Evaluating local thyroid cytopathology practices by molecular quality metrics: A multi-institutional study on 4651 FNAs with a focus on the role of the interventional cytopathologist.

BACKGROUND: The diagnostic accuracy of thyroid fine-needle aspiration (FNA) can be highly influenced by the technical skills of the operator performing the procedure and by interobserver variability in microscopic interpretation. This is particularly true for the indeterminate categories. Recently, molecular testing has been proposed as an ancillary tool for monitoring the performance of different thyroid cytopathology practices. The objective of this multicenter study was to evaluate the quality of different local cytopathology practices by assessing the impact of interventional cytopathologists on FNA adequacy for molecular testing and the variations in mutation rates across different health care centers operating in the Campania region. METHODS: The study included 4651 thyroid FNA samples diagnosed in different Southern Italian clinical laboratories belonging to the TIRNET (the Tiroide Network). FNA samples were collected by different proceduralists and were classified by local cytopathologists according to The Bethesda System for Reporting Thyroid Cytopathology. FNAs classified as atypia of undetermined significance, follicular neoplasm, suspicious for malignancy, and malignant were centralized for a real-time polymerase chain reaction-based, seven-gene test at the authors' institution. RESULTS: Centers that employed interventional cytopathologists obtained fewer unsatisfactory FNA samples for molecular testing (11.3%) than centers that employed noncytopathologists (16.7%; p < .05). Furthermore, a significant variation in the mutation rate was observed in FNAs diagnosed by different local cytopathologists; indeterminate categories had the highest percentage of mutation rate variability among centers. CONCLUSIONS: Interventional cytopathologists obtained higher yields of diagnostic material for molecular testing. Finally, the current results suggest that the variability in mutation rates among different centers may highlight the low reproducibility of microscopic criteria among cytopathologists, particularly for indeterminate cases.

D898_E901 RET Deletion Is Oncogenic, Responds to Selpercatinib, and Treatment Resistance Can Arise Via RET-Independent Mechanisms.

PURPOSE: We analyzed the oncogenic potential of RET Δ898-901 mutant and its response to selpercatinib, vandetanib, and cabozantinib in vitro and in a clinical case. MATERIALS AND METHODS: A 35-year-old man with a medullary thyroid cancer (MTC) harboring a somatic D898_E901 RET deletion was sequentially treated with vandetanib, selpercatinib, cabozantinib, and fluorouracil (5-FU)-dacarbazine. Functional study of RET Δ898-901 mutant was performed in HEK-293T, NIH-3T3, and Ba/F3 cells. RET C634R and wild-type cells served as positive and negative controls, respectively. RESULTS: The patient showed primary resistance to vandetanib and secondary resistance to selpercatinib after 12 months. Comprehensive next-generation sequencing of a progressing lesion during selpercatinib showed no additional RET mutation but an acquired complete genetic loss of CDKN2A, CDKN2B, and MTAP genes. Subsequent treatment with cabozantinib and 5-FU-dacarbazine had poor efficacy. In vitro, RET Δ898-901 showed higher ligand-independent RET autophosphorylation compared with RET C634R and similar proliferation rates in cell models. Subcutaneous injection of Δ898-901 NIH 3T3 cells in nude mice produced tumors of around 500 mm3 in 2 weeks, similarly to RET C634R cells. Selpercatinib inhibited cell growth of Ba/F3 RET Δ898-901 and RET C634R with a similar half maximal inhibitory concentration (IC50) of approximately 3 nM. Vandetanib was five-fold less effective at inhibiting cell growth promoted by RET Δ898-901 mutant (IC50, 564 nM) compared with RET C634R one (IC50, 91 nM). Cabozantinib efficiently inhibited Ba/F3 RET C634 proliferation (IC50, 25.9 nM), but was scarcely active in Ba/F3 RET 898-901 (IC50 > 1,350 nM). CONCLUSION: D898_E901 RET deletion is a gain-of-function mutation and responds to tyrosine kinase inhibitors in MTC. RET Δ898-901 mutant is sensitive to selpercatinib and vandetanib, and acquired resistance to selpercatinib may develop via RET-independent mechanisms.

Altered Thyroid Feedback Loop in Klinefelter Syndrome: From Infancy Through the Transition to Adulthood.

CONTEXT: It has been claimed that thyroid dysfunction contributes to the spectrum of Klinefelter syndrome (KS); however, studies are scarce. OBJECTIVE: In a retrospective longitudinal study, we aimed at describing the hypothalamic-pituitary-thyroid (HPT) axis and thyroid ultrasonographic (US) appearance in patients with KS throughout the life span. METHODS: A total of 254 patients with KS (25.9 ± 16.1 years) were classified according to their pubertal and gonadal status and compared with different groups of non-KS age-matched individuals with normal thyroid function, treated and untreated hypogonadism, or chronic lymphocytic thyroiditis. We assessed serum thyroid hormone levels, antithyroid antibodies, US thyroid parameters, and in vitro pituitary type 2 deiodinase (D2) expression and activity. RESULTS: Thyroid autoimmunity was more prevalent among individuals with KS at all ages, although the antibody (Ab)-negative vs Ab-positive cohorts were not different. Signs of thyroid dysfunction (reduced volume, lower echogenicity, and increased inhomogeneity) were more prominent in KS than in euthyroid controls. Free thyroid hormones were lower in prepubertal, pubertal, and adult patients with KS, whereas thyrotropin values were lower only in adults. Peripheral sensitivity to thyroid hormones was unaltered in KS, suggesting a dysfunctional HPT axis. Testosterone (T) was the only factor associated with thyroid function and appearance. In vitro testing demonstrated an inhibitory effect of T on pituitary D2 expression and activity, supporting enhanced central sensing of circulating thyroid hormones in hypogonadism. CONCLUSION: From infancy through adulthood, KS is characterized by increased morphofunctional abnormalities of the thyroid gland, combined with a central feedback dysregulation sustained by the effect of hypogonadism on D2 deiodinase.

Type 2 deiodinase is expressed in anaplastic thyroid carcinoma and its inhibition causes cell senescence.

Anaplastic thyroid cancer (ATC) is a rare thyroid tumor that frequently originates from the dedifferentiation of a well-differentiated papillary or follicular thyroid cancer. Type 2 deiodinase (D2), responsible for the activation of the thyroid hormone thyroxine into tri-iodothyronine (T3), is expressed in normal thyroid cells and its expression is strongly downregulated in papillary thyroid cancer. In skin cancer, D2 has been associated with cancer progression, dedifferentiation, and epithelial-mesenchymal transition. Here, we show that D2 is highly expressed in anaplastic compared to papillary thyroid cancer cell lines and that D2-derived T3 is required for ATC cell proliferation. D2 inhibition is associated with G1 growth arrest and induction of cell senescence, together with reduced cell migration and invasive potential. Finally, we found that mutated p5372R(R248W), frequently found in ATC, is able to induce D2 expression in transfected papillary thyroid cancer cells. Our results show that the action of D2 is crucial for ATC proliferation and invasiveness, providing a potential new therapeutic target for the treatment of ATC.

Deiodinases in thyroid tumorigenesis.

The three deiodinase selenoenzymes are key regulators of intracellular thyroid hormone (TH) levels. The two TH-activating deiodinases (type 1 deiodinase and type 2 deiodinase (D2)) are normally expressed in follicular thyroid cells and contribute to overall TH production. During thyroid tumorigenesis, the deiodinase expression profile changes to customize intracellular TH levels to different requirements of cancer cells. Differentiated thyroid cancers overexpress the TH-inactivating type 3 deiodinase (D3), likely to reduce the TH signaling within the tumor. Strikingly, recent evidence suggests that during the late stage of thyroid tumorigenesis, D2 expression raises and this, together with a reduction in D3 expression levels, increases TH intracellular signaling in dedifferentiated thyroid cancers. These findings call into question the different functions of TH in the various stages of thyroid cancers.

A Data-Driven Approach to Refine Predictions of Differentiated Thyroid Cancer Outcomes: A Prospective Multicenter Study.

CONTEXT: The risk stratification of patients with differentiated thyroid cancer (DTC) is crucial in clinical decision making. The most widely accepted method to assess risk of recurrent/persistent disease is described in the 2015 American Thyroid Association (ATA) guidelines. However, recent research has focused on the inclusion of novel features or questioned the relevance of currently included features. OBJECTIVE: To develop a comprehensive data-driven model to predict persistent/recurrent disease that can capture all available features and determine the weight of predictors. METHODS: In a prospective cohort study, using the Italian Thyroid Cancer Observatory (ITCO) database (NCT04031339), we selected consecutive cases with DTC and at least early follow-up data (n = 4773; median follow-up 26 months; interquartile range, 12-46 months) at 40 Italian clinical centers. A decision tree was built to assign a risk index to each patient. The model allowed us to investigate the impact of different variables in risk prediction. RESULTS: By ATA risk estimation, 2492 patients (52.2%) were classified as low, 1873 (39.2%) as intermediate, and 408 as high risk. The decision tree model outperformed the ATA risk stratification system: the sensitivity of high-risk classification for structural disease increased from 37% to 49%, and the negative predictive value for low-risk patients increased by 3%. Feature importance was estimated. Several variables not included in the ATA system significantly impacted the prediction of disease persistence/recurrence: age, body mass index, tumor size, sex, family history of thyroid cancer, surgical approach, presurgical cytology, and circumstances of the diagnosis. CONCLUSION: Current risk stratification systems may be complemented by the inclusion of other variables in order to improve the prediction of treatment response. A complete dataset allows for more precise patient clustering.

Vandetanib downregulates type 2 deiodinase in fibro/adipogenic progenitors.

Treatment with tyrosine kinase inhibitors (TKIs) has been associated with alterations in circulating thyroid hormone levels, possibly related to perturbations in peripheral thyroid hormone metabolism. In this study, we evaluated the effect of the multi-kinase inhibitor vandetanib on the expression of the three deiodinase selenoenzymes, responsible for the thyroid hormone activation (type 1 and type 2 deiodinases) or for its inactivation (type 3 deiodinase). Here, we show that the multi-kinase inhibitor vandetanib determines a strong cell-specific downregulation of type 2 deiodinase (D2) expression and a significant reduction in D2 enzymatic activity. This occurs in the diffused population of fibro/adipogenic progenitors, which reside in different tissues - including the muscles - and normally express D2. Given the widespread diffusion of mesenchymal cells within the body, our results may explain at least partially the alterations in thyroid hormone levels that occur in vandetanib-treated patients. Our findings represent a step forward into the understanding of the mechanisms by which TKIs induce hypothyroidism and identify a resident cell population in which such an effect takes place.

Type 2 Deiodinase Thr92Ala Polymorphism and Aging Are Associated with a Decreased Pituitary Sensitivity to Thyroid Hormone.

Background: The DIO2 Thr92Ala polymorphism (rs225014), which occurs in about 15-30% of Caucasian people, determines a less efficient type 2 deiodinase (D2) enzyme. The aim of this study was to determine the impact of DIO2 Thr92Ala polymorphism on the serum thyrotropin (TSH) levels in thyroidectomized patients with hypothyroidism and to evaluate whether TSH levels and aging could be related, at pituitary level, to D2 activity. Methods: This prospective study was performed on 145 thyroid cancer patients, treated with total thyroidectomy, and undergoing radioiodine treatment after 3 weeks of levothyroxine (LT4) withdrawal. A mouse model has been used to determine D2 protein and mRNA levels in pituitary during aging. Results: Genetic analysis identified DIO2 Thr92Ala polymorphism in 56% of participants: 64/145 (44%) patients were homozygous wild type (WT) (Thr/Thr), 64 (44%) heterozygous (Thr/Ala), and 17 (12%) homozygous mutant (Ala/Ala). A significant negative relationship was observed between aging and the rise in serum TSH levels during LT4 withdrawal. However, this negative correlation found in WT was reduced in heterozygous and lost in mutant homozygous patients (Thr/Thr r = -0.45, p = 0.0002, 95% confidence interval [CI] -0.63 to -0.23; Ala/Thr r = -0.39, p = 0.0012, CI -0.60 to -0.67; and Ala/Ala r = -0.30, p = 0.2347; CI -0.70 to 0.20). Accordingly, when we compared the TSH measured in each patient to its theoretical value predicted from age, the TSH did not reach its putative target in 47% of WT patients, in 70% of Ala/Thr, and 76% of Ala/Ala carrying patients (p = 0.0036). This difference was lost in individuals older than 60 years, suggesting a decline of D2 associated with aging. The hypothesis that the pituitary D2 decreases with age was confirmed by the evidence that D2 mRNA and protein levels were lower in pituitary from old versus young mice. Conclusion: An age-related decline in TSH production in response to hypothyroidism was correlated with decreased D2 levels in pituitary. The presence of DIO2 homozygous Ala/Ala polymorphism was associated with a reduced level of TSH secretion in response to hypothyroidism, indicating a decreased pituitary sensitivity to serum thyroxine variation (Institutional Research Ethics board approval number no. 433/21).

Adherence to the Mediterranean Diet as a Modifiable Risk Factor for Thyroid Nodular Disease and Thyroid Cancer: Results From a Pilot Study.

Iodine deficiency is the most important established nutritional risk factor for the development of thyroid nodular disease. Nevertheless, to the best of our knowledge, to date no study focused on the association between the adherence to the Mediterranean diet (MD) and thyroid nodular disease. Adherence to the MD was evaluated using the PREvención con DIetaMEDiterránea (PREDIMED) questionnaire. Physical activity, smoking habits, and anthropometric parameters were studied. PREDIMED was used to evaluate the degree of adherence to the MD. Evaluation of fine needle aspiration cytology of thyroid lesions based on 2013 Italian thyroid cytology classification system. Cytology of thyroid nodules was carried out through sonography-guided fine-needle aspiration and patients were divided into 5 categories: TIR2, TIR3a, TIR3b, TIR4, and TIR5. The study population consisted of 794 subjects (554 females, 69.8%), aged 18-65 years, with BMIs ranging from 19.4 to 55.3 kg/m2. Thyroid nodular disease was present in 391 participants (49.2%), and the most frequent cytological categories was TIR2 (18.3 %), followed by a TIR4 (8.9 %). The presence of thyroid nodules was also significantly associated with the lowest adherence to the MD (OR 6.16, p < 0.001). Patients with TIR5 had the lower adherence to the MD (2.15 ± 1.12 score) compared to other TIRs (p < 0.001). The cytological category with high-risk of malignancy (TIR4/TIR5) was significantly associated with the lowest adherence to the MD (OR 137.55, p < 0.001) and PREDIMED score (OR = 0.33, p < 0.001, 95% IC = 0.26-0.41, R 2 = 0.462). At multiple regression analysis, PREDIMED score was the main predictor of both the presence of nodules (p < 0.001) and the cytological category with high-risk of malignancy (p < 0.001). At ROC analysis PREDIMED score ≤ 5 and ≤ 4 (p = 0.001) were the values that predicted the presence of thyroid nodular disease and cytological category with high-risk of malignancy, respectively. In conclusion, our study demonstrated that the low adherence to the MD is associated with the presence of thyroid nodular disease and in particular with those at high-risk of malignancy.

The Impact of Thyroid Diseases on Patients' Work Functioning: A Pilot Study.

OBJECTIVE: This study aimed to investigate the impact of thyroid diseases (TDs) on patients' work ability (WA) and related influencing factors. METHODS: A total of 150 TD workers and matched healthy controls were enrolled from May 2020 to November 2021. The Work Ability Index was used to assess the workers' perception of WA. RESULTS: Overall, TD workers reported a good WA, although with a significantly lower mean score compared with controls (39 ± 6 vs 43 ± 4, P < 0.001). Subjects with Graves disease and follicular carcinoma showed the worst WA perception. Suffering from a TD ( ß = -0.396, P < 0.001) and job duration ( ß = -0.173, P < 0.001) were associated with poorer WA. CONCLUSIONS: Better understanding the impact that TD may have on work functioning can inform an interdisciplinary management of TD workers to support their personal, social, and professional lives.

Predictive molecular pathology in metastatic thyroid cancer: the role of RET fusions.

BACKGROUND: Rearranged during transfection (RET) gene fusions are detected in 10-20% of thyroid cancer patients. Recently, RET fusion-positive metastatic thyroid cancers have attracted much attention owing to the FDA approval of two highly selective anti-RET tyrosine kinase inhibitors, namely, selpercatinib, and pralsetinib. AREAS COVERED: This review summarizes the available evidence on the biological and predictive role of RET gene fusions in thyroid carcinoma patients and the latest screening assays currently used to detect these genomic alterations in histological and cytological specimens. EXPERT OPINION: Management of advanced thyroid carcinoma has significantly evolved over the last decade thanks to the approval of three multikinase inhibitors, i.e. sorafenib, lenvatinib, cabozantinib, and of two selective RET-tyrosine inhibitors, i.e. selpercatinib and pralsetinib. In this setting, the detection of RET-fusions in advanced thyroid cancer specimens through the use of next-generation sequencing has become a commonly used strategy in clinical practice to select the best treatment options.

The relevance of T3 in the management of hypothyroidism.

Levothyroxine monotherapy has been the standard of care for treatment of hypothyroidism for more than 40 years. However, patients treated with levothyroxine have relatively lower serum tri-iodothyronine (T3) concentrations than the general population, and symptoms of hypothyroidism persist for some patients despite normalisation of thyroid-stimulating hormone (TSH) concentrations. The understanding that maintenance of normal T3 concentrations is the priority for the thyroid axis has redirected the clinical focus to serum T3 concentrations in patients with hypothyroidism. This Personal View explores whether it is currently feasible to identify patients who could be considered for liothyronine supplementation in combination with levothyroxine. Genetic profiling stands out as a potential future tool to identify patients who do not respond well to levothyroxine due to suboptimal peripheral thyroxine (T4) activation. Moreover, new slow-release liothyronine preparations are being developed to be trialled in these symptomatic patients, in an attempt to restore T3 concentrations and provide conclusive results for the use of T4 plus T3 combination therapy.

Combination of Lenvatinib and Pembrolizumab as Salvage Treatment for Paucicellular Variant of Anaplastic Thyroid Cancer: A Case Report.

Anaplastic thyroid cancer (ATC) is a rare but aggressive thyroid cancer, responsible for about 50% of all thyroid cancer-related deaths. During the last two decades, the development of a multimodal personalized approach resulted in an increased survival. Here, we present an unusual case of a 54-year old woman with a paucicellular metastatic ATC, a rare variant of ATC, who was treated with a combination of surgery, radiation therapy and cytotoxic chemotherapy. More than two years later, when the disease was rapidly growing, a combination of lenvatinib and pembrolizumab induced a partial tumor response of lung metastasis that persisted over 18 months. Paucicellular ATC may initially show a less aggressive behavior compared to other histological ATC variants. However, over the time, its clinical course can rapidly progress like common ATC. The combination of lenvatinib and pembrolizumab was effective as a salvage therapy for a long period of time.

Thyroid Hormone Action in Muscle Atrophy.

Skeletal muscle atrophy is a condition associated with various physiological and pathophysiological conditions, such as denervation, cachexia, and fasting. It is characterized by an altered protein turnover in which the rate of protein degradation exceeds the rate of protein synthesis, leading to substantial muscle mass loss and weakness. Muscle protein breakdown reflects the activation of multiple proteolytic mechanisms, including lysosomal degradation, apoptosis, and ubiquitin-proteasome. Thyroid hormone (TH) plays a key role in these conditions. Indeed, skeletal muscle is among the principal TH target tissue, where TH regulates proliferation, metabolism, differentiation, homeostasis, and growth. In physiological conditions, TH stimulates both protein synthesis and degradation, and an alteration in TH levels is often responsible for a specific myopathy. Intracellular TH concentrations are modulated in skeletal muscle by a family of enzymes named deiodinases; in particular, in muscle, deiodinases type 2 (D2) and type 3 (D3) are both present. D2 activates the prohormone T4 into the active form triiodothyronine (T3), whereas D3 inactivates both T4 and T3 by the removal of an inner ring iodine. Here we will review the present knowledge of TH action in skeletal muscle atrophy, in particular, on the molecular mechanisms presiding over the control of intracellular T3 concentration in wasting muscle conditions. Finally, we will discuss the possibility of exploiting the modulation of deiodinases as a possible therapeutic approach to treat muscle atrophy.

Long-term management of lenvatinib-treated thyroid cancer patients: a real-life experience at a single institution.

PURPOSE: The efficacy of lenvatinib for advanced and progressive radioactive iodine refractory differentiated thyroid cancer is well established. Herein, we retrospectively evaluated the long-term safety and efficacy of lenvatinib in 23 patients treated at a single Institution. METHODS: Clinical data of all patients treated for a differentiated thyroid cancer with lenvatinib from April 2015 to September 2020 were retrospectively analyzed. RESULTS: A total of 23 patients were included. In all, 21 patients received lenvatinib as first-line systemic therapy. Median age at initiation of lenvatinib treatment was 68 (44-90) years. Median duration of the study from initiation of lenvatinib to study end was 23 (2-65) months. The indication for lenvatinib treatment was documented progression of distant metastases in 20 patients and of locally advanced disease in the other 3 and median duration of lenvatinib therapy was 15 (2-64) months. Best treatment responses were: partial response in 6 patients, stable disease in 14, progressive disease in 1, and not evaluable in 2. Median progression-free survival was 25 months (95% CI: 12-40) and median overall survival was 46 months (95% CI: 28-65). Three patients had to discontinue lenvatinib treatment due to serious adverse events and no drug-related death was observed. Ten patients continued lenvatinib for more than 24 months and the only newly registered adverse event after this period of time was one case of G2 proteinuria. Six patients continued lenvatinib treatment beyond documented tumor progression due to oligoprogression or slowly progressive disease (median time 18.5 months, 8-42 months). A total of 14 patients were alive at the end of the study: 11 showed partial response/stable disease on lenvatinib, including 3 who had a stable disease after local ablative therapy for oligoprogressive metastases; 3 had to change treatment, including 2 for lenvatinib-related serious adverse events and 1 for progressive disease. CONCLUSIONS: Long-term lenvatinib treatment is safe and some patients may experience persistent long-term control of the disease. Late treatment-related AEs rarely occurred. Oligoprogressive and slowly progressive disease can be managed without treatment withdrawal as long as there are some clinical benefits.

Safety and Quality-of-Life Data from an Italian Expanded Access Program of Lenvatinib for Treatment of Thyroid Cancer.

Background: Lenvatinib, a multikinase inhibitor, is for progressive radioiodine-refractory-differentiated thyroid cancer (RR-DTC) patients. However, there are a lot of drug-related adverse events (AEs) that can affect the quality of life (QoL) of patients. The aims of this study were (a) to evaluate, and compared with other series, the safety of lenvatinib used in RR-DTC patients enrolled in an Italian expanded access program (EAP), and (b) to evaluate their QoL during treatment with lenvatinib. Methods: To evaluate the safety, we recorded and graded all AEs during the 6 months of lenvatinib treatment in 39 RR-DTC patients. We compared the safety profile of lenvatinib observed in our patients with that reported in the study of (E7080) levatinib in differentiated cancer of the thyroid (SELECT) and tumeurs thyroidiennes refractaires (TUTHYREF) network studies. Moreover, we evaluated the QoL in our series by using the European Organization for Research and Treatment (EORTC) Quality of Life Questionnaire-Core 30 and the pain visual analogue scale (VAS). Results: The most frequent AEs among our 39 RR-DTC patients were hypertension (80.5%), fatigue (58.3%), diarrhea (36.1%), stomatitis (33.3%), hand/foot syndrome (33.3%), and weight loss (30.5%). The most prevalent grade 3/4 AE was hypertension (25%). When compared with previous studies (i.e., SELECT and TUTHYREF), a significantly lower percentage of our patients experienced diarrhea, nausea, proteinuria, and weight loss. No statistically significant differences in the QoL of our patients evaluated before, during, and at the end of follow-up (6 months after starting the therapy) were found. However, a slight improvement of the general health and emotional and cognitive status associated with a slightly worsening of physical role and social functioning was observed during these 6 months. Pain, dyspnea, insomnia, and constipation moved toward better values, while fatigue, nausea and vomiting, appetite loss, and diarrhea worsened. By comparing the pain VAS, an overall reduction of the level of pain was found. Conclusions: The safety profile of the drug was similar to that already reported with some differences in the prevalence and severity of the AEs. Regarding the QoL, the EAP showed a trend of improvement of the global health status and a reduction of symptoms correlated to the disease. The clinical impact of fatigue, anorexia/weight loss and stomatitis, mainly due to the drug itself, continues to represent the major issue in the management of these patients.

Targeting the right population for T3 + T4 combined therapy: where are we now and where to next?

The universal applicability of levothyroxine (LT4) monotherapy for the treatment of hypothyroidism has been questioned in recent years. Indeed, it is now clear that about 10-15% of LT4-treated hypothyroid patients are dissatisfied with their treatment. It is plausible that this subset of hypothyroid patients may need T3 + T4 combined therapy to restore peripheral euthyroidism. To address this issue, many clinical trials have investigated the effect of T3 + T4 combinations versus standard LT4-based therapy. However, to date, results have been inconclusive, mainly due to the lack of markers that identify candidates for combination therapy. A breakthrough in this field came with the recent finding that several single-nucleotide polymorphisms in the deiodinase genes are associated with the persistence of hypothyroid symptoms in biochemically euthyroid LT4-treated patients, and are thus markers of candidates for combination therapy. In addition, whole-genome association studies are expanding our knowledge of other genes of the thyroid hormone (TH) pathway that affect serum TH levels. To target the right population for the T3 + T4 combined therapy, the next step is to translate these new findings into prospective trials. Hopefully, this will pave the way to personalized therapy for each hypothyroid patient.

The Thyroid Hormone Inactivator Enzyme, Type 3 Deiodinase, Is Essential for Coordination of Keratinocyte Growth and Differentiation.

Background: Thyroid hormones (THs) are key regulators of development, tissue differentiation, and maintenance of metabolic balance in virtually every cell of the body. Accordingly, severe alteration of TH action during fetal life leads to permanent deficits in humans. The skin is among the few adult tissues expressing the oncofetal protein type 3 deiodinase (D3), the TH inactivating enzyme. Here, we demonstrate that D3 is dynamically regulated during epidermal ontogenesis. Methods: To investigate the function of D3 in a postdevelopmental context, we used a mouse model of conditional epidermal-specific D3 depletion. Loss of D3 resulted in tissue hypoplasia and enhanced epidermal differentiation in a cell-autonomous manner. Results: Accordingly, wound healing repair and hair follicle cycle were altered in the D3-depleted epidermis. Further, in vitro ablation of D3 in primary culture of keratinocytes indicated that various markers of stratified epithelial layers were upregulated, thereby confirming the pro-differentiative action of D3 depletion and the consequent increased intracellular triiodothyronine levels. Notably, loss of D3 reduced the clearance of systemic TH in vivo, thereby demonstrating the critical requirement for epidermal D3 in the maintenance of TH homeostasis. Conclusion: In conclusion, our results show that the D3 enzyme is a key TH-signaling component in the skin, thereby providing a striking example of a physiological context for deiodinase-mediated TH metabolism, as well as a rationale for therapeutic manipulation of deiodinases in pathophysiological contexts.

The NANOG Transcription Factor Induces Type 2 Deiodinase Expression and Regulates the Intracellular Activation of Thyroid Hormone in Keratinocyte Carcinomas.

Type 2 deiodinase (D2), the principal activator of thyroid hormone (TH) signaling in target tissues, is expressed in cutaneous squamous cell carcinomas (SCCs) during late tumorigenesis, and its repression attenuates the invasiveness and metastatic spread of SCC. Although D2 plays multiple roles in cancer progression, nothing is known about the mechanisms regulating D2 in cancer. To address this issue, we investigated putative upstream regulators of D2 in keratinocyte carcinomas. We found that the expression of D2 in SCC cells is positively regulated by the NANOG transcription factor, whose expression, besides being causally linked to embryonic stemness, is associated with many human cancers. We also found that NANOG binds to the D2 promoter and enhances D2 transcription. Notably, blockage of D2 activity reduced NANOG-induced cell migration as well as the expression of key genes involved in epithelial-mesenchymal transition in SCC cells. In conclusion, our study reveals a link among endogenous endocrine regulators of cancer, thyroid hormone and its activating enzyme, and the NANOG regulator of cancer biology. These findings could provide the basis for the development of TH inhibitors as context-dependent anti-tumor agents.

Management of one patient with oligoprogressive thyroid cancer during treatment with lenvatinib.

Recent thyroid cancer guidelines found it reasonable to use local therapies during treatment with tyrosine kinase inhibitors (TKIs) in selected patients with oligoprogressive disease, namely, in the presence of a single progressing lesion in an otherwise TKI-responsive metastatic cancer. However, there is a lack of experience in the management of oligoprogressive thyroid cancers. This report illustrates the case of one patient with oligoprogressive thyroid cancer during therapy with lenvatinib. We found that the application of local ablative therapy in oligoprogressive disease prolonged the progression-free survival and thus extended the time to therapy interruption. However, the optimal care for TKI-treated oligoprogressive cancers remains unclear and needs to be investigated in prospective trials.