RESUMEN
Anaplastic thyroid cancer (ATC) is one of the deadliest human cancers and represents <2% of thyroid carcinomas. A therapeutic target for ATC is represented by anaplastic lymphoma kinase (ALK) rearrangements, involved in tumor growth. Crizotinib is an oral small-molecule tyrosine kinase inhibitor of the ALK, MET, and ROS1 kinases, approved in ALK-positive non-small cell lung cancer. Until now, the effect of crizotinib in "primary human ATC cells" (pATCs) with transforming striatin (STRN)-ALK fusion has not been reported in the literature. In this study, we aimed to obtain pATCs with STRN-ALK in vitro and evaluate the in vitro antineoplastic action of crizotinib. Thyroid surgical samples were obtained from 12 ATC patients and 6 controls (who had undergone parathyroidectomy). A total of 10/12 pATC cultures were obtained, 2 of which with transforming STRN-ALK fusion (17%). Crizotinib inhibited proliferation, migration, and invasion and increased apoptosis in 3/10 pATC cultures (2 of which with/1 without STRN-ALK), particularly in those with STRN-ALK. Moreover, crizotinib significantly inhibited the proliferation of AF cells (a continuous cell line obtained from primary ATC cells). In conclusion, the antineoplastic activity of crizotinib has been shown in human pATCs (with STRN-ALK) in preclinical studies in vitro, opening the way to future clinical evaluation in these patients.
Asunto(s)
Quinasa de Linfoma Anaplásico , Apoptosis , Proliferación Celular , Crizotinib , Inhibidores de Proteínas Quinasas , Carcinoma Anaplásico de Tiroides , Neoplasias de la Tiroides , Humanos , Crizotinib/farmacología , Carcinoma Anaplásico de Tiroides/tratamiento farmacológico , Carcinoma Anaplásico de Tiroides/patología , Quinasa de Linfoma Anaplásico/antagonistas & inhibidores , Quinasa de Linfoma Anaplásico/genética , Quinasa de Linfoma Anaplásico/metabolismo , Proliferación Celular/efectos de los fármacos , Inhibidores de Proteínas Quinasas/farmacología , Apoptosis/efectos de los fármacos , Neoplasias de la Tiroides/tratamiento farmacológico , Neoplasias de la Tiroides/patología , Neoplasias de la Tiroides/genética , Neoplasias de la Tiroides/metabolismo , Masculino , Femenino , Antineoplásicos/farmacología , Persona de Mediana Edad , Movimiento Celular/efectos de los fármacos , Anciano , Proteínas de Fusión Oncogénica/genética , Proteínas de Fusión Oncogénica/metabolismo , Células Tumorales Cultivadas , Línea Celular Tumoral , Proteínas de Unión a Calmodulina , Proteínas de la Membrana , Proteínas del Tejido NerviosoRESUMEN
Thyroid cancer is the most common (~90%) type of endocrine-system tumor, accounting for 70% of the deaths from endocrine cancers. In the last years, the high-throughput genomics has been able to identify pathways/molecular targets involved in survival and tumor progression. Targeted therapy and immunotherapy individually have many limitations. Regarding the first one, although it greatly reduces the size of the cancer, clinical responses are generally transient and often lead to cancer relapse after initial treatment. For the second one, although it induces longer-lasting responses in cancer patients than targeted therapy, its response rate is lower. The individual limitations of these two different types of therapies can be overcome by combining them. Here, we discuss MAPK pathway inhibitors, i.e., BRAF and MEK inhibitors, combined with checkpoint inhibitors targeting PD-1, PD-L1, and CTLA-4. Several mutations make tumors resistant to treatments. Therefore, more studies are needed to investigate the patient's individual tumor mutation burden in order to overcome the problem of resistance to therapy and to develop new combination therapies.
Asunto(s)
Melanoma , Neoplasias de la Tiroides , Humanos , Inhibidores de Puntos de Control Inmunológico/farmacología , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Melanoma/patología , Recurrencia Local de Neoplasia/tratamiento farmacológico , Inhibidores de Proteínas Quinasas/farmacología , Inhibidores de Proteínas Quinasas/uso terapéutico , Proteínas Tirosina Quinasas/metabolismo , Proteínas Proto-Oncogénicas B-raf/metabolismo , Neoplasias de la Tiroides/tratamiento farmacológico , Neoplasias de la Tiroides/genéticaRESUMEN
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.
Asunto(s)
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
INTRODUCTION: Oncogenic tyrosine kinases (TK) are enzymes that play a key role in cell growth and proliferation and their mutations can lead to uncontrolled cell growth and development of aggressive cancer. This knowledge has led to the development of new classes of drugs, Tyrosine kinase inhibitors (TKI). They target oncogenic kinases who are associated with advanced radioactive iodine (RAI) refractory TC, which is not able to uptake RAI anymore and/or still grows between consecutive treatments with Iodine 131 (I131). AREAS COVERED: Since Lenvatinib and Sorafenib approval, several other molecular inhibitors have been studied and then introduced for the treatment of aggressive and refractory thyroid cancer (TC), and, although the development of adverse effects or tumor resistance mechanisms, more and more compounds are still under investigation. The literature search was executed in PubMed and ClinicalTrials.gov to identify relevant articles and clinical trials published until December 2023. EXPERT OPINION: In the context of clinical trials, driven by the presence of specific molecular mutations or even in the absence of both conditions, systemic therapy TKIs are valuable weapons to be used in patients affected by aggressive forms of TC, waiting for further expansion of the treatment landscape with more efficacious and safer drugs.
RESUMEN
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.
Asunto(s)
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
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.
Asunto(s)
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
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.
Asunto(s)
Exoftalmia , Oftalmopatía de Graves , Humanos , Oftalmopatía de Graves/tratamiento farmacológico , Calidad de Vida , Diplopía , InflamaciónRESUMEN
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.
RESUMEN
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.
RESUMEN
BACKGROUND: Papillary thyroid carcinoma (PTC) is the most common type of differentiated TC, while medullary TC (MTC) accounts for 4%. The concomitant presence of PTC and MTC is rare. METHODS: This is a retrospective, single-center observational study conducted over 16 years (2001-2017). The data were collected from the clinical records of patients who underwent total thyroidectomy at the Endocrine Unit-Department of Medicine of the University Hospital of Pisa, Italy. RESULTS: Over 690 analyzed cases, 650 (94.2%) were exclusive DTC, 19 exclusive MTC (2.75%) and 5 PTC/MTC (0.7%). No case of mixed medullary/follicular TC or hereditary MTC (familial MTC/multiple endocrine neoplasia type 2) was found. Among the five PTC/MTC cases, there was a male prevalence (M:F = 3:2), and all PTC components were at stage I, whereas 40% of MTC were at stage I and III and 20% of MTC were at stage II; microPTC (mPTC) was prevalent (80%) and also microMTCs were frequent (40%); 60% of MTC patients recovered, while 40% of patients developed metastatic disease. The search for germline mutations of the RET gene resulted in being negative in all cases. CONCLUSIONS: The incidence of PTC/MTC has been increasing over the past 30 years. The etiology of PTC/MTC forms is still unknown, and although this simultaneous occurrence could be only a coincidence, we cannot exclude the hypothesis of a shared genetic origin.
Asunto(s)
Carcinoma Medular , Carcinoma Papilar , Neoplasias de la Tiroides , Humanos , Masculino , Carcinoma Papilar/genética , Carcinoma Papilar/cirugía , Carcinoma Papilar/patología , Estudios Observacionales como Asunto , Proteínas Proto-Oncogénicas c-ret/genética , Estudios Retrospectivos , Cáncer Papilar Tiroideo/genética , Cáncer Papilar Tiroideo/cirugía , Neoplasias de la Tiroides/genética , Neoplasias de la Tiroides/cirugía , Neoplasias de la Tiroides/patología , FemeninoRESUMEN
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.
RESUMEN
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.
Asunto(s)
Enfermedad de Hashimoto , Hipotiroidismo , Tiroiditis Autoinmune , Enfermedad de Hashimoto/complicaciones , Humanos , Peróxido de Hidrógeno , Hipotiroidismo/tratamiento farmacológico , Inositol/uso terapéutico , Tiroiditis Autoinmune/complicaciones , TirotropinaRESUMEN
Since the beginning of the pandemic, numerous risk factors have been associated with SARS-CoV-2 infection and COVID-19 outcomes, such as older age, male sex, and the presence of comorbidities, such as hypertension, obesity, and diabetes. Preliminary data also suggest epidemiological association between SARS-CoV-2 infection and systemic autoimmune disease. For this reason, we investigated if patients affected by autoimmune thyroid disorders (AITD) are at risk of developing SARS-CoV-2 infection or COVID-19 disease. From April to September 2020, we have conducted a telephone survey that included 515 consecutive unselected patients with known thyroid disorders, of which 350 were affected by AITD. All 11 definitive diagnosis of COVID-19 (def-sympt-COVID-19) belonged to the AITD group, while the rest 14 cases highly suspected for COVID-19 (suspect-sympt-COVID-19) were equally detected in both group (7 in AITD and 7 in not-AITD). The overall prevalence of symptomatic COVID-19 (def-sympt-COVID-19 + suspect-sympt-COVID-19), recorded in the 350 AITD population was statistically significant higher compared to that reported in the Italian and Tuscan general population at the same time period of the present survey (18/350 = 5.14% vs 516/100000 = 0.51% [p < 0.001; OR = 10.45, 95% CI 6.45-16.92] and vs 394/100000 = 0.39% [p < 0.001; OR = 13.70, 95% CI 8.44-22.25], respectively). Therefore, our results suggest a higher prevalence of SARS-CoV-2 infection and COVID-19 disease in patients with AITD.