embase. Study quality was assessed using the Newcastle-Ottawa scale. RESULTS: A total of 25 eligible studies out of 3,021 screened articles were included. Most studies reported on smoking and alcohol, reporting conflicting results. Diet seems to have an influence on NET development, but few studies were published. Articles reporting on BMI were not unanimous on the effect on GEP-NETs. Diabetes was reported as a risk factor for NETs, while a protective effect was observed with metformin use. CONCLUSION: Different tissues, i.e., the pancreas and small intestine, may respond differently to exposure to alcohol and smoking. Evidence for diet so far is too limited to draw conclusions. Diabetes seems to be an important risk factor for the development of pancreatic NETs with a protective role in disease progression, while BMI is not unequivocally associated with the development and prognosis of NETs. Hence, our findings suggest that lifestyle factors play an important role in NET development as a disease course. Future research should consider lifestyle as an influence on disease progression and treatment response.

Non-functional pancreatic neuroendocrine tumours: ATRX/DAXX and alternative lengthening of telomeres (ALT) are prognostically independent from ARX/PDX1 expression and tumour size.

OBJECTIVE: Recent studies have found aristaless-related homeobox gene (ARX)/pancreatic and duodenal homeobox 1 (PDX1), alpha-thalassemia/mental retardation X-linked (ATRX)/death domain-associated protein (DAXX) and alternative lengthening of telomeres (ALT) to be promising prognostic biomarkers for non-functional pancreatic neuroendocrine tumours (NF-PanNETs). However, they have not been comprehensively evaluated, especially among small NF-PanNETs (≤2.0 cm). Moreover, their status in neuroendocrine tumours (NETs) from other sites remains unknown. DESIGN: An international cohort of 1322 NETs was evaluated by immunolabelling for ARX/PDX1 and ATRX/DAXX, and telomere-specific fluorescence in situ hybridisation for ALT. This cohort included 561 primary NF-PanNETs, 107 NF-PanNET metastases and 654 primary, non-pancreatic non-functional NETs and NET metastases. The results were correlated with numerous clinicopathological features including relapse-free survival (RFS). RESULTS: ATRX/DAXX loss and ALT were associated with several adverse prognostic findings and distant metastasis/recurrence (p<0.001). The 5-year RFS rates for patients with ATRX/DAXX-negative and ALT-positive NF-PanNETs were 40% and 42% as compared with 85% and 86% for wild-type NF-PanNETs (p<0.001 and p<0.001). Shorter 5-year RFS rates for ≤2.0 cm NF-PanNETs patients were also seen with ATRX/DAXX loss (65% vs 92%, p=0.003) and ALT (60% vs 93%, p<0.001). By multivariate analysis, ATRX/DAXX and ALT status were independent prognostic factors for RFS. Conversely, classifying NF-PanNETs by ARX/PDX1 expression did not independently correlate with RFS. Except for 4% of pulmonary carcinoids, ATRX/DAXX loss and ALT were only identified in primary (25% and 29%) and NF-PanNET metastases (62% and 71%). CONCLUSIONS: ATRX/DAXX and ALT should be considered in the prognostic evaluation of NF-PanNETs including ≤2.0 cm tumours, and are highly specific for pancreatic origin among NET metastases of unknown primary.

Assessing Outcomes After Adrenalectomy for Primary Aldosteronism - Early is Accurate: Retrospective Cohort Study.

OBJECTIVE: We aimed to investigate the postoperative trend in blood pressure (BP)-related outcomes [BP and antihypertensive (AHT) drug use] during the year following adrenalectomy for primary aldosteronism (PA) to determine the optimal timing for outcome assessment and to determine the necessary follow-up length. BACKGROUND: Since the course of BP-related outcomes after adrenalectomy is unknown, the optimal timing of outcome assessment and follow-up duration are not clear. METHODS: In this retrospective single center cohort study, we used a prospectively collected database with all patients referred for difficult-to-control-hypertension-analysis. All patients diagnosed with PA who underwent adrenalectomy were included. AHT drug use [in defined daily dose (DDD)] and home blood pressure measurements (HBPMs) during the first postoperative year were collected. A mixed-effects model was developed to assess the stability of DDD and HBPM over time and adjust for potential confounders. RESULTS: In total 1784 patients were assessed for difficult-to-control-hypertension of whom 41 were included. Both the DDD and HBPM showed the strongest decrease in the first postoperative month (mean 1.6DDD; mean 140/85 mm Hg) compared with preoperative values (4.5DDD; 153/92 mm Hg). Thereafter, both outcomes showed a stable course from 4 to 6 months (1.6DDD; 136/86 mm Hg) up to 12 months postoperatively (2.0DDD; 136/83 mm Hg). CONCLUSIONS: This study showed that AHT drug use and HBPM decreased substantially within the first month after adrenalectomy for PA and afterwards generally remained stable during the year following adrenalectomy. We propose that BP-related outcomes can be assessed reliably early after adrenalectomy and question the need for routine long-term follow-up in referral centers.

Primary Tumor Resection is Associated with Improved Disease-Specific Mortality in Patients with Stage IV Small Intestinal Neuroendocrine Tumors (NETs): A Comparison of Upfront Surgical Resection Versus a Watch and Wait Strategy in Two Specialist NET Centers.

INTRODUCTION: Small intestinal neuroendocrine tumors (SI-NETs) often present with metastatic disease. An ongoing debate exists on whether to perform primary tumor resection (PTR) in patients with stage IV SI-NETs, without symptoms of the primary tumor and inoperable metastatic disease. OBJECTIVE: The aim of this study was to compare a treatment strategy of upfront surgical resection versus a surveillance strategy of watch and wait. METHODS: This was a retrospective cohort study of patients with stage IV SI-NETs at diagnosis, between 2000 and 2018, from two tertiary referral centers (Netherlands Cancer Institute [NKI] and Aintree University Hospital [AUH]) who had adopted contrasting treatment approaches: upfront surgical resection and watch and wait, respectively. Patients without symptoms related to the primary tumor were included. Multivariable intention-to-treat (ITT), per-protocol (PP), and instrumental variable (IV) analyses using 'institute' as an IV were performed to assess the influence of PTR on disease-specific mortality (DSM). RESULTS: A total of 557 patients were identified, with 145 patients remaining after exclusion of stage I-III disease or symptoms of the primary tumor (93 from the NKI and 52 from AUH). The cohorts differed in performance status (PS; p = 0.006) and tumor grade (p < 0.001). PTR was independently associated with reduced DSM irrespective of statistical methods employed: ITT hazard ratio [HR] 0.60, p = 0.005; PP HR 0.58, p < 0.001; and IV HR 0.07, p = 0.019. Other factors associated with DSM were age, PS, high chromogranin A, and somatostatin analog treatment. CONCLUSION: Taking advantage of contrasting institutional treatment strategies, this study identified PTR as an independent predictor of DSM. Future prospective studies should aim to validate these results.

Update on the clinical management of multiple endocrine neoplasia type 1.

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.

Complications After Major Surgery for Duodenopancreatic Neuroendocrine Tumors in Patients with MEN1: Results from a Nationwide Cohort.

BACKGROUND: Little is known about complications after major duodenopancreatic surgery for duodenopancreatic neuroendocrine tumors (dpNETs) in multiple endocrine neoplasia type 1 (MEN1). Therefore, the incidence and severity of complications after major surgery for MEN1-related dpNETs were assessed. METHODS: Patients were selected from the population-based Dutch MEN1 database if they had undergone a Whipple procedure or total pancreatectomy from 2003 to 2017. Complications were graded according to the Clavien-Dindo classification (grade III or higher complications were considered a severe complication) and definitions from the International Study Group of Pancreatic Surgery. The Cumulative Complication Index (CCI®) was calculated as the sum of all complications weighted for their severity. Univariable logistic regression was performed to assess potential associations between predictor candidates and a severe complication. RESULTS: Twenty-seven patients (median age 43 years) underwent a major duodenopancreatic resection, including 14 Whipple procedures and 13 total pancreatectomies. Morbidity and mortality were 100% (27/27) and 4% (1/27), respectively. A severe complication occurred in 17/27 (63%) patients. The median CCI® was 47.8 [range 8.7-100]. Grade B/C pancreatic fistulas, delayed gastric emptying, bile leakage, hemorrhage, and chyle leakage occurred in 7/14 (50%), 10/27 (37%), 1/27 (4%), 7/27 (26%), 3/27 (11%) patients, respectively. Patients with a severe complication had longer operative time and higher blood loss. After Whipple, new-onset endocrine and exocrine insufficiency occurred in 1/13 and 9/14 patients, respectively. CONCLUSIONS: Major duodenopancreatic surgery in MEN1 is associated with a very high risk of severe complications and cumulative burden of complications and should therefore be reserved for a select subgroup of patients with MEN1-related dpNETs.

Children with multiple endocrine neoplasia type 2B: Not tall and marfanoid, but short with normal body proportions.

OBJECTIVE: Multiple endocrine neoplasia 2B (MEN2B) is characterised by early-onset medullary thyroid carcinoma (MTC), pheochromocytoma and several nonendocrine manifestations. Unfortunately, MEN2B is often diagnosed late, after the development of clinically significant MTC. Marfanoid habitus is considered an important related feature, which may lead to the assumption that patients with MEN2B have tall stature. Here, we describe the longitudinal growth and body proportions of eight MEN2B patients during childhood. DESIGN: It is a retrospective case series. METHODS: Patients were under the care of a Dutch MEN expertise centre. Growth patterns were assessed and interpreted in relation to body mass index (BMI), age at diagnosis and at thyroidectomy, extensiveness of disease manifestations and parental height. RESULTS: Seven patients were short during childhood, of whom four showed growth below target height range (THR) and three at the lowest margin of THR. Only one patient grew well within THR. All patients who attained final height (n = 4) ended within THR, despite short stature during childhood. Arm span/height ratio was not increased and upper segment/lower segment ratio was not reduced in any patient. Short stature in childhood in this study did not seem to be associated with age at diagnosis, age at thyroidectomy, extensiveness of MTC, endocrine deficiencies or BMI. CONCLUSIONS: This study shows that children with MEN2B may well present with short rather than tall stature. Thereafter, final height within THR was attained in those who already reached adulthood, but none had tall stature. Finally, body proportions were normal in all children and adults in this case series, not underlining a 'marfanoid' body habitus.

Driver mutations occur frequently in metastases of well-differentiated small intestine neuroendocrine tumours.

AIMS: To investigate the clinicopathological significance of driver mutations in metastatic well-differentiated small intestine neuroendocrine tumours (SI-NETs). METHODS AND RESULTS: Whole genome sequencing (WGS) of 35 metastatic SI-NETs and next-generation sequencing (NGS) of eight metastatic SI-NETs were performed. Biopsies were obtained between 2015 and 2019. Tumours were classified according to the 2019 World Health Organization classification. WGS included assessment of somatic mutations in all cancer-related driver genes, the tumour mutational burden (TMB), and microsatellite status. NGS entailed a cancer hotspot panel of 58 genes. Our cohort consisted of 21% grade 1, 60% grade 2 and 19% grade 3 SI-NETs. Driver mutations were identified in ~50% of SI-NETs. In total, 27 driver mutations were identified, of which 74% were in tumour suppressor genes (e.g. TP53, RB1, and CDKN1B) and 22% were in proto-oncogenes (e.g. KRAS, NRAS, and MET). Allelic loss of chromosome 18 (63%), complete loss of CDKN2A and CDKN1B (both 6%) and CDKN1B mutations (9%) were most common. Potential targetable genetic alterations were detected in 21% of metastasised SI-NETs. All tumours were microsatellite-stable and showed low TMBs (median 1.10; interquartile range 0.87-1.35). The Ki67 proliferation index was significantly associated with the presence of driver mutations (P = 0.015). CONCLUSION: Driver mutations occur in 50% of metastasised SI-NETs, and their presence is associated with a high Ki67 proliferation index. The identification of targetable mutations make these patients potentially eligible for targeted therapy.

Blood Molecular Genomic Analysis Predicts the Disease Course of Gastroenteropancreatic Neuroendocrine Tumor Patients: A Validation Study of the Predictive Value of the NETest®.

Reliable prediction of disease status is a major challenge in managing gastroenteropancreatic neuroendocrine tumors (GEP-NETs). The aim of the study was to validate the NETest®, a blood molecular genomic analysis, for predicting the course of disease in individual patients compared to chromogranin A (CgA). NETest® score (normal ≤20%) and CgA level (normal <100 µg/L) were measured in 152 GEP-NETs. The median follow-up was 36 (4-56) months. Progression-free survival was blindly assessed (Response Evaluation Criteria in Solid Tumors [RECIST] version 1.1). Optimal cutoffs (area under the receiver operating characteristic curve [AUC]), odds ratios, as well as negative and positive predictive values (NPVs/PPVs) were calculated for predicting stable disease (SD) and progressive disease (PD). Of the 152 GEP-NETs, 86% were NETest®-positive and 52% CgA-positive. -NETest® AUC was 0.78 versus CgA 0.73 (p = ns). The optimal cutoffs for predicting SD/PD were 33% for the NETest® and 140 µg/L for CgA. Multivariate analyses identified NETest® as the strongest predictor for PD (odds ratio: 5.7 [score: 34-79%]; 12.6 [score: ≥80%]) compared to CgA (odds ratio: 3.0), tumor grade (odds ratio: 3.1), or liver metastasis (odds ratio: 7.7). The NETest® NPV for SD was 87% at 12 months. The PPV for PD was 47 and 64% (scores 34-79% and ≥80%, respectively). NETest® metrics were comparable in the watchful waiting, treatment, and no evidence of disease (NED) subgroups. For CgA (>140 ng/mL), NPV and PPV were 83 and 52%. CgA could not predict PD in the watchful waiting or NED subgroups. The NETest® reliably predicted SD and was the strongest predictor of PD. CgA had lower utility. The -NETest® anticipates RECIST-defined disease status up to 1 year before imaging alterations are apparent.

Health-Related Quality of Life in Patients with Multiple Endocrine Neoplasia Type 1.

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.

Multiple Endocrine Neoplasia Type 1 and the Pancreas: Diagnosis and Treatment of Functioning and Non-Functioning Pancreatic and Duodenal Neuroendocrine Neoplasia within the MEN1 Syndrome - An International Consensus Statement.

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.

Reliability and Agreement of Radiological and Pathological Tumor Size in Patients with Multiple Endocrine Neoplasia Type 1-Related Pancreatic Neuroendocrine Tumors: Results from a Population-Based Cohort.

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.

PSMA PET/CT Identifies Intrapatient Variation in Salivary Gland Toxicity From Iodine-131 Therapy.

INTRODUCTION: Xerostomia is a well-known complication after iodine-131 (131I) therapy for thyroid carcinoma. It is currently insufficiently understood how the dose and biodistribution of 131I relates to salivary gland toxicity, and whether this is consistent for all salivary glands within a single patient. Prostate-specific membrane antigen (PSMA) positron emission tomography/computed tomography (PET/CT) was recently introduced as a new tool to evaluate the relative loss of vital acinar cells in individual salivary glands. We aimed to assess gland-specific salivary gland toxicity after 131I-therapy using PSMA PET/CT. METHODS: Five patients with differentiated thyroid cancer underwent [68Ga]Ga-PSMA-11 PET/CT to evaluate their eligibility for peptide radioligand therapy with [177Lu]Lu-PSMA-617. Uptake patterns in salivary glands were evaluated visually and quantitatively as an indicator of vital acinar cell loss after prior 131I-therapy. RESULTS: Four of 5 patients demonstrated significant lowered uptake in at least one salivary gland, after receiving at least 2 131I-treatments. Asymmetric loss of vital acinar cells occurred by gland type (parotid/submandibular) and location (right/left). The other salivary glands in these patients and all salivary glands in the fifth patient showed normal uptake, demonstrating high intrapatient and interpatient variability. CONCLUSIONS: 131I-therapy can induce salivary gland toxicity with high inter- but also high intrapatient variation among separate gland locations, which can be assessed with PSMA PET/CT. This new technique offers potential to guide further development and evaluation of protective measures in patients receiving 131I-therapy.

Adrenalectomy for Primary Aldosteronism: Significant Variability in Work-Up Strategies and Low Guideline Adherence in Worldwide Daily Clinical Practice.

BACKGROUND: Various diagnostic tests are available to establish the primary aldosteronism (PA) diagnosis and to determine the disease laterality. Combined with the controversies in the literature, unawareness of guidelines and technical demands and high costs of some of these diagnostics, this could lead to significant differences in work-up strategies worldwide. Therefore, we investigated the work-up before surgery for PA in daily clinical practice within a multicenter study. METHODS: Patients who underwent unilateral adrenalectomy for PA within 16 centers in Europe, Canada, Australia and the USA between 2010 and 2016 were included. We did not exclude patients based on the performed diagnostic tests during work-up to make our data representative for current clinical practice. Adherence to the Endocrine Society Guideline and variables associated with not performing adrenal venous sampling (AVS) were analyzed. RESULTS: In total, 435 patients were eligible. An aldosterone-to-renin ratio, confirmatory test, computed tomography (CT), magnetic resonance imaging and AVS were performed in 82.9%, 32.9%, 86.9%, 17.0% and 65.3% of patients, respectively. A complete work-up, as recommended by the guideline, was performed in 13.1% of patients. Bilateral disease or normal adrenal anatomy on CT (OR 16.19; CI 3.50-74.99), smaller tumor size on CT (OR 0.06; CI 0.04-0.08) and presence of hypokalemia (OR 2.00; CI 1.19-3.32) were independently associated with performing AVS. CONCLUSIONS: This study is the first to examine the daily clinical practice work-up of PA within a worldwide cohort of surgical patients. The results demonstrate significant variability in work-up strategies and low adherence to The Endocrine Society guideline.

Correction to: Validation of the Aldosteronoma Resolution Score Within Current Clinical Practice.

In the original article, two of the International CONNsortium Study Group collaborator's names are spelled wrong: Anton F. Engelsman and Els J.M. Nieveen van Dijkum. The spellings are correct as reflected here.

Prognostic factors and survival in MEN1 patients with gastrinomas: Results from the DutchMEN study group (DMSG).

BACKGROUND AND OBJECTIVES: Gastrinomas are the most prevalent functioning neuroendocrine tumors (NET) in multiple endocrine neoplasia type 1 (MEN1). Guidelines suggest medical therapy in most patients, but surgery may be considered in a subgroup. Currently, factors to guide management are necessary. This population-based cohort study assessed prognostic factors of survival in patients with MEN1-related gastrinomas. METHODS: Patients with MEN1 having gastrinomas were identified in the Dutch MEN1 database from 1990 to 2014 based on fasting serum gastrin (FSG) levels and/or pathology. Predictors of overall survival were assessed using Cox regression. RESULTS: Sixty-three patients with gastrinoma (16% of the MEN1 population) were identified. Five- and 10-year overall survival rates were 83% and 65%, respectively. Prognostic factors associated with overall survival were initial FSG levels ≥20x upper limit of normal (ULN) (hazard ratio [HR], 6.2 [95% confidence interval, 1.7-23.0]), pancreatic NET ≥2 cm (HR 4.5; [1.5-13.1]), synchronous liver metastases (HR 8.9; [2.1-36.7]), gastroduodenoscopy suspicious for gastric NETs (HR 12.7; [1.4-115.6]), and multiple concurrent NETs (HR 5.9; [1.2-27.7]). CONCLUSION: Life expectancy of patients with MEN1 gastrinoma is reduced. FSG levels and pancreatic NETs ≥2 cm are prognostic factors. FSG levels might guide surveillance intensity, step-up to additional diagnostics, or provide arguments in selecting patients who might benefit from surgery.

Validation of the Aldosteronoma Resolution Score Within Current Clinical Practice.

INTRODUCTION: Complete resolution of hypertension after adrenalectomy for primary aldosteronism is far from a certainty. This stresses the importance of adequate preoperative patient counseling. The aldosteronoma resolution score (ARS) is a simple and easy to use prediction model only including four variables: ≤ 2 antihypertensive medications, body mass index ≤ 25 kg/m2, duration of hypertension ≤ 6 years and female sex. However, because the model was developed and validated within the USA over a decade ago, the applicability in modern practice and outside of the USA is questionable. Therefore, we aimed to validate the ARS in current clinical practice within an international cohort. MATERIALS AND METHOD: Patients who underwent unilateral adrenalectomy, between 2010 and 2016, in 16 medical centers from the USA, Europe (EU), Canada (CA) and Australia (AU) were included. Resolution of hypertension was defined as normotension without antihypertensive medications. RESULTS: In total, 514 patients underwent adrenalectomy and 435 (85%) patients were eligible. Resolution of hypertension was achieved in 27% patients within the total cohort and in 22%, 30%, 40% and 38% of patients within USA, EU, CA and AU, respectively (p = 0.015). The area under the curve (AUC) for the complete cohort was 0.751. Geographic validation displayed a AUC within the USA, EU, CA and AU of 0.782, 0.681, 0.811 and 0.667, respectively. DISCUSSION: The ARS is an easy to use prediction model with a moderate to good predictive performance within current clinical practice. The model showed the highest predictive performance within North America but potentially has less predictive performance in EU and AU.

Early and Late Complications After Surgery for MEN1-related Nonfunctioning Pancreatic Neuroendocrine Tumors.

OBJECTIVE: To estimate short and long-term morbidity after pancreatic surgery for multiple endocrine neoplasia type 1 (MEN1)-related nonfunctioning pancreatic neuroendocrine tumors (NF-pNETs). BACKGROUND: Fifty percent of the MEN1 patients harbor multiple NF-pNETs. The decision to proceed to NF-pNET surgery is a balance between the risk of disease progression versus the risk of surgery-related morbidity. Currently, there are insufficient data on the surgical complications after MEN1 NF-pNET surgery. METHODS: MEN1 patients diagnosed with a NF-pNET who underwent surgery were selected from the DutchMEN1 study group database, including >90% of the Dutch MEN1 population. Early postoperative complications, new-onset diabetes mellitus, and exocrine pancreatic insufficiency were captured. RESULTS: Sixty-one patients underwent NF-pNET surgery at 1 of the 8 Dutch academic centers. Patients were young (median age 41 years) with low American Society of Anesthesiologists scores. Median NF-pNET size on imaging was 22 mm (3-157). Thirty-three percent (19/58) of the patients developed major early-Clavien-Dindo grade III to IV-complications mainly consisting International Study Group of Pancreatic Surgery grade B/C pancreatic fistulas. Twenty-three percent of the patients (14/61) developed endocrine or exocrine pancreas insufficiency. The development of major early postoperative complications was independent of the NF-pNET tumor size. Twenty-one percent of the patients (12/58) developed multiple major early complications. CONCLUSIONS: MEN1 NF-pNET surgery is associated with high rates of major short and long-term complications. Current findings should be taken into account in the shared decision-making process when MEN1 NF-pNET surgery is considered.

Management of MEN1 Related Nonfunctioning Pancreatic NETs: A Shifting Paradigm: Results From the DutchMEN1 Study Group.

OBJECTIVE: To assess if surgery for Multiple Endocrine Neoplasia type 1 (MEN1) related nonfunctioning pancreatic neuroendocrine tumors (NF-pNETs) is effective for improving overall survival and preventing liver metastasis. BACKGROUND: MEN1 leads to multiple early-onset NF-pNETs. The evidence base for guiding the difficult decision who and when to operate is meager. METHODS: MEN1 patients diagnosed with NF-pNETs between 1990 and 2014 were selected from the DutchMEN1 Study Group database, including > 90% of the Dutch MEN1 population. The effect of surgery was estimated using time-dependent Cox analysis with propensity score restriction and adjustment. RESULTS: Of the 152 patients, 53 underwent surgery and 99 were managed by watchful waiting. In the surgery group, tumors were larger and faster-growing, patients were younger, more often male, and were more often treated in centers that operated more frequently. Surgery for NF-pNETs was not associated with a significantly lower risk of liver metastases or death, [adjusted hazard ratio (HR) = 0.73 (0.25-2.11)]. Adjusted HR's after stratification by tumor size were: NF-pNETs <2 cm = 2.04 (0.31-13.59) and NF-pNETs 2-3 cm = 1.38 (0.09-20.31). Five out of the 6 patients with NF-pNETs >3 cm managed by watchful waiting developed liver metastases or died compared with 6 out of the 16 patients who underwent surgery. CONCLUSIONS: MEN1 patients with NF-pNETs <2 cm can be managed by watchful waiting, hereby avoiding major surgery without loss of oncological safety. The beneficial effect of a surgery in NF-pNETs 2 to 3 cm requires further research. In patients with NF-pNETs >3 cm, watchful waiting seems not advisable.

Merkel cell carcinoma: Clinical outcome and prognostic factors in 351 patients.

BACKGROUND: Merkel cell carcinoma (MCC) is a rare and aggressive neuroendocrine carcinoma of the skin. AIM: To describe clinical outcome and prognostic factors of MCC patients in two expert-centers. METHOD: Patients with histologically confirmed MCC in 1990-2014 were included. Data on patient, tumor characteristics and treatment were retrospectively collected. RESULTS: A total of 351 Patients were evaluated, 153 (44%) males, median age 74 years (range 28-94). Median follow-up time was 28 months (IQR 13-58). Median primary tumor size was 17 mm (range 2-135). At time of diagnosis 112 (32%) patients had lymph node metastases. The cohorts' 5-year overall survival (OS) was 58%. Using a competing risk analysis the 5-year relapse and MCC related death was 42% and 22%. Adjuvant radiation therapy (XRT) was associated with reduced recurrence (SDH 0.54; CI 0.3-0.9). Nodal involvement (SDH 2.7; CI 1.1-6.6) and the male gender were associated with higher MCC related death (SDH 3.1; CI 1.2-7.9) CONCLUSION: In a large cohort a low MCC related death, in the presence of a low OS was seen. This indicates that a significant number of MCC patients die due to other causes than MCC. Adjuvant XRT was associated with relapse. Male gender and nodal metastasis were associated with MCC related death.