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Active acromegaly is associated with impaired glucose metabolism, which improves upon treatment. Treatment options include surgery, medical therapy with somatostatin analogues (SSA) and Pegvisomant (PEG), and irradiation. The objective of the study was to describe the differential effect of various treatment regimens on the secretion of glucose, insulin, glucagon, glucagon-like peptide-1 (GLP-1), and glucose-dependent insulinotropic polypeptide (GIP) in patients with acromegaly.23 surgically treated, non-diabetic patients with acromegaly and 12 healthy controls underwent an oral glucose tolerance test (OGTT) and subsequently isoglycaemic intravenous glucose infusion on a separate day. Baseline hormone concentrations, time-to-peak and area under the curve (AUC) on the OGTT-day and incretin effect were compared according to treatment regimens.The patients treated with SSA (N = 15) had impaired GIP-response (AUC, P = 0.001), and numerical impairment of all other hormone responses (P 0.3). Patients co-treated with PEG (SSA + PEG, N = 4) had increased secretion of insulin and glucagon compared to patients only treated with SSA (SSA ÷ PEG, N = 11) (insulinSSA impaired the insulin, glucagon, and incretin hormone secretions. Co-treatment with PEG seemed to counteract the somatostatinergic inhibition of the glucagon and insulin response to OGTT. We speculate that PEG may exert its action through GH-receptors on pancreatic δ-cells. Clinical trial registration NCT02005978.

Aim: To evaluate survival distributions, long-term socioeconomic consequences, and health care costs in patients with childhood and adolescent onset of brain tumours in a Danish nationwide prospective cohort study. Method: A search of national registries identified 2283 patients (1198 males, 1085 females; mean age 9 years 6 months [SD 5 years 7 months]) diagnosed with a brain tumour between 1980 and 2015 and aged no older than 18 years at diagnosis. These were compared with sex-, age-, and residency-matched comparison individuals. Patients with malignant tumours were compared with those with benign tumours. Survival distributions were estimated by the Kaplan–Meier method and hazard ratio by the Cox proportional hazard model. Socioeconomic data at age 20 and 30 years were assessed. Results: The probability of mortality was highest during the first year after tumour diagnosis. In young adulthood, the patients were generally less likely to be married, had lower grade-point averages, educational levels, and income, were less likely to be in employment, and had higher health care costs than comparison individuals. Patients with malignant tumours had worse outcomes with respect to education, employment, and health care costs than those with benign tumours. Interpretation: A diagnosis of brain tumour in childhood and adolescence adversely affects survival and has negative long-term socioeconomic consequences, especially in patients with malignant tumours. These patients require continuous social support.

A 31-year-old woman was admitted to the local department of endocrinology for control of known anti-TPO positive hypothyroidism during pregnancy. The clinician noticed a remarkable hyperpigmentation. Primary adrenal insufficiency was diagnosed and treatment with cortico- and mineralosteroids commenced. Diagnosis of primary adrenal insufficiency during pregnancy is challenging as many symptoms overlap with normal symptoms of pregnancy. The usual diagnostic criteria cannot be used due to the altered hormone concentrations during pregnancy.

Introduction Patients with pituitary adenomas undergoing transsphenoidal surgery require pre- and post-surgery examination of pituitary hormones. There is currently no consensus on how to evaluate the adrenal axis post-surgery. The aims of this study were to investigate factors that may predict postoperative adrenal insufficiency (AI) and to investigate the overall effect of transsphenoidal surgery on pituitary function. Methods One hundred and forty-three consecutive patients who had undergone transsphenoidal surgery for pituitary adenomas were included. Data on tumour size, pituitary function pre-surgery, plasma basal cortisol measured within 48 h post-surgery and pituitary function 6 months post-surgery were collected. Patients with AI prior to surgery, perioperative glucocorticoid treatment, Cushing’s disease and no re-evaluation after 1 month were excluded (n = 93) in the basal cortisol analysis. Results Low plasma basal cortisol post-surgery, tumour size and previous pituitary surgery were predictors of AI (all P < 0.05). A basal cortisol cut-off concentration of 300 nmol/L predicted AI 6 months post-surgery with sensitivity and negative predictive value of 100%, specificity of 81% and positive predictive value of 25%. New gonadal, thyroid and adrenal axis insufficiencies accounted for 2, 10 and 10%, respectively. The corresponding recovery rates were 17, 7 and 24%, respectively Conclusion Transsphenoidal surgery had an overall beneficial effect on pituitary endocrine function. Low basal plasma cortisol measured within 48 h after surgery, tumour size and previous surgery were identified as risk factors for AI. Measurement of basal cortisol post-surgery may help to identify patients at risk of developing AI.

Objective:Active acromegaly is subject to sex differences in growth hormone (GH)and Insulin like growth factor 1 (IGF‐I) patterns as well as clinical features butwhether this also pertains to controlled disease is unclear.Design:In a cross‐sectional, multi‐centre study, 84 patients with acromegaly (F= 43,M= 41), who were considered controlled after surgery alone (n= 23) or duringcontinued somatostatin receptor ligand (SRL) treatment (n= 61), were examined.Methods:Serum concentrations of GH, insulin, glucose and free fatty acid (FFA)were measured during an oral glucose tolerance test (OGTT) together with baselineserum IGF‐I and completion of two HR‐Qol questionnaires (acromegaly quality oflife questionnaire [AcroQol] and Patient‐assessed Acromegaly Symptom Question-naire [PASQ]).Results:The mean age at the time of the study was 57 (±1.1) years and the majorityof females ( were postmenopausal. Females had significantly higher fasting GH butcomparable IGF‐I standard deviation scores (SDS). Using fasting GH < 1.0 μg/L as cutoff, disease control was less prevalent in females (F: 56% vs. M: 83%,p= .007)whereas a comparable figure was observed using IGF‐I SDS < 2 (F:79% vs. M:76%,p= .71). Compared with males, female patients showed impaired AcroQol physicalscore (p= .05), higher fasting FFA (p= .03) and insulin concentrations during theOGTT (p= .04).Conclusion:In patients with acromegaly considered controlled, postmenopausalfemales exhibited higher GH levels than males despite comparable IGF‐I levels,which also translated into impaired metabolic health and well‐being. Our findingspoint to the relevance of including GH measurements in the assessment of diseasecontrol and suggest that disease‐specific sex differences prevail after treatment.KEYWORDSacromegaly, age, FFA, GH, IGF‐I, insulin, pituitary adenoma, quality of life, sex

Replicating the physiological cortisol secretion is key in the treatment of glucocorticoid insufficient individuals and optimization may enhance quality of life. The study investigates fatigue measured by ecological momentary assessments in patients treated with conventional hydrocortisone compared with once-daily dual-release hydrocortisone (Plenadren). A 21-week open-label switch pilot trial included 30 patients with adrenal insufficiency due to hypopituitarism. Fatigue was assessed four times daily for 20 days using a momentary item version of the Multidimensional Fatigue Inventory on patients’ usual hydrocortisone regimen. Participants switched treatment to an identical daily dose of Plenadren for 16 weeks where fatigue assessments were repeated. Change in fatigue and diurnal variation of fatigue was analyzed using mixed models for repeated measurements. In four out of five fatigue subscales fatigue was significantly reduced 0.7–1.1 points (scales ranging from 4 to 20), when treated with Plenadren compared with conventional hydrocortisone, corresponding to small effect sizes below the scale-specific minimal important changes. However, 33% of the participants completing the study (9/27) experienced reductions in fatigue above the minimal important change. On Plenadren, we found larger between-person variances and smaller within-person variances. Finally, we identified diurnal fatigue curves for both treatments. The Plenadren-related reduction in fatigue was significant but not necessarily of clinical importance when looking at a group level. However, there was a large interindividual variation in treatment effect, why patients with a large benefit in quality of life should be identified. Future RCTs should be powered to detect the effect magnitudes identified here.

Glucocorticoid-induced adrenal insufficiency is caused by exogenous glucocorticoid suppression of the hypothalamic-pituitary-adrenal axis and is the most prevalent form of adrenal insufficiency. The condition is important to diagnose given the risk of life-threatening adrenal crisis and impact on patients’ quality of life. The diagnosis is made with a stimulation test such as the ACTH test. Until now, testing for glucocorticoid-induced adrenal insufficiency has often been based on clinical suspicion rather than routinely but accumulating evidence indicates that a significant number of cases will remain unrecognized. During ongoing oral glucocorticoid treatment or initially after withdrawal, ~50% of patients have adrenal insufficiency, but, outside clinical studies, ≤ 1% of patients have adrenal testing recorded. More than 70% of cases are identified during acute hospital admission, where the diagnosis can easily be missed because symptoms of adrenal insufficiency are nonspecific and overlap those of the underlying and intercurrent conditions. Treatment of severe glucocorticoid-induced adrenal insufficiency should follow the principles for treatment of central adrenal insufficiency. The clinical implications and thus indication to treat mild-moderate adrenal deficiency after glucocorticoid withdrawal has not been established. Also, the indication of adding stress dosages of glucocorticoid during ongoing glucocorticoid treatment remains unclear. In patients with established glucocorticoid-induced adrenal insufficiency, high rates of poor confidence in self-management and delayed glucocorticoid administration in the acute setting with an imminent adrenal crisis call for improved awareness and education of clinicians and patients. This article reviews different facets of glucocorticoid-induced adrenal insufficiency and discusses approaches to the condition in common clinical situations.

Background: The incidence of small intestinal (SI) and pancreatic neuroendocrine tumors (siNETs and pNETs) seems to have increased. The increased frequency of incidental findings might be a possible explanation. The study aimed to examine (1) changes in incidence and the stage at diagnosis (2010–2011 vs. 2019–2020), (2) changes in the initial indication for diagnostic workup and 3) the differences in stage between incidentally discovered vs. symptomatic disease during the entire study period. Methods: We performed a retrospective study, that includes consecutive siNET and pNET patients referred to the Copenhagen ENETS center of excellence in 2010–2011 and 2019–2020. Results: The annual incidence of siNET per 100,000 increased from 1.39 to 1.84, (p = 0.05). There was no change in the stage at diagnosis, and in both periods approximately 30% of patients were incidentally diagnosed (p = 0.62). Dissemination was found in 72/121 (60%) of symptomatic vs. 22/50 (44%) of incidentally discovered SI tumors in the entire cohort, (p = 0.06). The annual incidence of pNET increased from 0.42 to 1.39 per 100,000, (p &lt, 0.001). The proportion of patients with disseminated disease decreased from 8/21 (38%) to 12/75 (16%), (p = 0.02) and the number of incidental findings increased from 4/21 (19%) to 43/75 (57%), (p = 0.002). More symptomatic patients had disseminated disease compared to patients with incidentally discovered tumors (15/49 (31%) vs. 5/47 (11%), (p = 0.01)). Conclusion: The incidence of siNET and pNETs increased over the past decade. For siNETs, the stage of disease and the distribution of symptomatic vs. incidentally discovered tumors were unchanged between the two periods. Patients with pNETs presented with more local and incidentally discovered tumors in the latter period. Patients with incidentally discovered siNETs had disseminated disease in 44% of the overall cases. The vast majority of incidentally found pNETs were localized.

Context Hypothalamic injury often leads to rapid, intractable weight gain causing hypothalamic obesity, which is associated with increased risk of cardiovascular and metabolic morbidity and mortality. There are no approved or effective pharmacological treatments for hypothalamic obesity, and conventional lifestyle management remains ineffective. Objective To investigate the safety and efficacy of Tesomet (0.5 mg tesofensine/50 mg metoprolol) in adults with hypothalamic obesity. Methods Twenty-one adults with hypothalamic obesity (16 females) were randomized to Tesomet (0.5 mg/50 mg) or placebo for 24 weeks. Patients also received diet/lifestyle counselling. The primary endpoint was safety; secondary endpoints included measures of body weight, appetite scores, quality of life, and metabolic profile. Results Eighteen patients completed 24 weeks. Consent withdrawal, eligibility, and serious adverse events (SAE) unrelated to treatment resulted in dropouts. One patient experienced a Tesomet-related SAE of exacerbated pre-existing anxiety leading to treatment discontinuation. Tesomet-related adverse events were otherwise mostly mild and included sleep disturbances (Tesomet 50%, placebo 13%), dry mouth (Tesomet 43%, placebo 0%), and headache (Tesomet 36%, placebo 0%). No significant differences in heart rate or blood pressure were observed between groups. Compared to placebo, Tesomet resulted in additional mean (95% CI) weight change of −6.3% ((−11.3; −1.3); P = 0.017), increased the number of patients achieving ≥5% weight loss (Tesomet 8/13, placebo 1/8; P = 0.046), and tended to augment the reduction in waist circumference by 5.7 cm ((−0.1; 11.5); P = 0.054). Conclusion Tesomet was welltolerated, did not affect heart rate or blood pressure, and resulted in significant reductions in body weight compared to placebo in adults with hypothalamic obesity.

Objective To assess the safety and efficacy of Tesomet (tesofensine plus metoprolol) in adults with hypothalamic obesity, a rare disease with no approved therapy. Research Design and Methods Twenty-one adults with hypothalamic obesity (16 females, 5 males) were randomized to Tesomet (0.5 mg tesofensine/50 mg metoprolol) (n=14) or placebo (n=8) during a 24-week double-blind period. On completion of the double-blind period, 17 (81%) subjects (11 Tesomet; 6 placebo) entered in to a 24-week open-label extension period and were treated with Tesomet. The primary endpoint was safety while secondary endpoints included measures of body weight, waist circumference, and body composition. Trial NCT03845075. Results The most common adverse events following the 24-week double-blind period and the 24-week open-label extension period were sleep disorder, dizziness, dry mouth, and headache; the majority of these adverse events were mild to moderate in severity. No significant nor clinically meaningful changes in heart rate or blood pressure were observed during the study. On completion of the double-blind period mean change in body weight (kg) was -7.84 for the Tesomet group versus -0.34 kg for the placebo group (P=0. 03). At the end of the open-label extension period mean change in body weight (kg) from baseline was -6.34 for the Tesomet-Tesomet group and -6. 03 for the placebo-Tesomet group. On completion of the double-blind period mean change in waist circumference (cm) was -7. 09 cm for the Tesomet group versus -1.16 for the placebo group (P=NS). At the end of the open-label extension period mean change in waist circumference (cm) from baseline was -5.73 for the Tesomet-Tesomet group and -3. 04 for the placebo-Tesomet group. On completion of the double-blind period mean change in fat mass (kg) was -5.28 for the Tesomet group versus -1.11 for the placebo group (P=NS). At the end of the open-label extension period mean change in fat mass (kg) from baseline was -4.84 for the Tesomet-Tesomet group and -3.85 for the placebo-Tesomet group. On completion of the double-blind period mean change in lean tissue mass (kg) was -2.76 for the Tesomet group versus 0.36 for the placebo group (P Discussion Tesomet was generally well tolerated after 48 weeks treatment and resulted in clinically meaningful improvements in body weight and body composition measures in adults with hypothalamic obesity. In contrast to previous studies of tesofensine monotherapy in general obesity, no significant nor clinically meaningful changes in cardiovascular measures were observed during the study. Conclusion Tesomet is a promising new experimental treatment for hypothalamic obesity. A randomized, placebo controlled, multi-center, dose-finding, Phase 2b study has now been initiated. Presentation: No date and time listed

An increase in the Ki-67 index in neuroendocrine neoplasms over time in relation to prognosis has scarcely been investigated. We aimed to assess whether the Ki-67 index changed over time and also whether a change influenced prognosis. Second, we investigated the difference in the Ki-67 index between primary tumour and metastases. From 1 January 1995 to 31 December 2019, 108 consecutive patients with gastroenteropancreatic tumours were included. Patients were followed with regard to an increase in the Ki-67 index and all-cause mortality. Ki-67 determination of the primary tumour at diagnosis and at the time of radiological progression, including developed metastases, was performed. A significant increase in the Ki-67 index was defined as a doubling of the value at disease progression compared to the value at diagnosis. In addition, in 14 patients, the Ki-67 index of the primary tumour and present metastases at the time of diagnosis was investigated. At diagnosis, there were no differences in the Ki-67 index between primary tumours and metastases (P = .41). Sixty-five patients had a doubling of the Ki-67 index. The median Ki-67 index at the time of progression 17% (1%-90%) vs 5% (1%-60%) at the time of diagnosis (P = .006). A doubling of the Ki-67 index was independently associated with all-cause mortality (hazard ratio = 2.7 [1.3-6.3], P = 0.02), after adjustment for relevant co-variables including the Ki-67 index at baseline. Doubling of the Ki-67 index at the time of disease progression was associated with a significantly higher risk of all-cause mortality. We recommend that a Ki-67 index is obtained whenever disease progression is recorded by demonstrated progression because it may have impact on the choice of treatment.

IntroductionDiagnosis and pathological classification of insulinomas are challenging.AimTo characterize localization of tumors, surgery outcomes, and histopathology in patients with insulinoma.MethodsPatients with surgically resected sporadic insulinoma were included.ResultsEighty patients were included. Seven had a malignant tumor. A total of 312 diagnostic examinations were performed: endoscopic ultrasonography (EUS; n = 59; sensitivity, 70%), MRI (n = 33; sensitivity, 58%), CT (n = 55; sensitivity, 47%), transabdominal ultrasonography (US; n = 45; sensitivity, 40%), somatostatin receptor imaging (n = 17; sensitivity, 29%), 18F-fluorodeoxyglucose positron emission tomography/CT (n = 1; negative), percutaneous transhepatic venous sampling (n = 10; sensitivity, 90%), arterial stimulation venous sampling (n = 20; sensitivity, 65%), and intraoperative US (n = 72; sensitivity, 89%). Fourteen tumors could not be visualized. Invasive methods were used in 7 of these 14 patients and localized the tumor in all cases. Median tumor size was 15 mm (range, 7 to 80 mm). Tumors with malignant vs benign behavior showed less staining for insulin (3 of 7 vs 66 of 73; P = 0.015) and for proinsulin (3 of 6 vs 58 of 59; P < 0.001). Staining for glucagon was seen in 2 of 6 malignant tumors and in no benign tumors (P < 0.001). Forty-three insulinomas stained negative for somatostatin receptor subtype 2a.ConclusionLocalization of insulinomas requires many different diagnostic procedures. Most tumors can be localized by conventional imaging, including EUS. For nonvisible tumors, invasive methods may be a useful diagnostic tool. Malignant tumors showed reduced staining for insulin and proinsulin and increased staining for glucagon.

Central hypothyroidism (CH) is a rare cause of hypothyroidism. CH is frequently overlooked, as its clinical picture is subtle and includes non-specific symptoms; furthermore, if measurement of TSH alone is used to screen for thyroid function, TSH concentrations can be normal or even above the upper normal reference limit. Indeed, certain patients are at risk of developing CH, such as those with a pituitary adenoma or hypophysitis, those who have been treated for a childhood malignancy, have suffered a head trauma, sub-arachnoid hemorrhage or meningitis, and those who are on drugs capable to reduce TSH secretion. Keywords: Hypopituitarism, Central hypothyroidism, Thyrotropin deficiency, Congenital hypothyroidism

Gastroenteropancreatic (GEP) mixed neuroendocrine–non-neuroendocrine neoplasms (MiNEN), are rare tumors [1,2] comprising a neuroendocrine and a non-neuroendocrine component, both accounting for at ...

Background and objectives: Sleep disturbances are frequently reported in children with brain tumours. The objective of our cross-sectional study was to systematically examine sleep in these children. We hypothesised that children with tumours involving the sleep-wake-regulatory areas have an altered sleep-wake-regulation. Methods: Sixty-one patients aged 0–18 years and with a diagnosis of a primary brain or cervical medullary tumour were included. They were categorised based upon tumour location into two groups – those affecting the sleep-wake regulatory regions, i.e. brain stem, basal forebrain, hypothalamus, thalamus, and posterior fossa compressing the brain stem and those that did not. Sleep history, questionnaire surveys, polysomnography, and multiple sleep latency test were used, as indicated clinically. Surveys included Pediatric Daytime Sleepiness Scale, Children's Sleep Habits Questionnaire, Strengths and Difficulties Questionnaire, and Pediatric Quality of Life Inventory, Multidimensional Fatigue Scale and Generic Core Scale. Results: Patients with tumours involving the sleep-wake regulatory areas were sleepier/more fatigued (p = 0.03). Sleep apnoea was observed in 86% of all the patients and comorbid narcolepsy in 8%, without group differences (p ≥ 0.12). Patients with tumours involving the sleep-wake-regulatory areas had more emotional problems (p = 0.04), were more affected by mental health problems (p < 0.001), and had poorer quality of life (p ≤ 0.03). Conclusions: Many children with brain tumours suffer from disturbed sleep, poor mental health, and low quality of life. We recommend that systematic sleep evaluation is included in their routine care along with psychological and social support.

Background Single-nucleotide polymorphisms (SNPs) of the glucocorticoid receptor (GR) gene NR3C1 have been associated with an altered sensitivity to glucocorticoids, and thus may alter the therapeutic effects of glucocorticoids. We investigated the prevalence of adrenal suppression after treatment with glucocorticoids and evaluated whether GR SNPs were associated with altered risks of adrenal suppression and metabolic disorders in patients with chronic obstructive pulmonary disease (COPD). Methods In an observational prospective cohort study, we recruited 78 patients with severe COPD receiving 5 days glucocorticoid treatment for an exacerbation of COPD. In total, 55% of these patients were also receiving regular inhaled corticosteroids (ICS). Adrenal function was evaluated with a corticotropin test 30 days after the exacerbation. Patients were genotyped for Bcl1, N363S, ER22/23EK, and 9β SNPs. Results The prevalence of adrenal suppression (corticotropin-stimulated plasma-cortisol ≤ 420 nmol/L) 30 days after glucocorticoid treatment was 4/78 (5%). There was no difference between carriers and non-carriers of the polymorphisms (Bcl1, 9β, ER22/23K, and N363S) in corticotropin stimulated plasma-cortisol concentrations. In the haplotype analyses, we included the 50 patients who had a high-sensitivity (76%), a low-sensitivity (4%), or a wild-type (20%) GR haplotype. There was no difference in the frequency of adrenal suppression or metabolic disorders between the two stratified groups: (a) high-sensitivity (Bcl1 and/or N363S) haplotypes vs. (b) low-sensitivity (9β and/or ER22/23K) plus wild-type haplotypes (p > 0.05). Carriers of the high-sensitivity GR gene haplotype exhibited a steeper decline in stimulated P-cortisol with increased ICS dose (slope, –1.35 vs. 0.94; p = 0.17), compared to the group with low-sensitivity or wild-type haplotypes, respectively. Conclusions In total, 5% of patients exhibited insufficient adrenal function. The Bcl1 and N363S polymorphisms did not seem to increase the risk of glucocorticoid suppression or metabolic disorders in adults treated with glucocorticoids for COPD exacerbations.

Aim Children with brain and cervical medulla tumours may experience circadian abnormalities and poor health. We aimed to examine their circadian rhythm, fatigue and quality of life (QoL). Methods Children with a brain or cervical medulla tumour were recruited from the Paediatric Department, Rigshospitalet, Copenhagen, Denmark, between 2016 and 2020. They were grouped by tumour location involving the circadian regulatory system, defined as diencephalon, pineal gland, brain stem and cervical medulla, or other areas. Saliva melatonin and cortisol concentrations were measured. Sleep diaries and actigraphy assessed sleep-wake patterns. The Pediatric Quality of Life Inventory, Multidimensional Fatigue Scale and Generic Core Scale measured fatigue and QoL. Results We included 68 children (62 with a median age (25th-75th percentiles) of 12.2 (7.7-16.3) years. Children with tumours involving the circadian regulatory system typically had a lower melatonin peak (p=0.06) and experienced significantly more fatigue and poorer QoL. Low melatonin profiles were observed in 31shifted day-time peak, compared with 14 respectively, in children with tumours located elsewhere. Children with low melatonin profiles had significantly lower inter-daily stability than those with normal profiles. Conclusion Tumours involving the circadian regulatory system adversely affected circadian function, fatigue and QoL. AimChildren with brain and cervical medulla tumours may experience circadian abnormalities and poor health. We aimed to examine their circadian rhythm, fatigue and quality of life (QoL).MethodsChildren with a brain or cervical medulla tumour were recruited from the Paediatric Department, Rigshospitalet, Copenhagen, Denmark, between 2016 and 2020. They were grouped by tumour location involving the circadian regulatory system, defined as diencephalon, pineal gland, brain stem and cervical medulla, or other areas. Saliva melatonin and cortisol concentrations were measured. Sleep diaries and actigraphy assessed sleep-wake patterns. The Pediatric Quality of Life Inventory, Multidimensional Fatigue Scale and Generic Core Scale measured fatigue and QoL.ResultsWe included 68 children (62% males) with a median age (25th-75th percentiles) of 12.2 (7.7–16.3) years. Children with tumours involving the circadian regulatory system typically had a lower melatonin peak (p=0.06) and experienced significantly more fatigue and poorer QoL. Low melatonin profiles were observed in 31% and 4% had a phase-shifted daytime peak, compared with 14% and 0%, respectively, in children with tumours located elsewhere. Children with low melatonin profiles had significantly lower inter-daily stability than those with normal profiles.ConclusionTumours involving the circadian regulatory system adversely affected circadian function, fatigue and QoL.

Background: Single-nucleotide polymorphisms (SNPs) of the glucocorticoid receptor (GR) gene NR3C1 have been associated with an altered sensitivity to glucocorticoids (GC), and thus may affect the therapeutic effects of GCs. We investigated the prevalence of adrenal suppression after treatment with GCs and evaluated whether GR SNPs were associated with the risk of adrenal suppression and metabolic disorders in patients with chronic obstructive pulmonary disease (COPD). Methods: In an observational prospective cohort study, we recruited 77 patients with severe COPD receiving five days GC treatment for an exacerbation of COPD. 49% of patients also received regular inhaled corticosteroids. Adrenal function was evaluated with a corticotropin test 30 days after the exacerbation. Patients were genotyped for Bcl1, N363S, ER22/23EK and 9β SNPs. Results: The prevalence of adrenal suppression (corticotropin-stimulated plasma-cortisol ≤ 420 nmol/L) 1 month after GC treatment was 4/77 (5%). There was no correlation between high-sensitivity (p-value 0.79) or low-sensitivity (p-value 0.26) GR haplotypes and stimulated cortisol levels for COPD patients treated with GCs. There was no difference between adrenal suppression and metabolic disorders in COPD patients stratified for high vs. low GC-sensitivity GR haplotypes plus wild type (p-value > 0.05). Corticotropin stimulated P-cortisol did not differ between carriers and non-carriers for Bcl1, 9β, ER22/23K and N363S. For carriers of the high sensitivity GR gene haplotype, the association between inhaled corticosteroid dose and stimulated P-cortisol concentrations was more inverse (slope –0.25 vs. -0.10) than in patients with the low sensitivity haplotype. Conclusions: Five percent of patients had an insufficient adrenal function. The Bcl1 and N363S polymorphisms do not seem to increase the risk of adrenal suppression or metabolic disorders in adults treated with corticosteroids for COPD exacerbations.Trial Registration: The trial was registered at clinicaltrials.gov (NCT03140761) at May 4, 2017 with URL https://clinicaltrials.gov/ct2/show/NCT03140761.

Introduction Neuroendocrine neoplasms (NEN) of the appendix are often incidentally discovered after appendectomy. Appropriate management is debated. The purpose was to characterize a cohort of 335 appendix NEN and evaluate the risk of recurrence. Methods Retrospective collection of data from 335 patients referred to the Neuroendocrine Tumor Center at Rigshospitalet 2000–2019. Appendix goblet cell carcinoids and mixed neuroendocrine non-neuroendocrine neoplasms were excluded. Patients were followed until December 31st, 2019. No patients were lost to follow-up. Results Sixty-three percent of the patients were female. The median (range) age at diagnosis was 34 (9–92) years. Median follow-up was 66 (1–250) months. Median tumor size was 7 (1–45) mm with 10 (3%) tumors >20 mm. In 18 specimens (5%) resection margins were positive. Mesoappendiceal invasion was found in 113 (35%). Sixty-three (19%) patients underwent right-sided completion hemicolectomy (RHC) after appendectomy according to ENETS guidelines. Among these, 11 (17%) had lymph node metastases in the resected tissue. Further, one patient who underwent initial RHC due to colonic adenocarcinoma had lymph node metastases. All lymph node metastases were detected in patients with serotonin positive tumors. No patients with glucagon positive tumors (n = 85) had lymph node metastases. Mesoappendiceal invasion >3 mm and positive resection margins were associated with presence of lymph node metastases. No recurrences were recorded. Conclusion Following ENETS guidelines may lead to overtreatment of patients with respect to completion RHC. The risk of over- and undertreatment needs to be further evaluated.

BACKGROUND: Plasma chromogranin A (CgA) is related to tumor burden and recommended in the follow-up of patients diagnosed with neuroendocrine tumors (NETs). The use of CgA in the workup of a suspected NET is more questionable.OBJECTIVE: To assess the positive predictive value (PPV) of CgA plasma concentrations above the upper reference limit (URL) in patients with suspected NET.METHOD: Patients referred to the NET Centre, Rigshospitalet, Copenhagen from 2015 to 2019 with clinically suspected NET were included if a CgA measurement was performed prior to referral. The utility of CgA was assessed by comparing pre-referral CgA concentrations to the outcome of a thorough workup. In 47 selected cases with continuously unexplained elevated CgA concentrations, a processing-independent analysis (PIA) for CgA was performed.RESULTS: A total of 197 patients were included. NET was ultimately diagnosed in 25 patients. CgA plasma concentrations were above the URL (elevated) in 19/25 patients diagnosed with NET. In total, 167/197 had elevated CgA concentrations at referral. The positive predictive value (PPV) of elevated CgA concentration was 11% (19/167). Proton pump inhibitor (PPI) treatment was identified as the possible cause of CgA elevation in 55/148 patients with falsely elevated CgA. CgA concentration was normal in 28/47 patients when using PIA.CONCLUSION: Our data do not support using measurement of CgA for screening when NET is suspected since the PPV was rather low. PPI treatment is a common cause of increased CgA concentrations and should always be discontinued before CgA measurement. PIA of CgA could be a way of excluding NET when suspicion is based primarily on elevated CgA.

Background: Glucocorticoids (GCs) are widely used in patients with acute exacerbation of COPD. Single-nucleotide polymorphism (SNP) of the GC receptor gene (NR3C1) has been associated with individual differences in GC sensitivity and may be linked to response to GC-treatment. Objectives: i) Assess the prevalence of adrenal suppression (AS) in severe COPD patients 1 month after GCs course for exacerbation ii) Whether high GC sensitivity SNPs (BclI-G or N363S-G) is associated with increased AS and metabolic syndrome compared with SNPs associated with low GC sensitivity(ER22/23EK, 9β, wild type and mixed type). Methods: Observational prospective cohort study, we recruited 76 patients between 2017—2019 with severe COPD treated with 5 days of GCs. All patients were genotyped for all 4 SNPs. Results: AS frequency (corticotropin stimulated P-cortisol≤420 nmol/l) was 5.4% after 1-month. No difference was observed in baseline characteristics, the frequency of AS or other metabolic outcomes (figure 1) between high GC sensitivity and the low GC sensitivity genotypes. Conclusions: Carrier status of the BclI-G or N363S-G alleles was not associated with the development of AS or metabolic syndrome at 1-month after completing GC treatment, suggesting that genotyping for these SNPs can not identify COPD patients with a high risk of side effects.

CONTEXT: Acromegaly is usually a sporadic disease, but familial cases occur. Mutations in the aryl hydrocarbon receptor-interacting protein (AIP) gene are associated with familial pituitary adenoma predisposition. However, the pathogenicity of some AIP variants remains unclear and additional unknown genes may be involved.OBJECTIVE: To explore the phenotype and genotype of a large kindred carrying the p.R304Q AIP variant.METHODS: The family comprised 52 family members at risk of carrying the p.R304Q AIP variant including a case with gigantism and one with acromegaly and several family members with acromegalic features. Nine family members (three trios) underwent exome sequencing to identify putative pathogenic variants.RESULTS: We identified 31 p.R304Q carriers, and based on two cases with somatotropinomas, the disease penetrance was 6%. We observed physical signs of acromegaly in several family members, which were independent of AIP status. Serum insulin-like growth factor-I (IGF-I) levels in all family members were above the mean for age and sex (IGF-I SDS: +0.6 [CI95% +0.4-0.9], P < .01). Exome analysis identified two candidate genes: PDE11A, known to be associated with the development of adrenal tumours, and ALG14. Ten asymptomatic p.R304Q family members (age >50 years) were screened for the PDE11A and ALG14 variant; both variants were present in five of ten persons.CONCLUSIONS: This large family adds new information on the p.R304Q AIP variant, and data suggest two new candidate genes could be associated with growth hormone excess.

Replicating the physiological cortisol secretion is key in the treatment of glucocorticoid insufficient individuals and optimization may enhance quality of life. The study investigates fatigue measured by ecological momentary assessments in patients treated with conventional hydrocortisone compared with once-daily dual-release hydrocortisone (Plenadren).A 21-week open-label switch pilot trial included 30 patients with adrenal insufficiency due to hypopituitarism. Fatigue was assessed four times daily for 20 days using a momentary item version of the Multidimensional Fatigue Inventory on patients' usual hydrocortisone regimen. Participants switched treatment to an identical daily dose of Plenadren for 16 weeks where fatigue assessments were repeated. Change in fatigue and diurnal variation of fatigue was analyzed using mixed models for repeated measurements.In four out of five fatigue subscales fatigue was significantly reduced 0.7-1.1 points (scales ranging from 4 to 20), when treated with Plenadren compared with conventional hydrocortisone, corresponding to small effect sizes below the scale-specific minimal important changes. However, 33% of the participants completing the study (9/27) experienced reductions in fatigue above the minimal important change. On Plenadren, we found larger between-person variances and smaller within-person variances. Finally, we identified diurnal fatigue curves for both treatments.The Plenadren-related reduction in fatigue was significant but not necessarily of clinical importance when looking at a group level. However, there was a large interindividual variation in treatment effect, why patients with a large benefit in quality of life should be identified. Future RCTs should be powered to detect the effect magnitudes identified here.