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Jose Italo Soares Mota, Rui Milton Patrício Silva-Júnior, Clarissa Silva Martins, Ana Carolina Bueno, Luiz Eduardo Wildemberg, Ximene Lima da Silva Antunes, Jorge Guilherme Okanobo Ozaki, Fernanda Borchers Coeli-Lacchini, Carlos Garcia-Peral, Antonio Edson Rocha Oliveira, Antônio Carlos Santos, Ayrton Custodio Moreira, Helio Rubens Machado, Marcelo Volpon dos Santos, Leandro M Colli, Monica R Gadelha, Sonir Roberto R Antonini, and Margaret de Castro

Objectives

To evaluate how telomere length behaves in adamantinomtous craniopharyngioma (aCP) and if it contributes to the pathogenesis of aCPs with and without CTNNB1 mutations.

Design

Retrospective cross-sectional study enrolling 42 aCP patients from 2 tertiary institutions.

Methods

Clinicopathological features were retrieved from the patient’s charts. Fresh frozen tumors were used for RNA and DNA analyses. Telomere length was evaluated by qPCR (T/S ratio). Somatic mutations in TERT promoter (TERTp) and CTNNB1 were detected by Sanger and/or whole-exome sequencing. We performed RNA-Seq to identify differentially expressed genes in aCPs presenting with shorter or longer telomere lengths.

Results

Mutations in CTNNB1 were detected in 29 (69%) tumors. There was higher frequency of CTNNB1 mutations in aCPs from patients diagnosed under the age of 15 years (85% vs 15%; P = 0.04) and a trend to recurrent disease (76% vs 24%; P = 0.1). No mutation was detected in the TERTp region. The telomeres were shorter in CTNNB1-mutated aCPs (0.441, IQR: 0.297–0.597vs 0.607, IQR: 0.445–0.778; P = 0.04), but it was neither associated with clinicopathological features nor with recurrence. RNAseq identified a total of 387 differentially expressed genes, generating two clusters, being one enriched for short telomeres and CTNNB1-mutated aCPs.

Conclusions: CTNNB1

mutations are more frequent in children and adolescents and appear to associate with progressive disease. CTNNB1-mutated aCPs have shorter telomeres, demonstrating a relationship between the Wnt/β-catenin pathway and telomere biology in the pathogenesis of aCPs.

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Junichi Ishigami, Yasuyuki Honda, Amy B Karger, Josef Coresh, Elizabeth Selvin, Pamela L Lutsey, and Kunihiro Matsushita

Objective

Fibroblast growth factor 23 (FGF23) concentration increases in response to declining kidney function to preserve normal phosphate concentrations. However, the etiological association of change in FGF23 concentration with mortality has not been examined in the general population.

Design and methods

We analyzed 5458 participants of the Atherosclerosis Risk in Communities Study who had intact FGF23 and estimated glomerular filtration rate (eGFR) assessed during midlife (visit 3, 1993–1995, mean age: 58 years) and late life (visit 5, 2011–2013, 76 years) to examine the association of FGF23 change over 18 years from mid-life to late life with the subsequent risk of mortality in late life using Cox regression models.

Results

The median 18-year change in intact FGF23 was +17.3 pg/mL. During a median follow-up of 7.2 years following visit 5, 1176 participants died. In multivariable Cox models, elevated mortality was seen in the highest quartile of FGF23 change (ΔFGF23: ≥31.3 pg/mL) (adjusted hazard ratio (aHR): 1.61 (95%CI: 1.36–1.90), or 1.37 (1.15–1.64) after additionally adjusting for eGFR change, compared with the lowest quartile (≤6.4 pg/mL)). When both FGF23 change and FGF23 in late life were simultaneously entered into the Cox model, FGF23 in late life, but not FGF23 change, was an independent predictor of mortality; however, we observed a high correlation between FGF23 change from midlife to late life and FGF23 in late life (r = 0.77).

Conclusions

Serum intact FGF23 change from midlife to late life was associated with subsequent risk of mortality independent of decline in kidney function. Our findings further support the implications of FGF23 beyond its association with kidney function.

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Cheng-Hsuan Tsai, Che-Wei Liao, Xue-Ming Wu, Zheng-Wei Chen, Chien-Ting Pan, Yi-Yao Chang, Bo-Ching Lee, Chia-Tung Shun, Wen-Fen Wen, Chia-Hung Chou, Vin-Cent Wu, Chi-Sheng Hung, Yen-Hung Lin, and the TAIPAI Study Group

Objective

The presence of autonomous cortisol secretion (ACS) in patients with primary aldosteronism (PA) is common and potentially associated with poor outcomes. The aim of this study was to investigate the association between ACS and vascular remodeling in PA patients.

Design and methods

We prospectively enrolled 436 PA patients from October 2006 to November 2019. ACS (defined as a cortisol level >1.8 μg/dL after a 1 mg dexamethasone suppression test) was detected in 23% of the PA patients. Propensity score matching (PSM) with age, sex, systolic and diastolic blood pressure was performed. The brachial-ankle pulse wave velocity (baPWV) was examined at baseline and 1 year after targeted treatment. Small arteries of periadrenal fat in 46 patients were stained with Picro Sirus red to quantify the severity of vascular fibrosis.

Results

After PSM, the PA patients with ACS had a significantly higher prevalence of diabetes mellitus, higher plasma aldosterone concentration and higher aldosterone-to-renin ratio. The baseline mean baPWV was also significantly higher in the PA patients with ACS. After multivariable regression analysis, the presence of ACS was a significant predictor of worse baseline mean baPWV (β: 235.745, 95% CI: 59.602–411.888, P = 0.010). In addition, the PA patients with ACS had worse vascular fibrosis (fibrosis area: 25.6 ± 8.4%) compared to those without ACS (fibrosis area: 19.8 ± 7.7%, P = 0.020). After 1 year of PA treatment, baPWV significantly improved in both groups.

Conclusion

The presence of ACS in PA patients is associated with worse arterial stiffness and vascular remodeling.

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Chao Ling, Xiafei Hong, Mengyue Xu, Yutong Wang, Xiaosen Ma, Yunying Cui, Rui Jiang, Dingyan Cao, Huanwen Wu, Anli Tong, Yupei Zhao, and Wenming Wu

Objectives

The pancreatic neuroendocrine tumors (PanNETs) are a group of clinically heterogeneous neoplasms. Although previous studies illustrated the somatic mutation pattern for PanNETs, the germline mutation pattern is still unclear. Here, we comprehensively screened the underlying germline mutations in a cohort of multiple endocrine neoplasia type 1 (MEN1)-related and sporadic PanNETs to reveal the characteristics of germline mutation in PanNET patients.

Methods

Patients diagnosed with PanNETs by biopsy or surgical pathology were enrolled in this study. Peripheral blood samples were used for genomic DNA purification and subsequent sequencing. The following sequencing techniques were used and compared for validation: (1) targeted gene capture with a customized panel; (2) whole exome sequencing data from previous study.

Results

A total of 184 PanNET patients were enrolled, including 20 MEN1-related and 164 sporadic cases. In this study, MEN1 mutation rate in MEN1-related PanNETs was 60% (12/20), of which 50% were novel mutation sites. For sporadic PanNETs, the overall germline mutation rate was very low. Besides the rare MEN1 mutation, previously unreported germline variant in DAXX was found in one non-functional PanNET.

Conclusions

This study revealed distinctive germline mutation rates between MEN1-related and sporadic PanNETs. The novel MEN1 mutations contribute to revealing the spectrum of MEN1 mutations in PanNETs. The newly discovered germline variant of DAXX in sporadic PanNET implies a tendency of convergence between germline and somatic mutation genes.

Open access

Rasmus Juul Kildemoes, Christian Hollensen, Beverly M K Biller, Gudmundur Johannsson, Yutaka Takahashi, and Michael Højby Rasmussen

Objective

Growth hormone (GH) replacement therapy in patients with adult growth hormone deficiency (AGHD) is individually titrated due to variable dose–responses among patients. The aim of this study was to provide clinical guidance on dosing and titration of the novel long-acting GH derivative somapacitan based on analyses of somapacitan dose–insulin-like growth factor I (IGF-I) responses in AGHD patients.

Design

Analyses of dosing information, 4364 somapacitan concentration samples and 4880 IGF-I samples from 330 AGHD patients treated with somapacitan in three phase 3 trials.

Methods

Pharmacokinetic/pharmacodynamic modelling was used to evaluate starting dose groups by age and oral oestrogen therapy, characterise the dose–IGF-I response in the overall AGHD population and patient subgroups, predict the IGF-I response to dose changes and simulate missed dosing.

Results

The analyses supported the clinical recommendations of higher starting doses for younger patients and women on oral oestrogen replacement therapy. For patients switching from daily GH treatment, the mean maintenance dose ratio between somapacitan (mg/week) and somatropin (mg/day) was predicted to be 8.2 (observed interquartile range of 6.7–9.1). Simulations of IGF-I SDS profiles confirmed the appropriate time for IGF-I sampling to be 3–4 days after somapacitan dosing and supported somapacitan administration with up to 3 days delay in case of missed dosing. Subgroup analyses characterised the dose–exposure–IGF-I response in patient subgroups and indicated that dose requirements are mainly influenced by sex and oral oestrogen treatment.

Conclusions

This study extends the knowledge of the somapacitan dose–IGF-I response and provides information on clinical dosing of once-weekly somapacitan in patients with AGHD.

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Marie Lindhardt Ljubicic, Alexander S Busch, Emmie N Upners, Margit Bistrup Fischer, Katharina M Main, Anna-Maria Andersson, Trine Holm Johannsen, Casper P Hagen, and Anders Juul

Objective

Little is known about the ratio between luteinizing hormone (LH) and follicle-stimulating hormone (FSH) during infancy. This study aimed to evaluate serum and urinary LH/FSH as a marker of sex with age-specific cutoffs in healthy infants.

Design

A prospective, longitudinal cohort study of healthy infants aged 0–1.2 years.

Methods

In total, 236 healthy infants (122 boys and 114 girls) from The COPENHAGEN Minipuberty Study (ClinicalTrials.gov ID: NCT02784184), with 567 serum and 603 urine samples, were included. Measures of diagnostic accuracy, including sensitivity and specificity, were used to assess the ability of LH/FSH to detect sex in healthy infants.

Results

In both serum and urine, LH/FSH was highest in males with minimal overlap between the sexes. In contrast to isolated LH and FSH concentrations, LH/FSH ratios in both serum and urine were excellent markers of sex from 0 to 1.2 years with median sensitivities and specificities ranging from 93 to 100% with correspondingly narrow 95% CIs.

Conclusions

Serum and urinary LH/FSH ratios are excellent discriminators of sex in healthy infants during the entire first year of life. The clinical role and application of the ratio remain to be elucidated.

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Chantal A Lebbink, Lisa H de Vries, Inne H M Borel Rinkes, Arthur J A T Braat, Rachel S van Leeuwaarde, Lutske Lodewijk, Mark J C van Treijen, Menno R Vriens, Gerlof D Valk, Hanneke M van Santen, and Bart de Keizer

Objective

To evaluate the usefulness of [18F]fluorodeoxyglucose (FDG) positron emissive tomography (PET)/CT in patients with low detectable thyroglobulin levels suspicious for persistent or recurrent differentiated thyroid cancer (DTC).

Methods

A retrospective case series study evaluating FDG PET/CT in patients with detectable thyroglobulin (Tg) levels (≥0.20 and <10.00 ng/mL) after initial treatment with total thyroidectomy and I-131 thyroid remnant ablation for pT1-3aN0-1bM0 DTC. Sensitivity, specificity, positive (PPV) and negative predictive value (NPV) of FDG PET/CT were calculated.

Results

Twenty-seven patients underwent FDG PET/CT. Median Tg level at FDG PET/CT was 2.00 ng/mL (range 0.30–9.00). FDG PET/CT was positive in 14 patients (51.9%): lesions suspicious for lymph node metastases were depicted in 12 patients, and lung metastases in 2. DTC was confirmed in 13/14 FDG PET/CT-positive patients. In 9/13 patients with a negative FDG PET/CT, DTC was confirmed ≤3 months after FDG PET/CT. The sensitivity, PPV, specificity and NPV were 59.1, 92.9, 80.0 and 30.8%, respectively.

Conclusions

This case series shows that FDG PET/CT might be useful to detect persistent or recurrent DTC in patients with low detectable Tg. However, when FDG PET/CT is negative, this does not rule out DTC and further investigations are necessary.

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Cihan Atila, Odile Gaisl, Deborah R Vogt, Laura Werlen, Gabor Szinnai, and Mirjam Christ-Crain

Background

The differential diagnosis of diabetes insipidus is challenging. The most reliable approaches are copeptin measurements after hypertonic saline infusion or arginine, which is a known growth hormone secretagogue but has recently also been shown to stimulate the neurohypophysis. Similar to arginine, glucagon stimulates growth hormone release, but its effect on the neurohypophysis is poorly studied.

Design

Double-blind, randomized, placebo-controlled trial including 22 healthy participants, 10 patients with central diabetes insipidus, and 10 patients with primary polydipsia at the University Hospital Basel, Switzerland.

Methods

Each participant underwent the glucagon test (s.c. injection of 1 mg glucagon) and placebo test. The primary objective was to determine whether glucagon stimulates copeptin and to explore whether the copeptin response differentiates between diabetes insipidus and primary polydipsia. Copeptin levels were measured at baseline, 30, 60, 90, 120, 150, and 180 min after injection.

Results

In healthy participants, glucagon stimulated copeptin with a median increase of 7.56 (2.38; 28.03) pmol/L, while placebo had no effect (0.10 pmol/L (−0.70; 0.68); P < 0.001). In patients with diabetes insipidus, copeptin showed no relevant increase upon glucagon, with an increase of 0.55 (0.21; 1.65) pmol/L, whereas copeptin was stimulated in patients with primary polydipsia with an increase of 15.70 (5.99; 24.39) pmol/L. Using a copeptin cut-off level of 4.6pmol/L had a sensitivity of 100% (95% CI: 100–100) and a specificity of 90% (95% CI: 70–100) to discriminate between diabetes insipidus and primary polydipsia.

Conclusion

Glucagon stimulates the neurohypophysis, and glucagon-stimulated copeptin has the potential for a safe, novel, and precise test in the differential diagnosis of diabetes insipidus.

Open access

Bu B Yeap, Ross J Marriott, Laurens Manning, Girish Dwivedi, Graeme J Hankey, Frederick C W Wu, Jeremy K Nicholson, and Kevin Murray

Objective

Men are at greater risk from COVID-19 than women. Older, overweight men, and those with type 2 diabetes, have lower testosterone concentrations and poorer COVID-19-related outcomes. We analysed the associations of premorbid serum testosterone concentrations, not confounded by the effects of acute SARS-CoV-2 infection, with COVID-19-related mortality risk in men.

Design

This study is a United Kingdom Biobank prospective cohort study of community-dwelling men aged 40–69 years.

Methods

Serum total testosterone and sex hormone-binding globulin (SHBG) were measured at baseline (2006–2010). Free testosterone values were calculated (cFT). the incidence of SARS-CoV-2 infections and deaths related to COVID-19 were ascertained from 16 March 2020 to 31 January 2021 and modelled using time-stratified Cox regression.

Results

In 159 964 men, there were 5558 SARS-CoV-2 infections and 438 COVID-19 deaths. Younger age, higher BMI, non-White ethnicity, lower educational attainment, and socioeconomic deprivation were associated with incidence of SARS-CoV-2 infections but total testosterone, SHBG, and cFT were not. Adjusting for potential confounders, higher total testosterone was associated with COVID-19-related mortality risk (overall trend P = 0.008; hazard ratios (95% CIs) quintile 1, Q1 vs Q5 (reference), 0.84 (0.65–1.12) Q2:Q5, 0.82 (0.63–1.10); Q3:Q5, 0.80 (0.66–1.00); Q4:Q5, 0.82 (0.75–0.93)). Higher SHBG was also associated with COVID-19 mortality risk (P = 0.008), but cFT was not (P = 0.248).

Conclusions

Middle-aged to older men with the highest premorbid serum total testosterone and SHBG concentrations are at greater risk of COVID-19-related mortality. Men could be advised that having relatively high serum testosterone concentrations does not protect against future COVID-19-related mortality. Further investigation of causality and potential underlying mechanisms is warranted.