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Open access

Agnieszka Adamska, Vitalii Ulychnyi, Katarzyna Siewko, Anna Popławska-Kita, Małgorzata Szelachowska, Marcin Adamski, Angelika Buczyńska, and Adam Jacek Krętowski

Cardiovascular risk factors could be present in mild adrenal autonomous cortisol secretion (MACS). However, the most frequent cardiovascular risk factors in MACS have not been established. The aim of the presseent study was to analyse the difference in cardiovascular risk factors in patients with MACS in comparison to those with non-functioning adrenal tumour (NFAT). A total of 295 patients with adrenal incidentaloma were included in this retrospective study. We divided our group into those who showed suppression in 1 mg overnight dexamethasone suppression test (DST) (NFAT) (serum cortisol level ≤1.8 μg/dL) and those who did not show suppression in the DST (MACS) (serum concentration of cortisol > 1.8 μg/dL and ≤5 μg/dL). In the studied groups, we analysed the presence of cardiovascular risk factors, such as obesity, prediabetes, type 2 diabetes mellitus (T2DM), hypertension, hyperlipidaemia, chronic kidney disease and cardiovascular events. In our study, 18.9% of patients were defined as MACS. Importantly, T2DM was diagnosed in 41% of MACS vs 23% of NFAT (P < 0.01) and higher frequency of occurrence of hyperlipidaemia in NFAT (72.4%) vs MACS (53.6%) (P = 0.01) was observed. We did not observed differences in the frequency of obesity, hypertension, chronic kidney disease, prediabetes, atrial fibrillation, stroke, ST and non-ST elevation myocardial infarction and coronary angioplasty between patients with MACS and NFAT (all P > 0.05; respectively). In MACS, T2DM is more prevalent than in NFAT; hyperlipidaemia is more prevalent in NFAT. Accordingly, no differences were found in the incidence of obesity, hypertension, prediabetes, chronic kidney disease between studied groups as well as cardiovascular events.

Open access

J Gebauer, R Skinner, R Haupt, L Kremer, H van der Pal, G Michel, G T Armstrong, M M Hudson, L Hjorth, H Lehnert, and T Langer

Many long-term childhood cancer survivors suffer from treatment-related late effects, which may occur in any organ and include a wide spectrum of conditions. Long-term follow-up (LTFU) is recommended to facilitate early diagnosis and to ensure better health outcomes. Due to the heterogeneity of these sequelae, different specialists work together in the diagnosis and treatment of these conditions. Experts from both pediatric and internal medicine are involved in age-appropriate care by providing a transition process. Hence, LTFU of childhood cancer survivors is a prototypic example of multidisciplinary care for patients with complex needs treated in a specialized setting. International collaborations of healthcare professionals and scientists involved in LTFU of childhood cancer survivors, such as the International Guideline Harmonization Group, compile surveillance recommendations that can be clinically adopted all over the world. These global networks of clinicians and researchers make a joint effort to address gaps in knowledge, increase visibility and awareness of cancer survivorship and provide an excellent example of how progress in clinical care and scientific research may be achieved by international and multidisciplinary collaboration.

Open access

Olli Helminen, Tytti Pokka, Susanna Aspholm, Jorma Ilonen, Olli G Simell, Mikael Knip, and Riitta Veijola

Objective

Subtypes in type 1 diabetes pathogenesis have been implicated based on the first-appearing autoantibody (primary autoantibody). We set out to describe the glucose metabolism in preclinical diabetes in relation to the primary autoantibody in children with HLA-conferred disease susceptibility.

Design and methods

Dysglycemic markers are defined as a 10% increase in HbA1c in a 3–12 months interval or HbA1c ≥5.9% (41 mmol/mol) in two consecutive samples, impaired fasting glucose or impaired glucose tolerance, or a random plasma glucose value ≥7.8 mmol/L. A primary autoantibody could be detected in 295 children who later developed at least 1 additional biochemical autoantibody. These children were divided into three groups: insulin autoantibody (IAA) multiple (n  = 143), GAD antibody (GADA) multiple (n  = 126) and islet antigen 2 antibody (IA-2A) multiple (n  = 26). Another 229 children seroconverted to positivity only for a single biochemical autoantibody and were grouped as IAA only (n  = 87), GADA only (n  = 114) and IA-2A only (n  = 28).

Results

No consistent differences were observed in selected autoantibody groups during the preclinical period. At diagnosis, children with IAA only showed the highest HbA1c (P < 0.001 between groups) and the highest random plasma glucose (P = 0.005 between groups). Children with IA-2A only progressed to type 1 diabetes as frequently as those with IA-2A multiple (46% vs 54%, P = 0.297) whereas those with IAA only or GADA only progressed less often than children with IAA multiple or GADA multiple (22% vs 62% (P < 0.001) and 7% vs 43% (P < 0.001)), respectively.

Conclusions

The phenotype of preclinical diabetes defined by the primary autoantibody is not associated with any discernible differences in glucose metabolism before the clinical disease manifestation.

Open access

Martin Bidlingmaier, Helena Gleeson, Ana Claudia Latronico, and Martin O Savage

Precision medicine incorporates knowledge of a patient’s genetic makeup, environment and lifestyle for accurate diagnosis, and to develop individualised treatment and prevention strategies. Precision medicine has improved management in a number of disease areas, most notably in oncology, and it has the potential to positively impact others, including endocrine disorders. The accuracy of diagnosis in patients with growth disorders can be improved by using biomarkers. Insulin-like growth factor I (IGF-I) is the most widely accepted biomarker of growth hormone secretion, but its predictive value for recombinant human growth hormone treatment response is modest and various factors can affect the accuracy of IGF-I measurements. These factors need to be taken into account when considering IGF-I as a component of precision medicine in the management of growth hormone deficiency. The use of genetic analyses can assist with diagnosis by confirming the aetiology, and facilitate treatment decisions, guide counselling and allow prompt intervention in children with pubertal disorders, such as central precocious puberty and testotoxicosis. Precision medicine has also proven useful during the transition of young people with endocrine disorders from paediatric to adult services, when patients are at heightened risk of dropping out from medical care. An understanding of the likelihood of ongoing GH deficiency, using tools such as magnetic resonance imaging, detailed patient history and IGF-I levels, can assist in determining the need for continued recombinant human growth hormone treatment during the process of transitional care.

Open access

Shu-Meng Hu, Yang-Juan Bai, Ya-Mei Li, Ye Tao, Xian-Ding Wang, Tao Lin, Lan-Lan Wang, and Yun-Ying Shi

Introduction

Tertiary hyperparathyroidism (THPT) and vitamin D deficiency are commonly seen in kidney transplant recipients, which may result in persistently elevated fibroblast growth factor 23 (FGF23) level after transplantation and decreased graft survival. The aim of this study is to evaluate the effect of vitamin D supplementation on THPT, FGF23-alpha Klotho (KLA) axis and cardiovascular complications after transplantation.

Materials and methods

Two hundred nine kidney transplant recipients were included and further divided into treated and untreated groups depending on whether they received vitamin D supplementation. We tracked the state of THPT, bone metabolism and FGF23–KLA axis within 12 months posttransplant and explored the predictors and risk factors for intact FGF23 levels, KLA levels, THPT and cardiovascular complications in recipients.

Results

Vitamin D supplementation significantly improved FGF23 resistance, THPT and high bone turnover status, preserved better graft function and prevented coronary calcification in the treated group compared to the untreated group at month 12. The absence of vitamin D supplementation was an independent risk factor for THPT and a predictor for intact FGF23 and KLA levels at month 12. Age and vitamin D deficiency were independent risk factors for coronary calcification in recipients at month 12.

Conclusion

Vitamin D supplementation effectively improved THPT, FGF23 resistance and bone metabolism, preserved graft function and prevented coronary calcification after transplantation.

Open access

Fidéline Bonnet-Serrano, Maxime Barat, Anna Vaczlavik, Anne Jouinot, Lucas Bouys, Christelle Laguillier-Morizot, Corinne Zientek, Catherine Simonneau, Etienne Larger, Laurence Guignat, Lionel Groussin, Guillaume Assié, Jean Guibourdenche, Ioannis Nicolis, Marie-Claude Menet, and Jérôme Bertherat

Objective

Large response of steroid precursors, including 17-hydroxyprogesterone, to adrenocorticotropic hormone (ACTH) has been described in adrenocortical tumors, suggesting the existence of intra-tumoral enzymatic deficiencies. This study aimed to compare steroidogenesis enzymes activity in unilateral and bilateral benign tumors using serum steroid profiling in liquid chromatography coupled with tandem mass spectrometry (LC-MS/MS) in the basal state and after ACTH 1-24 stimulation.

Design and methods

A serum profile of seven consecutive adrenal steroids was determined in LC-MS/MS in the basal state (T0) and after ACTH 1-24 stimulation (T60) in 35 patients with bilateral adrenocortical tumors (BL), 38 patients with unilateral tumors (UL) and 37 control subjects (CT). Response amplitude of each individual steroid was evaluated by T60/T0 ratio, whereas enzymatic activity was assessed by the downstream/upstream steroid ratio. Adrenal volume was quantified by a semi-automatic segmentation method.

Results

For the seven steroids assayed, the amplitude of response to ACTH was higher in BL than in UL and in CT. The difference between BL and UL persisted even after matching patients on adrenal volume. On glucocorticoids pathway, enzymatic activity of CYP11B1 was significantly decreased in BL (78.3 (43.1-199.4)) in comparison to both UL (122.7 (13.8-228.4), P = 0.0002) and CT (186.8 (42.1-1236.3), P < 0.0001). On mineralocorticoids and androgens pathways, the enzymatic activity of CYP11B2 and CYP17A1-17,20 lyase was also lower in BL than UL and CT.

Conclusions

Decreased activity of distal steroidogenesis enzymes CYP11B1, CYP11B2 and CYP17A1-17,20 lyase, responsible for an explosive response to ACTH of upstream precursors in bilateral tumors, limits the synthesis of bioactive steroids, in particular cortisol, despite the increase in adrenal mass.

Significance statement

Activity of distal steroidogenesis enzymes (CYP11B1, CYP11B2 and CYP17A1 on glucocorticoids, mineralocorticoids and androgens pathways, respectively) is decreased in adrenocortical benign tumors. This decrease is more pronounced in bilateral lesions and seems to depend more on the nature of the lesion than on the increase in adrenal volume. It is responsible for the explosive response to ACTH of steroid precursors located upstream of these enzymes. It probably allows bioactive steroids, particularly cortisol, to stay in the normal range for a long time despite the increase in adrenal mass.

Open access

Huifei Sophia Zheng, Jeffrey G Daniel, Julia M Salamat, Laci Mackay, Chad D Foradori, Robert J Kemppainen, Satyanarayana R Pondugula, Ya-Xiong Tao, and Chen-Che Jeff Huang

Glucocorticoids have short- and long-term effects on adrenal gland function and development. RNA sequencing (RNA-seq) was performed to identify early transcriptomic responses to the synthetic glucocorticoid, dexamethasone (Dex), in vitro and in vivo. In total, 1711 genes were differentially expressed in the adrenal glands of the 1-h Dex-treated mice. Among them, only 113 were also considered differentially expressed genes (DEGs) in murine adrenocortical Y-1 cells treated with Dex for 1 h. Gene ontology analysis showed that the upregulated DEGs in the adrenal gland of the 1-h Dex-treated mice were highly associated with the development of neuronal cells, suggesting the adrenal medulla had a rapid response to Dex. Interestingly, only 4.3% of Dex-responsive genes in the Y-1 cell line under Dex treatment for 1 h were differentially expressed under Dex treatment for 24 h. The heatmaps revealed that most early responsive DEGs in Y-1 cells during 1 h of treatment exhibited a transient response. The expression of these genes under treatment for 24 h returned to basal levels similar to that during control treatment. In summary, this research compared the rapid transcriptomic effects of Dex stimulation in vivo and in vitro. Notably, adrenocortical Y-1 cells had a transient early response to Dex treatment. Furthermore, the DEGs had a minimal overlap in the 1-h Dex-treated group in vivo and in vitro.

Open access

Elizabeth J de Koster, Olga Husson, Eveline W C M van Dam, G Sophie Mijnhout, Romana T Netea-Maier, Wim J G Oyen, Marieke Snel, Lioe-Fee de Geus-Oei, Dennis Vriens, and

Objective

This study assessed the health-related quality of life (HRQoL) in patients undergoing 2-[18F]fluoro-2-deoxy-D-glucose (FDG)-PET/CT for an indeterminate (Bethesda III/IV) thyroid nodule. FDG-PET/CT accurately rules out malignancy and prevents 40% of futile diagnostic surgeries in these nodules.

Design

Secondary analyses of HRQoL data from a randomised controlled multicentre trial (NCT02208544) in 126 patients from 15 hospitals in the Netherlands were done.

Methods

Longitudinal HRQoL assessment was performed using the EuroQol 5-dimension 5-level (EQ-5D-5L), the RAND 36-item Health Survey v2.0 (RAND-36), and the Thyroid Patient-Reported Outcome (ThyPRO) questionnaire on baseline, 3, 6, and 12 months, relative to the date of the FDG-PET/CT scan.

Results

Patients who were randomised to active surveillance following an FDG-negative nodule instead of diagnostic surgery reported stable HRQoL scores throughout the year. Univariate analysis indicated better HRQoL for patients undergoing surveillance than surgical patients with benign histopathology on multiple physical and psychosocial domains. Univariate within-group analysis suggested both temporary and continued HRQoL deteriorations in patients with benign histopathology over time. Multivariate within-group analysis demonstrated no significant longitudinal HRQoL changes in patients undergoing active surveillance. In contrast, in patients with benign histopathology, worse HRQoL was observed with regard to ThyPRO cognitive impairment (P = 0.01) and cosmetic complaints (P = 0.02), whereas goitre symptoms (P < 0.001) and anxiety (P = 0.04) improved over time. In patients with malignant histopathology, anxiety also decreased (P = 0.05).

Conclusions

The reassurance of a negative FDG-PET/CT resulted in sustained HRQoL throughout the first year of active surveillance. Diagnostic surgery for a nodule with benign histopathology resulted in more cognitive impairment and physical problems including cosmetic complaints, but improved goitre symptoms and anxiety. Anxiety was also reduced in patients with malignant histopathology.

Open access

Mark J C van Treijen, Tiny Korse, Wieke Verbeek, Margot Tesselaar, and Gerlof D. Valk

Objective: Up to now, serial NETest measurements in individuals assessing disease course of gastro-entero-pancreatic neuro-endocrine tumors (GEPNETs) at long term follow-up and treatment response were not studied.

Design: Longitudinal validation study of serial NETest measurements – a blood based gene expression signature – in 132 patients with GEPNETs on therapy or watch-and-wait strategy.

Methods :Serial samples were collected during 46 (range 6-71) months of follow-up. NETest scores were compared with RECIST1.1 defined treatment response [e.g. no evidence of disease (NED), stable disease (SD) or progressive disease (PD)].

Results: Consecutive NETest scores fluctuated substantially [range 0-100] over time in individuals with SD (n=28) and NED (n=30). Follow-up samples were significantly higher in SD (samples 3-5) and NED subgroup (samples 2-5) compared with baseline results, without changes on imaging. In 82% of untreated patients with PD, consecutive NETest scores consistently remained high. In patients undergoing systemic treatment, the median pre-treatment NETest score in treatment-responders was 76.5 (n=22) versus 33 (n=12) in non-responders (p=0.001). Patients with low pre-treatment scores had 21 months reduced progression-free survival (10 vs 31 months; p=0.01). The accuracy of the NETest for treatment response prediction was 0.73 (p=0.009).

Conclusion: In patients not undergoing treatment consecutive low NETest scores are associated with indolent behavior. Patients who develop PD exhibit elevated scores. Elevated results have important predictive value for treatment responsiveness and could be used for individualizing decisions on systemic therapy. The clinical value of follow-up NETest scores for patients who choose to watch-and-wait requires further study.