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Contains fulltext : 237734.pdf (Publisher’s version ) (Open Access) OBJECTIVE: Obesity is associated with impaired gut microbiota diversity, which has been linked to the development of type 2 diabetes. This study aims to examine the effects of an 8-week aerobic exercise intervention on insulin sensitivity, visceral adiposity, and gut microbiota diversity and composition in participants with obesity. METHODS: Fourteen participants (mean [SD], age 51 [11] years; BMI 34.9 [4.9] kg/m(2) ) performed an 8-week exercise intervention (2 to 4 times/week on 65% to 85% of heart rate reserve). Insulin sensitivity (hyperinsulemic euglycemic clamp), cardiorespiratory fitness (maximal oxygen uptake), visceral adiposity (dual-energy X-ray absorptiometry scan) and gut microbiota composition (16S rRNA gene sequencing) were measured before and after the intervention. RESULTS: Insulin sensitivity showed a significant increase (pre: 3.8 [1.9] mg/min/kg; post: 4.5 [1.7] mg/min/kg; p = 0.007) after training, whereas visceral adiposity decreased (pre: 959 [361] cm(3) ; post: 897 [364] cm(3) ; p = 0.02). No change in gut microbiota α- or β-diversity was found. At the genus level, the abundance of Ruminococcus gauvreauii (p = 0.02); Lachnospiraceae FCS020 group (p = 0.04), and Anaerostipes (p = 0.04) significantly increased after exercise training. Significant positive correlations were present for M-value (R. gauvreauii) and VO(2) max (R. gauvreauii and Anaerostipes). CONCLUSIONS: Eight-week exercise training in humans with obesity leads to marked improvements in insulin sensitivity and body composition and is accompanied by modest changes in 3 gut microbiome genera, all belonging to the Firmicutes phylum.

Objective To develop a primary aldosteronism (PA) disease-specific Health-Related Quality of Life (HRQoL) questionnaire. Methods We included newly diagnosed patients with PA (n = 26), and patients with PA after adrenalectomy (n = 25) or treated with mineralocorticoid receptor antagonists (n = 25). According to the guidelines for developing HRQoL questionnaires from the European Organization for Research and Treatment of Cancer (EORTC): Phase I: systematic literature review followed by focus group meetings with patients (n = 13) resulting in a list of 94 HRQoL issues. Relevance of issues was rated by 18 other patients and by health care professionals (n = 15), resulting in 30 remaining issues. Phase II: selected issues were converted into questions. Phase III: the provisional questionnaire was pre-tested by a third group of patients (n = 45) who also completed the EORTC core Quality of Life questionnaire (QLQ-C30). Psychometric testing resulted in a final selection of questions with their scale structure. Results After the collection and selection of HRQoL issues a provisional questionnaire consisting of 30 items was formed. Of these items, 26 could be assigned to one of the four scales ‘physical and mental fatigue’, ‘anxiety and stress’, ‘fluid balance’ and ‘other complaints’ cumulatively accounting for 68% of variation in all items. All scales had good reliability and validity. There was a significant correlation of all four scales with the QLQ-C30 in most cases. Conclusions We developed the first PA-specific HRQoL questionnaire (PA-QoL) using standard, methodologically proven guidelines. After completion of the final validation (phase IV, international field testing), the questionnaire can be implemented into clinical practice.

Objective To assess the effect of somatostatin analogs (SSAs) on mortality in relation to disease control of acromegaly after pituitary surgery. Design A retrospective study in two large tertiary referral centers in The Netherlands. Methods Overall, 319 patients with acromegaly in whom pituitary surgery was performed as primary therapy between January 1980 and July 2017 were included. Postoperative treatment with SSA was prescribed to 174 (55%) patients because of persistent or recurrent disease. Disease control at last visit was assessed by IGF1 standard deviation score (SDS). Adequate disease control was defined as IGF1 SDS ≤2. Univariate determinants of mortality and standardized mortality ratios (SMRs) were calculated for groups with and without SSA at any moment postoperatively and at last visit. Results In total, 27 deaths were observed. In univariate analysis, determinants of mortality were inadequate disease control (relative risk (RR): 3.41, P = 0.005), surgery by craniotomy (RR: 3.53, P = 0.013) and glucocorticoid substitution (RR: 2.11, P = 0.047). There was a strong trend toward increased mortality for patients who used SSA (RR: 2.01, P = 0.067) and/or dopamine agonists (RR: 2.54, P = 0.052) at last visit. The SMR of patients with adequate disease control who used SSA at any moment postoperatively (1.07, P = 0.785) and at last visit (1.19; P = 0.600) was not increased. Insufficiently controlled patients had a significantly raised SMR (3.92, P = 0.006). Conclusions Postoperative use of SSA is not associated with increased mortality in patients with acromegaly who attain adequate disease control. In contrast, inadequate disease control, primary surgery by craniotomy and glucocorticoid substitution are associated with increased mortality.

ContextProlonged adrenal stimulation by corticotropin, as in long-standing Cushing disease (CD), leads to diffuse to nodular hyperplasia. Adrenal functional autonomy has been described in a subset of patients with CD, leading to the hypothesis of transition from ACTH-dependent to ACTH-independent hypercortisolism.ObjectiveWith the consideration that the catalytic α subunit of protein kinase A (PKA; PRKACA) somatic mutations are the most common finding in adrenal adenomas associated with ACTH-independent Cushing syndrome, our aim was to analyze PRKACA mutations in adrenals of patients with persistent/long-standing CD.DesignCross-sectional.SettingUniversity hospital.PatientsTwo patients with long-standing CD and suspicion of coexistence of autonomous adrenal hyperfunction, according to pre and postoperative evaluations, were selected for this study, following an intensive literature search and patient-chart reviewing.InterventionClinical data were analyzed. DNA was extracted from adrenal tissue for PRKACA sequencing. PKA activity was assayed.Main Outcome MeasurePRKACA somatic mutations.ResultsBoth patients showed mutations of PRKACA in the macronodule in the context of micronodular adrenal hyperplasia. One patient harbored the previously described p.Leu206Arg substitution, whereas a p.Ser213Arg missense variation was detected in the adrenal nodule of the second patient. No mutations were detected in the adjacent adrenal cortex of the second patient. In silico analysis predicts that p.Ser213Arg can interfere with the interaction between the regulatory and catalytic subunits of PKA.ConclusionsOur study shows that PRKACA somatic mutations can be found in adrenal nodules of patients with CD. These genetic alterations could represent a possible mechanism underlying adrenal nodule formation and autonomous cortisol hyperproduction in a subgroup of patients with long-standing CD.

Item does not contain fulltext OBJECTIVES: Obesity is characterized by a pro-inflammatory state, which plays a role in the pathogenesis of metabolic and cardiovascular disease. An exercise bout causes a transient increase in pro-inflammatory cytokines, whilst training has anti-inflammatory effects. No previous study examined whether the exercise-induced increase in pro-inflammatory cytokines is altered with repeated prolonged exercise bouts and whether this response differs between lean and overweight/obese individuals. DESIGN: Lean (n=25, BMI 22.9+/-1.5kg/m(2)) and age-/sex-matched overweight/obese (n=25; BMI 27.9+/-2.4kg/m(2)) individuals performed walking exercise for 30, 40 or 50km per day on four consecutive days (distances similar between groups). METHODS: Circulating cytokines (IL-6, IL-10, TNF-alpha, IL-1beta and IL-8) were examined at baseline and

Objective Cushing’s syndrome (CS) is associated with osteoporosis and high fracture risk. Besides male sex, it is unknown which variables influence bone mineral density (BMD) at diagnosis and it is unclear to what extent BMD normalizes during long-term follow-up after treatment of CS. The aim of this study was to determine factors associated with BMD at diagnosis of CS and to determine the long-term course of BMD and fracture rate after successful treatment of CS. Design Retrospective cross-sectional and longitudinal cohort study. Methods Data were collected from 231 patients with CS who were treated at the Radboud University Medical Centre between 1968 and 2020. Results At diagnosis, male sex was associated with lower Z-scores at the lumbar spine (LS) compared with female sex: −0.97s.d. (−1.45 to −0.49) after correction for possible confounders. Shorter duration of symptoms and younger age were also associated with lower Z-scores at diagnosis, while etiology of CS, urinary cortisol excretion and gonadal status were not associated with Z-scores at diagnosis. Z-scores improved up to 20 years after treatment. Fifteen years after treatment, men showed larger improvements of Z-scores than women; +2.56 (1.82–3.30) increase in LS Z-score vs +1.48 (0.96–2.00) respectively. Fracture incidence was highest during the 2 years before diagnosis and decreased after treatment. Conclusion Male sex, younger age and shorter duration of symptoms are associated with lower BMD at diagnosis of CS. BMD continues to improve up to 20 years after treatment of CS. Fracture rate decreases after treatment of CS.

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.

Background: Active acromegaly is characterized by Growth Hormone and Insulin-like Growth Factor (IGF)-1 excess. Voice complaints are common in active acromegaly and are suggested to be caused by effects of Growth Hormone or IGF-1 on vocal folds and the surrounding soft tissues. Prospective studies on the course of voice characteristics in acromegaly patients are scarce and results are conflicting. This study investigates objective changes in voice parameters, self-reported perception of voice and laryngostroboscopic features during the first 2.5 years of acromegaly treatment. Material and Method: In this prospective study, acoustic voice analysis (and videolaryngostroboscopic examination were performed in 27 consecutive treatment-naive acromegaly patients at diagnosis (T0), after 1 year (T1) and after 2.5 years (T2) of treatment. The voice handicap index (VHI-30) questionnaire was taken. Results: During acromegaly treatment, VHI scores decreased, and mucosal edema & hypertrophy diminished. No significant changes in objective voice parameters were detected. The within-subject change in serum IGF-1 levels (97.3 (40.6–208) to 22.4 (10.2–34.1) nmol/L (P < 0.001)) during follow-up correlated positively with the changes in VHI questionnaire scores (R 0.32–0.45; P = 0.002–0.03). Conclusions: At diagnosis and during acromegaly treatment, mean VHI scores were in the normal range, although they decreased during follow-up. Mucosal edema and hypertrophy largely resolved during treatment. No significant changes in objective voice parameters were observed. Voice characteristics are in the normal range in patients with acromegaly, but may change during treatment. However, voice complaints are important to discuss, since they may influence quality of life.

To investigate whether adrenal volumetry provides better agreement with adrenal vein sampling (AVS) than conventional CT for subtyping PA. Furthermore, we evaluated whether the size of this contralateral adrenal was a prognostic factor for clinical outcome after unilateral adrenalectomy.We retrospectively analyzed volumes of both adrenal glands of the 180 CT-scans (88/180 with unilateral and 92/180 with bilateral disease) of the patients with PA included in the SPARTACUS trial of which 85 also had undergone an AVS. In addition, we examined CT-scans of 20 healthy individuals to compare adrenal volumes with published normal values.Adrenal volume was higher for the left than the right adrenal (mean and SD: 6.49 ± 2.77 ml versus 5.25 ± 1.87 ml for the right adrenal; p 0.001). Concordance between volumetry and AVS in subtyping was 58.8%, versus 51.8% between conventional CT results and AVS (p = NS). The volumes of the contralateral adrenals in the patients with unilateral disease (right 4.78 ± 1.37 ml; left 6.00 ± 2.73 ml) were higher than those of healthy controls reported in the literature (right 3.62 ± 1.23 ml p 0.001; left 4.84 ± 1.67 ml p = 0.02). In a multivariable analysis the contralateral volume was not associated with biochemical or clinical success, nor with the defined daily doses of antihypertensive agents at 1 year follow-up.Volumetry of the adrenal glands is not superior to current assessment of adrenal size by CT for subtyping patients with PA. Furthermore, in patients with unilateral disease the size of the contralateral adrenal is enlarged but its size is not associated with outcome.

Background Learned placebo effects induced by pharmacological conditioning affect immune and endocrine outcomes and may offer new possibilities for clinical applications. Whether or not cortisol is subject to this type of associative learning processes, and whether conditioning may affect responses to stress, is currently unclear. Method A randomized placebo-controlled trial was conducted in 48 healthy young women. During acquisition, participants received a pill containing either 100 mg hydrocortisone (unconditioned stimulus) or placebo, paired with a gustatory conditioned stimulus on three consecutive days. During evocation, all participants received placebo paired with the conditioned stimulus, again on three consecutive days. During the third evocation trial, participants underwent a psychosocial stress task. The main outcome parameter salivary cortisol and secondary outcome parameters salivary alpha-amylase, self-reported positive affect and tension, heart rate, and skin conductance level were measured at several time points. Results Significant baseline group differences on cortisol were found at several time points, which complicate the interpretation of group differences. During the first evocation session, the conditioned group showed a moderately smaller cumulative decrease in salivary cortisol from baseline than the placebo control group. No significant differences were found between the groups on cortisol during the second and third evocation or in response to stress, nor on other outcome measures. Conclusion Although the results provide potential further indications for effects of conditioning on cortisol, baseline differences make it impossible to draw clear conclusions. No indications for possible effects of conditioning on the cortisol stress response or autonomous or affective responses to stress were found.

Objective Acromegaly has a negative influence on health-related quality of life (HRQoL). Previous studies provide limited information on the course of HRQoL during treatment. This study aims to assess the effect of treatment on the course of HRQoL at six predefined time points. Design This prospective study examines HRQoL in treatment-naive patients before and during the first 2.5 years of acromegaly treatment. Methods Therapy-naive acromegaly patients completed three validated questionnaires (RAND-36, AcroQoL, and the Appearance Self-Esteem (ASE)) at six predetermined time points before, during, and after treatment. Outcomes were correlated to IGF1 levels and disease control status. Results Twenty-seven acromegaly patients completed the questionnaires at all time points. After treatment, all patients had controlled acromegaly. Scores of RAND-36 domains General health, Vitality and Health change, and all AcroQoL dimensions (except for Relations) improved during treatment (P ≤ 0.003); the largest changes were detected during the first year. Gender influenced HRQoL scores, since AcroQoL scores significantly improved in males but not in females. Over time, IGF1 levels were negatively correlated with HRQoL. After 2.5 years of follow-up, HRQoL of controlled patients was still lower than in the general population. Conclusion HRQoL of acromegaly patients was considerably reduced at diagnosis. Disease control was associated with an improvement of HRQoL scores. Males showed a more pronounced improvement than females. The largest changes were detected in the first year of treatment. However, HRQoL during and after treatment remained impaired in acromegaly patients, emphasizing the need of additional support.

Contains fulltext : 229551.pdf (Publisher’s version ) (Open Access) Acromegaly is characterized by Growth Hormone (GH) and Insulin-like Growth Factor 1 (IGF-1) excess. Uncontrolled acromegaly is associated with a strongly increased risk of cardiovascular disease (CVD), and numerous cardiovascular risk factors remain present after remission. GH and IGF-1 have numerous effects on the immune and cardiovascular system. Since endothelial damage and systemic inflammation are strongly linked to the development of CVD, and have been suggested to be present in both controlled as uncontrolled acromegaly, they may explain the presence of both micro- and macrovascular dysfunction in these patients. In addition, these changes seem to be only partially reversible after remission, as illustrated by the often reported presence of endothelial dysfunction and microvascular damage in controlled acromegaly. Previous studies suggest that insulin resistance, oxidative stress, and endothelial dysfunction are involved in the development of CVD in acromegaly. Not surprisingly, these processes are associated with systemic inflammation and respond to GH/IGF-1 normalizing treatment.

Background Inhaled or nasal corticosteroids can cause suppression of the hypothalamic–pituitary–adrenal (HPA) axis. Early detection is important because this suppression can be associated with significant morbidity. Objective To explore the adverse effect of hypothalamic–pituitary–adrenal suppression by local corticosteroids in HIV-infected patients. Method Ambulatory HIV-infected patients were selected if they used both antiretroviral treatment and inhaled or nasal corticosteroid. Suppression of hypothalamic–pituitary–adrenal axis was defined as a morning plasma cortisol below 80 nmol/L or a cortisol below 550 nmol/L during a 250 mcg adrenocorticotropic hormone-stimulation test. Results Twelve patients were tested; four of them were taking a CYP3A4 inhibitor. All patients had a normal morning plasma cortisol. Suppression of the hypothalamic–pituitary–adrenal axis during the ACTH stimulation test was identified in three of the twelve patients. None of these three individuals were taking a CYP3A4 inhibitor. Conclusion Hypothalamic–pituitary–adrenal axis suppression is frequently identified in patients on inhaled or nasal corticosteroids. CYP3A4 inhibitors such as ritonavir or cobicistat may increase the chance of this adverse effect. In this study we did not identify HPA axis suppression in patients taking CYP3A4 inhibitors. This may be related to the fact that 2 of these 4 patients used beclomethasone, a corticosteroid not metabolized by CYP3A4.ClinicalTrials.gov Identifier NCT02501486.

Background: Adrenocortical carcinoma is a rare malignancy with a poor prognosis. We hypothesized that patients with adrenocortical carcinoma are at high risk for venous thromboembolism, given the numerous risk factors such as malignancy, abdominal surgery, immobility and hormonal excess. The aim of this study was to determine retrospectively the incidence of venous thromboembolisms after surgical treatment in patients with adrenocortical carcinoma. Materials and methods: A retrospective study was performed, collecting data from all patients diagnosed with adrenocortical carcinoma from 2003 to 2018 at the Radboud University Medical Centre, The Netherlands. Results: In 34 patients, eight postoperative venous thromboembolisms, all pulmonary embolisms, were diagnosed in the first 6 months after adrenalectomy (23.5%). In addition, one patient developed pulmonary embolism just prior to surgery and one patient 7 years after surgery. Five of the eight patients with postoperative venous thromboembolisms presented with symptomatic pulmonary embolism whereas the other three pulmonary embolisms were incidentally found on regular follow up CT scans. Seven of the eight venous thromboembolisms occurred within 10 weeks after surgery. Seven of the eight patients had advanced stage adrenocortical carcinoma and four patients already received low-molecular weight heparin during the development of the venous thromboembolism. There was one case of fatal pulmonary embolism in a patient with a cortisol producing tumor with pulmonary metastases, despite the use of a therapeutic dose thromboprophylaxis. Conclusion: Patients with adrenocortical carcinoma are at high risk of developing postoperative venous thromboembolisms. Prolonged postoperative thromboprophylaxis could be considered in these patients.

Background Obstructive sleep apnea syndrome (OSAS) is common in active acromegaly and negatively influences quality of life, morbidity, and mortality. This prospective study with 3 predetermined timepoints and a standardized treatment protocol investigates changes in sleep parameters during the first 2.5 years of acromegaly treatment. Methods Before initiation of acromegaly treatment (medical pretreatment followed by surgery), polysomnography (PSG) was performed in 27 consecutive patients with treatment-naive acromegaly. PSG was repeated after 1 year (N = 24) and 2.5 years (N = 23), and anthropometric and biochemical parameters were obtained. Results At baseline, 74.1% of the patients was diagnosed with OSAS. The respiratory disturbance index (RDI; P = 0.001), oxygen desaturation index (ODI; P = 0.001), lowest oxygen saturation (LSaO2; P = 0.007) and the Epworth Sleepiness Scale (ESS; P < 0.001) improved significantly during treatment, with the greatest improvement in the first year. After 2.5 years of treatment, all patients had controlled acromegaly. Of the 16 patients with repeated PSG and OSAS at baseline, 11 (68.8%) were cured of OSAS. Changes in RDI, ODI, LSaO2, and ESS correlated with insulin-like growth factor 1 levels. Conclusion OSAS has a high prevalence in active acromegaly. There is a substantial decrease in prevalence and severity of OSAS following acromegaly treatment, with the largest improvement during the first year. Most patients recover from OSAS following surgical or biochemical control of the acromegaly. Therefore, a PSG is advised after diagnosis of acromegaly. When OSAS is present, it should be treated and PSG should be repeated during acromegaly treatment.

Background Although major improvements are achieved after cure of Cushing syndrome (CS), fatigue and decreased quality of life persist. This is the first study to measure aerobic exercise capacity in patients in remission of CS for more than 4 years in comparison with matched controls, and to investigate whether the reduction in exercise capacity is related to alterations in muscle tissue. Methods Seventeen patients were included. A control individual, matched for sex, estrogen status, age, body mass index, smoking, ethnicity, and physical activity level was recruited for each patient. Maximal aerobic capacity (VO2peak) was assessed during incremental bicycle exercise to exhaustion. In 8 individually matched patients and controls, a percutaneous muscle biopsy was obtained and measures were made of cross-sectional areas, capillarization, and oxphos complex IV (COXIV) protein content as an indicator of mitochondrial content. Furthermore, protein content of endothelial nitric oxide synthase (eNOS) and eNOS phosphorylated on serine1177 and of the NAD(P)H-oxidase subunits NOX2, p47phox, and p67phox were measured in the microvascular endothelial layer. Findings Patients showed a lower mean VO2peak (SD) (28.0 [7.0] vs 34.8 [7.9] ml O2/kg bw/min, P < .01), maximal workload (SD) (176 [49] vs 212 [67] watt, P = .01), and oxygen pulse (SD) (12.0 [3.7] vs 14.8 [4.2] ml/beat, P < .01) at VO2peak. No differences were seen in muscle fiber type–specific cross-sectional area, capillarization measures, mitochondrial content, and protein content of eNOS, eNOS-P-ser1177, NOX2, p47phox, and p67phox. Interpretation Because differences in muscle fiber and microvascular outcome measures are not statistically significant, we hypothesize that cardiac dysfunction, seen in active CS, persists during remission and limits blood supply to muscles.

Objective: Multiple endocrine neoplasia type 1 (MEN1) is a hereditary disease characterized by a high risk of developing primary hyperparathyroidism, duodenopancreatic neuroendocrine tumors, and pituitary tumors (PITs). It is unclear if having MEN1 leads to psychological distress because of fear of disease occurrence (FDO), thereby potentially affecting quality of life.Design: A cross-sectional study was performed using the Dutch MEN1 cohort. All patients received the Cancer Worry Scale (a score >= 14 reflects high FDO), the Medical Outcomes Study 36-item Short-Form Health Survey (SF-36), and questions on sociodemographic and medical history.Results: A total of 227 of 285 (80%) eligible patients with MEN1 completed the questionnaire. The mean (+/- standard deviation) age was 47 6 15 years. Overall, patients experienced an FDO of 15.1 +/- 4.7, with 58% of patients having a score >= 14. This is higher than reported in previous studies assessing fear of cancer recurrence in different cancer populations (31% to 52%). Adjusted for age and sex, the FDO score was negatively associated with almost all SF-36 subscales. In multivariable analysis, the diagnosis of a PIT, a pancreatic neuroendocrine tumor, and not being employed were associated with FDO (P Conclusion: The majority of patients with MEN1 have FDO for themselves and even more for their relatives. This psychological distress is associated with a lower health-related quality of life. Therefore, in the medical care for MEN1, emphasis should also be placed on FDO and quality of life.

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 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 3 cm, watchful waiting seems not advisable.

Purpose: Pancreatic neuroendocrine tumors are a major manifestation of multiple endocrine neoplasia type 1 (MEN1). This tumor syndrome is caused by germline mutations in MEN1, encoding menin. Insight into pathogenesis of these tumors might lead to new biomarkers and therapeutic targets for these patients. Several lines of evidence point towards a role for p27Kip1 and p18Ink4c in MEN1-related tumor development in animal models for MEN1, but their contribution to human MEN1-related pancreatic neuroendocrine tumor development is not known. Methods: In this study, we characterized protein expression of p27Kip1 and p18Ink4c in human MEN1-related PanNETs by immunohistochemistry. From the nationwide DutchMEN1 Study Group database including > 90% of the Dutch MEN1 population, MEN1-patients, who underwent pancreatic surgery, were selected. A tissue micro-array was constructed with available paraffin tissue blocks, and PanNETs from 61 MEN1 patients were eligible for analysis. Results: Expression of p27Kip1 was high in 57 (93%) PanNETs and 67% of the tumors showed low expression of p18Ink4c (67.3%). No association was found between expression of either p27Kip1 or p18Ink4c and clinic-pathological characteristics. Conclusions: These findings indicate that loss of p18Ink4c, but not p27Kip1, is a common event in the development of MEN1-related PanNETs. Restoration of p18Ink4c function through CDK4/6 inhibitors could be a therapeutic option for MEN1-related PanNETs.

Contains fulltext : 190805.pdf (Publisher’s version ) (Open Access) BACKGROUND: It is unclear which patients have the greatest risk of developing complications in the first days after endoscopic transsphenoidal pituitary surgery (ETS) and how long patients should stay hospitalized after surgery. The objective of this study is to identify which patients are at risk for early postoperative medical and surgical reinterventions to optimize the length of hospitalization. METHODS: The medical records of 146 patients who underwent ETS for a pituitary adenoma between January 2013 and July 2016 were reviewed retrospectively. Data were collected on baseline patient-related characteristics, characteristics of the pituitary adenoma, perioperative complications and interventions, and postoperative outcomes. Patients who underwent additional interventions on days 2, 3, and 4 after ETS were identified as cases, and patients who did not have any interventions after day 1 postoperatively were identified as controls. RESULTS: Diabetes mellitus (odds ratio [OR], 4.279; 95% confidence interval [CI], 1.149-15.933; P = 0.03), incomplete adenoma resection (OR, 2.840; 95% CI, 1.228-6.568; P = 0.02) and increased morning sodium concentration on day 2 after surgery (OR, 5.211; 95% CI, 2.158-12.579; P

ContextIt has been suggested that stimulation of lipolysis by diazoxide (DZX)-mediated insulin suppression may be useful in treating obesity. However, the optimal dose to promote lipolysis without causing hyperglycemia is unknown.ObjectiveTo assess the effects of DZX in nondiabetic obese men on lipid and glucose metabolism.DesignDouble-blind, placebo (PL)-controlled, 6-month trial in men with a body mass index of 30 to 37.5 kg/m2 treated with a combination of caloric restriction, a standardized exercise program, and DZX or PL dose escalation.ResultsThe mean maximal tolerated dose of DZX was 422 ± 44 mg/d (range, 200 to 700 mg/d). Dose-limiting events were edema (n = 11), hyperglycemia (n = 6), and nausea (n = 2). After dose reduction to a level free of clinical side effects, DZX treatment was associated with a markedly greater decrease in fasting insulin levels than PL (−72.3 ± 3.5% vs −23.0 ± 12.6%; P < 0.001) and a significant improvement of blood pressure and plasma lipid levels. The decline in insulin levels occurred at the cost of a small increase in plasma glucose (0.6 ± 0.2 mmol/L vs −0.1 ± 0.1 mmol/L; P = 0.04) and hemoglobin A1C (0.2 ± 0.1% vs 0.0 ± 0.1%; P = 0.17).ConclusionIn nondiabetic obese men, insulin levels can be reduced up to 70% without major metabolic side effects. The marked intersubject variation in maximal tolerated dose indicates that DZX dose titration needs to be individualized.

Contains fulltext : 200153.pdf (Publisher’s version ) (Closed access) Context: Obesity-related hyperinsulinism may impede lifestyle-initiated weight loss. Objective: Proof-of-concept study to investigate the amplifying effects of diazoxide (DZX)-mediated insulin suppression on lifestyle-induced weight loss in nondiabetic, hyperinsulinemic, obese men. Design: Twelve-month study comprising an initial 6-month, double-blind trial, followed by a partially de-blinded 6-month extension in men with obesity with a body mass index of 30 to 37.5 kg/m2 and a fasting serum C-peptide level >1.00 nM. Patients were randomized into three treatment groups: DZX + placebo (DZX + PL), DZX + metformin (DZX + MTF), and double PL (PL + PL). Results: At 6 months, DZX treatment was associated with a 6.1-kg PL-subtracted decline in fat mass (FM), and at 12 months, FM had decreased by a total of 15.7 +/- 2.5 kg. Twelve months of DZX treatment was also associated with a significant decline in systolic (-6.6%) and diastolic (-8.6%) blood pressure and low-density lipoprotein-cholesterol (-18%) and triglycerides (-43%) and a 39% rise in high-density lipoprotein-cholesterol. These effects were achieved at the cost of a small rise in fasting glucose (95% CI: 0.2 to 1.0 mM) and hemoglobin A1c (95% CI: -0.08% to 0.44%). There were no differences between DZX monotherapy and the combination of DZX + MTF. Conclusion: High-dose DZX treatment of 1 year resulted in a substantial decrease in FM, blood pressure, and lipid levels at the cost of a small rise in blood glucose levels.

ObjectiveEpigenetic changes contribute to pancreatic neuroendocrine tumor (PanNET) development. Hypermethylation of promoter DNA as a cause of tumor suppressor gene silencing is a well-established oncogenic mechanism that is potentially reversible and therefore an interesting therapeutic target. Multiple endocrine neoplasia type 1 (MEN1) is the most frequent cause of inherited PanNETs. The aim of this study was to determine promoter methylation profiles in MEN1-related PanNETs.Design and methodsMethylation-specific multiplex ligation-dependent probe amplification was used to assess promoter methylation of 56 tumor suppressor genes in MEN1-related (n = 61) and sporadic (n = 34) PanNETs. Differences in cumulative methylation index (CMI), individual methylation percentages and frequency of promoter hypermethylation between subgroups were analyzed.ResultsWe found promoter methylation of a large number of potential tumor suppressor genes. CMI (median CMI: 912 vs 876,P = 0.207) was the same in MEN1-related and sporadic PanNETs. We found higher methylation percentages ofCASP8in MEN1-related PanNETs (median: 59% vs 16.5%,P = 0.002). In MEN1-related non-functioning PanNETs, the CMI was higher in larger PanNETs (>2 cm) (median: 969.5 vs 838.5;P = 0.021) and in PanNETs with liver metastases (median: 1036 vs 869;P = 0.013). Hypermethylation ofMGMT2was more frequent in non-functioning PanNETs compared to insulinomas (median: 44.7% vs 8.3%;P = 0.022). Hypermethylation of the Von Hippel–Lindau gene promoter was observed in one MEN1-related PanNET and was associated with loss of protein expression.ConclusionPromoter hypermethylation is a frequent event in MEN1-related and sporadic PanNETs. Targeting DNA methylation could be of therapeutic value in MEN1 patients with advanced PanNETs.

The aim of this review was to determine the impact of primary aldosteronism on health-related quality of life (HRQoL) and mental health. We performed a systematic literature search up to July 2017 in six electronic databases. First, we screened the articles derived from this search based on title and abstract. Second, the selected studies were systematically reviewed and checked for our predefined inclusion criteria. The search yielded 753 articles, of which 15 studies met our inclusion criteria. Untreated patients with primary aldosteronism showed an impaired physical and mental HRQoL as compared to the general population. Multiple domains of HRQoL were affected. This applied to patients with both an aldosterone-producing adenoma and bilateral adrenal hyperplasia. Adrenalectomy improves HRQoL. Conflicting results have been reported on the extent of this improvement, the improvement after initiation of medical treatment, and whether there is a difference in HRQoL after both treatments. Similarly, psychopathological symptoms of anxiety, demoralization, stress, depression and nervousness were more frequently reported in untreated patients with primary aldosteronism than in the general population and patients with hypertension. Also an impaired sleep quality has been reported. Improvement of these symptoms was observed after treatment with both adrenalectomy and mineralocorticoid receptor antagonists. This review shows that HRQoL is impaired and psychopathology is more frequently reported in patients with primary aldosteronism. This seems to be at least partly reversible after treatment but the extent of improvement remains unknown. To assess HRQoL in these patients more precisely a primary aldosteronism-specific HRQoL questionnaire is required.

Agranulocytosis is a rare and serious adverse effect of antithyroid drugs, with unknown etiology. The present study aimed to uncover genetic susceptibility and underlying mechanisms of antithyroid drug-induced agranulocytosis (ATDAC). We studied two independent families with familial Graves' disease, of which several members developed ATDAC. In addition, six sporadic ATDAC patients with Graves' disease were investigated. Whole exome sequencing analysis of affected and unaffected family members was performed to identify genetic susceptibility variants for ATDAC, followed by functional characterization of primary granulocytes from patients and unrelated healthy controls. Whole exome sequencing, cosegregation analysis, and stringent selection criteria of candidate gene variants identified NOX3 as a genetic factor related to ATDAC. Functional studies revealed increased apoptosis of methimazole-treated granulocytes from patients carrying NOX3 variants. In conclusion, genetic variants in NOX3 may confer susceptibility to antithyroid drug-induced apoptosis of granulocytes. These findings contribute to the understanding of the mechanisms underlying ATDAC. Refereed/Peer-reviewed

Background Medical treatment in Cushing’s disease (CD) is limited due to poor understanding of its pathogenesis. Pathogenic variants of ubiquitin specific peptidase 8 (USP8) have been confirmed as causative in around half of corticotroph tumors. We aimed to further characterize the molecular landscape of those CD tumors lacking USP8 mutations in a large cohort of patients. Methods Exome sequencing was performed on 18 paired tumor–blood samples with wild-type USP8 status. Candidate gene variants were screened by Sanger sequencing in 175 additional samples. The most frequent variant was characterized by further functional in vitro assays. Results Recurrent somatic hotspot mutations in another deubiquitinase, USP48, were found in 10.3% of analyzed samples. Several possibly damaging variants were found in TP53 in 6 of 18 samples. USP48 variants were associated with smaller tumors and trended toward higher frequency in female patients. They also changed the structural conformation of USP48 and increased its catalytic activity toward its physiological substrates histone 2A and zinc finger protein Gli1, as well as enhanced the stimulatory effect of corticotropin releasing hormone (CRH) on pro-opiomelanocortin production and adrenocorticotropic hormone secretion. Conclusions USP48 pathogenic variants are relatively frequent in USP8 wild-type tumors and enhance CRH-induced hormone production in a manner coherent with sonic hedgehog activation. In addition, TP53 pathogenic variants may be more frequent in larger CD tumors than previously reported.

Static single–time-frame 18F-FDG PET/CT is useful for the localization and functional characterization of pheochromocytomas and paragangliomas (PPGLs). 18F-FDG uptake varies between PPGLs with different genotypes, and the highest SUVs are observed in cases of succinate dehydrogenase (SDH) mutations, possibly related to enhanced aerobic glycolysis in tumor cells. The exact determinants of 18F-FDG accumulation in PPGLs are unknown. We performed dynamic PET/CT scanning to assess whether in vivo 18F-FDG pharmacokinetics has added value over static PET to distinguish different genotypes. Methods: Dynamic 18F-FDG PET/CT was performed on 13 sporadic PPGLs and 13 PPGLs from 11 patients with mutations in SDH complex subunits B and D, von Hippel-Lindau (VHL), RET, and neurofibromin 1 (NF1). Pharmacokinetic analysis was performed using a 2-tissue-compartment tracer kinetic model. The derived transfer rate-constants for transmembranous glucose flux (K1 [in], k2 [out]) and intracellular phosphorylation (k3), along with the vascular blood fraction (Vb), were analyzed using nonlinear regression analysis. Glucose metabolic rate (MRglc) was calculated using Patlak linear regression analysis. The SUVmax of the lesions was determined on additional static PET/CT images. Results: Both MRglc and SUVmax were significantly higher for hereditary cluster 1 (SDHx, VHL) tumors than for hereditary cluster 2 (RET, NF1) and sporadic tumors (P, 0.01 and P, 0.05, respectively). Median k3 was significantly higher for cluster 1 than for sporadic tumors (P, 0.01). Median Vb was significantly higher for cluster 1 than for cluster 2 tumors (P, 0.01). No statistically significant differences in K1 and k2 were found between the groups. Cutoffs for k3 to distinguish between cluster 1 and other tumors were established at 0.015 min−1 (100% sensitivity, 15.8% specificity) and 0.636 min−1 (100% specificity, 85.7% sensitivity). MRglc significantly correlated with SUVmax (P 5 0.001) and k3 (P 5 0.002). Conclusion: In vivo metabolic tumor profiling in patients with PPGL can be achieved by assessing 18F-FDG pharmacokinetics using dynamic PET/CT scanning. Cluster 1 PPGLs can be reliably identified by a high 18F-FDG phosphorylation rate.

Background. Transition from ACTH-dependent to ACTH-independent hypercortisolism has been described in patients with long-standing Cushing´s disease (CD). The underlying molecular mechanisms are unknown. Clinical case.Case 1. A 41-years old woman was referred for Cushing’s syndrome (cortisol after 1-mg dexamethasone suppression test (DST) 410 nmol/L, urinary free cortisol (UFC) 2xULN, midnight cortisol 440 nmol/L). High-dose DST: no suppression. CRH test: no ACTH/cortisol increase. Basal ACTH: 18 pmol/L. Pituitary MRI showed a 7-mm adenoma. The inferior petrosal sinus sampling showed central source of ACTH. She was treated by trans-sphenoidal surgery (pituitary adenoma confirmed histologically) followed by clinical remission. Cushing’s syndrome recurred 1 year after. ACTH was undetectable and pituitary MRI normal. Abdominal CT-scan showed a left adrenal macronodule. Left adrenalectomy was performed, followed by glucocorticoid replacement therapy (1 year) and clinical/biochemical remission at last follow-up (15 years). Histopathology showed a 35-mm adrenal nodule and micronodular hyperplasia. We found a p.L206R missense mutation of PRKACA in the adrenal nodule. The functional implication of the mutation has been described (1). Case 2. A 31-years old woman was referred for Cushing´s syndrome (cortisol after 1-mg DST 579 nmol/L, UFC 4xULN, midnight cortisol 773 nmol/L). Basal ACTH: 18 pmol/L. CRH and desmopressin tests: indicative of CD. High-dose DST: no suppression. A pituitary MRI revealed a microadenoma, treated by trans-sphenoidal surgery (confirmed by histology). She had persistence of Cushing’s syndrome, undetectable basal ACTH and negative pituitary MRI. An abdominal CT-scan showed bilateral adrenal enlargement with a left nodule, treated by bilateral adrenalectomy. Histology showed a macronodule in micronodular hyperplasia. We found a p.S213R somatic missense mutation of PRKACA in the adrenal macronodule. Functional analyses showed that mutant cells had higher cAMP-independent PKA activity than wild-type, and similar to the L206R mutation. Conclusion. This is the first evidence showing that PRKACA somatic mutations can be found in adrenal nodules of patients with CD, possibly explaining the mechanism underlying transition from ACTH-dependent to ACTH-independent hypercortisolism. References. 1. Calebiro D et al. PKA catalytic subunit mutations in adrenocortical Cushing's adenoma impair association with the regulatory subunit. Nat Commun. 2014;5:5680.

Context Multiple endocrine neoplasia type 1 (MEN1) is an autosomal dominant disease caused by mutations in the tumor suppressor gene MEN1 and can be diagnosed based on clinical, familial and/or genetic criteria. We present a family in which we found both germline and somatic mosaicism for MEN1. Family description In our proband, we diagnosed MEN1. The mutation was not detected in her parents (DNA extracted from leucocytes). When her brother was found to harbor the same MEN1 mutation as our proband and, around the same time, their father was diagnosed with a neuroendocrine carcinoma, this tumor was investigated for the MEN1 mutation as well. In the histologic biopsy of this tumor, the same MEN1 mutation was detected as previously found in his children. Re-analysis of his blood using multiplex ligation-dependent probe amplification (MLPA) showed a minimal, but consistently decreased signal for the MEN1-specific MLPA probes. The deletion was confirmed in his son by high-resolution array analysis. Based on the array data, we concluded that the deletion was limited to the MEN1 gene and that the father had both germline and somatic mosaicism for MEN1. Conclusions To our knowledge, this is the first reported family with combined germline and somatic mosaicism for MEN1. This study illustrates that germline mosaicism is important to consider in apparently sporadic de novo MEN1 mutations, because of its particular importance for genetic counseling, specifically when evaluating the risk for family members and when considering the possibility of somatic mosaicism in the parent with germline mosaicism.

Objective Acromegaly is characterized by an excess of growth hormone (GH) and insulin-like growth factor 1 (IGF1). Cardiovascular disease (CVD) risk factors are common in acromegaly and often persist after treatment. Both acute and long-lasting pro-inflammatory effects have been attributed to IGF1. Therefore, we hypothesized that inflammation persists in treated acromegaly and may contribute to CVD risk. Methods In this cross-sectional study, we assessed cardiovascular structure and function, and inflammatory parameters in treated acromegaly patients. Immune cell populations and inflammatory markers were assessed in peripheral blood from 71 treated acromegaly patients (with controlled or uncontrolled disease) and 41 matched controls. Whole blood (WB) was stimulated with Toll-like receptor ligands. In a subgroup of 21 controls and 33 patients with controlled disease, vascular ultrasound measurements were performed. Results Leukocyte counts were lower in patients with controlled acromegaly compared to patients with uncontrolled acromegaly and controls. Circulating IL18 concentrations were lower in patients; concentrations of other inflammatory mediators were comparable with controls. In stimulated WB, cytokine production was skewed toward inflammation in patients, most pronounced in those with uncontrolled disease. Vascular measurements in controlled patients showed endothelial dysfunction as indicated by a lower flow-mediated dilatation/nitroglycerine-mediated dilatation ratio. Surprisingly, pulse wave analysis and pulse wave velocity, both markers of endothelial dysfunction, were lower in patients, whereas intima-media thickness did not differ. Conclusions Despite treatment, acromegaly patients display persistent inflammatory changes and endothelial dysfunction, which may contribute to CVD risk and development of CVD.

Background: Health-related quality of life in patients with Addison's disease has been assessed in various European countries, indicating a reduced quality of life. However, no studies have addressed the impact of Addison's disease on physical activity. Objective: The aim of this study was to investigate the quality of life in Dutch patients with Addison's disease particularly regarding the presence of fatigue and the ability to be physically active. Methods: In this cross-sectional study, a postal survey was performed among Dutch patients with Addison's disease on stable glucocorticoid replacement therapy with hydrocortisone or cortisone acetate. For quality of life and physical activity assessment, patients completed general and health-related quality of life and physical activity questionnaires, and scores were compared to Dutch controls. Results: A total of 328 patients with Addison's disease were studied. In patients with Addison's disease, only 45·7% met the standard of physical activity (Combinorm) compared to 67·8% of Dutch controls (P < 0·01). Forty-eight per cent of patients showed abnormal fatigue, while 61% had severe fatigue. The CIS fatigue scores were significantly higher compared to controls (P < 0·01). We found reduced general subjective health-related QoL scores in both male and female patients, especially in younger patients

Objective: Identifying a germline mutation in the multiple endocrine neoplasia type 1 (MEN1) gene in an index case has consequences for a whole family. Eligible family members should be offered genetic counseling and MEN1 mutation testing. Subsequently, clinical screening of mutation carriers according to the guidelines should be initiated. We assessed whether there is a lag time from MEN1 diagnosis of the index case to MEN1 diagnosis of family members. In addition, we determined whether this lag time was associated with an increased morbidity and mortality risk. Design: A cohort study was performed using the Dutch MEN1 database, including >90% of the Dutch MEN1 population >16 years of age (n = 393). Results: Fifty-eight MEN1 families were identified, of whom 57 were index cases and 247 were non-index cases (n = 304). The median lag time in MEN1 diagnosis of family members was 3.5 (range, 0–30) years. At the time of MEN1 diagnosis, 30 (12.1%) non-index cases had a duodenopancreatic neuroendocrine tumor, of whom 20% had metastases with a mean lag time of 10.9 years, in comparison with 7.1 years without metastases. Twenty-five (10.1%) non-index cases had a pituitary tumor, of whom 80% had a microadenoma and 20% had a macroadenoma, with mean lag times of 7.2 and 10.6 years, respectively. Ninety-five (38.4%) non-index cases had a primary hyperparathyroidism with a mean lag time of 9.5 years in comparison with seven patients without a primary hyperparathyroidism with a mean lag time of 3 years (P = .005). Ten non-index cases died because of a MEN1-related cause that developed during or before the lag time. Conclusion: There is a clinically relevant delay in MEN1 diagnosis in families because of a lag time between the diagnosis of an index case and the rest of the family. More emphasis should be placed on the conduct of proper counseling and genetic testing in all eligible family members.

Objective To evaluate the detection of pituitary lesions at 7.0 T compared to 1.5 T MRI in 16 patients with clinically and biochemically proven Cushing’s disease. Methods In seven patients, no lesion was detected on the initial 1.5 T MRI, and in nine patients it was uncertain whether there was a lesion. Firstly, two readers assessed both 1.5 T and 7.0 T MRI examinations unpaired in a random order for the presence of lesions. Consensus reading with a third neuroradiologist was used to define final lesions in all MRIs. Secondly, surgical outcome was evaluated. A comparison was made between the lesions visualized with MRI and the lesions found during surgery in 9/16 patients. Results The interobserver agreement for lesion detection was good at 1.5 T MRI (κ = 0.69) and 7.0 T MRI (κ = 0.62). In five patients, both the 1.5 T and 7.0 T MRI enabled visualization of a lesion on the correct side of the pituitary gland. In three patients, 7.0 T MRI detected a lesion on the correct side of the pituitary gland, while no lesion was visible at 1.5 T MRI. Conclusion The interobserver agreement of image assessment for 7.0 T MRI in patients with Cushing’s disease was good, and lesions were detected more accurately with 7.0 T MRI. Key Points • Interobserver agreement for lesion detection on 1.5 T MRI was good; • Interobserver agreement for lesion detection on 7.0 T MRI was good; • 7.0 T enabled confirmation of unclear lesions at 1.5 T; • 7.0 T enabled visualization of lesions not visible at 1.5 T. Electronic supplementary material The online version of this article (doi:10.1007/s00330-015-3809-x) contains supplementary material, which is available to authorized users.

Static single–time-frame (18)F-FDG PET/CT is useful for the localization and functional characterization of pheochromocytomas and paragangliomas (PPGLs). (18)F-FDG uptake varies between PPGLs with different genotypes, and the highest SUVs are observed in cases of succinate dehydrogenase (SDH) mutations, possibly related to enhanced aerobic glycolysis in tumor cells. The exact determinants of (18)F-FDG accumulation in PPGLs are unknown. We performed dynamic PET/CT scanning to assess whether in vivo (18)F-FDG pharmacokinetics has added value over static PET to distinguish different genotypes. Methods: Dynamic (18)F-FDG PET/CT was performed on 13 sporadic PPGLs and 13 PPGLs from 11 patients with mutations in SDH complex subunits B and D, von Hippel-Lindau (VHL), RET, and neurofibromin 1 (NF1). Pharmacokinetic analysis was performed using a 2-tissue-compartment tracer kinetic model. The derived transfer rate-constants for transmembranous glucose flux (K(1) [in], k(2) [out]) and intracellular phosphorylation (k(3)), along with the vascular blood fraction (V(b)), were analyzed using nonlinear regression analysis. Glucose metabolic rate (MR(glc)) was calculated using Patlak linear regression analysis. The SUV(max) of the lesions was determined on additional static PET/CT images. Results: Both MR(glc) and SUV(max) were significantly higher for hereditary cluster 1 (SDHx, VHL) tumors than for hereditary cluster 2 (RET, NF1) and sporadic tumors (P < 0.01 and P < 0.05, respectively). Median k(3) was significantly higher for cluster 1 than for sporadic tumors (P < 0.01). Median V(b) was significantly higher for cluster 1 than for cluster 2 tumors (P < 0.01). No statistically significant differences in K(1) and k(2) were found between the groups. Cutoffs for k(3) to distinguish between cluster 1 and other tumors were established at 0.015 min(−1) (100% sensitivity, 15.8% specificity) and 0.636 min(−1) (100% specificity, 85.7% sensitivity). MR(glc) significantly correlated with SUV(max) (P = 0.001) and k(3) (P = 0.002). Conclusion: In vivo metabolic tumor profiling in patients with PPGL can be achieved by assessing (18)F-FDG pharmacokinetics using dynamic PET/CT scanning. Cluster 1 PPGLs can be reliably identified by a high (18)F-FDG phosphorylation rate.

In this chapter, we review recent studies on conditioned pharmacological effects on immune and endocrine responses in humans, and discuss challenges and opportunities for bringing these effects into clinical practice. By altering physiological mechanisms in part independent of pharmacological agents, pharmacological conditioning has high clinical relevance, as illustrated in some patient studies. Methodological challenges for further investigation include broadening the spectrum of opportunities for conditioned pharmacological effects, by investigating conditioning of substances that have not or not often been used before (e.g., corticosteroids) and unraveling mechanisms by which pharmacological responses become conditioned, thereby identifying characteristics that make conditioning designs effective. As an opportunity to optimize external validity, we introduce a design in which the potential of pharmacological conditioning can be pretested in the laboratory. The feasibility of this design is demonstrated by a pilot study.

Context In primary aldosteronism (PA), two subtypes are distinguished: aldosterone-producing adenoma (APA) and bilateral adrenal hyperplasia (BAH). In general, these are treated by adrenalectomy (ADX) and mineralocorticoid receptor antagonists (MRA), respectively. Objective To compare the effects of surgical treatment and medical treatment on quality of life (QoL). Design Post hoc comparative effectiveness study within the Subtyping Primary Aldosteronism: A Randomized Trial Comparing Adrenal Vein Sampling and Computed Tomography Scan (SPARTACUS) trial. Setting Twelve Dutch hospitals and one Polish hospital. Participants Patients with PA (n = 184). Interventions ADX or MRAs. Main Outcome Measures At baseline and 6-month and 1-year follow-up, we assessed QoL by two validated questionnaires: RAND 36-Item Health Survey 1.0 (RAND SF-36) and European Quality of Life–5 Dimensions (EQ-5D). Results At baseline, seven of eight RAND SF-36 subscales and both summary scores, as well as three of five EQ-5D dimensions and the visual analog scale, were lower in patients with PA compared with the general population, especially in women. The beneficial effects of ADX were larger than for MRAs for seven RAND SF-36 subscales, both summary scores, and health change. For the EQ-5D, we detected a difference in favor of ADX in two dimensions and the visual analog scale. Most differences in QoL between both treatments exceeded the minimally clinically important difference. After 1 year, almost all QoL measures had normalized for adrenalectomized patients. For patients on medical treatment, most QoL measures had improved but not all to the level of the general population. Conclusion Both treatments improve QoL in PA, underscoring the importance of identifying these patients. QoL improved more after ADX for suspected APA than after initiation of medical treatment for suspected BAH.

Objective Somatic mutations in the ubiquitin-specific protease 8 (USP8) gene are frequent in corticotroph tumors causing Cushing’s disease (CD). Corticotroph tumor progression, the so-called Nelson’s syndrome (NS), is a potentially life-threatening complication of bilateral adrenalectomy in patients with refractory CD that is caused by the development of an ACTH-secreting tumor of the pituitary gland. Whether USP8 alterations are also present in progressive Nelson’s tumors has not been studied in detail so far. Design and Methods Retrospective, multicenter study involving tumors from 33 patients with progressive corticotroph tumors (29 females) and screening for somatic mutations on the mutational hotspot of the USP8 gene in the exon 14 with Sanger sequencing. Results Fifteen out of 33 tumors (45%) presented with a mutation in the exon 14 of USP8, with c.2159C>A (p.Pro720Gln) being the most frequent (9/33), followed by c.2155_2157delTCC (p.Ser718del, 4/33) and c.2152T>C (p.Ser718Pro, 2/33). This prevalence is similar to that previously reported for CD. Mutations were found exclusively in females. Other variables, such as age at diagnosis with NS, body mass index, hyperpigmentation, visual field defects, adenoma size or mortality, did not significantly differ between patients with wild-type and mutant tumors. Patients with USP8 mutant tumors exhibited higher levels of plasma ACTH after surgery (median: 640 vs 112 pg/mL, P = 0.03). No differences were observed in ACTH normalization ( Conclusion Somatic mutations in USP8 are common in Nelson’s tumors, indicating that they do not drive the corticotroph tumor progression that leads to NS, and may be associated with a less favorable biochemical outcome after surgery for Nelson’s tumor.

Contains fulltext : 154296.pdf (Publisher’s version ) (Closed access) BACKGROUND: In populations with mild iodine deficiency, the serum level of thyrotropin (TSH) is negatively and the serum free thyroxine (FT4) is positively associated with age. An ongoing decrease of TSH and increase of FT4 can be found after iodine supplementation. The aim of this study was to investigate whether there are current differences in the relation between thyroid function and age in relation to differences in iodine intake in the past. METHODS: Eight medical laboratories in several regions of The Netherlands, which are all iodine sufficient at present but with a difference in iodine status in the past, provided the results of all TSH and FT4 measurements performed from 2006 until 2011, resulting in 330,802 TSH and 103,940 FT4 measurements. RESULTS: The negative association between TSH and age in the elderly is only present in areas with a historical iodine deficiency (regression coefficients [RC] -0.008, 95% confidence interval [CI] -0.009; -0.007). In the historically iodine-sufficient population, TSH shows no obvious increase or decrease with age. In both the historically iodine-sufficient and iodine-deficient populations, FT4 levels were positively associated with age in the elderly (RC 0.009, 95% CI 0.008; 0.010 and RC 0.008, 95% CI 0.007; 0.010, respectively). CONCLUSIONS: There are differences in relation between thyroid function and age between populations with differences in iodine intake in the past, despite an adequate iodine status at present. This raises the question whether the present but also historical iodine status of a population should be taken into account when establishing the reference limits of TSH and FT4.

Context: Testicular adrenal rest tumors (TART) are one of the major long term complications in patients with congenital adrenal hyperplasia. Although several adrenal-like properties have been assigned to these benign lesions, the etiology has not been confirmed yet. Objective: The aim of this study was to describe TART in more detail by analyzing several (steroidogenic) characteristics that may be classified as adrenal cortex or Leydig cell specific. Methods: Gene expression analysis by qPCR was performed for 14 genes in TART tissue (n = 12) and compared with the expression in healthy control fibroblasts (nonsteroidogenic control). In addition, a comparison was made with the expression levels in testis tissue (n = 9) and adrenal tissue (n = 13). Results: Nearly all genes were highly expressed in TART tissue, including all genes that encode the key steroidogenic enzymes. TART expression levels are in the majority almost identical to those found in adrenal tissue. The expression of adrenal cortex specific genes (CYP11B1, CYP11B2, and MC2R) in both TART and adrenal tissue is approximately 1000–10 000 times higher compared to that in testes samples. In addition, the Leydig cell markers INSL3 and HSD17B3 were not only found in testes, but also in TART, both at significantly higher levels than in the adrenal (p < 0.01). Conclusion: Our study shows for the first time that TART have multiple steroidogenic properties, which include not only the expression of adrenal cortex but also of Leydig cell markers. Therefore, the origin of these tumors might be a more totipotent embryonic cell type.

Context: Guidelines advise lifelong radiological followup for asymptomatic pituitary adenomas (PITs) because of the risk for growth and subsequent visual field defects. In the context of multiple endocrine neoplasia type 1 (MEN 1) an even more comprehensive screening is advised because PITs are presumed to manifest more aggressive behavior. We studied the long-term course of MEN 1related PITs, which may be used as a model for sporadically occurring PITs.Objective: The aim of our study is to assess the results of systematic pre-symptomatic PIT screening and subsequent long-term followup of PITs with emphasis on nonfunctioning microadenomas diagnosed by screening.Patients and Methods: A cohort study was performed using the Dutch national MEN1 database, including greater than 90"/o of the Dutch MEN 1 population older than 16 years (n = 323).Main Outcome Measures: Screening results, natural course, and effects of treatment of PIT were assessed.Results: PIT was diagnosed in 123 patients with M EN 1 (38.1 %), of whom 66 were diagnosed by MEN 1-related screening. Ninety-one percent of the nonfunctioning PIT detected during screening (n = 35), did not require intervention during followup (median, 6.0 y). Three microadenomas showed limited growth but did not progress toward macroadenomas. Both screening-detected and prevalent prolactinomas (n = 52) responded well to treatment with dopamine agonists.Conclusion: Systematic presymptomatic screening for PIT in patients with MEN 1 predominantly results in detection of nonfunctioning microadenomas. Prolactinoma in patients with MEN1 responded well to medical treatment. Microadenomas grew only occasionally and after many years without clinical consequences. Frequent magnetic resonance imaging followup of nonfunctioning microadenomas in the context of MEN1 and sporadically occurring PITs therefore seems debatable.

Item does not contain fulltext CONTEXT AND OBJECTIVE: Pheochromocytomas and paragangliomas (PGLs) are neuroendocrine tumors of sympathetic or parasympathetic paraganglia. Nearly 40% of PGLs are caused by germline mutations. The present study investigated the effect of genetic alterations on metabolic networks in PGLs. DESIGN: Homogenates of 32 sporadic PGLs and 48 PGLs from patients with mutations in SDHB, SDHD, SDHAF-2, VHL, RET, and NF-1 were subjected to proton ((1)H) nuclear magnetic resonance (NMR) spectroscopy at 500 MHz for untargeted and HPLC tandem mass spectrometry for targeted metabolite profiling. RESULTS: (1)H NMR spectroscopy identified 28 metabolites in PGLs of which 12 showed genotype-specific differences. Part of these results published earlier reported low complex II activity (P < .0001) and low ATP/ADP/AMP content (P < .001) in SDH-related PGLs compared with sporadics and PGLs of other genotypes. Extending these results, low levels of N-acetylaspartic acid (NAA; P < .05) in SDH tumors and creatine (P < .05) in VHL tumors were observed compared with sporadics and other genotypes. Positive correlation was observed between NAA and ATP/ADP/AMP content (P < .001) and NAA and complex II activity (P < .0001) of PGLs. Targeted purine analysis in PGLs showed low adenine in cluster 1 compared with cluster 2 tumors (SDH P < .0001; VHL P < .05) whereas lower levels (P < .05) of guanosine and hypoxanthine were observed in RET tumors compared with SDH tumors. Principal component analysis (PCA) of metabolites could distinguish PGLs of different genotypes. CONCLUSIONS: The present study gives a comprehensive picture of alterations in energy metabolism in SDH- and VHL-related PGLs and establishes the interrelationship of energy metabolism and amino acid and purine metabolism in PGLs.

Context:An association between ABO blood type and the development of cancer, in particular, pancreatic cancer, has been reported in the literature. An association between blood type O and neuroendocrine tumors in multiple endocrine neoplasia type 1 (MEN1) patients was recently suggested. Therefore, blood type O was proposed as an additional factor to personalize screening criteria for neuroendocrine tumors in MEN1 patients.Objective:The aim of this study was to assess the association between blood type O and the occurrence of neuroendocrine tumors in the national Dutch MEN1 cohort.Design:This is a cohort study using the Dutch National MEN1 database, which includes more than 90% of the Dutch MEN1 population. Demographic and clinical data were analyzed by blood type. Chi-square tests and Fisher exact tests were used to determine the association between blood type O and occurrence of neuroendocrine tumors. A cumulative incidence analysis (Gray's test) was performed to assess the equality of cumulative incidence of neuroendocrine tumors in blood type groups, taking death into account as a competing risk.Results:The ABO blood type of 200 of 322 MEN1 patients was known. Demographic and clinical characteristics were similar among blood type O and non-O type cohorts. The occurrence of neuroendocrine tumors of the lung, thymus, pancreas, and gastrointestinal tract was equally distributed across the blood type O and non-O type cohorts (Grays's test for equality; P = 0.72). Furthermore, we found no association between blood type O and the occurrence of metastatic disease or survival.Conclusions:An association between blood type O and the occurrence of neuroendocrine tumors in MEN1 patients was not confirmed. For this reason, the addition of the blood type to screening and surveillance practice seems not to be of additional value for identifying MEN1 patients at risk for the development of neuroendocrine tumors, metastatic disease, or a shortened survival.

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Background: The prognostic value of WHO grade in pancreatic neuroendocrine tumors (PanNETs) in patients with Multiple Endocrine Neoplasia Type 1 (MEN1) is unknown. Methods: We performed a cohort study using the Dutch National MEN1 database, which includes >90% of the Dutch MEN1 population with data collected between 1990 and 2014. Formalin-fixed paraffin embedded tissue blocks from the largest resected PanNET per patient were collected. MIB1 staining was performed and KI67 labeling index (LI) was determined by manual eye-counting under a microscope and by digital image analysis. Mitotic count was evaluated from hematoxylin & eosin stains. Association between WHO grade and (time until) development of liver metastases was calculated. Results: Sixty-nine MEN1 patients who underwent pancreatic surgery were included. Ten patients (14%) developed liver metastases and all had PanNETs >= 3 cm. WHO G1, G2 and G3 PanNETs were seen in 83% (n = 57), 16% (n = 11) and 1% (n = 1) respectively. In non-functioning PanNETs >2 cm, liver metastases occurred in 80% of WHO G2 PanNETs (4/5) compared to 23% (5/22) in WHO G1 PanNETs (p = 0.03) when WHO grade was based on mitotic count only. This significant association was not seen for WHO grade based on Ki67 LI. After five years, liver metastases in non-functioning PanNETs were not seen in tumors

ContextPatients with pituitary disease report impairments in Quality of Life (QoL) despite optimal biomedical care. Until now, the effects of a self-management intervention (SMI) addressing psychological and social issues for these patients and their partners have not been studied.ObjectiveTo examine the effects of a SMI i.e. Patient and Partner Education Programme for Pituitary disease (PPEP-Pituitary).Design and subjectsA multicentre randomized controlled trial included 174 patients with pituitary disease, and 63 partners were allocated to either PPEP-Pituitary or a control group. PPEP-Pituitary included eight weekly sessions (90 min). Self-efficacy, bother and needs for support, illness perceptions, coping and QoL were assessed before the intervention (T0), directly after (T1) and after six months (T2). Mood was assessed before and after each session.ResultsPatients in PPEP-Pituitary reported improved mood after each session (except for session 1). In partners, mood only improved after the last three sessions. Patients reported higher self-efficacy at T1 (P = 0.016) which persisted up to T2 (P = 0.033), and less bother by mood problems directly after PPEP-Pituitary (P = 0.01), but more bother after six months (P = 0.001), although this increase was not different from baseline (P = 0.346). Partners in PPEP-Pituitary reported more vitality (P = 0.008) which persisted up to T2 (P = 0.034). At T2, partners also reported less anxiety and depressive symptoms (P ≤ 0.014).ConclusionThis first study evaluating the effects of a SMI targeting psychosocial issues in patients with pituitary disease and their partners demonstrated promising positive results. Future research should focus on the refinement and implementation of this SMI into clinical practice.

Item does not contain fulltext OBJECTIVE: Duodenopancreatic neuroendocrine tumors (DP-NETs) develop in a majority of patients with multiple endocrine neoplasia type 1 (MEN1) and are the leading cause of death. Overall survival (OS) and prognostic factors for patients with liver metastases from DP-NETs are not known. METHODS: This was a cohort study using the Dutch National MEN1 database, which includes >90% of the Dutch MEN1 population treated between 1990 and 2014. OS was assessed with time to event analysis, and prognostic factors were evaluated. RESULTS: A total of 56% of the MEN1 patients (n = 220) were diagnosed with a DP-NET, of who 34 (15%) developed DP-NET liver metastases. Median age at liver metastases diagnosis was 53 years (range 31-74). Of those patients, 16 patients (47%) had died after a median follow-up of 4 years (range 0.3-12.3). OS at 2, 5, and 10 years were 91%, 65%, and 50%, respectively. A trend towards worse survival was seen in males compared to females (5-year OS 58% versus 75%, P = .07) and also in patients with multiple liver metastases compared to patients with solitary liver metastasis (59 versus 83%, P = .09). CONCLUSION: Despite the fairly indolent course of DP-NET liver metastases in MEN1 patients, half of the population was deceased after 10 years. Sex and tumor load at diagnosis of liver metastases are possible prognostic factors for worse survival. ABBREVIATIONS: DMSG = DutchMEN1 Study Group; D-NET = duodenal neuroendocrine tumor; DP-NET = duodenopancreatic neuroendocrine tumor; HPF = high-power field; Ki67 LI = Ki67 labeling index; MEN1 = multiple endocrine neoplasia type 1; NET = neuroendocrine tumor; OS = overall survival; P-NET = pancreatic neuroendocrine tumor; PPI = proton pump inhibitor; ULN = upper limit of normal; WHO = World Health Organization. 01 juni 2017

Acromegaly is characterized by growth hormone (GH) and insulin-like growth factor 1 (IGF1) excess and is accompanied by an increased cardiovascular diseases (CVD) risk. As innate immune responses are crucial in CVD development, and IGF1 is linked to subclinical inflammation, we hypothesized that GH/IGF1 excess contributes to CVD development by potentiating systemic inflammation. We aimed to assess the effects of GH/IGF1 on inflammatory cytokine production. Whole blood from acromegaly patients and healthy volunteers and peripheral blood mononuclear cells (PBMCs) from healthy volunteers were stimulated with Toll-like receptor (TLR) ligands, with or without adding GH or IGF1 (in PBMC). Cytokine concentrations were measured by ELISA. The underlying signalling pathways were investigated by the inhibition of downstream targets of the IGF1 receptor. The following results were obtained. GH or IGF1 alone did not influence cytokine production in PBMCs. GH did not affect TLR-induced cytokine production, but co-stimulation with IGF1 dose dependently increased the TLR ligand-induced production of IL6 (P P = 0.02) and IFNg (P P = 0.01). IGF1 had no effect on IL1B, IL17 and IL22 production. Inhibition of the MAPK pathway, but not mTOR, completely abrogated the synergistic effect of IGF1 on the LPS-induced IL6 and TNF alpha production. In whole blood of acromegaly patients,ex vivoIL6 production was increased (P