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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.
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Hipotiroidismo , Tiroxina , Humanos , Hipotiroidismo/tratamiento farmacológico , Hipotiroidismo/epidemiología , Tiroxina/uso terapéutico , Tiroxina/administración & dosificación , Masculino , Femenino , Estudios Retrospectivos , Persona de Mediana Edad , Anciano , Gastropatías/tratamiento farmacológico , Tirotropina/sangre , Adulto , Terapia de Reemplazo de Hormonas/métodos , Neoplasias Gástricas/tratamiento farmacológicoRESUMEN
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.
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Enfermedades Cardiovasculares , Hipotiroidismo , Humanos , Hipotiroidismo/complicaciones , Hipotiroidismo/metabolismo , Hipotiroidismo/epidemiología , Hipotiroidismo/fisiopatología , Enfermedades Cardiovasculares/etiología , Enfermedades Cardiovasculares/metabolismo , Hormonas Tiroideas/metabolismo , Hormonas Tiroideas/uso terapéutico , Tiroxina/uso terapéutico , Factores de RiesgoRESUMEN
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.
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Hipotiroidismo , Intolerancia a la Lactosa , Tiroxina , Humanos , Intolerancia a la Lactosa/tratamiento farmacológico , Tiroxina/uso terapéutico , Tiroxina/farmacocinética , Hipotiroidismo/tratamiento farmacológico , Hipotiroidismo/metabolismo , Lactosa , Femenino , Síndromes de Malabsorción/tratamiento farmacológico , Síndromes de Malabsorción/metabolismo , Masculino , Persona de Mediana Edad , Tirotropina/sangre , Tirotropina/metabolismo , AdultoRESUMEN
BACKGROUND:
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Inositol , Obesidad , Síndrome del Ovario Poliquístico , Inositol/uso terapéutico , Humanos , Femenino , Síndrome del Ovario Poliquístico/tratamiento farmacológico , Síndrome del Ovario Poliquístico/metabolismo , Obesidad/metabolismo , Obesidad/tratamiento farmacológico , Resistencia a la Insulina/fisiologíaRESUMEN
The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the etiological culprit of COronaVIrus Disease 19 (COVID-19), can enter the cells via the angiotensin-converting enzyme 2 (ACE2) receptor, which has been found in several tissues including in endocrine organs, such as the ovaries, testes, pancreas, and thyroid. Several thyroid disorders have been associated with SARS-CoV-2 infection [subacute thyroiditis (SAT), thyrotoxicosis, and non-thyroidal illness syndrome (NTIS)] and, in part, they are believed to be secondary to the local virus replication within the gland cells. However, as documented for other viruses, SARS-CoV-2 seems to interfere with several aspects of the immune system, inducing the synthesis of autoantibodies and triggering latent or new onset autoimmune disease (AID), including autoimmune thyroid disease (AITD), such as Hashimoto Thyroiditis (HT) and Graves' disease (GD). Several mechanisms have been hypothesized to explain this induction of autoimmunity by SARS-CoV-2 infection: the immune system hyper-stimulation, the molecular mimicry between the self-antigens of the host and the virus, neutrophils extracellular traps, and finally, the virus induced transcriptional changes in the immune genes; nonetheless, more evidence is needed especially from large, long-term cohort studies involving COVID-19 patients, to establish or reject this pathogenetic relationship.
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Background: Vitamins are involved in various human physiological and biochemical mechanisms due to their antioxidant properties and their ability to enhance the immune response. Deficiency of some serum vitamins has been reported to be associated with an increased risk of developing cancer, including thyroid cancer. However, medical literature dealing with cholecalciferol supplementation was not able to show the potential of this intervention in cancer prevention. The aim of this paper is to highlight the association between lower serum vitamins levels and papillary thyroid cancer occurrence. Methods: This case-control study was conducted between September 2018 and October 2019. Cases were defined as patients with histologically diagnosed papillary thyroid cancer who underwent thyroidectomy were retrospectively recruited and serum levels of various vitamins were assessed by examining their relationships with clinical, pathological and molecular data (n=51). Controls matched on sex and thyroid surgery were randomly selected from the same population (n=49). Results: In this study, serum concentrations of vitamins A and E in neoplastic patients were significantly lower than in controls (1.40 vs. 1.78, P<0.003 and 23.9 vs. 29.1, P<0.003, respectively). Serum concentrations of vitamin D and methylmalonic acid were borderline significantly low (15.6 vs. 17.9, P=0.06 and 100.3 vs. 110.4, P=0.055, respectively), while homocysteine was statistically similar in the two groups. Furthermore, serum vitamin levels were compared with the pathological characteristics of cancer patients, and vitamin D concentrations were significantly lower in BRAF-positive than in BRAF-negative neoplastic patients (8.2 vs. 16.0, P=0.021). On the other hand, no significant differences were observed in the correlation between serum levels of vitamins and other pathological characteristics, in particular with regard to lymph node metastases. Conclusions: In conclusion, albeit with the analysis of a limited sample, this study highlighted the phenomenon that deficiencies in vitamins A and E can be associated with a higher frequency of occurrence of papillary thyroid cancer.
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Breast cancer (BC), the most commonly diagnosed malignancy, frequently metastasizes to the bone, lungs, brain and liver at advanced stages, whereas the thyroid gland represents a rare target site for secondary disease. We examined the most recent literature about thyroid metastasis (TM) from BC after we encountered a peculiar case of a 71-year-old woman who developed sudden dysphagia, severe hypothyroidism and hypoparathyroidism due to TM 18 years after the diagnosis of her primary cancer. Based on published data, the prevalence of TM in BC ranges from 3% to 34%, with a median onset time of 48.2 months, although longer time intervals are not infrequent. TM negatively impacts the prognosis of these patients, however thyroid surgery can limit the local disease burden. Therefore, we suggest that clinicians involved in the follow-up care of BC patients should consider a differential diagnosis of secondary thyroid malignancy when incidental lesions are diagnosed during radiological evaluations or local symptoms affect the cervical region, even many years after the diagnosis of the primary cancer.
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In the original publication [...].
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INTRODUCTION: Thyroid eye disease (TED) is an autoimmune disease characterized by inflammation of orbital and extraocular muscles. It induces proptosis and diplopia, leading to a worsening of quality of life (QoL) because of its impact on physical appearance, and visual function. The natural history involves an 'active TED,' which is an autoimmune inflammatory response targeting orbital soft tissues, and 'inactive TED,' where there is tissue expansion remodeling. To date, glucocorticoids represent the main medical therapy, even if often ineffective and associated with side effects. AREAS COVERED: In TED, the autoimmune process leads to production of TSH-R and IGF-1 R autoantibodies. This induces inflammatory changes in the orbital tissue, and activation of fibroblasts with accumulation of glycosaminoglycans, leading to consequent proptosis, and diplopia. In two previous randomized, double-masked, placebo-controlled, parallel-group, multicenter trials, teprotumumab has been shown to be effective in improving proptosis, inflammation, diplopia, and QoL. More recently, it has been shown that teprotumumab is also effective in chronic-inactive TED. Teprotumumab was approved by the FDA on 21 January 2020 for the treatment of TED. EXPERT OPINION: For the above-mentioned reasons teprotumumab represents a potential first line therapy for TED that could replace the use of steroids in the next future.
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Exoftalmia , Oftalmopatía de Graves , Humanos , Oftalmopatía de Graves/tratamiento farmacológico , Calidad de Vida , Diplopía , InflamaciónRESUMEN
CONTEXT: Preconception optimization of thyroid function in women with Hashimoto thyroiditis (HT) is highly recommended to prevent/reduce the risk of thyroid insufficiency at early gestation. OBJECTIVE: This work aimed to evaluate the prevalence of first-trimester thyroid insufficiency in HT women with preconception thyrotropin (T0-TSH) values consistently less than or equal to 2.5 mIU/L with or without levothyroxine (LT4) treatment, and to calculate T0-TSH cutoffs that best preconceptionally identified HT women requiring first-trimester LT4 adjustment/prescription. METHODS: Serum TSH was obtained at 4- to 6-week intervals from 260 HT pregnant women (122 on LT4 [Hypo-HT]; 138 euthyroid without LT4 [Eu-HT]), prospectively followed from preconception up to pregnancy term. Receiver operating characteristic (ROC) curves were plotted to identify T0-TSH cutoffs best predicting first-trimester TSH levels greater than 2.5 mIU/L (diagnostic criterion [DC] 1) and greater than 4.0 mIU/L (DC 2). RESULTS: At first trimester, TSH was greater than 2.5 mIU/L in approximately 30% of both Hypo-HT and Eu-HT women, and greater than 4.0 mIU/L in 19.7% Hypo-HT and 10.1% Eu-HT women (P = .038). The optimal ROC-based T0-TSH cutoffs found were 1.24 mIU/L/1.74 mIU/L in Hypo-HT, and 1.73 mIU/L/2.07 mIU/L in Eu-HT women, for DC 1 and DC 2, respectively. T0-TSH values exceeding these cutoffs resulted in a statistically significantly increased risk of first-trimester thyroid insufficiency (odds ratio [OR] [95% CI)] 15.92 [5.06-50.15] and 16.68 [5.13-54.24] in Hypo-HT; 16.14 [6.47-40.30] and 17.36 [4.30-70.08] in Eu-HT women, for DC 1 and DC 2, respectively). CONCLUSION: The preconception TSH cutoffs that guaranteed a first-trimester TSH less than 2.5 mU/L in hypothyroid- and euthyroid-HT women were, respectively, almost 50% (1.24 mU/L) and 30% (1.73 mU/L) lower than this gestational target, and 1.74 mU/L and 2.07 mU/L in hypothyroid- and euthyroid-HT women, respectively, for a gestational target of 4.0 mU/L.
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Enfermedad de Hashimoto , Hipotiroidismo , Complicaciones del Embarazo , Femenino , Embarazo , Humanos , Enfermedad de Hashimoto/epidemiología , Complicaciones del Embarazo/epidemiología , Complicaciones del Embarazo/diagnóstico , Hipotiroidismo/diagnóstico , Tirotropina , Tiroxina , Pruebas de Función de la TiroidesRESUMEN
[This corrects the article DOI: 10.3389/fendo.2012.00094.].
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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 (H2O2) 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.
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Enfermedad de Hashimoto , Hipotiroidismo , Tiroiditis Autoinmune , Enfermedad de Hashimoto/complicaciones , Humanos , Peróxido de Hidrógeno , Hipotiroidismo/tratamiento farmacológico , Inositol/uso terapéutico , Tiroiditis Autoinmune/complicaciones , TirotropinaRESUMEN
BACKGROUND: The possible relationships between breast and thyroid diseases have been reported in the literature. The purpose of our study was to evaluate the occurrence of histologically verified thyroid pathologies in women who were diagnosed with breast cancer and, after mastectomy/quadrantectomy complemented by oncological treatment, were thyroidectomized based on their periodic thyroid evaluation. PATIENTS AND METHODS: Our series consist of 31 women with a mean age of 62.9 ± 10.9 years (range, 45-81) treated for breast cancer (18 right-sided, 11 left-sided, and 2 bilateral), of whom 29 were thyroidectomized, since two women who developed Graves' disease refused thyroidectomy. These 31 women belong to a cohort of 889 women who referred to the Breast Surgery Unit of our university hospital during the period January 2010 through December 2020. RESULTS: The mean time interval between breast cancer and thyroid pathologies was 48.1 ± 23.4 months (range, 12-95). The final diagnosis at histopathology was infiltrating ductal breast carcinoma in 26 women (with 2/26 patients having bilateral carcinoma) and infiltrating lobular breast carcinoma in the other 5 women. Ten of the twenty-nine thyroidectomized women (34.5%) had a thyroid malignancy on histology: five papillary carcinomas, three papillary micro-carcinomas and two follicular carcinomas. Two of the five women with papillary carcinoma also had histological evidence of chronic lymphocytic thyroiditis/Hashimoto's thyroiditis, which was also detected in another five women with benign thyroid diseases. CONCLUSIONS: We suggest that breast cancer survivors should be made aware of the possible increased risk of thyroid pathologies (including thyroid malignancy) so that they can undergo screening and follow-up.
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Benefits of the omega-3 polyunsaturated fatty acids (PUFA) on a number of clinical disorders, including autoimmune diseases, are widely reported in the literature. One major dietary source of PUFA are fish, particularly the small oily fish, like anchovy, sardine, mackerel and others. Unfortunately, fish (particularly the large, top-predator fish like swordfish) are also a source of pollutants, including the heavy metals. One relevant heavy metal is mercury, a known environmental trigger of autoimmunity that is measurable inside the thyroid. There are a number of interactions between the omega-3 PUFA and thyroid hormones, even at the level of the thyroid hormone transport proteins. Concerning the mechanisms behind the protection from/amelioration of autoimmune diseases, including thyroiditis, that are caused by the omega-3 PUFA, one can be the decreased production of chemokines, a decrease that was reported in the literature for other nutraceuticals. Recent studies point also to the involvement of resolvins. The intracellular increase in resolvins is associated with the tissue protection from inflammation that was observed in experimental animals after coadministration of omega-3 PUFA and thyroid hormone. After having presented data on fish consumption at the beginning, we conclude our review by presenting data on the market of the dietary supplements/nutraceuticals. The global omega-3 products market was valued at USD 2.10 billion in 2020, and was projected to go up at a compound annual growth rate of 7.8% from 2020 to 2028. Among supplements, fish oils, which are derived mainly from anchovies, are considered the best and generally safest source of omega-3. Taking into account (i) the anti-autoimmunity and anti-cancer properties of the omega-3 PUFA, (ii) the increasing incidence of both autoimmune thyroiditis and thyroid cancer worldwide, (iii) the predisposing role for thyroid cancer exerted by autoimmune thyroiditis, and (iv) the risk for developing metabolic and cardiovascular disorders conferred by both elevated/trendwise elevated serum TSH levels and thyroid autoimmunity, then there is enough rationale for the omega-3 PUFA as measures to contrast the appearance and/or duration of Hashimoto's thyroiditis as well as to correct the slightly elevated serum TSH levels of subclinical hypothyroidism.
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Enfermedades Autoinmunes , Contaminantes Ambientales , Ácidos Grasos Omega-3 , Neoplasias de la Tiroides , Tiroiditis Autoinmune , Animales , Ácidos Grasos , Ácidos Grasos Omega-3/metabolismo , Ácidos Grasos Insaturados/metabolismo , Peces/metabolismo , TirotropinaRESUMEN
Introduction: Thyroid function tests (TFT) are extensively used in daily clinical practice. Here, we described a case of incongruent TFT both in a pregnant woman and in her newborn. Case presentation: A 32-year-old woman, diagnosed with autoimmune thyroiditis during her first pregnancy, was monitored during her second gestation. At week 5 + 2 days, thyroid-stimulating hormone (TSH) and free thyroxine (FT4) values (Dimension VISTA 1500, Siemens Healthineers) were within normal limits. At week 19 + 5 days, TSH remained normal while FT4 increased approximately by three-fold. FT4 inconsistency was with both TSH and the clinical status since she continued to be clinically euthyroid. On the same serum sample, thyroid autoantibodies were negative. At week 25 + 4 days, the patient complained of palpitations and dyspnea, with tachycardia. Even though TSH was normal, high levels of both FT4 and free triiodothyronine (FT3) were interpreted as evidence of thyroid overactivity and methimazole was started. TFT of the pregnant woman continued to be monitored throughout gestation. Postpartum FT4 and FT3 gradually returned to normal. TFT, performed on the daughter's serum, 3 days after birth, showed the same inconsistency as her mother but without clinical signs of congenital hyperthyroidism. Based on the clinical and laboratory setting, the presence of circulating autoantibodies against T3 and T4 (THAb) was suspected and demonstrated by radioimmunoprecipitation. Conclusion: Analytical interferences should be supposed when TFT do not fit with the clinical picture and despite their infrequency, THAb must also be considered. To our knowledge, this is the first case describing the passage of THAb to the newborn.
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PURPOSE: Indole-3-acetic acid is a protein-bound indolic uremic toxin deriving from tryptophan metabolism. Increased levels are associated with higher thrombotic risk and both cardiovascular and all-cause mortality. An emerging biomarker of cardiovascular disease is the monocyte-to-high-density lipoprotein ratio (MHR). The main purpose of this study was to investigate the association of indole-3-acetic acid with MHR and other markers of cardiovascular risk in patients with chronic kidney disease (CKD). METHODS: We enrolled 61 non-dialysis CKD patients and 6 dialysis patients. Indole-3-acetic acid levels were measured with ELISA technique. RESULTS: In the whole cohort of 67 patients, indole-3-acetic acid was directly related to Ca × P (ρ = 0.256; P = 0.0365) and MHR (ρ = 0.321; P = 0.0082). In the 40 patients with previous cardiovascular events, indole-3-acetic acid correlated with uric acid (r = 0.3952; P = 0.0116) and MHR (ρ = 0.380; P = 0.0157). MHR was related with fibrinogen (ρ = 0.426; P = 0.0010), arterial hypertension (ρ = 0.274; P = 0.0251), C-reactive protein (ρ = 0.332; P = 0.0061), gender (ρ = - 0.375; P = 0.0017; 0 = male, 1 = female), and CKD stage (ρ = 0.260; P = 0.0337). A multiple regression analysis suggested that indole-3-acetic acid might be an independent predictor of MHR. CONCLUSION: This study shows a significant association between indole-3-acetic acid and MHR. Prospective studies are required to evaluate if decreasing indole-3-acetic acid concentrations may reduce MHR levels and cardiovascular events and improve clinical outcomes.
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Enfermedades Cardiovasculares , Insuficiencia Renal Crónica , Biomarcadores/metabolismo , Enfermedades Cardiovasculares/etiología , Enfermedades Cardiovasculares/metabolismo , HDL-Colesterol , Femenino , Humanos , Ácidos Indolacéticos , Lipoproteínas HDL , Masculino , Monocitos , Insuficiencia Renal Crónica/complicaciones , Insuficiencia Renal Crónica/metabolismoRESUMEN
INTRODUCTION: The most common altered signaling found in aggressive iodine-refractory thyroid cancers derived from follicular cells (RAI-TC) are RTK, MAPK, PI3K, WNT, BRAF, RAS, RET, and TP53. Tyrosine Kinase Inhibitors (TKI) are multi-kinase inhibitors able to act against different pathways, that elicit an anti-neoplastic activity. AREAS COVERED: The aim of this paper is to review recent novel molecular therapies of RAI-TC. Recently, sorafenib and lenvatinib, have been approved for the treatment of aggressive RAI-TC. Other studies are evaluating vandetanib and selumetinib in RAI-TC. Furthermore, preliminary studies have evaluated dabrafenib, and vemurafenib in BRAF mutated RAI-TC patients to re-induce 131-iodine uptake. The interplay between cells of the immune system and cancer cells can be altered by immune checkpoints inhibitors. The expression of PDL1 in RAI-TC was related to tumor recurrence and poor survival. Several clinical trials are investigating a combination of different therapies, such as lenvatinib and pembrolizumab. EXPERT OPINION: Mechanisms of resistance to TKIs inhibitors can be of intrinsic or acquired origin. An acquired resistance to lenvatinib, or sorafenib can be due to upregulation of FGFR; therefore, anti-FGFR agents are evaluated. A new strategy is to combine TKIs with immunotherapy. Several studies are evaluating lenvatinib and pembrolizumab in RAI-TC patients.
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Antineoplásicos , Quinolinas , Neoplasias de la Tiroides , Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico , Humanos , Recurrencia Local de Neoplasia/tratamiento farmacológico , Compuestos de Fenilurea/uso terapéutico , Inhibidores de Proteínas Quinasas/farmacología , Inhibidores de Proteínas Quinasas/uso terapéutico , Quinolinas/farmacología , Quinolinas/uso terapéutico , Transducción de Señal , Sorafenib/uso terapéutico , Neoplasias de la Tiroides/tratamiento farmacológico , Neoplasias de la Tiroides/patologíaRESUMEN
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 131I 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 (BRAFV600E inhibitor) and trametinib (MEK inhibitor) for the treatment of BRAFV600E-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.
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Thyroid cancer (TC) is the eighth most frequently diagnosed cancer worldwide with a rising incidence in the past 20 years. Surgery is the primary strategy of therapy for patients with medullary TC (MTC) and differentiated TC (DTC). In DTC patients, radioactive iodine (RAI) is administered after thyroidectomy. Neck ultrasound, basal and thyroid-stimulating hormone-stimulated thyroglobulin are generally performed every three to six months for the first year, with subsequent intervals depending on initial risk assessment, for the detection of possible persistent/recurrent disease during the follow up. Distant metastases are present at the diagnosis in â¼5 % of DTC patients; up to 15 % of patients have recurrences during the follow up, with a survival reduction (70 %-50 %) at 10-year. During tumor progression, the iodide uptake capability of DTC cancer cells can be lost, making them refractory to RAI, with a negative impact on the prognosis. Significant advances have been done recently in our understanding of the molecular pathways implicated in the progression of TCs. Several drugs have been developed, which inhibit signaling kinases or oncogenic kinases (BRAFV600E, RET/PTC), such as those associated with Platelet-Derived Growth Factor Receptor and Vascular Endothelial Growth Factor Receptor. Tyrosine kinase receptors are involved in cancer cell proliferation, angiogenesis, and lymphangiogenesis. Several tyrosine kinase inhibitors (TKIs) are emerging as new treatments for DTC, MTC and anaplastic TC (ATC), and can induce a clinical response and stabilize the disease. Lenvatinib and sorafenib reached the approval for RAI-refractory DTC, whereas cabozantinib and vandetanib for MTC. These TKIs extend median progression-free survival, but do not increase the overall survival. Severe side effects and drug resistance can develop in TC patients treated with TKIs. Additional studies are needed to identify a potential effective targeted therapy for aggressive TCs, according to their molecular characterization.