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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.

Open access

Treena Cranston, Hannah Boon, Mie K Olesen, Fiona J Ryan, Deborah Shears, Rosemary London, Hussam Rostom, Taha Elajnaf, Rajesh V Thakker, and Fadil M Hannan

Objective

The autoimmune polyendocrine syndrome type 1 (APS-1) is an autosomal recessive disorder characterised by immune dysregulation and autoimmune endocrine gland destruction. APS-1 is caused by biallelic mutations affecting the autoimmune regulator (AIRE) gene on chromosome 21q22.3, which facilitates immunological self-tolerance. The objective was to investigate >300 probands with suspected APS-1 or isolated hypoparathyroidism for AIRE abnormalities.

Methods

Probands were assessed by DNA sequence analysis. Novel variants were characterised using 3D modelling of the AIRE protein. Restriction enzyme and microsatellite analysis were used to investigate for uniparental isodisomy.

Results

Biallelic AIRE mutations were identified in 35 probands with APS-1 and 5 probands with isolated hypoparathyroidism. These included a novel homozygous p.(His14Pro) mutation, predicted to disrupt the N-terminal caspase activation recruitment domain of the AIRE protein. Furthermore, an apparently homozygous AIRE mutation, p.Leu323fs, was identified in an APS-1 proband, who is the child of non-consanguineous asymptomatic parents. Microsatellite analysis revealed that the proband inherited two copies of the paternal mutant AIRE allele due to uniparental isodisomy. Hypoparathyroidism was the most common endocrine manifestation in AIRE mutation-positive probands and >45% of those harbouring AIRE mutations had at least two diseases out of the triad of candidiasis, hypoparathyroidism, and hypoadrenalism. In contrast, type 1 diabetes and hypothyroidism occurred more frequently in AIRE mutation-negative probands with suspected APS-1. Around 30% of AIRE mutation-negative probands with isolated hypoparathyroidism harboured mutations in other hypoparathyroid genes.

Conclusions

This study of a large cohort referred for AIRE mutational analysis expands the spectrum of genetic abnormalities causing APS-1.

Open access

Steven G Waguespack, Alexander Drilon, Jessica J Lin, Marcia S Brose, Ray McDermott, Mohammed Almubarak, Jessica Bauman, Michela Casanova, Anuradha Krishnamurthy, Shivaani Kummar, Serge Leyvraz, Do-Youn Oh, Keunchil Park, Davendra Sohal, Eric Sherman, Ricarda Norenberg, Josh D Silvertown, Nicoletta Brega, David S Hong, and Maria E Cabanillas

Objective

Larotrectinib is a highly selective tropomyosin receptor kinase (TRK) inhibitor with demonstrated efficacy across various TRK fusion-positive solid tumours. We assessed the efficacy and safety of larotrectinib in patients with TRK fusion-positive thyroid carcinoma (TC).

Methods

We pooled data from three phase I/II larotrectinib clinical trials (NCT02576431, NCT02122913, and NCT02637687). The primary endpoint was the investigator-assessed objective response rate (ORR) per Response Evaluation Criteria in Solid Tumors v1.1. Secondary endpoints included duration of response (DoR), progression-free survival (PFS), overall survival (OS), and safety. Data cut-off: July 2020.

Results

Twenty-nine patients (median age: 60; range: 6–80) with TRK fusion-positive TC were treated. Tumour histology was papillary (PTC) in 20 (69%) patients, follicular (FTC) in 2 (7%), and anaplastic (ATC) in 7 (24%) patients. Among 28 evaluable patients, ORR was 71% (95% CI: 51–87); best responses were complete response in 2 (7%) patients, partial response in 18 (64%), stable disease in 4 (14%), progressive disease in 3 (11%), and undetermined in 1 (4%) due to clinical progression prior to the first post-baseline assessment. ORR was 86% (95% CI: 64–97) for PTC/FTC and 29% (95% CI 4–71) for ATC. Median time to response was 1.87 months (range 1.64–3.68). The 24-month DoR, PFS, and OS rates were 81, 69, and 76%, respectively. Treatment-related adverse events were mainly grades 1–2.

Conclusion

In TRK fusion-positive TC, larotrectinib demonstrates rapid and durable disease control and a favourable safety profile in patients with advanced disease requiring systemic therapy.

Significance statement

NTRK gene fusions are known oncogenic drivers and have been identified in various histologies of thyroid carcinoma, most commonly in papillary thyroid carcinoma. This is the first publication specifically studying a TRK inhibitor in a cohort of TRK fusion-positive thyroid carcinoma patients. In the current study, the highly selective TRK inhibitor larotrectinib showed durable antitumour efficacy and a favourable safety profile in patients with TRK fusion-positive thyroid carcinoma. Our findings show that patients with advanced non-medullary thyroid carcinoma who may require systemic therapy could be considered for testing for gene fusions by next-generation sequencing.

Open access

Niamh-Maire McLennan, Jonathan Hazlehurst, Shakila Thangaratinam, and Rebecca M Reynolds

There is an increase in maternal metabolic burden due to the rise in pregnancies complicated by obesity, gestational diabetes, type 2 diabetes and polycystic ovary syndrome. Metabolic dysfunction during pregnancy is associated with increased risks of long-term morbidity and mortality for women and their offspring. Lifestyle interventions in pregnancy in women at risk of metabolic dysfunction have demonstrated short-term improvements such as reduced gestational weight gain and lowered risk of gestational diabetes. It is not known whether these interventions lead to sustained improvements in the metabolic health of the mother and baby. Pharmacological interventions have also shown benefits for the mother and baby in pregnancy, including improvements in glycaemic control, reduction in gestational weight gain and reduction in large for gestational age infants; however, there remains uncertainty over long-term outcomes for mother and child. Existing studies on interventions targeting metabolic health are limited to selected populations in the preconception and postpartum periods and lack follow-up beyond delivery of the intervention. The COVID-19 pandemic has refocused our attention on the effects of maternal metabolic ill-health that play a role in contributing to premature morbidity and mortality. There is an urgent need for strategies to accurately identify the growing number of women and offspring at risk of long-term adverse metabolic health. Strategies which focus on early identification and risk stratification using individualised risk scores in the pre and inter-conception periods must take priority if we are to target and improve the metabolic health of women and their offspring who are at highest risk.

Open access

A Nordenström, S F Ahmed, E van den Akker, J Blair, M Bonomi, C Brachet, L H A Broersen, H L Claahsen-van der Grinten, A B Dessens, A Gawlik, C H Gravholt, A Juul, C Krausz, T Raivio, A Smyth, P Touraine, D Vitali, and O M Dekkers

An Endo-European Reference Network guideline initiative was launched including 16 clinicians experienced in endocrinology, pediatric and adult and 2 patient representatives. The guideline was endorsed by the European Society for Pediatric Endocrinology, the European Society for Endocrinology and the European Academy of Andrology. The aim was to create practice guidelines for clinical assessment and puberty induction in individuals with congenital pituitary or gonadal hormone deficiency. A systematic literature search was conducted, and the evidence was graded according to the Grading of Recommendations, Assessment, Development and Evaluation system. If the evidence was insufficient or lacking, then the conclusions were based on expert opinion. The guideline includes recommendations for puberty induction with oestrogen or testosterone. Publications on the induction of puberty with follicle-stimulation hormone and human chorionic gonadotrophin in hypogonadotropic hypogonadism are reviewed. Specific issues in individuals with Klinefelter syndrome or androgen insensitivity syndrome are considered. The expert panel recommends that pubertal induction or sex hormone replacement to sustain puberty should be cared for by a multidisciplinary team. Children with a known condition should be followed from the age of 8 years for girls and 9 years for boys. Puberty induction should be individualised but considered at 11 years in girls and 12 years in boys. Psychological aspects of puberty and fertility issues are especially important to address in individuals with sex development disorders or congenital pituitary deficiencies. The transition of these young adults highlights the importance of a multidisciplinary approach, to discuss both medical issues and social and psychological issues that arise in the context of these chronic conditions.

Open access

Kim Huynh, Marianne Klose, Kim Krogsgaard, Jørgen Drejer, Sarah Byberg, Sten Madsbad, Faidon Magkos, Abdellatif Aharaz, Berit Edsberg, Jacob Tfelt-Hansen, Arne Vernon Astrup, and Ulla Feldt-Rasmussen

Context

Hypothalamic injury often leads to rapid, intractable weight gain causing hypothalamic obesity, which is associated with increased risk of cardiovascular and metabolic morbidity and mortality. There are no approved or effective pharmacological treatments for hypothalamic obesity, and conventional lifestyle management remains ineffective.

Objective

To investigate the safety and efficacy of Tesomet (0.5 mg tesofensine/50 mg metoprolol) in adults with hypothalamic obesity.

Methods

Twenty-one adults with hypothalamic obesity (16 females) were randomized to Tesomet (0.5 mg/50 mg) or placebo for 24 weeks. Patients also received diet/lifestyle counselling. The primary endpoint was safety; secondary endpoints included measures of body weight, appetite scores, quality of life, and metabolic profile.

Results

Eighteen patients completed 24 weeks. Consent withdrawal, eligibility, and serious adverse events (SAE) unrelated to treatment resulted in dropouts. One patient experienced a Tesomet-related SAE of exacerbated pre-existing anxiety leading to treatment discontinuation. Tesomet-related adverse events were otherwise mostly mild and included sleep disturbances (Tesomet 50%, placebo 13%), dry mouth (Tesomet 43%, placebo 0%), and headache (Tesomet 36%, placebo 0%). No significant differences in heart rate or blood pressure were observed between groups. Compared to placebo, Tesomet resulted in additional mean (95% CI) weight change of −6.3% ((−11.3; −1.3); P  = 0.017), increased the number of patients achieving ≥5% weight loss (Tesomet 8/13, placebo 1/8; P  = 0.046), and tended to augment the reduction in waist circumference by 5.7 cm ((−0.1; 11.5); P  = 0.054).

Conclusion

Tesomet was welltolerated, did not affect heart rate or blood pressure, and resulted in significant reductions in body weight compared to placebo in adults with hypothalamic obesity.

Open access

Margaret C S Boguszewski, Cesar L Boguszewski, Wassim Chemaililly, Laurie E Cohen, Judith Gebauer, Claire Higham, Andrew R Hoffman, Michel Polak, Kevin C J Yuen, Nathalie Alos, Zoltan Antal, Martin Bidlingmaier, Beverley M K Biller, George Brabant, Catherine S Y Choong, Stefano Cianfarani, Peter E Clayton, Regis Coutant, Adriane A Cardoso-Demartini, Alberto Fernandez, Adda Grimberg, Kolbeinn Guðmundsson, Jaime Guevara-Aguirre, Ken K Y Ho, Reiko Horikawa, Andrea M Isidori, Jens Otto Lunde Jørgensen, Peter Kamenicky, Niki Karavitaki, John J Kopchick, Maya Lodish, Xiaoping Luo, Ann I McCormack, Lillian Meacham, Shlomo Melmed, Sogol Mostoufi Moab, Hermann L Müller, Sebastian J C M M Neggers, Manoel H Aguiar Oliveira, Keiichi Ozono, Patricia A Pennisi, Vera Popovic, Sally Radovick, Lars Savendahl, Philippe Touraine, Hanneke M van Santen, and Gudmundur Johannsson

Growth hormone (GH) has been used for over 35 years, and its safety and efficacy has been studied extensively. Experimental studies showing the permissive role of GH/insulin-like growth factor 1 (IGF-I) in carcinogenesis have raised concerns regarding the safety of GH replacement in children and adults who have received treatment for cancer and those with intracranial and pituitary tumours. A consensus statement was produced to guide decision-making on GH replacement in children and adult survivors of cancer, in those treated for intracranial and pituitary tumours and in patients with increased cancer risk. With the support of the European Society of Endocrinology, the Growth Hormone Research Society convened a Workshop, where 55 international key opinion leaders representing 10 professional societies were invited to participate. This consensus statement utilized: (1) a critical review paper produced before the Workshop, (2) five plenary talks, (3) evidence-based comments from four breakout groups, and (4) discussions during report-back sessions. Current evidence reviewed from the proceedings from the Workshop does not support an association between GH replacement and primary tumour or cancer recurrence. The effect of GH replacement on secondary neoplasia risk is minor compared to host- and tumour treatment-related factors. There is no evidence for an association between GH replacement and increased mortality from cancer amongst GH-deficient childhood cancer survivors. Patients with pituitary tumour or craniopharyngioma remnants receiving GH replacement do not need to be treated or monitored differently than those not receiving GH. GH replacement might be considered in GH-deficient adult cancer survivors in remission after careful individual risk/benefit analysis. In children with cancer predisposition syndromes, GH treatment is generally contraindicated but may be considered cautiously in select patients.

Open access

Jakob Skov, Ralf Kuja-Halkola, Patrik K E Magnusson, Soffia Gudbjörnsdottir, Olle Kämpe, and Sophie Bensing

Objective

Type 1 diabetes and Hashimoto’s thyroiditis frequently cluster in individuals and in families, indicating shared origins. The objective of this study was to investigate familial co-aggregation of these diseases and to quantify shared genetic and environmental factors.

Design

This study is a twin cohort study.

Methods

National health registers were used to identify cases among 110 814 Swedish twins. Co-aggregation was calculated as risk ratios for type 1 diabetes among co-twins of individuals with Hashimoto’s thyroiditis, and vice-versa. Variance explained by genetics (i.e. heritability), and the proportions thereof shared between the diseases, was estimated by contrasting associations in monozygotic and dizygotic twins using structural equation models.

Results

Individuals with one disease were at a high risk for the other disease (adjusted risk ratio: 11.4 (95% CI: 8.5–15.3)). Co-aggregation was more common in monozygotic than in dizygotic pairs, with adjusted risk ratios of 7.0 (95% CI: 3.2–15.1) and 1.7 (95% CI: 0.7–4.1), respectively. Genetic effects shared across diseases accounted for 11% of the variance for type 1 diabetes and 9% of the variance for Hashimoto’s thyroiditis, while environmental factors unique to individual twins, but shared across diseases, accounted for 10% of the variance for type 1 diabetes and 18% of the variance for Hashimoto’s thyroiditis.

Conclusions

Both genes and environment unique to individual twins contribute to considerable etiologic overlap between type 1 diabetes and Hashimoto’s thyroiditis. These findings add to the current knowledge on the mechanisms behind autoimmune disease clustering and could guide future research aimed at identifying pathophysiological mechanisms and intervention targets.

Open access

Anne Jouinot, Juliane Lippert, Mathilde Sibony, Florian Violon, Lindsay Jeanpierre, Daniel De Murat, Roberta Armignacco, Amandine Septier, Karine Perlemoine, Franck Letourneur, Brigitte Izac, Bruno Ragazzon, Karen Leroy, Eric Pasmant, Marie-Odile North, Sébastien Gaujoux, Bertrand Dousset, Lionel Groussin, Rossella Libe, Benoit Terris, Martin Fassnacht, Cristina L Ronchi, Jérôme Bertherat, and Guillaume Assie

Design

Molecular classification is important for the diagnosis and prognosis of adrenocortical tumors (ACT). Transcriptome profiles separate adrenocortical adenomas ‘C2’ from carcinomas, and identify two groups of carcinomas ‘C1A’ and ‘C1B’, of poor and better prognosis respectively. However, many ACT cannot be profiled because of improper or absent freezing procedures, a mandatory requirement so far. The main aim was to determine transcriptome profiles on formalin-fixed paraffin-embedded (FFPE) samples, using the new 3’-end RNA-sequencing technology. A secondary aim was to demonstrate the ability of this technique to explore large FFPE archives, by focusing on the rare oncocytic ACT variants.

Methods

We included 131 ACT: a training cohort from Cochin hospital and an independent validation cohort from Wuerzburg hospital. The 3’ transcriptome was generated from FFPE samples using QuantSeq (Lexogen, Vienna, Austria) and NextSeq500 (Illumina, San Diego, CA, USA).

Results

In the training cohort, unsupervised clustering identified three groups: ‘C1A’ aggressive carcinomas (n = 28, 29%), ‘C1B’ more indolent carcinomas (n = 28, 29%), and ‘C2’ adenomas (n = 39, 41%). The prognostic value of FFPE transcriptome was confirmed in the validation cohort (5-year OS: 26% in ‘C1A’ (n = 26) and 100% in ‘C1B’ (n = 10), P  = 0.003). FFPE transcriptome was an independent prognostic factor in a multivariable model including tumor stage and Ki-67 (OS HR: 7.5, P  = 0.01). Oncocytic ACT (n = 19) did not form any specific cluster. Oncocytic carcinomas (n = 6) and oncocytic ACT of uncertain malignant potential (n = 4) were all in ‘C1B’.

Conclusions

The 3’ RNA-sequencing represents a convenient solution for determining ACT molecular class from FFPE samples. This technique should facilitate routine use and large retrospective studies.