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Introduction: This is an observational and retrospective study, in which we have analyzed data from patients affected by gastric diseases (p) who have been treated with liquid L-T4 (L-LT4;84 p), or tablet L-T4 (T-LT4;120 p), for the replacement therapy of hypothyroidism. The aim of the study is to compare the stability of TSH [normal range, 0.3-3.5 μIU/ml] in these patients., Methods: All p assumed L-T4 30 minutes before breakfast. The types of gastric disease were: a) T-LT4 group: 74 chronic gastritis (CG); 4 gastrectomy for gastric cancer (GTx); 42 gastro-plastics (GP); b) L-LT4 group: 60 CG; 3 GTx; 21 GP (p>0.05). 66% p in T-LT4 group were chronically treated with proton pump inhibitors (PPI), against 51% in L-LT4 group (p>0.05). The frequency of Helicobacter Pylori infection was 17% in both T-LT4 and L-LT4 groups. The gender distribution, mean age and body weight were similar in the 2 groups (p>0.05). The mean L-T4 dosage in T-LT4 group at the basal evaluation was 1.22+/-0.27 μg/kg/die, in the L-LT4 group 1.36+/-0.22 μg/kg/die (p>0.05)., Results: At the basal evaluation the prevalence of patients with a TSH>3.5 μIU/mL in T-LT4 group was 36%, in L-LT4 group 46% (p<0.05). After adjustment of the dosage of the LT-4 therapy, the p were re-evaluated in an interval range of 5-9 months, for 4 times, during an overall period ranging from 23 to 31 months. At the first re-evaluation, the prevalence of p with a TSH>3.5 μIU/mL was 13% in both groups. At the second re-evaluation, the prevalence of p with a TSH>3.5 μIU/mL in T-LT4 group was 26%, in L-LT4 group 13% (p>0.05). At the third re-evaluation, the prevalence of p with TSH<3.5 μIU/mL in T-LT4 group was 19%, in L-LT4 group 9% (p=0.05). At the fourth and last re-evaluation, the prevalence of patients with a TSH>3.5 μIU/mL in T-LT4 group was 18%, in L-LT4 group 5% (p<0.05). Mean FT4 and FT3 circulating levels were not significantly different in the two group at each visit., Discussion: These data suggest that the liquid L-T4 formulation therapy can result in a more stable control of TSH levels in hypothyroid patients with gastric disorders in the long-term follow-up., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The reviewer EB declared a shared affiliation with the author AA to the handling editor at the time of review. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (Copyright © 2024 Fallahi, Ragusa, Patrizio, Mazzi, Botrini, Elia, Balestri, Barozzi, Rugani, Palmisano, Cosenza, Varricchi, Ulisse, Benvenga, Ferrari and Antonelli.)

Cardiovascular disease (CVD) remains the leading cause of death worldwide, representing a major health issue of social and economic relevance. Both hyperthyroidism and hypothyroidism are very common in the adult population, and both disorders may contribute to the onset and progression of CVD. After a brief description of the role of thyroid hormones (THs) on the physiology of the cardiovascular system and the potential mechanism that links THs alterations with changes in cardiac function, blood pressure, endothelial function, and lipid levels, we review updated data about the clinical impact of overt hypothyroidism (OH) and subclinical hypothyroidism (SCH) on CV risk, CVD, and mortality. Furthermore, we summarize the current evidence for treating SCH with levothyroxine (L-T4). Several guidelines of distinguished endocrine societies recommend treatment for SCH with TSH higher than 10 mIU/L, where the benefit of L-T4 therapy is more evident for younger people, but still controversial in those aged over 65 years. Based on current knowledge, more research efforts are needed to better address the clinical management of CV risk and CVD in the elderly affected by SCH., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Patrizio, Ferrari, Elia, Ragusa, Balestri, Botrini, Rugani, Mazzi, Antonelli, Fallahi and Benvenga.)

In hypothyroid patients needing large doses of levothyroxine (L-T4) (>1.7-2 μg/kg/day) to reach euthyroidism, lactose intolerance (LI) needs to be excluded, owing to the high prevalence in the population. If LI is present, a lactose-free diet decreases the rate of L-T4 malabsorption. However, an increased requirement of L-T4 is described in patients with LI, which can be beneficially treated using lactose-free L-T4 formulation. The lactose-free liquid L-T4 formulation is able to circumvent LI malabsorption leading to the normalization of thyroid-stimulating hormone (TSH) in patients with subclinical hypothyroidism and long-term stable TSH levels., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (Copyright © 2024 Ferrari, Patrizio, Mazzi, Ragusa, Botrini, Elia, Balestri, Barozzi, Rugani, Bracchitta, Stoppini, Frenzilli, Baldini, Virili, Benvenga, Fallahi and Antonelli.)

Poorly differentiated thyroid cancer (PDTC) and anaplastic thyroid cancer (ATC) have a worse prognosis with respect to well differentiated TC, and the loss of the capability of up-taking 131 I is one of the main features characterizing aggressive TC. The knowledge of the genomic landscape of TC can help clinicians to discover the responsible alterations underlying more advance diseases and to address more tailored therapy. In fact, to date, the antiangiogenic multi-targeted kinase inhibitor (aaMKIs) sorafenib, lenvatinib, and cabozantinib, have been approved for the therapy of aggressive radioiodine (RAI)-resistant papillary TC (PTC) or follicular TC (FTC). Several other compounds, including immunotherapies, have been introduced and, in part, approved for the treatment of TC harboring specific mutations. For example, selpercatinib and pralsetinib inhibit mutant RET in medullary thyroid cancer but they can also block the RET fusion proteins-mediated signaling found in PTC. Entrectinib and larotrectinib, can be used in patients with progressive RAI-resistant TC harboring TRK fusion proteins. In addition FDA authorized the association of dabrafenib (BRAF V600E inhibitor) and trametinib (MEK inhibitor) for the treatment of BRAF V600E -mutated ATC. These drugs not only can limit the cancer spread, but in some circumstance they are able to induce the re-differentiation of aggressive tumors, which can be again submitted to new attempts of RAI therapy. In this review we explore the current knowledge on the genetic landscape of TC and its implication on the development of new precise therapeutic strategies., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Elia, Patrizio, Ragusa, Paparo, Mazzi, Balestri, Botrini, Rugani, Benvenga, Materazzi, Spinelli, Antonelli, Fallahi and Ferrari.)

Myoinositol (Myo) is an isoform of inositol, a cyclic polyol with 6 hydroxyl groups. Myo is mainly derived from dietary intake while its endogenous production is generated from glucose by enzymatic reactions. Moreover, Myo is also synthesized de novo by catabolism of phosphatidylinositol (PI), phosphoinositides (PIP), and inositol phosphates (IP). Myo has a determinant role in thyroid function and autoimmune diseases as it regulates iodine organification and thyroid hormone biosynthesis by the formation of hydrogen peroxide (H 2 O 2 ) in thyrocytes. Depletion of Myo that is involved in the thyroid stimulating hormone (TSH) signaling pathway, may cause the development of thyroid diseases such as hypothyroidism. TSH levels significantly decreased in patients with subclinical hypothyroidism, with or without autoimmune thyroiditis, after treatment with Myo plus Selenium (Myo+Se). In addition to TSH, antithyroid autoantibodies are reduced. This review summarizes the role of Myo in the thyroidal physiology and its role in the management of some thyroid diseases., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Paparo, Ferrari, Patrizio, Elia, Ragusa, Botrini, Balestri, Guarneri, Benvenga, Antonelli and Fallahi.)

Graves' disease (GD) is an organ-specific autoimmune disorder of the thyroid, which is characterized by circulating TSH-receptor (TSH-R) stimulating antibodies (TSAb), leading to hyperthyroidism. Graves' ophthalmopathy (GO) is one of GD extra-thyroidal manifestations associated with the presence of TSAb, and insulin-like growth factor-1 receptor (IGF-1R) autoantibodies, that interact with orbital fibroblasts. Cytokines are elevated in autoimmune (i.e., IL-18, IL-6) and non-autoimmune hyperthyroidism (i.e., TNF-α, IL-8, IL-6), and this could be associated with the chronic effects of thyroid hormone increase. A prevalent Th1-immune response (not related to the hyperthyroidism per se , but to the autoimmune process) is reported in the immune-pathogenesis of GD and GO; Th1-chemokines (CXCL9, CXCL10, CXCL11) and the (C-X-C)R3 receptor are crucial in this process. In patients with active GO, corticosteroids, or intravenous immunoglobulins, decrease inflammation and orbital congestion, and are considered first-line therapies. The more deepened understanding of GO pathophysiology has led to different immune-modulant treatments. Cytokines, TSH-R, and IGF-1R (on the surface of B and T lymphocytes, and fibroblasts), and chemokines implicated in the autoimmune process, are possible targets of novel therapies. Drugs that target cytokines (etanercept, tocilizumab, infliximab, adalimumab) have been tested in GO, with encouraging results. The chimeric monoclonal antibody directed against CD20, RTX, reduces B lymphocytes, cytokines and the released autoantibodies. A multicenter, randomized, placebo-controlled, double-masked trial has investigated the human monoclonal blocking antibody directed against IGF-1R, teprotumumab, reporting its effectiveness in GO. In conclusion, large, controlled and randomized studies are needed to evaluate new possible targeted therapies for GO., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Fallahi, Ferrari, Elia, Ragusa, Paparo, Patrizio, Camastra, Miccoli, Cavallini, Benvenga and Antonelli.)

Anaplastic thyroid carcinoma (ATC) is a malignant tumor of the thyroid gland, infrequent but with a very poor prognosis, as it rapidly causes death (mean survival of about 6 months). ATC treatment includes a multimodal protocol consisting of surgery, chemotherapy (doxorubicin and cisplatin), and hyperfractionated accelerated external beam radiotherapy (median patient survival of 10 months). For this reason, the identification of an effective systemic treatment for ATC would be a major advance in the management of this deadly thyroid cancer. The opportunity to test the sensitivity to different drugs of primary cells from ATC (pATC) cultures, obtained from each patients, could improve the effectiveness of the treatment. Then, the administration of inactive therapeutics could be avoided. Our aim is to investigate the antineoplastic effect of two tyrosine kinase inhibitors (TKIs; lenvatinib, vandetanib) in pATC obtained both from biopsy (biop-pATC), and from fine needle aspiration (FNA-pATC). The antiproliferative activity of lenvatinib and vandetanib was evaluated in 6 ATC patients, on biop-pATC, such as on FNA-pATC. A significant reduction of proliferation (obtained by WST-1 assay) vs. control was shown with lenvatinib and vandetanib in FNA-pATC, as well as in biop-pATC. The percentage of apoptosis in FNA-pATC, or biop-pATC, increased with both compounds dose-dependently. pATC cells from FNA, or biopsy, had a similar sensitivity to lenvatinib and vandetanib. In conclusion, primary cells (biop-pATC or FNA-pATC) have a similar sensitivity to TKIs, and lenvatinib and vandetanib are effective in reducing cell growth, increasing apoptosis in ATC. The possibility to test the sensitivity to different TKIs in each patient could open the way to personalized treatments, avoiding the administration of ineffective, and potentially dangerous, drugs.