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Jes Sloth Mathiesen,1,2 Jens Peter Kroustrup,3 Peter Vestergaard,3,4 Kirstine Stochholm,5,6 Per Løgstrup Poulsen,6 Åse Krogh Rasmussen,7 Ulla Feldt-Rasmussen,7 Sten Schytte,8 Stefano Christian Londero,8 Henrik Baymler Pedersen,9 Christoffer Holst Hahn,10 Jens Bentzen,11 Sören Möller,2,12 Mette Gaustadnes,13 Maria Rossing,14 Finn Cilius Nielsen,14 Kim Brixen,2 Anja Lisbeth Frederiksen,2,15 Christian Godballe1 On behalf of the Danish Thyroid Cancer Group (DATHYRCA) 1Department of ORL Head & Neck Surgery and Audiology, Odense University Hospital, Odense, Denmark; 2Department of Clinical Research, University of Southern Denmark, Odense, Denmark; 3Department of Clinical Medicine and Endocrinology, Aalborg University Hospital, Aalborg, Denmark; 4Steno Diabetes Center North Jutland, Aalborg, Denmark; 5Department of Internal Medicine and Endocrinology, Aarhus University Hospital, Aarhus, Denmark; 6Center for Rare Diseases, Aarhus University Hospital, Aarhus, Denmark; 7Department of Medical Endocrinology, Copenhagen University Hospital, Copenhagen, Denmark; 8Department of ORL Head and Neck Surgery, Aarhus University Hospital, Aarhus, Denmark; 9Department of ORL Head & Neck Surgery, Aalborg University Hospital, Aalborg, Denmark; 10Department of ORL Head & Neck Surgery, Copenhagen University Hospital, Copenhagen, Denmark; 11Department of Oncology, Herlev Hospital, Herlev, Denmark; 12Odense Patient data Explorative Network (OPEN), Odense University Hospital, Odense, Denmark; 13Department of Molecular Medicine, Aarhus University Hospital, Aarhus, Denmark; 14Center for Genomic Medicine, Copenhagen University Hospital, Copenhagen, Denmark; 15Department of Clinical Genetics, Odense University Hospital, Odense, Denmark Background: The completeness of REarranged during Transfection (RET) testing in patients with medullary thyroid carcinoma (MTC) was recently reported as 60%. However, the completeness on a population level is unknown. Similarly, it is unknown if the first Danish guidelines from 2002, recommending RET testing in all MTC patients, improved completeness in Denmark. We conducted a nationwide retrospective cohort study aiming to evaluate the completeness of RET testing in the Danish MTC cohort. Additionally, we aimed to assess the completeness before and after publication of the first Danish guidelines and characterize MTC patients who had not been tested.Methods: The study included 200 patients identified from the nationwide Danish MTC cohort 1997–2013. To identify RET tested MTC patients before December 31, 2014, the MTC cohort was cross-checked with the nationwide Danish RET cohort 1994–2014. To characterize MTC patients who had not been RET tested, we reviewed their medical records and compared them with MTC patients who had been tested.Results: Completeness of RET testing in the overall MTC cohort was 87% (95% CI: 0.81–0.91; 173/200). In the adjusted MTC cohort, after excluding patients diagnosed with hereditary MTC by screening, completeness was 83% (95% CI: 0.76–0.88; 131/158). Completeness was 88% (95% CI: 0.75–0.95; 42/48) and 81% (95% CI: 0.72–0.88) (89/110) before and after publication of the first Danish guidelines, respectively. Patients not RET tested had a higher median age at diagnosis compared to those RET tested. Median time to death was shorter in those not tested relative to those tested.Conclusion: The completeness of RET testing in MTC patients in Denmark seems to be higher than reported in other cohorts. No improvement in completeness was detected after publication of the first Danish guidelines. In addition, data indicate that advanced age and low life expectancy at MTC diagnosis may serve as prognostic indicators to identify patients having a higher likelihood of missing the compulsory RET test. Keywords: RET testing, medullary thyroid carcinoma, Denmark

Jes Sloth Mathiesen,1,2 Jens Peter Kroustrup,3 Peter Vestergaard,3,4 Kirstine Stochholm,5,6 Per Løgstrup Poulsen,5 Åse Krogh Rasmussen,7 Ulla Feldt-Rasmussen,7 Sten Schytte,8 Henrik Baymler Pedersen,9 Christoffer Holst Hahn,10 Jens Bentzen,11 Sören Möller,2,12 Mette Gaustadnes,13 Maria Rossing,14 Finn Cilius Nielsen,14 Kim Brixen,2 Anja Lisbeth Frederiksen,2,15 Christian Godballe1 1Department of ORL Head & Neck Surgery and Audiology, Odense University Hospital, Odense, Denmark; 2Department of Clinical Research, University of Southern Denmark, Odense, Denmark; 3Department of Clinical Medicine and Endocrinology, Aalborg University Hospital, Aalborg, Denmark; 4Steno Diabetes Center North Jutland, Aalborg, Denmark; 5Department of Internal Medicine and Endocrinology, Aarhus University Hospital, DK-8000 Aarhus, Denmark; 6Center for Rare Diseases, Aarhus University Hospital, Aarhus N, Denmark; 7Department of Medical Endocrinology, Copenhagen University Hospital, Copenhagen, Denmark; 8Department of ORL Head and Neck Surgery, Aarhus University Hospital, Aarhus, Denmark; 9Department of ORL Head and Neck Surgery, Aalborg University Hospital, Aalborg, Denmark; 10Department of ORL Head and Neck Surgery, Copenhagen University Hospital, Copenhagen, Denmark; 11Department of Oncology, Herlev Hospital, Herlev, Denmark; 12Odense Patient data Explorative Network (OPEN), Odense University Hospital, Odense, Denmark; 13Department of Molecular Medicine, Aarhus University Hospital, Aarhus, Denmark; 14Center for Genomic Medicine, Copenhagen University Hospital, Copenhagen, Denmark; 15Department of Clinical Genetics, Odense University Hospital, Odense, Denmark Background: The incidence and prevalence of multiple endocrine neoplasia 2A (MEN2A) have only been reported once in a nationwide setting. However, it is unclear whether the figures are representative of other populations, as the major component of the syndrome, hereditary medullary thyroid carcinoma (MTC), has been reported as rare in the same country. We conducted a nationwide retrospective cohort study of MEN2A in Denmark from 1901 to 2014, aiming to describe the incidence and prevalence. Methods: This study included 250 unique MEN2A patients born or resident in Denmark before December 31, 2014. Patients were identified through the Danish REarranged during Transfection (RET) cohort, linkage of MEN2A pedigrees, the Danish MTC cohort, a nationwide collaboration of MEN2 centers, cross-checking of other relevant cohorts, and a systematic literature search. Results: The incidence from 1971 to 2000 was 28 (95% CI: 21–37) per million live births per year. Incidence for the specific mutations or for the overall MEN2A group did not change significantly from 1901 to 2014 (P>0.05). Point prevalence at January 1, 2015, was 24 per million (95% CI: 20–28). Conclusion: The incidence and prevalence of MEN2A in Denmark seem higher than those reported in other countries. This is likely explained by the Danish C611Y founder effect. Also, our data indicate no significant change in MEN2A incidence during the last century. Keywords: multiple endocrine neoplasia 2A, incidence, prevalence, Denmark

Andreas Ebbehoj,1,2 Sarah Forslund Jacobsen,3 Christian Trolle,1 Maciej Grzegorz Robaczyk,4 Åse Krogh Rasmussen,3 Ulla Feldt-Rasmussen,3 Reimar Wernich Thomsen,5 Per Løgstrup Poulsen,1 Kirstine Stochholm,1 Esben Søndergaard1 1Department of Endocrinology and Internal Medicine, Aarhus University Hospital, Aarhus, Denmark; 2Department of Clinical Medicine, Aarhus University, Aarhus, Denmark; 3Department of Endocrinology, Rigshospitalet, Copenhagen, Denmark; 4Department of Endocrinology, Aalborg University Hospital, Aalborg, Denmark; 5Department of Clinical Epidemiology, Aarhus University Hospital, Aarhus, Denmark Background: Pheochromocytoma and catecholamine-secreting paraganglioma (PPGL) are rare but potentially life-threatening tumors. We aimed to validate diagnosis codes for PPGL in the Danish National Patient Registry, the Danish National Pathology Registry, and the Danish Registry of Causes of Death and to create a national cohort of incident PPGL patients by linking these three registries. Patients and methods: We obtained data from the three abovementioned registries for all individuals registered with pheochromocytoma or catecholamine hypersecretion in Denmark during 1977–2016 (average population 5.30 million). We then reviewed health records for all individuals living in the North Denmark Region and Central Denmark Region (average population 1.75 million) to validate the diagnosis of PPGL. We tested a number of algorithms for accurately identifying true cases of PPGL to maximize positive predictive values (PPVs) and completeness. The best algorithm was subsequently validated in an external sample. Results: We identified 2626 individuals with a PPGL diagnosis code in Denmark, including 787 (30.0%) in the North Denmark Region and Central Denmark Region. In this subsample, we retrieved the health records of 771/787 (98.0%) individuals and confirmed 198 incident PPGL patients (25.3%). The PPV of PPGL diagnosis codes was 21.7% in the Danish National Patient Registry, 50.0% in the Danish Registry of Causes of Death, and 79.5% in the Danish National Pathology Registry. By combining patterns of registrations in the three registries, we could increase the PPV to 93.1% (95% confidence interval [CI]: 88.5–96.3) and completeness to 88.9% (95% CI: 83.7–92.9), thus creating a national PPGL cohort of 588 patients. PPV for the optimal algorithm was 95.3% (95% CI: 88.5–98.7) in the external validation sample. Conclusion: Diagnosis codes for pheochromocytoma had low PPV in several individual health registries. However, with a combination of registries we were able to identify a near-complete national cohort of PPGL patients in Denmark, as a valuable source for epidemiological research. Keywords: registry-based research, International Classification of Diseases, ICD, Systematized Nomenclature of Medicine, SNOMED, hospital register diagnoses, pathology register, cause of death register

AIMS: To characterize left ventricular function in hypertensive patients with Type 2 diabetes and normal ejection fraction, and to relate these findings to pathogenic factors and clinical risk markers. METHODS: We examined 70 hypertensive patients with Type 2 diabetes mellitus with ejection fraction > 0.55 and fractional shortening > 0.25, all without any cardiac symptoms. Thirty-five non-diabetic subjects served as control subjects. Left ventricular longitudinal function was examined by tissue Doppler derived myocardial strain rate and peak systolic velocities. RESULTS: Hypertensive patients with diabetes had a significantly higher systolic strain rate (-1.1 +/- 0.3 s(-1) vs. -1.6 +/- 0.3 s(-1), P < 0.001) and lower systolic peak velocities (3.3 +/- 1.0 vs. 5.6 +/- 1.0 cm/s, P < 0.001) compared with control subjects. Myocardial systolic strain rate correlated significantly to left ventricular mass (r = 0.40, P < 0.01) and to both HbA1c (r = 0.43, P < 0.01), and fructosamine (r = 0.40, P < 0.01), but was not related to serum levels of carboxymethyllysine, albuminuria, blood pressure (dipping/non-dipping), or oral hypoglycaemic therapy. Patients with diastolic dysfunction had significantly higher levels of urine albumin [21.0 (5-2500) mg/l, vs. 9.5 (1-360), P < 0.01], heart rate (78 +/- 13 vs. 67 +/- 10 b.p.m., P < 0.005), and seated diastolic blood pressure (85 +/- 6 vs. 81 +/- 7 mmHg, P < 0.05) and non-dipping diastolic blood pressure was more frequent. CONCLUSIONS: Long axis left ventricular systolic function was significantly decreased in hypertensive patients with Type 2 diabetes mellitus, and is associated with hyperglycaemia and left ventricular hypertrophy. Diastolic dysfunction was closely related to increased diastolic blood pressure, non-dipping and increased urinary albumin excretion. [ABSTRACT FROM AUTHOR]

Objective: To assess and compare the long-term effects of the combination of candesartan and lisinopril with high-dose lisinopril on systolic blood pressure in patients with hypertension and diabetes.Research Design and Methods: This was a prospective, randomized, parallel-group, double-blind, double-dummy study with a 12-month follow-up. Drug therapy was either lisinopril 40 mg once daily or dual-blockade treatment with candesartan 16 mg once daily and lisinopril 20 mg once daily. The study comprised 75 type 1 and type 2 diabetic patients aged 35-74 years. The main outcome measures were seated and 24-h ambulatory systolic blood pressure.Results: Reduction in systolic blood pressure (24-h systolic blood pressure) reduction was obtained in both treatment arms (mean reduction at final follow-up: dual blockade 6 mmHg vs. lisinopril 2 mmHg), but no significant difference was found between dual-blockade and lisinopril 40 mg once daily (P = 0.10). Both treatments were generally well tolerated, and similar low rates of side effects were found in the two groups.Conclusions: There was no statistically significant difference between lisinopril 40 mg once daily and lisinopril 20 mg in combination with candesartan 16 mg once daily in reducing systolic blood pressure in hypertensive patients with diabetes. [ABSTRACT FROM AUTHOR]

Several clinical trials have consistently shown that antihypertensive treatment, particularly with angiotensin-converting enzyme inhibitors (ACE-I) reduces albuminuria in Type 1 diabetic patients. More recently, data on the beneficial effects of ACE-I on the preservation of glomerular filtration rate and renal ultrastructure have emerged. However, in general, these trials have recruited a wide spectrum of diabetics, including some patients with severe albuminuria. Thus, the question of the ideal stage at which to instigate what is likely to be lifelong therapy in young people still remains unanswered. Exercise is known to significantly increase both blood pressure (BP) and urinary albumin excretion (UAE), both of which are important determinants of progression of nephropathy in diabetes. Thus, it is possible that exercise may have an adverse effect on diabetic renal disease. The effects of ACE-I on exercise-BP and exercise-UAE in microalbuminuric Type 1 diabetic patients has not been examined in long-term placebo-controlled studies. In the second part of this two-part review, we examine the effects of the ACE-I, lisinopril, 20 mg o.d. for two years, in comparison with placebo, on UAE, 24-hour ambulatory BP, exercise-BP, exercise-UAE and renal haemodynamics in 22 patients with Type 1 diabetes and low-grade microalbuminuria. We further discuss the effects of ACE-I on nephropathy and other complications of diabetes. [ABSTRACT FROM AUTHOR]

Objective: This study aims to investigate the continuum of glucose control from normoglycemia to dysglycemia (HbA1c ≥ 5.7%/39 mmol/mol) using metrics derived from continuous glucose monitoring (CGM). In addition, we aim to develop a machine learning-based classification model to classify dysglycemia based on observed patterns. Methods: Data from five distinct studies, each featuring at least two days of CGM, were pooled. Participants included individuals classified as healthy, with prediabetes, or with type 2 diabetes mellitus (T2DM). Various CGM indices were extracted and compared across groups. The data set was split 70/30 for training and testing two classification models (XGBoost/Logistic Regression) to differentiate between prediabetes or dysglycemia and the healthy group. Results: The analysis included 836 participants (healthy: n = 282; prediabetes: n = 133; T2DM: n = 432). Across all CGM indices, a progressive shift was observed from the healthy group to those with diabetes ( P < 0.001). Statistically significant differences ( P < 0.01) were noted in mean glucose, time below range, time above 140 mg/dl, mobility, multiscale complexity index, and glycemic risk index when transitioning from health to prediabetes. The XGBoost models achieved the highest receiver operating characteristic area under the curve values on the test data set ranging from 0.91 [confidence interval (CI): 0.87-0.95] (prediabetes identification) to 0.97 [CI: 0.95-0.98] (dysglycemia identification). Conclusion: Our findings demonstrate a gradual deterioration of glucose homeostasis and increased glycemic variability across the spectrum from normo- to dysglycemia, as evidenced by CGM metrics. The performance of CGM-based indices in classifying healthy individuals and those with prediabetes and diabetes is promising.

Aims/hypothesis: The apparent diffusion coefficient (ADC) derived from diffusion-weighted MRI (DWI-MRI) has been proposed as a measure of changes in kidney microstructure, including kidney fibrosis. In advanced kidney disease, the kidneys often become atrophic; however, in the initial phase of type 2 diabetes, there is an increase in renal size. Glucagon-like peptide-1 receptor agonists and sodium-glucose cotransporter 2 inhibitors both provide protection against progression of kidney disease in diabetes. However, the mechanisms are incompletely understood. To explore this, we examined the effects of semaglutide, empagliflozin and their combination on renal ADC and total kidney volume (TKV)., Methods: This was a substudy of a randomised clinical trial on the effects of semaglutide and empagliflozin alone or in combination. Eighty patients with type 2 diabetes and high risk of CVD were randomised into four groups (n=20 in each) receiving either tablet placebo, empagliflozin, a combination of semaglutide and tablet placebo (herein referred to as the 'semaglutide' group), or the combination of semaglutide and empagliflozin (referred to as the 'combination-therapy' group). The semaglutide and the combination-therapy group had semaglutide treatment for 16 weeks and then had either tablet placebo or empagliflozin added to the treatment, respectively, for a further 16 weeks; the placebo and empagliflozin groups were treated with the respective monotherapy for 32 weeks. We analysed the effects of treatment on changes in ADC (cortical, medullary and the cortico-medullary difference [ΔADC; medullary ADC subtracted from cortical ADC]), as well as TKV measured by MRI., Results: Both semaglutide and empagliflozin decreased cortical ADC significantly compared with placebo (semaglutide: -0.20×10 -3 mm 2 /s [95% CI -0.30, -0.10], p<0.001; empagliflozin: -0.15×10 -3 mm 2 /s [95% CI -0.26, -0.04], p=0.01). No significant change was observed in the combination-therapy group (-0.05×10 -3 mm 2 /s [95%CI -0.15, 0.05]; p=0.29 vs placebo). The changes in cortical ADC were not associated with changes in GFR, albuminuria, TKV or markers of inflammation. Further, there were no changes in medullary ADC in any of the groups compared with placebo. Only treatment with semaglutide changed ΔADC significantly from placebo, showing a decrease of -0.13×10 -3 mm 2 /s (95% CI -0.22, -0.04; p=0.01). Compared with placebo, TKV decreased by -3% (95% CI -5%, -0.3%; p=0.04), -3% (95% CI -5%, -0.4%; p=0.02) and -5% (95% CI -8%, -2%; p<0.001) in the semaglutide, empagliflozin and combination-therapy group, respectively. The changes in TKV were associated with changes in GFR, albuminuria and HbA 1c ., Conclusions/interpretation: In a population with type 2 diabetes and high risk of CVD, semaglutide and empagliflozin significantly reduced cortical ADC compared with placebo, indicating microstructural changes in the kidneys. These changes were not associated with changes in GFR, albuminuria or inflammation. Further, we found a decrease in TKV in all active treatment groups, which was possibly mediated by a reduction in hyperfiltration. Our findings suggest that DWI-MRI may serve as a promising tool for investigating the underlying mechanisms of medical interventions in individuals with type 2 diabetes but may reflect effects not related to fibrosis., Trial Registration: European Union Drug Regulating Authorities Clinical Trials Database (EudraCT) 2019-000781-38., (© 2024. The Author(s).)

Background and Aims: Obstructive sleep apnea (OSA) may accelerate arterial calcification, but the relation remains unexplored in diabetic kidney disease (DKD). We examined the associations between OSA, coronary calcification and large artery stiffness in patients with DKD and reduced renal function., Methods: Patients with type 2 diabetes, estimated glomerular filtration rate (eGFR) < 60 ml/min/1.73 m 2 and urine albumin-creatinine ratio (UACR) > 30 mg/g were tested for OSA quantified by the apnea-hypopnea index (AHI, events/hour). Patients without OSA (AHI< 5) were compared to patients with moderate (AHI 15-29) or severe (AHI ≥30) OSA and underwent computed tomography angiography with coronary Agatston scoring (CAS) to quantify coronary calcification. Arterial stiffness was determined as carotid-femoral pulse wave velocity (PWV)., Results: Among 114 patients with acceptable AHI recordings had 43 no OSA, 33 mild OSA and 38 moderate-severe OSA. Mean age of the 74 patients completing the study was 71.5 ± 9.4 years (73% males), eGFR 32.2 ± 12.3 ml/min/1.73 m 2 and UACR 533 (192-1707) mg/g. CAS (ln-transformed) was significantly higher in patients with OSA compared to patients without (6.6 ± 1.7 vs. 5.6 ± 2.4, p = 0.04), and the same was observed for PWV (11.9 ± 2.7 vs. 10.5 ± 2.2 m/s, p = 0.02). In multivariable linear regression analyses adjusted for sex, age, body mass index, UACR, and mean arterial pressure, moderate-severe OSA remained significantly associated with PWV but not with CAS. Dominance analysis revealed OSA as the third and second most important factor relative to CAS and PWV respectively., Conclusions: In DKD patients, moderate-severe OSA is a significant predictor of arterial stiffness but is not independently associated with coronary calcification., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Author(s). Published by Elsevier B.V. All rights reserved.)

Aim: Despite the increasing use of combination treatment with sodium-glucose cotransporter 2 inhibitors and glucagon-like peptide-1 receptor agonists, data are limited on the effects of combination treatment on markers of cardiovascular disease. This study aimed to investigate the effect of empagliflozin, semaglutide, and their combination on vascular function., Materials and Methods: In total, 120 patients with type 2 diabetes were randomized into four groups (n = 30 in each) for 32 weeks: placebo, semaglutide, empagliflozin, and their combination. The study had two co-primary outcomes: change in arterial stiffness and kidney oxygenation. This paper reports on arterial stiffness assessed as carotid-femoral pulse wave velocity. Secondary outcomes included 24-h blood pressure (BP), 24-h central BP, urinary albumin to creatinine ratio and glycaemic control assessed by both continuous glucose monitoring and glycated haemoglobin., Results: The carotid-femoral pulse wave velocity did not change significantly in any of the groups compared with placebo. Twenty-four-hour systolic BP was reduced by 10 mmHg (95% CI 6-14), p < .001 in the combination group, significantly superior to both placebo and monotherapy (p < .05). Combination treatment increased glycaemic time in range from 72% at baseline to 91% at week 32, p < .001, without increasing time below range. The urinary albumin to creatinine ratio decreased by 36% (95% CI 4-57), p = .03 in the combination group compared with placebo., Conclusions: Empagliflozin, semaglutide, or their combination did not reduce arterial stiffness. Combination treatment showed a substantial and clinically important reduction in 24-h systolic BP compared with either treatment alone. Combination treatment increased glycaemic time in range without increasing the risk of hypoglycaemia., (© 2024 The Authors. Diabetes, Obesity and Metabolism published by John Wiley & Sons Ltd.)

The objective of this study was to assess the feasibility of the Arteriograph 24 device to measure 24-hour PWV and central systolic blood pressure (cSBP) in patients with type 2 diabetes (T2DM) and non-diabetic controls and compare daytime and nighttime characteristics in the two groups. Twenty-four-hour PWV and cSBP was measured in 58 patients with T2DM (mean age: 66 ± 9 years, 50% women, mean duration of T2DM: 7.8 ± 1.5 years) and 62 age- and sex-matched controls. Seventy percent of participants (71% T2DM patients and 69% controls) had sufficient readings to generate an acceptable 24-hour report (≥14 day and ≥7 night readings). Lower nocturnal than daytime PWV and cSBP were observed in both groups. Nocturnal PWV and cSBP dipping were attenuated in T2DM patients compared to controls (PWV: -0.3 ± 0.9 vs. -0.7 ± 0.9 m/s, P  = 0.04, cSBP: -8 ± 14 vs. -18 ± 18 mmHg, P  < 0.01). No group differences in PWV or cSBP were observed during daytime (T2D vs. controls, PWV: 9.2 ± 1.1 vs. 9.2 ± 1.3 m/s, P  = 0.99, cSBP: 133 ± 19 vs. 137 ± 25 mmHg, P  = 0.42) or nighttime (PWV: 8.9 ± 1.3 vs. 8.4 ± 1.3 m/s, P  = 0.14, cSBP 124 ± 20 vs. 118 ± 27 mmHg, P  = 0.26). The study findings indicate that the nocturnal dipping of PWV and cSBP is attenuated in T2DM patients. The significant number of missing measurements raises concerns regarding the clinical utility of the Arteriograph 24 device., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Introduction: Pheochromocytomas and paragangliomas are rare neuroendocrine tumours that originate from chromaffin cells within the adrenal medulla or extra-adrenal sympathetic ganglia. Management of disseminated or metastatic pheochromocytomas and paragangliomas continues to pose challenges and relies on limited evidence., Method: In this study, we report retrospective data on median overall survival (OS) and median progression-free survival (PFS) for all Danish patients treated with peptide receptor radionuclide therapy (PRRT) with 177 Lu-Dotatate or 90 Y-Dotatate over the past 15 years. One standard treatment of PRRT consisted of 4 consecutive cycles with 8-14-week intervals., Results: We included 28 patients; 10 were diagnosed with pheochromocytoma and 18 with paraganglioma. Median age at first PRRT was 47 (IQR 15-76) years. The median follow-up time was 31 (IQR 17-37) months. Eight patients died during follow-up. Median OS was 72 months, and 5-year survival was 65% with no difference between pheochromocytoma and paraganglioma. Patients with germline mutations had better survival than patients without mutations ( p = 0.041). Median PFS after the first cycle of PRRT was 30 months. For patients who previously received systemic treatment, the median PFS was 19 months, compared with 32 months for patients with no previous systemic treatment ( p = 0.083)., Conclusions: The median OS of around 6 years and median PFS of around 2.5 years found in this study are comparable to those reported in previous studies employing PRRT. Based on historical data, the efficacy of PRRT may be superior to 131 I-MIBG therapy, and targeted therapy with sunitinib and PRRT might therefore be considered as first-line treatment in this patient group.

Background: SGLT2 (sodium-glucose cotransporter 2) inhibitors (SGLT2i) can protect the kidneys and heart, but the underlying mechanism remains poorly understood., Methods: To gain insights on primary effects of SGLT2i that are not confounded by pathophysiologic processes or are secondary to improvement by SGLT2i, we performed an in-depth proteomics, phosphoproteomics, and metabolomics analysis by integrating signatures from multiple metabolic organs and body fluids after 1 week of SGLT2i treatment of nondiabetic as well as diabetic mice with early and uncomplicated hyperglycemia., Results: Kidneys of nondiabetic mice reacted most strongly to SGLT2i in terms of proteomic reconfiguration, including evidence for less early proximal tubule glucotoxicity and a broad downregulation of the apical uptake transport machinery (including sodium, glucose, urate, purine bases, and amino acids), supported by mouse and human SGLT2 interactome studies. SGLT2i affected heart and liver signaling, but more reactive organs included the white adipose tissue, showing more lipolysis, and, particularly, the gut microbiome, with a lower relative abundance of bacteria taxa capable of fermenting phenylalanine and tryptophan to cardiovascular uremic toxins, resulting in lower plasma levels of these compounds (including p-cresol sulfate). SGLT2i was detectable in murine stool samples and its addition to human stool microbiota fermentation recapitulated some murine microbiome findings, suggesting direct inhibition of fermentation of aromatic amino acids and tryptophan. In mice lacking SGLT2 and in patients with decompensated heart failure or diabetes, the SGLT2i likewise reduced circulating p-cresol sulfate, and p-cresol impaired contractility and rhythm in human induced pluripotent stem cell-derived engineered heart tissue., Conclusions: SGLT2i reduced microbiome formation of uremic toxins such as p-cresol sulfate and thereby their body exposure and need for renal detoxification, which, combined with direct kidney effects of SGLT2i, including less proximal tubule glucotoxicity and a broad downregulation of apical transporters (including sodium, amino acid, and urate uptake), provides a metabolic foundation for kidney and cardiovascular protection., Competing Interests: Disclosures Dr Rinschen declares pending research funding from Novo Nordisk unrelated to this work. Over the past 12 months, Dr Vallon has served as a consultant for Lexicon and received speaker honoraria from AstraZeneca and grant support for investigator-initiated research from AstraZeneca, Boehringer Ingelheim, Gilead, Lexicon, Maze, Merck, and Novo-Nordisk. Dr Magnussen receives study-specific funding from the German Center for Cardiovascular Research (DZHK; Promotion of Women Scientists Programme; FKZ 81X3710112), the Deutsche Stiftung für Herzforschung, the Dr Rolf M. Schwiete Stiftung, NDD, and Loewenstein Medical unrelated to the current work. Dr Magnussen has received speaker fees from AstraZeneca, Novartis, Boehringer Ingelheim/Lilly, Bayer, Pfizer, Sanofi, Aventis, Apontis, and Abbott outside this work. Dr Dugourd and R. Fallegger report funding from Pfizer. Dr Saez-Rodriguez reports funding from GSK, Pfizer, and Sanofi and fees from Travere Therapeutics, Stadapharm, and Astex. Dr Hoxha served on advisory boards for Novartis, Morphosys AG, Sotio, and Argenx. The other authors declare no conflict of interest.

Aims: To evaluate the effect of treatment with semaglutide and empagliflozin on the cortico-medullary sodium gradient (MCR; medulla/cortex ratio), urine sodium/creatinine ratio (UNACR), and estimated plasma volume (ePV) and to compare the MCR between persons with and without type 2 diabetes., Methods: Using the 23 Na magnetic resonance imaging ( 23 Na-MRI) technique, we investigated the effects of 32 weeks of treatment with semaglutide, empagliflozin or their combination on MCR in 65 participants with type 2 diabetes and high risk of cardiovascular disease. The participants were recruited from a randomized, controlled interventional trial and further characterized by UNACR and ePV. In addition, in a cross-sectional design, we compared MCR by 23 Na-MRI in 12 persons with type 2 diabetes and 17 matched controls. Data from the interventional trial were analyzed using a single, multivariate linear mixed model strategy for repeated measurements. Data from the cross-sectional study were analyzed by fitting a linear regression model adjusted for age and sex., Results: Compared to placebo, semaglutide, but not empagliflozin, significantly decreased the MCR (-9 %, 95%CI (-18, -0.06)%, p = 0.035 and -0.05 %, 95%CI(-0.15, 0.05)%, p = 0.319, respectively). The UNACR decreased in the semaglutide group(-35 %, 95 % CI(-52, -14) %, p = 0.003) but not in the empagliflozin group (7 %, 95 % CI(-21, 44)%, p = 0.657), whereas the ePV decreased in the combination group. The MCR was not different between persons with and without type 2 diabetes., Conclusion: 23 Na magnetic resonance imaging can identify drug induced changes in the MCR in persons with type 2 diabetes, and 32 weeks of semaglutide decreases the MCR in such persons. There is no difference in the MCR between persons with and without type 2 diabetes., Trial Number and Registry: EUDRACT 2019-000781-38, clinicaltrialsregister.eu., Competing Interests: Declaration of competing interest The authors declare no conflicts of interests., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Both [ 18 F]FDOPA (FDOPA) and [ 68 Ga]DOTATOC PET/CT (DOTATOC) are widely used for detection of pheochromocytomas/paraganglioma (PPGL). However, direct comparisons of the performance of the two tracers are only available in small series. We conducted a retrospective comparative analysis of FDOPA and DOTATOC to assess their sensitivity and accuracy in detecting PPGL when administered based on suspicion of PPGL. We consecutively included patients referred on suspicion of PPGL or PPGL recurrence who were scanned with both FDOPA and DOTATOC. Both scans were reviewed retrospectively by two experienced observers, who were blinded to the final diagnosis. The assessment was made both visually and quantitatively. The final diagnosis was primarily based on pathology., Results: In total, 113 patients were included (97 suspected of primary PPGL and 16 suspected of recurrence). Of the 97 patients, 51 had pheochromocytomas (PCC) (in total 55 lesions) and 6 had paragangliomas (PGL) (in total 7 lesions). FDOPA detected and correctly localized all 55 PCC, while DOTATOC only detected 25 (sensitivity 100% vs. 49%, p < 0.0001; specificity 95% vs. 98%, p = 1.00). The negative predictive value (100% vs. 63%, p < 0.001) and diagnostic accuracy (98% vs. 70%, p < 0.01) were higher for FDOPA compared to DOTATOC. FDOPA identified 6 of 6 patients with hormone producing PGL, of which one was negative on DOTATOC. Diagnostic performances of FDOPA and DOTATOC were similar in the 16 patients with previous PPGL suspected of recurrence., Conclusions: FDOPA is superior to DOTATOC for localization of PCC. In contrast to DOTATOC, FDOPA also identified all PGL but with a limited number of patient cases., (© 2023. The Author(s).)

Introduction: Central aortic blood pressure (BP) could be a better risk predictor than brachial BP. This study examined whether invasively measured aortic systolic BP improved outcome prediction beyond risk prediction by conventional cuff-based office systolic BP in patients with and without chronic kidney disease (CKD)., Methods: In a prospective, longitudinal cohort study, aortic and office systolic BPs were registered in patients undergoing elective coronary angiography (CAG). CKD was defined as estimated glomerular filtration rate (eGFR) <60 ml/min per 1.73 m 2 . Multivariable Cox models were used to determine the association with incident myocardial infarction (MI), stroke, and death., Results: Aortic and office systolic BPs were available in 39,866 patients (mean age: 64 years; 58% males; 64% with hypertension) out of which 6605 (17%) had CKD. During a median follow-up of 7.2 years (interquartile range: 4.6-10.1 years), 1367 strokes (CKD: 353), 1858 MIs (CKD: 446), and 7551 deaths (CKD: 2515) occurred. CKD increased the risk of stroke, MI, and death significantly. Office and aortic systolic BP were both associated with stroke in non-CKD patients (adjusted hazard ratios with 95% confidence interval per 10 mm Hg: 1.08 [1.05-1.12] and 1.06 [1.03-1.09], respectively) and with MI in patients with CKD (adjusted hazard ratios: 1.08 [1.03-1.13] and 1.08 [1.04-1.12], respectively). There was no significant difference between prediction of outcome with office or aortic systolic BP when adjusted models were compared with C-statistics., Conclusion: Regardless of CKD status, invasively measured central aortic systolic BP does not improve the ability to predict outcome compared with brachial office BP measurement., (© 2023 International Society of Nephrology. Published by Elsevier Inc.)

Introduction: A total of 10% of older individuals harbour adrenal incidentalomas and need dedicated adrenal CT to exclude malignancy and biochemical evaluation. These investigations tax medical resources, and diagnostic delay may cause anxiety for the patient. We implemented a no-need-to-see pathway (NNTS) in which low-risk patients only attend the clinic if adrenal CT or hormonal evaluation is abnormal., Methods: We investigated the impact of a NNTS pathway on the share of patients not requiring an attendance consultation, time to malignancy and hormonal clarification, and time to end of investigation. We prospectively registered adrenal incidentaloma cases (n = 347) and compared them with historical controls (n = 103)., Results: All controls attended the clinic. A total of 63% of cases entered and 84% completed the NNTS pathway without seeing an endocrinologist; 53% of consultations were avoided. Time-to-event analysis revealed a shorter time to clarification of malignancy (28 days; 95% confidence interval (CI): 24-30 days versus 64 days; 95% CI: 47-117 days) and hormonal status (43 days; 95% CI: 38-48 days versus 56 days; 95% CI: 47-68 days) and a shorter time to end of pathway (47 days; 95% CI: 42-55 days versus 112 days; 95% CI: 84-131 days) in cases than controls (p ≤ 0.01)., Conclusion: We demonstrated that NNTS pathways may be an efficient way of handling the increased burden of incidental radiological findings, avoiding 53% of attendance consultations and achieving a shorter time to end of pathway., Funding: Supported by a grant from Regional Hospital Central Denmark, Denmark. The study was approved by the institutional review boards of all participating hospitals., Trial Registration: Not relevant., (Articles published in the DMJ are “open access”. This means that the articles are distributed under the terms of the Creative Commons Attribution Non-commercial License, which permits any non-commercial use, distribution, and reproduction in any medium, provided the original author(s) and source are credited.)

Aims: Semaglutide and empagliflozin have shown cardiovascular protection. In SUSTAIN-6, semaglutide was associated with an increased risk of diabetic retinopathy. We investigated whether changes in retinal oxygenation, retinal vascular autoregulation, and central retinal thickness are altered by semaglutide, empagliflozin or the combination., Methods: This study was a prespecified, secondary outcome from a randomised, 32 weeks partly placebo-controlled, partly open-label, clinical trial on the effects of semaglutide and empagliflozin on arterial stiffness and kidney oxygenation. A total of 120 participants with type 2 diabetes, established or high risk of cardiovascular disease and age ≥50 years were randomised into four parallel groups (semaglutide, empagliflozin, the combination or tablet placebo, n = 30 for each group). We primarily hypothesized that semaglutide would increase venular oxygenation., Results: We found no changes in retinal arteriolar, venular or venular-arteriolar oxygenation nor in retinal vessel diameter regardless of treatment group. Semaglutide increased central retinal thickness compared to placebo with ~1 % (3.8 μm 95 % CI [0.9;6.7], p = 0.009) with no changes in the empagliflozin or combination group., Conclusion: Neither semaglutide, empagliflozin nor the combination alters markers of retinal function. The effect of semaglutide on central retinal thickness was small, but the clinical significance is uncertain., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Aims/hypothesis: Glucagon-like peptide-1 receptor agonists (GLP-1ras) and sodium-glucose cotransporter 2 inhibitors (SGLT2is) have shown kidney-protective effects. Improved kidney oxygenation and haemodynamic changes are suggested mechanisms; however, human data are scarce. We therefore investigated whether semaglutide (GLP-1ra), empagliflozin (SGLT2i) or their combination improve kidney oxygenation and perfusion., Methods: The trial was undertaken at Aarhus University Hospital, Denmark. A total of 120 people with type 2 diabetes (HbA 1c ≥48 mmol/mol [6.5%]) and at high risk of CVD (age ≥50 years) were randomised into four parallel groups (n=30 in each group) for 32 weeks: 1.0 mg semaglutide (open label); 10 mg empagliflozin (blinded to participants, caregivers, examiners and outcome assessors); their combination (1.0 mg semaglutide open label plus 10 mg empagliflozin blinded to participants, caregivers, examiners and outcome assessors); and placebo tablet (blinded to participants, caregivers, examiners and outcome assessors). Sequentially numbered, sealed envelopes containing computer-generated randomisation codes, provided by Glostrup Pharmacy, Glostrup, Denmark, determined the intervention. The two co-primary outcomes were change in kidney oxygenation and change in arterial stiffness. This paper reports on kidney oxygenation, for which 80 individuals as prespecified, 20 in each group, underwent MRI. We primarily hypothesised that kidney oxygenation would be improved in the active treatment groups compared with placebo after 32 weeks. Secondary outcomes included changes in kidney perfusion, erythropoietin, haematocrit, urine albumin/creatinine ratio (UACR) and GFR (measured using technetium-99m) compared with baseline and between treatment groups at week 32., Results: Our model estimated a common baseline R2* value across all four groups in the cortex and the medulla. At baseline, the value was 24.5 (95% CI 23.9, 24.9) Hz in the medulla. After 32 weeks, the R2* values in the medulla were estimated to be 25.4 (95% CI 24.7, 26.2) Hz in the empagliflozin group and 24.5 (95% CI 23.9, 25.1) Hz in the placebo group (p=0.016) (higher R2* corresponds to a lower oxygenation). Semaglutide decreased perfusion in both the cortex and the medulla. Empagliflozin increased erythropoietin and haematocrit. All three active treatments decreased GFR but not UACR. Ten serious adverse events were reported, among them two occurrences of semaglutide-associated obstipation., Conclusions/interpretation: Our hypothesis, that semaglutide, empagliflozin or their combination improve kidney oxygenation, was rejected. On the contrary, empagliflozin induced a reduction in medullary kidney oxygenation. Semaglutide substantially reduced kidney perfusion without affecting oxygenation., Trial Registration: Clinicaltrialsregister.eu EudraCT 2019-000781-38 FUNDING: Novo Nordisk Foundation, Central Denmark Region Research Fund and Danish Medical Associations Research Foundation., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Background: Diabetic kidney disease (DKD) accounts for ∼50% of end-stage kidney disease. Renal hypoxia is suggested as a main driver in the pathophysiology underlying chronic DKD. Blood oxygenation level-dependent magnetic resonance imaging (BOLD-MRI) has made noninvasive investigations of renal oxygenation in humans possible. Whether diabetes per se contributes to measurable changes in renal oxygenation by BOLD-MRI remains to be elucidated. We investigated whether renal oxygenation measured with BOLD-MRI differs between people with type 2 diabetes (T2DM) with normal to moderate chronic kidney disease (CKD) (Stages 1-3A) and matched controls. The repeatability of the BOLD-MRI method was also assessed., Methods: In this matched cross-sectional study, 20 people with T2DM (age 69.2 ± 4.7 years, duration of diabetes 10.5 ± 6.7 years, male 55.6%) and 20 matched nondiabetic controls (mean age 68.8 ± 5.4 years, male 55.%) underwent BOLD-MRI analysed with the 12-layer concentric object method (TLCO). To investigate the repeatability, seven in the T2DM group and nine in the control group were scanned twice., Results: A significant reduction in renal oxygenation from the cortex to medulla was found in both groups (P < .01) but no intergroup difference was detected [0.71/s (95% confidence interval -0.28-1.7), P = .16]. The median intraindividual coefficient of variation (CV) varied from 1.2% to 7.0%., Conclusion: T2DM patients with normal to moderate CKD do not seem to have lower renal oxygenation when measured with BOLD-MRI and TLCO. BOLD-MRI has a low intraindividual CV and seems like a reliable method for investigation of renal oxygenation in T2DM., (© The Author(s) 2022. Published by Oxford University Press on behalf of the ERA.)

Introduction: Accumulating evidence support that mannan-binding lectin (MBL) is a promising prognostic biomarker for risk-stratification of diabetic micro- and macrovascular complications. Serum MBL levels are predominately genetically determined and depend on MBL genotype. However, Type 1 diabetes (T1D) is associated with higher MBL serum levels for a given MBL genotype, but it remains unknown if this is also the case for patients with T2D. In this study, we evaluated the impact of MBL genotypes on renal function trajectories serum MBL levels and compared MBL genotypes in newly diagnosed patients with T2D with age- and sex-matched healthy individuals. Furthermore, we evaluated differences in parameters of insulin resistance within MBL genotypes., Methods: In a cross-sectional study, we included 100 patients who were recently diagnosed with T2D and 100 age- and sex-matched individuals. We measured serum MBL levels, MBL genotype, standard biochemistry, and DEXA, in all participants. A 5-year clinical follow-up study was conducted, followed by 12-year data on follow-up biochemistry and clinical status for the progression to micro- or macroalbuminuria for the patients with T2D., Results: We found similar serum MBL levels and distribution of MBL genotypes between T2D patients and healthy individuals. The serum MBL level for a given MBL genotype did not differ between the groups neither at study entry nor at 5-year follow-up. We found that plasma creatinine increased more rapidly in patients with T2D with the high MBL expression genotype than with the medium/low MBL expression genotype over the 12-year follow-up period (p = 0.029). Serum MBL levels did not correlate with diabetes duration nor with HbA1c. Interestingly, serum MBL was inversely correlated with body fat percentage in individuals with high MBL expression genotypes both at study entry (p=0.0005) and 5-years follow-up (p=0.002)., Discussion: Contrary to T1D, T2D is not per se associated with increased MBL serum level for a given MBL genotype or with diabetes duration. Serum MBL was inversely correlated with body fat percentage, and T2D patients with the high MBL expression genotype presented with deterioration of renal function., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Dørflinger, Høyem, Laugesen, Østergaard, Funck, Steffensen, Poulsen, Hansen and Bjerre.)

Context: The long-term somatic and psychiatric consequences of Cushing's syndrome are well-described, but the socioeconomic consequences are largely unknown., Objective: We studied employment status, educational level, risk of depression, and other socioeconomic outcomes of Cushing's syndrome in the years before diagnosis and after surgery., Design: Nationwide register-based cohort study., Methods: We used a validated algorithm to identify 424 patients operated for adrenal (n = 199) or pituitary Cushing's syndrome (n = 225) in Denmark from January 1, 1986 to December 31, 2017. We obtained socioeconomic registry data from 10 years before diagnosis (year -10) to 10 years after surgery (year +10) and included a sex- and age-matched reference population. We identified prognostic factors for returning to work using modified Poisson regression., Results: Compared to the reference population, the patients' employment was permanently reduced from year -6 [relative risk (RR) 0.92, 95% CI 0.84-0.99] to year +10 (RR 0.66, 95% CI 0.57-0.76). Sick leave (RR 2.15, 95% CI 1.40-3.32) and disability pension (RR 2.60, 95% CI 2.06-3.27) were still elevated in year +10. Annual income, education, parenthood, relationship status, and risk of depression were also negatively impacted, but parenthood and relationship status normalized after surgery. Among patients, negative predictors of full-time employment after surgery included female sex, low education, comorbidity, and depression., Conclusion: Cushing's syndrome negatively affects a wide spectrum of socioeconomic variables many years before diagnosis of which only some normalize after treatment. The data underpin the importance of early diagnosis and continuous follow-up of Cushing's syndrome and, not least, the pervasive health threats of glucocorticoid excess., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

BACKGROUND Hypokalemia (serum potassium level below 3.5 mmol/L) is present in approximately 11% of patients admitted to emergency departments. Hypokalemia can be a manifestation of many underlying causes and if untreated can be fatal. A careful approach to work-up and management is required in hypokalemic patients. CASE REPORT Here we report a 26-year-old previously healthy male patient who was admitted to the Emergency Department with rapidly progressing paresis of the lower and upper extremities. Initial laboratory results revealed severe hypokalemia of 2.1 mmol/l, which aggravated to 1.6 mmol/l before receiving treatment with intravenous potassium chloride supplementation. In addition, the patient developed rhabdomyolysis secondary to prolonged paralysis and immobilization induced by hypokalemia. Following this treatment, the patient's symptoms eased rapidly, and his potassium concentration was normalized. The patient admitted to smoking cannabis the day before admission. In this case report, we systematically elaborate and exclude the causes of hypokalemia in this otherwise healthy young adult, including medication, gastrointestinal symptoms, licorice consumption, and genetical testing. Cannabis has been associated with hypokalemia, proposedly through activation of the cannabinoid receptor 1 (CB1)-mediated activation of G protein-coupled inwardly rectifying potassium (GIRK) channels. CONCLUSIONS This case report emphasizes that hypokalemia can cause paralysis and cannabis should be included in the diagnostic mindset.

Background Estimated pulse wave velocity (ePWV) calculated by equations using age and blood pressure has been suggested as a new marker of mortality and cardiovascular risk. However, the prognostic potential of ePWV during long-term follow-up in patients with symptoms of stable angina remains unknown. Methods and Results In this study, ePWV was calculated in 25 066 patients without diabetes, previous myocardial infarction (MI), stroke, heart failure, or valvular disease (mean age 63.7±10.5 years, 58% male) with stable angina pectoris undergoing elective coronary angiography during 2003 to 2016. Multivariable Cox models were used to assess the association with incident all-cause mortality, MI, and stroke. Discrimination was assessed using Harrell´s C-index. During a median follow-up period of 8.5 years (interquartile range 5.5-11.3 years), 779 strokes, 1233 MIs, and 4112 deaths were recorded. ePWV was associated with all-cause mortality (hazard ratio [HR] per 1 m/s, 1.13; 95% CI, 1.05-1.21) and MI (HR per 1 m/s 1.23, 95% CI, 1.09-1.39) after adjusting for age, systolic blood pressure, body mass index, smoking, estimated glomerular filtration rate, Charlson Comorbidity Index score, antihypertensive treatment, statins, aspirin, and number of diseased coronary arteries. Compared with traditional risk factors, the adjusted model with ePWV was associated with a minor but likely not clinically relevant increase in discrimination for mortality, 76.63% with ePWV versus 76.56% without ePWV, P <0.05. Conclusions In patients with stable angina pectoris, ePWV was associated with all-cause mortality and MI beyond traditional risk factors. However, the added prediction of mortality was not improved to a clinically relevant extent.

Background: Data regarding adrenal metastasectomy are limited. Here, clinical outcomes, safety, and prognostic factors in patients undergoing adrenal metastasectomy were evaluated in a large nationwide study., Methods: Patients undergoing adrenal metastasectomy between 2000 and 2018 were identified in the Danish National Pathology Registry. Medical records were reviewed to confirm eligibility and to collect clinical data. The primary outcome was overall survival (OS). Cox multivariable regression analyses were? adjusted for baseline factors., Results: In total, 435 patients underwent adrenal metastasectomy; the primary cancer origins were renal (n = 195, 45 per cent), lung (n = 121, 28 per cent), colorectal (n = 50, 11 per cent), and other (n = 69, 16 per cent). The median (interquartile range; i.q.r.) age was 66 (59-71) years, and 280 (64 per cent) were men. The 5-year OS was 31 per cent. The 30-day mortality was 1.8 per cent. Complications were more frequent and severe in patients who underwent open surgery compared with laparoscopic surgery (Clavien-Dindo III-V, 31.5 per cent versus 11.8 per cent respectively, P < 0.001). Factors associated with poor survival included non-radical pR2 resection (hazard ratio (HR) 3.57, 95 per cent c.i. 1.96 to 6.48), tumour size more than 50 mm (HR 1.79, 95 per cent c.i. 1.26 to 2.52), lung cancer origin (HR 1.77, 95 per cent c.i. 1.31 to 2.40), open surgical approach (HR 1.33, 95 per cent c.i. 1.04 to 1.71), presence of extra-adrenal metastases (HR 1.31, 95 per cent c.i. 1.01 to 1.71), and increasing Charlson co-morbidity index factors (HR 1.14 per one-point increase, 95 per cent c.i. 1.03 to 1.27)., Conclusion: Adrenal metastasectomy is safe and may result in long-term survival in a subset of patients. Non-radical resection, large tumour size, lung cancer origin, open approach, presence of extra-adrenal metastases, and co-morbidity were associated with inferior outcomes., (© The Author(s) 2022. Published by Oxford University Press on behalf of BJS Society Ltd.)

Background: It was recently shown that new-onset diabetes patients without previous cardiovascular disease have experienced a markedly reduced risk of adverse cardiovascular events from 1996 to 2011. However, it remains unknown if similar improvements are present following the diagnosis of chronic coronary syndrome. The purpose of this study was to examine the change in cardiovascular risk among diabetes patients with chronic coronary syndrome from 2004 to 2016., Methods: We included patients with documentation of coronary artery disease by coronary angiography between 2004 and 2016 in Western Denmark. Patients were stratified by year of index coronary angiography (2004-2006, 2007-2009, 2010-2012, and 2013-2016) and followed for two years. The main outcome was major adverse cardiovascular events (MACE) defined as myocardial infarction, ischemic stroke, or death. Analyses were performed separately in patients with and without diabetes. We estimated two-year risk of each outcome and adjusted incidence rate ratios (aIRR) using patients examined in 2004-2006 as reference., Results: Among 5931 patients with diabetes, two-year MACE risks were 8.4% in 2004-2006, 8.5% in 2007-2009, and then decreased to 6.2% in 2010-2012 and 6.7% in 2013-2016 (2013-2016 vs 2004-2006: aIRR 0.70, 95% CI 0.53-0.93). In comparison, 23,540 patients without diabetes had event rates of 6.3%, 5.2%, 4.2%, and 3.9% for the study intervals (2013-2016 vs 2004-2006: aIRR 0.57, 95% CI 0.48-0.68)., Conclusions: Between 2004 and 2016, the two-year relative risk of MACE decreased by 30% in patients with diabetes and chronic coronary syndrome, but slightly larger absolute and relative reductions were observed in patients without diabetes., (© 2021. The Author(s).)

Introduction: Type 2 diabetes (T2D) is related to an increased fracture risk and low bone turnover. However, the mechanisms are not elucidated. In the present study we investigate the association between glycemic variability and bone turnover markers., Methods: 100 participants with T2D and 100 age and gender matched controls were included in this cross-sectional study. All participants with T2D were equipped with a continuous glucose monitoring (CGM) sensor for 3 days (CGMS iPro Continuous Glucose Recorder; Medtronic MiniMed). The dawn glucose levels were defined as a morning period starting 1 h before breakfast ending 1 h post ingestion. On all participants serum (s)-C-terminal cross-linked telopeptide of type-I collagen (CTX), s-procollagen type 1 amino terminal propeptide (P1NP), and s-sclerostin were measured., Results: Participants with T2D displayed significantly lower levels of the bone resorption marker s-CTX and the bone formation marker s-P1NP compared to controls. S-CTX was significantly negatively associated with the mean amplitude of glycemic excursions (MAGE) and the dawn glucose levels whereas s-P1NP only was significantly negatively associated with the dawn glucose levels while it was borderline significantly associated with MAGE (p = 0.05). S-CTX and s-P1NP were significantly lower among the 50% with the highest dawn glucose levels compared to the 50% lowest dawn glucose levels also after adjustment for age, gender, glycated hemoglobin A1c (HbA1c), and body mass index (BMI)., Conclusion: We observed that the amplitude of glycemic excursions and rise in dawn glucose was negatively associated with bone turnover markers. Future research is needed to determine whether reduction of the amplitude of glycemic excursions increase bone turnover markers., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: The long-term association between physical activity and endothelial function has not previously been investigated in patients with type 2 diabetes. Therefore, we aimed to evaluate the relationship between physical activity and endothelial function, assessed by peripheral arterial tonometry, in patients with type 2 diabetes and non-diabetic controls after 5 years of follow-up., Methods: We included 51 patients with newly diagnosed type 2 diabetes and 53 sex- and age matched controls. Participants underwent baseline clinical characterization including objective measurement of physical activity level using accelerometery. After 5 years of follow-up, participants were re-examined, and endothelial function was assessed as natural logarithm of reactive hyperemia index (lnRHI)., Results: Physical activity at baseline was associated with lnRHI after 5 years of follow-up in both patients with type 2 diabetes and controls. An increase of 1 standard deviation (SD) in daytime physical activity corresponded to a 6.7 % increase in RHI (95 % confidence interval: 1.1;12.5 %, p = 0.02). We found no difference in lnRHI between patients with diabetes and controls (0.67 ± 0.29 vs. 0.73 ± 0.31, p = 0.28)., Conclusions: Daytime physical activity is associated with endothelial function after 5 years of follow-up in patients with type 2 diabetes and controls., (© 2021. The Author(s).)

Background: Stroke is a serious complication in patients with type 2 diabetes (T2DM). Arterial stiffness may improve stroke prediction. We investigated the association between carotid-femoral pulse wave velocity [PWV] and the progression of cerebral white matter hyperintensities (WMH), a marker of stroke risk, in patients with T2DM and controls., Methods: In a 5-year cohort study, data from 45 patients and 59 non-diabetic controls were available for analysis. At baseline, participants had a mean (± SD) age of 59  ±  10 years and patients had a median (range) diabetes duration of 1.8 (0.8-3.2) years. PWV was obtained by tonometry and WMH volume by an automated segmentation algorithm based on cerebral T2-FLAIR and T1 MRI (corrected by intracranial volume, cWMH). High PWV was defined above 8.94 m/s (corresponding to the reference of high PWV above 10 m/s using the standardized path length method)., Results: Patients with T2DM had a higher PWV than controls (8.8  ±  2.2 vs. 7.9  ±  1.4 m/s, p  <  0.01). WMH progression were similar in the two groups (p  =  0.5). One m/s increase in baseline PWV was associated with a 16% [95% CI 1-32%], p  <  0.05) increase in cWMH volume at 5 years follow-up after adjustment for age, sex, diabetes, pulse pressure and smoking. High PWV was associated with cWMH progression in the combined cohort (p  <  0.05). We found no interaction between diabetes and PWV on cWMH progression., Conclusions: PWV is associated with cWMH progression in patients with type 2 diabetes and non-diabetic controls. Our results indicate that arterial stiffness may be involved early in the pathophysiology leading to cerebrovascular diseases.

Context: Pheochromocytoma and sympathetic paraganglioma (PPGL) are rare catecholamine-secreting tumors but recent studies suggest increasing incidence. Traditionally, PPGL are described to present with paroxysmal symptoms and hypertension, but existing data on clinical presentation of PPGL come from referral centers., Objective: We aimed to describe time trends in clinical presentation and incidence of PPGL in a population-based study., Methods: We conducted a nationwide retrospective cohort study of a previously validated cohort of 567 patients diagnosed with PPGL in Denmark 1977-2015. We collected clinical data from medical records of a geographic subcohort of 192 patients. We calculated age-standardized incidence rates (SIRs) and prevalence for the nationwide cohort and descriptive statistics on presentation for the subset with clinical data., Results: SIRs increased from 1.4 (95% CI 0.2-2.5) per million person-years in 1977 to 6.6 (95% CI 4.4-8.7) per million person-years in 2015, corresponding to a 4.8-fold increase. The increase was mainly due to incidentally found tumors that were less than 4 cm and diagnosed in patients older than 50 years with no or limited paroxysmal symptoms of catecholamine excess. On December 31, 2015, prevalence of PPGL was 64.4 (CI 95% 57.7-71.2) per million inhabitants. Of 192 patients with clinical data, 171 (89.1%) had unilateral pheochromocytoma, while unilateral paraganglioma (n = 13, 6.8%) and multifocal PPGL (n = 8, 4.2%) were rare., Conclusion: Incidence of PPGL has increased 4.8-fold from 1977 to 2015 due to a "new" group of older patients presenting with smaller incidentally found PPGL tumors and few or no paroxysmal symptoms., (© The Author(s) 2021. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Objective: Aortic pulse pressure (PP) represents the hemodynamic cardiac and cerebral burden more directly than cuff PP. The objective of this study was to investigate whether invasively measured aortic PP confers additional prognostic value beyond cuff PP for cardiovascular events and death. With increasing age, cuff PP progressively underestimates aortic PP. Whether the prognostic association between cuff PP and outcomes is age-dependent remains to be elucidated., Methods: Cuff PP and invasively measured aortic PP were recorded in 21 908 patients (mean age 63 years, 58% men, 14% with diabetes) with stable angina pectoris undergoing elective coronary angiography during January 2001--December 2012. Multivariate Cox models were used to assess the association with incident myocardial infarction, stroke, and death. Discrimination was assessed using Harrell's C-index., Results: During a median follow-up period of 3.7 years (range 0.1-10.8 years), 422 strokes, 511 myocardial infarctions, and 1530 deaths occurred. Both cuff and aortic PP were associated with stroke, myocardial infarction, and death in crude analyses. However, only cuff PP remained associated with stroke (hazard ratio per 10 mmHg, 1.06 (95% confidence interval (CI) 1.01--1.12)] and myocardial infarction [hazard ratio per 10 mmHg 1.05 (95% CI 1.01--1.11)] in multivariate Cox models. Both cuff and aortic PP lost significance as predictors of death in multivariate models. Age did not modify the prognostic association between cuff PP and stroke, myocardial infarction, and death., Conclusion: Invasively measured aortic PP did not add prognostic information about cardiovascular outcomes and death beyond cuff PP in patients with stable angina pectoris., (Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.)

With wider application and technical improvement of imaging the discovery of adrenal incidentalomas (AI) has been skyrocketing. AI need to be investigated for evidence of hormonal hypersecretion and malignancy, and this causes a considerable use of health resources and potential medicalisation. In the "no-need-to-see" process, the clinical assessment of the citizen will only take place, if the diagnostic tests are abnormal. In this review, we examine the predictive values of imaging and paraclinical testing and argue, that normal test results in people without extra-adrenal cancer exclude disease.

Aim: Obstructive sleep apnoea (OSA) is frequent in type 2 diabetes (T2D). The aim was to investigate the effect of a 12-week treatment with continuous positive airway pressure (CPAP) on glycaemic control assessed by continuous glucose monitoring (CGM), HbA1c and fasting blood glucose in patients with T2D and newly detected OSA., Methods: In a randomized controlled multicentre study, 72 participants with T2D and moderate to severe OSA (78% male, age 62 ± 7, AHI 35 ± 15) were recruited from outpatient clinics in three Danish hospitals and were randomized to CPAP intervention or control. The main outcome was glycaemic control assessed by 6 days CGM at baseline and after 12-week therapy, as well as by HbA1c and fasting blood glucose., Results: No significant changes were found in average glucose levels, time in glucose range, time with hypoglycaemia, time with hyperglycaemia or coefficient of variability. HbA1c decreased 0.7 mmol/mol (0.07%; P  = .8) in the CPAP group and increased 0.8 mmol/mol (0.08%; P  = .6) in the control group (intergroup difference, P  = .6). Fasting blood glucose increased by 0.2 mmol/L ( P  = .02) in the CPAP group and by 0.4 mmol/L ( P  = .01) in the control group (intergroup difference, P  = .7). In a prespecified subgroup analysis comparing participants with high adherence (minimum usage of four hours/night for 70% of all nights) to CPAP to the control group, no significant changes were observed either, although these participants had a tendency towards better glycaemic indices., Conclusions: CPAP treatment for 12 weeks does not significantly change glycaemic control in patients with type 2 diabetes and OSA., Competing Interests: Fleischer J. is the co‐inventor of Vagus™ device and holds stock in Medicus Engineering. No other author has reported conflicts of interest. ResMed Maribo have not had any influence on the design or conducting of the study, nor have they influenced the analysis of data or the manuscript., (© 2020 The Authors. Endocrinology, Diabetes & Metabolism published by John Wiley & Sons Ltd.)

The objective of this study was to evaluate the effect of continuous positive airway pressure treatment on pulse wave velocity and blood pressure in patients with type 2 diabetes and obstructive sleep apnea. A randomized controlled study was performed, including 72 patients with type 2 diabetes and newly diagnosed obstructive sleep apnea recruited from outpatient clinics at three Danish hospitals. The patients were randomized to continuous positive airway pressure for 12 weeks or no continuous positive airway pressure. Office measurements were performed at baseline, 4 weeks and 12 weeks. At baseline and 12 weeks, a 24-hr measurement of pulse wave velocity and blood pressure was performed. No significant change was observed in the primary outcome variable of carotid-femoral pulse wave velocity measured with SphygmoCor. With the Mobil-O-Graph, changes in office pulse wave velocity between the groups were significant: 0.3 m/s; 95% confidence interval, 0.1-0.6; p = .02. The group receiving continuous positive airway pressure had a larger decrease in pulse wave velocity than controls but none of the changes within the groups were significant. No significant change in ambulatory blood pressure was observed in any of the two groups after 12 weeks. In conclusion, continuous positive airway pressure treatment for 12 weeks does not significantly reduce pulse wave velocity or blood pressure in patients with type 2 diabetes and obstructive sleep apnea., (© 2020 European Sleep Research Society.)

Background: Diabetes is considered a risk factor for myocardial infarction. However, we have previously found that diabetes was not a short-term risk factor for myocardial infarction in the absence of obstructive coronary artery disease., Methods: We conducted a cohort study of patients undergoing coronary angiography from 2003 to 2012 and followed them by cross-linking Danish health registries. Patients were stratified according to coronary artery disease and diabetes. Endpoints included myocardial infarction, cardiac death, all-cause death and coronary revascularization., Results: 86,202 patients were included in total (diabetes: n  = 12,652). Median follow-up was 8.8 years. Using patients with neither coronary artery disease nor diabetes as reference (cumulative myocardial infarction incidence 2.6%), the risk of myocardial infarction was low and not substantially increased for patients with diabetes alone (3.2%; hazard ratio 1.202, 95% confidence interval 0.996-1.451), was increased for patients with coronary artery disease alone (9.3%; hazard ratio 2.75, 95% confidence interval 2.52-3.01) and was highest for patients with both coronary artery disease and diabetes (12.3%; hazard ratio 3.79, 95% confidence interval 3.43-4.20). Similar associations were observed for cardiac death and coronary revascularization., Conclusion: Diabetes patients without coronary artery disease by coronary angiography have a low risk of myocardial infarction, not substantially increased compared to patients with neither coronary artery disease nor diabetes. In the presence of coronary artery disease, however, diabetes increases the risk of myocardial infarction.

Aim: To evaluate if diffusion-tensor-imaging MR-Neurography (DTI-MRN) can detect lesions of peripheral nerves due to polyneuropathy in patients with type 2 diabetes., Methods: Ten patients with type 2 diabetes with polyneuropathy (DPN), 10 patients with type 2 diabetes without polyneuropathy (nDPN) as well as 20 healthy controls (HC) were included. DTI-MRN covered proximal (sciatic nerve) and distal regions (tibial nerve) of the lower extremity. Fractional-anisotropy (FA) and diffusivity (mean (MD), axial (AD) and radial (RD)) were calculated and compared to neuropathy severity. Conventional T2-relaxation-time and proton-spin-density data were obtained from a multi-echo SE sequence. Furthermore, we evaluated sensitivity and specificity of DTI-MRN from receiver operating characteristics (ROC)., Results: The proximal and distal FA was lowest in patients with DPN compared with nDPN and HC (p < 0.01). Likewise, proximal and distal RD was highest in patients with DPN (p < 0.01). MD and AD were also significantly different though less pronounced. ROC curve analyses of DTI separated nDPN and DPN with area-under-the-curve values ranging from 0.65 to 0.98. T2-relaxation-time and proton-spin-density could not differentiate between nDPN and DPN., Conclusion: DTI-MRN accurately detects DPN by lower nerve FA and higher RD. These alterations are likely to reflect both proximal and distal nerve fiber pathology in patients with type 2 diabetes., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Aims: We examined whether severity of coronary artery disease (CAD) measured by coronary computed tomography angiography can be used to predict rates of myocardial infarction (MI) and death in patients with and without diabetes., Methods and Results: A cohort study of consecutive patients (n = 48 731) registered in the Western Denmark Cardiac Computed Tomography Registry from 2008 to 2016. Patients were stratified by diabetes status and CAD severity (no, non-obstructive, or obstructive). Endpoints were MI and death. Event rates per 1000 person-years, unadjusted and adjusted incidence rate ratios were computed. Median follow-up was 3.6 years. Among non-diabetes patients, MI event rates per 1000 person-years were 1.4 for no CAD, 4.1 for non-obstructive CAD, and 9.1 for obstructive CAD. Among diabetes patients, the corresponding rates were 2.1 for no CAD, 4.8 for non-obstructive CAD, and 12.6 for obstructive CAD. Non-diabetes and diabetes patients without CAD had similar low rates of MI [adjusted incidence rate ratio 1.40, 95% confidence interval (CI): 0.71-2.78]. Among diabetes patients, the adjusted risk of MI increased with severity of CAD (no CAD: reference; non-obstructive CAD: adjusted incidence rate ratio 1.71, 95% CI: 0.79-3.68; obstructive CAD: adjusted incidence rate ratio 4.42, 95% CI: 2.14-9.17). Diabetes patients had higher death rates than non-diabetes patients, irrespective of CAD severity., Conclusion: In patients without CAD, diabetes patients have a low risk of MI similar to non-diabetes patients. Further, MI rates increase with CAD severity in both diabetes and non-diabetes patients; with diabetes patients with obstructive CAD having the highest risk of MI., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2019. For permissions, please email: journals.permissions@oup.com.)

Background and Aims: Attenuated retinal vasoreactivity in patients with type 2 diabetes preceding diabetic retinopathy development has been proposed to reflect local endothelial dysfunction. Whether retinal vessel reactivity is associated with peripheral endothelial dysfunction and large artery stiffness in patients with type 2 diabetes remains to be elucidated., Methods: Twenty patients with type 2 diabetes without retinopathy and 20 sex- and age matched controls (diabetes duration: 9.9 years (range 6.0;12.4), 40% male, age: 66.5 ± 7.3 (diabetes) and 65.2 ± 7.6 years (controls)) were included. Endothelial function was assessed using EndoPAT. Arterial stiffness was assessed by carotid-femoral pulse wave velocity using the SphygmoCor. Retinal blood supply regulation was examined by retinal arteriolar diameter change during 1) isometric exercise (hand-weight lifting), 2) exposure to flickering lights, and 3) a combined stimulus of 1) + 2) using the Dynamic Vessel Analyzer., Results: No significant differences were observed in retinal vessel reactivity in T2DM patients compared to controls. Endothelial function was associated with mean arteriolar diameter change during only the combination intervention, (Beta = 0.033 [0.0013;0.064], p = 0.042) in the overall population of patients and controls. When groups were analyzed separately, the associations was statistically significant only in controls. However, formal test for interaction was not statistically significant, p = 0.40. No association was observed between pulse wave velocity and retinal arteriolar %-diameter change in patients or controls., Conclusion: Peripheral endothelial function was associated with retinal arteriolar diameter change in the combined sample. The association seemed to be driven primarily by the controls. Our findings indicate that peripheral endothelial function is reflective of endothelial function in the retina mainly in subjects without T2DM, whereas an association in T2DM without retinopathy was not observed. Further studies are needed in T2DM patients with more advanced retinopathy., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Aim: We investigated whether the effect of low-dose aspirin on endothelium-dependent vasodilation and arterial stiffness in people with Type 2 diabetes is different from a matched control group. We examined acute and chronic effects, and effects over the 24h dosing interval., Methods: In an open-label parallel group intervention study, we included 21 participants with Type 2 diabetes and 21 age- and sex-matched controls. Endothelium-dependent vasodilation was assessed as the reactive hyperaemia index (lnRHI) measured by peripheral arterial tonometry (EndoPAT ® ). Arterial stiffness was assessed as pulse wave velocity (PWV) measured by applanation tonometry (SphygmoCor ® ). Measurements were performed prior to aspirin intake and 1h after aspirin administration (75 mg). Participants were then treated for 6 days, and measurements were repeated at 24 h and 1 h after aspirin intake., Results: Baseline lnRHI did not differ between groups. The controls had an immediate increase in lnRHI after the first aspirin tablet. This was not observed in participants with diabetes (difference between groups; P < 0.05). After 1 week, both groups demonstrated increased lnRHI compared with baseline (P < 0.01). In participants with diabetes, lnRHI was significantly lower 24 h after aspirin administration compared with 1 h after administration (P < 0.05). This difference was not observed in controls (P = 0.84, difference between groups; P = 0.12). The effect on PWV did not differ between groups., Conclusion: Aspirin had a reduced immediate effect on endothelium-dependent vasodilation in participants with diabetes. Both groups had improved endothelial function after 1 week of treatment. Further, the effect of aspirin on endothelial function may be declining during a 24 h dosing interval in people with Type 2 diabetes. (Clinical Trial Registry No: 2016-000515-32)., (© 2019 Diabetes UK.)

Objectives: Coronary atherosclerosis in patients with type 2 diabetes mellitus may be promoted by regional fat distribution. We investigated the association between anthropometric measures of obesity, truncal fat mass, epicardial adipose tissue and coronary atherosclerosis in asymptomatic patients and matched controls., Methods: We examined 44 patients and 59 controls [mean (standard deviation) age 64.4 ± 9.9 vs 61.8 ± 9.7, male 50% vs 47%, diabetes duration mean (standard deviation) 7.7 ± 1.5] with coronary computed tomography angiography. Coronary plaques were quantified as total, calcified, non-calcified and low-density non-calcified plaque volumes (mm 3 ). Regional fat distribution was assessed by dual-energy X-ray absorptiometry, body mass index (kg/m 2 ), waist circumference (cm) and epicardial fat volume (mm 3 ). Endothelial function and systemic inflammation were evaluated by peripheral arterial tonometry (log transformed Reactive Hyperemia Index) and C-reactive protein (mg/L)., Results: Body mass index and waist circumference ( p  < 0.02) were associated with coronary plaque volumes. Body mass index was associated with low-density non-calcified plaque volume after adjustment for age, sex and diabetes status ( p  < 0.01). Truncal fat mass ( p  > 0.51), waist circumference ( p  > 0.06) and epicardial adipose tissue ( p  > 0.17) were not associated with coronary plaque volumes in adjusted analyses., Conclusion: Body mass index is associated with coronary plaque volumes in diabetic as well as non-diabetic individuals.

Background: Survival of medullary thyroid carcinoma (MTC) subgroups in relation to the general population is poorly described. Data on the factors predicting long-term biochemical cure in MTC patients are nonexistent at a population level. A nationwide retrospective cohort study of MTC in Denmark from 1997 to 2014 was conducted, aiming to detect subgroups with survival similar to that of the general population and to identify prognostic factors for disease-specific survival and long-term biochemical cure., Methods: The study included 220 patients identified from the nationwide Danish MTC cohort between 1997 and 2014. As a representative sample of the general population, a reference population matched 50:1 to the MTC cohort was used., Results: Patients diagnosed with hereditary MTC by screening (hazard ratio [HR] = 1.5 [confidence interval (CI) 0.5-4.3]), patients without regional metastases (HR = 1.4 [CI 0.9-2.3]), and patients with stage I (HR = 1.3 [CI 0.6-3.1]), stage II (HR = 1.1 [CI 0.6-2.3]), and III (HR = 1.3 [CI 0.4-4.2]) disease had an overall survival similar to the reference population. On multivariate analysis, the presence of distant metastases (HR = 12.3 [CI 6.0-25.0]) predicted worse disease-specific survival, while the absence of regional lymph node metastases (odds ratio = 40.1 [CI 12.0-133.7]) was the only independent prognostic factor for long-term biochemical cure., Conclusions: Patients with hereditary MTC diagnosed by screening, patients without regional metastases, and patients with stages I, II, and III disease may have similar survival as the general population. The presence of distant metastases predicted worse disease-specific survival, while the absence of regional metastases predicted long-term biochemical cure.