Genetic Basis of ACTH-Secreting Adenomas.

Cushing's disease represents 60-70% of all cases of Cushing's syndrome, presenting with a constellation of clinical features associated with sustained hypercortisolism. Molecular alterations in corticotrope cells lead to the formation of ACTH-secreting adenomas, with subsequent excessive production of endogenous glucocorticoids. In the last few years, many authors have contributed to analyzing the etiopathogenesis and pathophysiology of corticotrope adenomas, which still need to be fully clarified. New molecular modifications such as somatic mutations of USP8 and other genes have been identified, and several case series and case reports have been published, highlighting new molecular alterations that need to be explored. To investigate the current knowledge of the genetics of ACTH-secreting adenomas, we performed a bibliographic search of the recent scientific literature to identify all pertinent articles. This review presents the most recent updates on somatic and germline mutations underlying Cushing's disease. The prognostic implications of these mutations, in terms of clinical outcomes and therapeutic scenarios, are still debated. Further research is needed to define the clinical features associated with the different genotypes and potential pharmacological targets.

Italian Guidelines for the Management of Sporadic Primary Hyperparathyroidism.

AIM: This guideline (GL) is aimed at providing a clinical practice reference for the management of sporadic primary hyperparathyroidism (PHPT) in adults. PHPT management in pregnancy was not considered. METHODS: This GL has been developed following the methods described in the Manual of the Italian National Guideline System. For each question, the panel appointed by Associazione Medici Endocrinology (AME) and Società Italiana dell'Osteoporosi, del Metabolismo Minerale e delle Malattie dello Scheletro (SIOMMMS) identified potentially relevant outcomes, which were then rated for their impact on therapeutic choices. Only outcomes classified as "critical" and "important" were considered in the systematic review of evidence. Those classified as "critical" were considered for the clinical practice recommendations. RESULTS: The present GL provides recommendations about the roles of pharmacological and surgical treatment for the clinical management of sporadic PHPT. Parathyroidectomy is recommended in comparison to surveillance or pharmacologic treatment in any adult (outside of pregnancy) or elderly subject diagnosed with sporadic PHPT who is symptomatic or meets any of the following criteria: • Serum calcium levels >1 mg/dL above the upper limit of normal range. • Urinary calcium levels >4 mg/kg/day. • Osteoporosis disclosed by DXA examination and/or any fragility fracture. • Renal function impairment (eGFR <60 mL/min). • Clinic or silent nephrolithiasis. • Age ≤50 years. Monitoring and treatment of any comorbidity or complication of PHPT at bone, kidney, or cardiovascular level are suggested for patients who do not meet the criteria for surgery or are not operated on for any reason. Sixteen indications for good clinical practice are provided in addition to the recommendations. CONCLUSION: The present GL is directed to endocrinologists and surgeons - working in hospitals, territorial services or private practice - and to general practitioners and patients. The recommendations should also consider the patient's preferences and the available resources and expertise.

Vocal Cord Monitoring by Flexible Fiberoptic Laryngoscopy During Thyroid Radiofrequency Ablation.

Introduction: Thermal injury to recurrent laryngeal nerve (RLN) during radiofrequency ablation (RFA) can produce temporary or permanent vocal cord paralysis.1 Hydrodissection with cold 5% glucose of "danger triangle" protects RLN during RFA.2 When RFA is performed under local anesthesia, RLN function is monitored by patients producing vocal sounds.3 Large lesions requiring longer RFAs warrant general sedation where voice cannot be assessed, therefore, an additional technique for RLN protection is advisable. Observation of passive symmetrical vocal cord movements during breathing by laryngeal ultrasonography is useful in assessing vocal cord function4; however, flexible-fiberoptic fibrolaringoscopy (FFL) is gold standard for assessing vocal cord movements,5 anticipating potential RLN damage. We report FFL monitoring during RFA under general sedation on a large thyroid nodule. FFL during RFA may detect RLN irritation and dysfunction if asymmetry in passive vocal cord movements is noted. Should asymmetry appear, RFA operator stops delivering energy and repositions electrode needle. Materials and Methods: Thyroid function tests, blood glucose, creatinine, transaminase, International-Normalized-Ratio, and electrocardiogram were performed. Operating room (OR) layout created sufficient space for ear-nose-throat (ENT) and RFA operators. An examination with a fiberscope camera demonstrated normal vocal cord adduction during phonation and abduction during breathing. The procedure was assisted by an anesthetist administering fentanyl 50 mcg, midazolam 1.5 to 5.0 mg, and propofol infusion 2 mg/(kg·h). General sedation was conducted so that reflexes were attenuated but still observable. Incorporating in OR by an anesthetist who performs general sedation reduces side effects and complications.6 Ultrasonography showed a 34-mL right lobe nodule abutting on the RLN area. After sedation with propofol, the ENT specialist inserted an endoscope until the glottic plane. During calm breathing, vocal cords moved symmetrically. After obtaining anterior nodule hydrodissection from strap and sternocleidomastoid muscles with 10 mL of 2% lidocaine, posterior hydrodissection was achieved by ultrasound-guided administration of 30 mL of 5% cold glucose. Anterior and posterior hydrodissections merged, separating nodule from neck structures. The radiofrequency electrode needle was then inserted into the nodule, initially positioned in inferior nodule portion adjacent to danger triangle previously isolated by hydrodissection. Initial power was 30 watts. Moving-shot technique was used. Results: FFL was performed throughout thyroid RFA. Symmetric vocal cord movements during breathing demonstrated no RLN irritation. FFL monitoring allowed observation of natural reflexive phenomena, including swallowing. Complete nodule ablation was achieved. FFL performed post-RFA confirmed normal vocal cord motility. Conclusions: We report the first-time use of FFL for vocal cord monitoring during RFA. FFL was easily performed by the ENT specialist and well tolerated by the patient. Avoiding danger triangle and precise RFA needle positioning is key in preventing RLN injury. Benign nodules regrow if total ablation is not achieved7 and some authors propose additional procedures to complete ablation8 that obviously incurs costs. Total RFA nodule ablation-assisted FFL monitoring eliminates the need for repetitive RFAs, thus reducing overall treatment costs. Finally, FFL monitoring does not prolong procedure, as it is performed simultaneously with RFA. FFL is a valid technique when used in conjunction with hydrodissection to further prevent RLN thermal injury during RFA, especially indicated for large thyroid nodule ablation and professional voice users. Patient Consent and Permission: The patient provided written consent for FFL monitoring and permission to use his portrayals and ultrasonographic images during RFA. The study was completed in accordance with the Declaration of Helsinki as revised in 2013. Adherence to institutional review board protocols was granted. Disclaimer: Representation of any instrumentation within the video does not indicate any endorsement of the product and/or company by the publisher, the American Thyroid Association, or the authors. No competing financial interests exist. Runtime of video: 9 mins 39 secs.

Impact of the introduction of minimally invasive treatments of the thyroid (MITT) for benign thyroid nodules in an Italian hospital: a cost-minimization analysis.

BACKGROUND: Prevalence of thyroid nodules is high in the adult population, approaching 60% in women and older people. Most thyroid nodules are benign and asymptomatic. However, a not negligible part of them causes compressive symptoms and/or cosmetic concerns and need to be treated. In the last two decades, minimally-invasive treatments of the thyroid (MITT) have been proposed in routine clinical practice as a reliable cost-effective alternative to surgery in patients with symptomatic benign thyroid nodules (SBTNs). AIM OF THE STUDY: To perform a cost-minimization analysis comparing direct, indirect and intangible costs of radiofrequency (RFA) and laser thermal ablation (LTA) with traditional surgery in patients with SBTNs. METHODS: Data of patients treated by MITT for SBTNs from October 1st 2019 to September 30th 2022 in a single Italian tertiary Center were analyzed. Costs were compared to those of traditional surgery reported in the 2022 Associazione Medici Endocrinologi Guidelines on the Management of SBTNs. RESULTS: In the study lapse, 157 MITT of SBTNs were performed in 148 patients, 114 females and 34 males (mean age: 59 yrs; median age: 57 yrs). Before MITT, the mean thyroid nodule volume was 19 ml; 1 year after MITT, volume reduction rate >50% and symptom relief were achieved in 89% and 93% of patients, respectively. No major complications occurred. Adding up pre-operative, operative and post-operative costs, total direct costs per single procedure are the following: 1361.43 € for LTA when using one optic fiber; 1761.43 € for LTA when using two optic fibers; 1968.53 € for RFA; 3338.39 € for hemithyroidectomy plus isthmectomy; 4034.99 € for total thyroidectomy. Surgery was impactful on direct-i.e., preoperative, operative and postoperative-costs, due to longer operating room occupation time and hospital stay. Overall, a total saving for the Italian National Health Service of 285,377.15 € has been obtained treating the 148 patients by MITT instead of surgery. Likewise, MITT was advantageous also for indirect costs-i.e., those related to "loss of productivity" caused by time off work due to hospital stay and recovery time-, for both the self-employed workers and the Government, the latter saving 53,838.50 € overall. Finally, intangible costs, related to patients' quality of life-e.g., residual surgical scar, stress related to general anesthesia, convalescence, and life-long intake of L-Thyroxine replacement therapy-were all in favor of MITT. CONCLUSIONS: This real-life cost-minimization analysis demonstrates that LTA and RFA are safe and cost-effective procedures for the treatment of SBTNs. In our 3 years experience, adding the savings of 285,377.15 € for direct costs to those of 53.838,50 € for indirect costs, in total 339,215.65 € were saved. The saving concern patients, the National Health System and the Government.

A New de novo Mosaic Mutation of PHEX Gene: A Case Report of a Boy with Hypophosphatemic Rickets.

BACKGROUND: X-linked hypophosphatemia is the most prevalent form of heritable rickets, characterized by an X-linked dominant inheritance pattern. The genetic basis of X-linked hypophosphatemia is a loss-of-function mutation in the PHEX gene (Phosphate regulating gene with Homology to Endopeptidases on the X chromosome), which leads to an enhanced production of phosphaturic hormone FGF23. X-linked hypophosphatemia causes rickets in children and osteomalacia in adults. Clinical manifestations are numerous and variable, including slowdown in growth, swing-through gait and progressive tibial bowing, related to skeletal and extraskeletal actions of FGF23. PHEX gene spans over 220 kb and consists of 22 exons. To date, hereditary and sporadic mutations are known (missense, nonsense, deletions and splice site mutations). CASE PRESENTATION: Herein, we describe a male patient carrying a novel de novo mosaic nonsense mutation c.2176G>T (p.Glu726Ter) located in exon 22 of PHEX gene. CONCLUSION: We highlight this new mutation among possible causative of X-linked hypophosphatemia and suggest that mosaicism of PHEX mutations is not so uncommon and should be excluded in diagnostic workflow of heritable rickets both in male and female patients.

Discovery, preclinical development, and clinical application of pralsetinib in the treatment of thyroid cancer.

INTRODUCTION: The use of targeted drug therapies has substantially increased in the treatment of RET-mutated thyroid and other solid cancers over the last decade. Multi-Kinase Inhibitors (MKI) have been approved by FDA, but limited efficacies and side effects make them uneasy to tolerate. Pralsetinib is an oral highly selective RET inhibitor drug that has been generated and clinically validated to have higher potency and less toxicity. AREAS COVERED: The present paper offers a brief summary of RET-related thyroid cancer genetics, an overview of the preclinical development of pralsetinib and reviews its clinical validation in the treatment of thyroid cancer. EXPERT OPINION: Pralsetinib is a new generation oral treatment that has been approved by the FDA for patients with RET-mutated thyroid cancer. Pralsetinib showed a safer toxicity profile compared to previously approved MKI, probably due to lower inhibition of other tyrosine kinases, especially VEGFR. The approval study ARROW trial showed that patients with RET-mutant medullary thyroid cancer had a better overall response rate to pralsetinib compared to standard-of-care treatments. Additional clinical trials or data enrichment of existing databases are desirable in order to verify and further describe the clinical benefit of pralsetinib in such patients to fully understand its pharmacological profile.

An innovative synthetic support for immunocytochemical assessment of cytologically indeterminate (Bethesda III) thyroid nodules.

Background: Fine needle aspiration (FNA) is the procedure of choice in the evaluation of thyroid nodules. Nodules with indeterminate cytological categories, Bethesda III and IV, pose challenges in clinical practice and are frequently submitted to diagnostic surgery. CytoFoam Core (CFCS) uses an absorbent foam device inserted into the needle hub to collect the cytological sample aspirated during FNA. Specimen is formalin-fixed and paraffin-embedded. Aim of the study: Assessing diagnostic efficacy of CFCS, compared to traditional cytology, in re-evaluating thyroid nodules classified as Bethesda III, using post-surgical histology as reference standard. Method: Retrospective study on 89 patients with a first indeterminate cytological report who were referred to the Department of Endocrinology of Regina Apostolorum Hospital (Albano L. Rome, Italy) for a second FNA. FNA was performed after at least one month under ultrasound guidance with a 23G needle according to the established procedure. During the second procedure, both traditional cytological (TC) smears and a single-pass CFCS specimen were obtained for each patient. On CFCS samples immunocytochemical staining for Galectin-3, HBME-1, and CK-19 was also performed. 51 patients eventually underwent surgery, and their histological diagnoses were compared to the TC and CFCS reports. Four parameters were evaluated: inadequacy rate, rate of persistent indeterminate (Bethesda III and IV) reports, rate of malignancy in persistently indeterminate nodules, and rate of cancer in lesions cytologically classified as malignant. Results: Non-diagnostic samples were 6 (11.8%) in TC vs 3 (5.9%) in CFCS (p=0.4). Persistent indeterminate samples were 31 (60.8%) in TC vs 19 (37.2%) in CFCS (p=0.01). Rate of malignancy in persistently indeterminate nodules was 8/19 (42.1%) in CFCS vs 9/31 (29%) in TC group (p=0.3). Nine/51 (17.6%) samples were classified as benign by TC vs 21/51 (41.2%) samples by CFCS (p<0.01). All nodules resulted benign at post-surgical evaluation. Five/51 (9.8%) samples were classified as suspicious for malignancy/malignant in TC group against 8/51 (15.7%) samples in CFCS (p=0.5). Post-surgical evaluation confirmed malignancy in all these cases. Conclusion: CFCS demonstrated greater diagnostic accuracy than TC in repeat FNA assessment of cytologically indeterminate nodules. CFCS increased the conclusive diagnosis rate and decreased the number of cytologically indeterminate cases.

Pregnancy and Prenatal Management of Congenital Adrenal Hyperplasia.

Congenital adrenal hyperplasia (CAH) is a group of autosomal recessive diseases that may cause cortisol insufficiency together with other hormonal alterations. The most common form is 21-hydroxylase deficiency, in which the lack of pituitary negative feedback causes an increase in ACTH and adrenal androgens. Classical forms of CAHs can lead to severe adrenal failure and female virilization. To date, the appropriate management of pregnant CAH patients is still debated regarding appropriate maternal therapy modifications during pregnancy and the risks and benefits of prenatal treatment of the fetus. We conducted a literature search of relevant papers to collect current evidence and experiences on the topic. The most recent and significant articles were selected, and current international guidelines were consulted to update current recommendations and guide clinical practice. Given the lack of randomized clinical trials and other high-quality scientific evidence, the issue is still debated, and great heterogeneity exists in current practice in terms of risk/benefit evaluation and pharmacological choices for pregnancy and prenatal treatment. Glucocorticoid therapy is advised not only in classical CAH patients but also in non-classical, milder forms. The choice of which glucocorticoid to use, and the safety and benefits of dexamethasone therapy aimed at preventing genital virilization are still debated issues. Several advances, however, have been made, especially in terms of fertility and reproduction. This review aims to present the most recent scientific and real-world updates on pregnancy and prenatal management of CAH, with the presentation of various clinical scenarios and specific case-by-case recommendations.

Radiofrequency ablation and related ultrasound-guided ablation technologies for treatment of benign and malignant thyroid disease: An international multidisciplinary consensus statement of the American Head and Neck Society Endocrine Surgery Section with the Asia Pacific Society of Thyroid Surgery, Associazione Medici Endocrinologi, British Association of Endocrine and Thyroid Surgeons, European Thyroid Association, Italian Society of Endocrine Surgery Units, Korean Society of Thyroid Radiology, Latin American Thyroid Society, and Thyroid Nodules Therapies Association.

BACKGROUND: The use of ultrasound-guided ablation procedures to treat both benign and malignant thyroid conditions is gaining increasing interest. This document has been developed as an international interdisciplinary evidence-based statement with a primary focus on radiofrequency ablation and is intended to serve as a manual for best practice application of ablation technologies. METHODS: A comprehensive literature review was conducted to guide statement development and generation of best practice recommendations. Modified Delphi method was applied to assess whether statements met consensus among the entire author panel. RESULTS: A review of the current state of ultrasound-guided ablation procedures for the treatment of benign and malignant thyroid conditions is presented. Eighteen best practice recommendations in topic areas of preprocedural evaluation, technique, postprocedural management, efficacy, potential complications, and implementation are provided. CONCLUSIONS: As ultrasound-guided ablation procedures are increasingly utilized in benign and malignant thyroid disease, evidence-based and thoughtful application of best practices is warranted.