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Alessandro Prete, Richard J Auchus, and Richard J Ross

Background

Patients with 21-hydroxylase deficiency congenital adrenal hyperplasia (21OHD-CAH) have poor health outcomes with increased mortality, short stature, impaired fertility, and increased cardiovascular risk factors such as obesity. To address this, there are therapies in development that target the clinical goal of treatment, which is to control excess androgens with an adrenal replacement dose of glucocorticoid.

Methods

Narrative review of publications on recent clinical developments in the pharmacotherapy of congenital adrenal hyperplasia.

Summary

Therapies in clinical development target different levels of the hypothalamo–pituitary–adrenal axis. Two corticotrophin-releasing factor type 1 (CRF1) receptor antagonists, Crinecerfont and Tildacerfont, have been trialled in poorly controlled 21OHD-CAH patients, and both reduced ACTH and androgen biomarkers while patients were on stable glucocorticoid replacement. Improvements in glucocorticoid replacement include replacing the circadian rhythm of cortisol that has been trialled with continuous s.c. infusion of hydrocortisone and Chronocort, a delayed-release hydrocortisone formulation. Chronocort optimally controlled 21OHD-CAH in 80% of patients on an adrenal replacement dose of hydrocortisone, which was associated with patient-reported benefits including restoration of menses and pregnancies. Adrenal-targeted therapies include the steroidogenesis-blocking drug Abiraterone acetate, which reduced adrenal androgen biomarkers in poorly controlled patients.

Conclusions

CRF1 receptor antagonists hold promise to avoid excess glucocorticoid replacement in patients not controlled on standard or circadian glucocorticoid replacement such as Chronocort. Gene and cell therapies are the only therapeutic approaches that could potentially correct both cortisol deficiency and androgen excess.

Restricted access

Alessandro Prete, Carla Gambale, Virginia Cappagli, Valeria Bottici, Piercarlo Rossi, Marco Caciagli, Piermarco Papini, Donatella Taddei, Luciano Gabbrielli, Alessandro Celi, Simona Ortori, Gabriele Materazzi, Rossella Elisei, and Antonio Matrone

Objective: Selpercatinib is a highly selective RET-inhibitor drug, approved for the treatment of RET-altered lung and thyroid cancers. So far, RET-altered medullary thyroid cancer (MTC) patients treated with selpercatinib showed a remarkable objective response rate and safety profile. However, new treatment emerging adverse events (TEAEs) have been recently reported. The aim of this study was to evaluate the prevalence, features, and clinical management of effusions that are one of these TEAEs.

Design: Ten of 11 patients with advanced MTC enrolled in the LIBRETTO-201 clinical trial at Endocrinology Unit of the Pisa University Hospital were evaluated for the presence and management of effusions.

Methods: We retrospectively evaluated MTC patients treated with selpercatinib. The presence of pleural, pericardial, abdominal and/or pelvic effusions was evaluated by reviewing the computerized tomography scan performed during the study protocol and up to 24 months of observation.

Results: All but one MTC patient experienced previous MKIs treatment. Three patients already had effusions before starting selpercatinib treatment. New effusions appeared in 8/10 (80%) patients during the treatment. In patients submitted to fluid aspiration a chylous nature was documented. Whenever a dose reduction was performed a significant positive effect was observed.

Conclusions: Chylous effusions are a new TEAE of selpercatinib treatment. They can appear or worsening at any time during the treatment. Cases with asymptomatic and mild effusions, active surveillance may be appropriate and safe. In symptomatic and/or moderate/severe cases, aspiration of the fluid and a dose reduction can improve this AE, strongly supporting a cause-effect correlation with selpercatinib.

Free access

Antonio Matrone, Carla Gambale, Margherita Biagini, Alessandro Prete, Paolo Vitti, and Rossella Elisei

Abstract

Objective

Recently, several scientific societies designed ultrasound (US) risk stratification systems (RSS) to guide the workup of thyroid nodules and decide which nodules should undergo fine-needle aspiration cytology (FNAC). However, these systems have been developed against papillary thyroid carcinoma, and scanty data on their role in identifying medullary thyroid carcinoma (MTC) are available. The aims of this study are to describe the US features of MTC and evaluate the performance of RSS in identifying MTC.

Methods

Data of 152 consecutive patients with MTC was evaluated. The results of the pre-operative neck US of all patients were collected. Ultrasound features of each MTC were evaluated and classified according to the five main RSS available.

Results

Median MTC dimension was 1.3 cm. Most of the nodules showed solid composition, hypoechoic pattern, and regular margins. About half of them showed the presence of calcifications, but only a subgroup had microcalcifications. A minority of the nodules showed a 'taller than wide' shape. Only 7.9% of all MTC showed the simultaneous presence of at least four US features suggestive of malignancy. Ultrasonographic high-risk of malignancy of the MTC included in the five RSS, varied from 45.4 to 47.4%, and performing FNAC was suggested in only 48.7 to 63.8% of all MTC.

Conclusions

In this series, neither single nor the association of US features are specific for MTC. The five main RSS correctly identify less than 50% of MTC and do not suggest performing FNAC in about half of them with potentially missed or delayed diagnosis.