RESUMEN
Lenvatinib is a tyrosine kinase inhibitor (TKI) with antiproliferative and antiangiogenic effects indicated for the treatment of progressive, locally advanced or metastatic progressive thyroid carcinoma, refractory to radioactive iodine therapy. Antiangiogenic therapies induce ischemic necrosis of tumor tissue, with increased risk of hemorrhagic complications. The management of hemorrhagic risk is based on precautionary measures and for any surgical procedure, it is advised to interrupt the treatment in order to avoid complications. 'Flare-up' of tumor activity may follow TKI interruption. However, it is not known if continuing TKIs during minimally invasive interventions is safe. We report here the first case in which an embolization of metastasis is performed without interrupting lenvatinib treatment. The procedure was successful and free of complications.
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Adenoma Oxifílico/tratamiento farmacológico , Embolización Terapéutica , Compuestos de Fenilurea/administración & dosificación , Quinolinas/administración & dosificación , Neoplasias de la Tiroides/tratamiento farmacológico , Adenoma Oxifílico/diagnóstico por imagen , Adenoma Oxifílico/patología , Inhibidores de la Angiogénesis/administración & dosificación , Inhibidores de la Angiogénesis/efectos adversos , Terapia Combinada , Humanos , Ilion/efectos de los fármacos , Ilion/patología , Radioisótopos de Yodo/administración & dosificación , Masculino , Persona de Mediana Edad , Metástasis de la Neoplasia , Estadificación de Neoplasias , Compuestos de Fenilurea/efectos adversos , Quinolinas/efectos adversos , Neoplasias de la Tiroides/diagnóstico por imagen , Neoplasias de la Tiroides/patologíaRESUMEN
BACKGROUND: The purpose of the study was to evaluate in a sample of insulin-treated diabetic patients, with type 1 or type 2 diabetes, the psychometric characteristics of the Italian version of the DEPS-R scale, a diabetes-specific self-report questionnaire used to analyze disordered eating behaviors. METHODS: The study was performed on 211 consecutive insulin-treated diabetic patients attending two specialist centers. Lifetime prevalence of eating disorders (EDs) according to DSM-IV and DSM-5 criteria were assessed by means of the Module H of the Structured Clinical Interview for DSM IV Axis I Disorder and the Module H modified, according to DSM-5 criteria. The following questionnaires were administered: DEPS-R and the Eating Disorder Inventory - 3 (EDI-3). Test/retest reproducibility was assessed on a subgroup of 70 patients. The factorial structure, internal consistency, test-retest reliability and concurrent validity of DEPS-R were assessed. RESULTS: Overall, 21.8% of the sample met criteria for at least one DSM-5 diagnosis of ED. A "clinical risk" of ED was observed in 13.3% of the sample. Females displayed higher scores at DEPS-R, a higher percentage of at least one diagnosis of ED and a higher clinical risk for ED. A high level of reproducibility and homogeneity of the scale were revealed. A significant correlation was detected between DEPS-R and the 3 ED risk scales of EDI-3. CONCLUSIONS: The data confirmed the overall reliability and validity of the scale. In view of the significance and implications of EDs in diabetic patients, it should be conducted a more extensive investigation of the phenomenon by means of evaluation instruments of demonstrated validity and reliability.
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Diabetes Mellitus Tipo 1 , Diabetes Mellitus Tipo 2 , Trastornos de Alimentación y de la Ingestión de Alimentos/diagnóstico , Encuestas y Cuestionarios/normas , Adulto , Conducta Alimentaria , Femenino , Humanos , Italia , Masculino , Psicometría , Reproducibilidad de los ResultadosRESUMEN
Autoimmune thyroid diseases (AITD) are common, affecting 2-5% of the general population. Individuals with positive thyroid peroxidase antibodies (TPOAbs) have an increased risk of autoimmune hypothyroidism (Hashimoto's thyroiditis), as well as autoimmune hyperthyroidism (Graves' disease). As the possible causative genes of TPOAbs and AITD remain largely unknown, we performed GWAS meta-analyses in 18,297 individuals for TPOAb-positivity (1769 TPOAb-positives and 16,528 TPOAb-negatives) and in 12,353 individuals for TPOAb serum levels, with replication in 8,990 individuals. Significant associations (P<5×10(-8)) were detected at TPO-rs11675434, ATXN2-rs653178, and BACH2-rs10944479 for TPOAb-positivity, and at TPO-rs11675434, MAGI3-rs1230666, and KALRN-rs2010099 for TPOAb levels. Individual and combined effects (genetic risk scores) of these variants on (subclinical) hypo- and hyperthyroidism, goiter and thyroid cancer were studied. Individuals with a high genetic risk score had, besides an increased risk of TPOAb-positivity (OR: 2.18, 95% CI 1.68-2.81, Pâ=â8.1×10(-8)), a higher risk of increased thyroid-stimulating hormone levels (OR: 1.51, 95% CI 1.26-1.82, Pâ=â2.9×10(-6)), as well as a decreased risk of goiter (OR: 0.77, 95% CI 0.66-0.89, Pâ=â6.5×10(-4)). The MAGI3 and BACH2 variants were associated with an increased risk of hyperthyroidism, which was replicated in an independent cohort of patients with Graves' disease (OR: 1.37, 95% CI 1.22-1.54, Pâ=â1.2×10(-7) and OR: 1.25, 95% CI 1.12-1.39, Pâ=â6.2×10(-5)). The MAGI3 variant was also associated with an increased risk of hypothyroidism (OR: 1.57, 95% CI 1.18-2.10, Pâ=â1.9×10(-3)). This first GWAS meta-analysis for TPOAbs identified five newly associated loci, three of which were also associated with clinical thyroid disease. With these markers we identified a large subgroup in the general population with a substantially increased risk of TPOAbs. The results provide insight into why individuals with thyroid autoimmunity do or do not eventually develop thyroid disease, and these markers may therefore predict which TPOAb-positives are particularly at risk of developing clinical thyroid dysfunction.
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Autoanticuerpos/genética , Enfermedad de Graves/genética , Enfermedad de Hashimoto/genética , Yoduro Peroxidasa/genética , Autoanticuerpos/aislamiento & purificación , Sitios Genéticos , Estudio de Asociación del Genoma Completo , Enfermedad de Graves/patología , Enfermedad de Hashimoto/patología , Humanos , Yoduro Peroxidasa/inmunología , Factores de Riesgo , Tiroiditis Autoinmune , Tirotropina/metabolismoRESUMEN
Thyroid hormone is essential for normal metabolism and development, and overt abnormalities in thyroid function lead to common endocrine disorders affecting approximately 10% of individuals over their life span. In addition, even mild alterations in thyroid function are associated with weight changes, atrial fibrillation, osteoporosis, and psychiatric disorders. To identify novel variants underlying thyroid function, we performed a large meta-analysis of genome-wide association studies for serum levels of the highly heritable thyroid function markers TSH and FT4, in up to 26,420 and 17,520 euthyroid subjects, respectively. Here we report 26 independent associations, including several novel loci for TSH (PDE10A, VEGFA, IGFBP5, NFIA, SOX9, PRDM11, FGF7, INSR, ABO, MIR1179, NRG1, MBIP, ITPK1, SASH1, GLIS3) and FT4 (LHX3, FOXE1, AADAT, NETO1/FBXO15, LPCAT2/CAPNS2). Notably, only limited overlap was detected between TSH and FT4 associated signals, in spite of the feedback regulation of their circulating levels by the hypothalamic-pituitary-thyroid axis. Five of the reported loci (PDE8B, PDE10A, MAF/LOC440389, NETO1/FBXO15, and LPCAT2/CAPNS2) show strong gender-specific differences, which offer clues for the known sexual dimorphism in thyroid function and related pathologies. Importantly, the TSH-associated loci contribute not only to variation within the normal range, but also to TSH values outside the reference range, suggesting that they may be involved in thyroid dysfunction. Overall, our findings explain, respectively, 5.64% and 2.30% of total TSH and FT4 trait variance, and they improve the current knowledge of the regulation of hypothalamic-pituitary-thyroid axis function and the consequences of genetic variation for hypo- or hyperthyroidism.
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Hipertiroidismo/genética , Hipotiroidismo/genética , Glándula Tiroides , Tirotropina/genética , Tiroxina/sangre , Femenino , Estudio de Asociación del Genoma Completo , Humanos , Hipertiroidismo/sangre , Hipotiroidismo/sangre , Masculino , Fenotipo , Polimorfismo Genético , Polimorfismo de Nucleótido Simple , Caracteres Sexuales , Transducción de Señal/genética , Glándula Tiroides/metabolismo , Glándula Tiroides/fisiopatología , Tirotropina/sangre , Tiroxina/genéticaAsunto(s)
Histiocitosis de Células de Langerhans/patología , Enfermedades de la Piel/patología , Dermatitis Seborreica/etiología , Diabetes Insípida/complicaciones , Histiocitosis de Células de Langerhans/complicaciones , Histiocitosis de Células de Langerhans/diagnóstico , Humanos , Hipopituitarismo/complicaciones , Masculino , Persona de Mediana Edad , Enfermedades de la Piel/complicaciones , Enfermedades de la Piel/diagnósticoRESUMEN
This study aimed to investigate the presence of structural and functional changes in extraocular muscles (EMs) among patients with inactive Graves' orbitopathy (GO) classified according to the Clinical Activity Score (CAS). Sixty-seven patients with Graves' disease (GD) and inactive GO were included. The data collected included clinical parameters, thyroid function, autoantibody levels, EOM morphology via orbital ultrasound (US), and ocular motility. Patients were stratified into Red Filter Test (RFT)-positive or RFT-negative groups based on the presence or absence of latent diplopia during the RFT examination. Thirty-three patients (49.25%) exhibited latent diplopia on the RFT, despite not reporting double vision during standard ocular motility tests. Significant differences were observed between the two groups in terms of age, disease duration, intraocular pressure (IOP) elevation in up-gaze, and medial rectus muscle thickness (p < 0.05). No significant differences were found in thyroid status, TRAb and ATA levels, CASs, exophthalmos, or lateral rectus thickness between the two groups. This study revealed that in inactive GO, subclinical EM dysfunction and morphological changes may be present, which might not be apparent through routine ocular examinations. The RFT is effective in detecting latent diplopia, highlighting its utility in identifying subtle ocular motility issues and subclinical muscle involvement. Comprehensive evaluations combining functional tests like the RFT and imaging are essential for early detection of GO-related abnormalities, enabling tailored and prompt management and improving patient outcomes.
RESUMEN
PURPOSE: The FNA-CT is useful for the diagnosis of MTC. The aim of this study was to evaluate the performance of FNA-CT in TNs coexisting with CCH. METHODS: This study retrospectively reviewed the records of 11 patients with TNs submitted to thyroidectomy on the basis of elevated basal and/or stimulated serum CT values, which at histology were not confirmed to be MTC. The results obtained in this group were compared with those of a previously reported group of histologically proven MTC patients submitted to an identical presurgical evaluation. All patients, negative for known mutations in the RET proto-oncogene, were preoperatively submitted to neck ultrasound, FNA-cytology, and FNA-CT. RESULTS: Approximately 6 of 11 patients showed increased (>36 ng/mL, as established in previous studies not involving patients with CCH) FNA-CT. All these patients showed diffuse CCH at histology in the thyroid lobe submitted to FNA; 5 of them were benign at histology, while only one was malignant (papillary thyroid carcinoma, PTC). The remaining 5 of 11 patients had low FNA-CT (<36 ng/mL), and all of them showed only focal CCH in the lobe submitted to FNA; three of them were malignant (2 PTC, 1 follicular carcinoma), while two were benign. CONCLUSIONS: Employing the currently proposed cut-off values, false-positive FNA-CT results may be observed in benign/malignant TNs with coexisting diffuse CCH. FNA-CT must therefore be cautiously used in the diagnostic approach for patients with TNs and a slightly increased basal or stimulated serum CT concentration in order to avoid unnecessary surgery.
RESUMEN
We compared changes in the morphology of mitochondrial cristae with those in the blood and adrenal content of steroid hormones after the stimulation or inhibition of steroidogenesis. Rats were treated with adrenocorticotrophic hormone or angiotensin II to elicit steroidogenesis and with dexamethasone to inhibit it. Blood and adrenal glands were collected after several time intervals for measurements of steroids and their main intermediates. In the zona fasciculata, mitochondrial ultrastructure was investigated by high resolution scanning electron microscopy. We found that the morphometric data correlated well with the measurements of hyper- or hypo-activity of steroidogenesis over short periods of time (4 h) but not over longer observation times. A peculiar finding was that, contrary to previous reports, 11-deoxycortisol was present in adult rat adrenal tissue.
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Corteza Suprarrenal/ultraestructura , Mitocondrias/ultraestructura , Corteza Suprarrenal/efectos de los fármacos , Hormona Adrenocorticotrópica/farmacología , Angiotensina II/farmacología , Animales , Dexametasona/farmacología , Masculino , Mitocondrias/efectos de los fármacos , Ratas , Ratas Sprague-DawleyRESUMEN
BACKGROUND: Diagnosis of multiple endocrine neoplasia type 1 (MEN1) is commonly based on clinical criteria, and confirmed by genetic testing. In patients without known MEN1-related germline mutations, the possibility of a casual association between two or more endocrine tumors cannot be excluded and subsequent management may be difficult to plan. We describe a very uncommon case of functioning glucagonoma associated with primary hyperparathyroidism (pHPT) in which genetic testing failed to detect germline mutations of MEN-1 and other known genes responsible for MEN1. CASE PRESENTATION: The patient, a 65-year old woman, had been suffering for more than 1 year from weakness, progressive weight loss, angular cheilitis, glossitis and, more recently, skin rashes on the perineum, perioral skin and groin folds. After multidisciplinary investigations, functioning glucagonoma and asymptomatic pHPT were diagnosed and, since family history was negative, sporadic MEN1 was suspected. However, genetic testing revealed neither MEN-1 nor other gene mutations responsible for rarer cases of MEN1 (CDKN1B/p27 and other cyclin-dependent kinase inhibitor genes CDKN1A/p15, CDKN2C/p18, CDKN2B/p21). The patient underwent distal splenopancreatectomy and at the 4-month follow-up she showed complete remission of symptoms. Six months later, a thyroid nodule, suspected to be a malignant neoplasia, and two hyperfunctioning parathyroid glands were detected respectively by ultrasound with fine needle aspiration cytology and 99mTc-sestamibi scan with SPECT acquisition. Total thyroidectomy was performed, whereas selective parathyroidectomy was preferred to a more extensive procedure because the diagnosis of MEN1 was not supported by genetic analysis and intraoperative intact parathyroid hormone had revealed "adenoma-like" kinetics after the second parathyroid resection. Thirty-nine and 25 months after respectively the first and the second operation, the patient is well and shows no signs or symptoms of recurrence. CONCLUSIONS: Despite well-defined diagnostic criteria and guidelines, diagnosis of MEN1 can still be challenging. When diagnosis is doubtful, appropriate management may be difficult to establish.
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Glucagonoma/complicaciones , Hiperparatiroidismo Primario/complicaciones , Neoplasia Endocrina Múltiple Tipo 1 , Neoplasias Pancreáticas/complicaciones , Neoplasias de la Tiroides/complicaciones , Adenoma Oxifílico/complicaciones , Adenoma Oxifílico/fisiopatología , Anciano , Femenino , Glucagonoma/fisiopatología , Humanos , Hiperparatiroidismo Primario/fisiopatología , Hiperparatiroidismo Primario/cirugía , Neoplasias Pancreáticas/fisiopatología , Neoplasias de la Tiroides/fisiopatologíaRESUMEN
Papillary thyroid cancer (PTC) often co-occurs with Hashimoto's thyroiditis, an association that has long been reported in clinical studies, remaining controversial. Experimental evidence has recently shown that pre-existing thyroiditis has a beneficial effect on PTC growth and progression by a distinctive expansion of effector memory CD8 T cells. Although the link between inflammation and PTC might involve different components of the immune system, a deep characterization of them which includes T cells, B cells and tertiary lymphoid structures, Mye-loid cells, Neutrophils, NK cells and dendritic cells will be desirable. The present review article considers the role of the adaptive and innate immune response surrounding PTC in the context of Hashimoto's thyroiditis. This review will focus on the current knowledge by in vivo and in vitro studies specifically performed on animals' models; thyroid cancer cells and human samples including (i) the dual role of tumor-infiltrating lymphocytes; (ii) the emerging role of B cells and tertiary lymphoid structures; (iii) the role of myeloid cells, dendritic cells, and natural killer cells; (iv) the current knowledge of the molecular biomarkers implicated in the complex link between thyroiditis and PTC and the potential implication of cancer immunotherapy in PTC patients in the context of thyroiditis.
RESUMEN
Thyroid-stimulating hormone (TSH) controls thyroid growth and hormone secretion through binding to its G protein-coupled receptor (TSHR) and production of cyclic AMP (cAMP). Serum TSH is a sensitive indicator of thyroid function, and overt abnormalities in thyroid function lead to common endocrine disorders affecting approximately 10% of individuals over a life span. By genotyping 362,129 SNPs in 4,300 Sardinians, we identified a strong association (p = 1.3 x 10(-11)) between alleles of rs4704397 and circulating TSH levels; each additional copy of the minor A allele was associated with an increase of 0.13 muIU/ml in TSH. The single-nucleotide polymorphism (SNP) is located in intron 1 of PDE8B, encoding a high-affinity cAMP-specific phosphodiesterase. The association was replicated in 4,158 individuals, including additional Sardinians and two genetically distant cohorts from Tuscany and the Old Order Amish (overall p value = 1.9 x 10(-20)). In addition to association of TSH levels with SNPs in PDE8B, our genome scan provided evidence for association with PDE10A and several biologically interesting candidates in a focused analysis of 24 genes. In particular, we found evidence for association of TSH levels with SNPs in the THRB (rs1505287, p = 7.3 x 10(-5)), GNAQ (rs10512065, p = 2.0 x 10(-4)), TG (rs2252696, p = 2.2 x 10(-3)), POU1F1 (rs1976324, p = 3.9 x 10(-3)), PDE4D (rs27178, p = 8.3 x 10(-3)), and TSHR (rs4903957, p = 8.6 x 10(-3)) loci. Overall, the results suggest a primary effect of PDE8B variants on cAMP levels in the thyroid. This would affect production of T4 and T3 and feedback to alter TSH release by the pituitary. PDE8B may thus provide a candidate target for the treatment of thyroid dysfunction.
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3',5'-AMP Cíclico Fosfodiesterasas/genética , Variación Genética , Glándula Tiroides/enzimología , Glándula Tiroides/fisiología , Tirotropina/sangre , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Mapeo Cromosómico , AMP Cíclico/metabolismo , Retroalimentación , Femenino , Humanos , Desequilibrio de Ligamiento , Masculino , Persona de Mediana Edad , Hipófisis/fisiología , Polimorfismo de Nucleótido Simple , Enfermedades de la Tiroides/enzimología , Enfermedades de la Tiroides/genética , Enfermedades de la Tiroides/fisiopatología , Tiroxina/biosíntesis , Triyodotironina/biosíntesisRESUMEN
This review focuses attention on some practical aspects of the relationship between thyroid disorders and hypocoagulability, as related to an impairment of hemostasis and fibrinolysis. An understanding of this topic in daily clinical practice is important given that the interaction between hemostatic abnormalities and thyroid disorders is still poorly recognized by the medical community. Even if the bleeding tendency is in general mild and may be reversed by restoration of an euthyroid state, severe hemorrhagic events may complicate the course of both hyper- and hypothyroidism, as precipitated by such conditions as thrombocytopenia, acquired von Willebrand syndrome, and acquired hemophilia. The pathogenesis of the hemostatic abnormalities resides in either the direct effect of thyroid hormones or some conditions in an autoimmune mechanism. Physicians and endocrinologists should pay close attention to both clinical hemorrhagic events in their patients as well as to any laboratory abnormalities identified by blood coagulation testing.
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Trastornos de la Coagulación Sanguínea/sangre , Enfermedades de la Tiroides/sangre , Hemostasis , Humanos , Hipotiroidismo/sangre , Enfermedades de von Willebrand/sangreRESUMEN
Autoimmunity is not believed to be involved in tissue damage of Β-Thalassemia (Β-Thal), although nonspecific triggering of autoimmunity by iron overload has been suggested. We recently re-evaluated thyroid function and autoimmunity in 132 Β-Thal patients born and living in Sardinia Island, where a high prevalence of both Β-Thal and autoimmune disease is well documented and in 1002 age and sex-matched euthyroid individuals from the general population. The prevalence of primary hypothyroidism in Β-Thal patients was 28.7% (38/132), without significant difference between males (M) and females (F). Hypothyroidism was associated with smaller and hypoechoic glands, while no difference in the prevalence of anti-thyroid antibodies (ATA) was found between Β-Thal patients with or without thyroid failure. Interestingly, the prevalence of ATA in Β-Thal women (9.2%) was significantly lower than that found in age-matched euthyroid women (20.0%). Our study confirms that thyroid autoimmunity has no role in the pathogenesis of hypothyroidism in b-Thal. Moreover, the lower ATA prevalence in Β-Thal women suggests that iron overload may inhibit rather then trigger thyroid autoimmunity.
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Tiroiditis Autoinmune/epidemiología , Tiroiditis Autoinmune/inmunología , Talasemia beta/epidemiología , Talasemia beta/inmunología , Adulto , Autoanticuerpos/sangre , Estudios de Cohortes , Femenino , Humanos , Hipotiroidismo/epidemiología , Hipotiroidismo/inmunología , Sobrecarga de Hierro/epidemiología , Sobrecarga de Hierro/inmunología , Italia/epidemiología , Masculino , Persona de Mediana Edad , Prevalencia , Estudios SeroepidemiológicosRESUMEN
Adequate iodine intake is necessary for normal thyroid function. Iodine deficiency is associated with serious complications, but also iodine excess can lead to thyroid dysfunction, and iodine supplementation aimed to prevent iodine deficiency disorders has been associated with development of thyroid autoimmunity. The epidemiology of thyroid diseases has undergone profound changes since the implementation of iodoprophylaxis, notably by means of iodine-enriched salt, specifically resulting in decreased prevalence of goiter and neonatal hypothyroidism, improved cognitive function development in infancy, and reduced incidence of more aggressive forms of thyroid cancer. The main question we address with this review is the clinical relevance of the possible effect on autoimmunity exerted by the use of iodine-enriched salt to correct iodine deficiency. In animal models, exogenous iodine is able to trigger or exacerbate thyroid autoimmunity, but it is still not clear whether the observed immunological changes are due to a direct effect of iodine on immune response, or whether they represent a secondary response to a toxic effect of iodine on thyroid tissue. Previous iodine status of a population seems to influence the functional thyroid response to increased iodine intake and possibly the development of thyroid autoimmunity. Moreover, the prevalence of thyroid antibodies, regarded as hallmark of autoimmune thyroid disease, varies between populations under the influence of genetic and environmental factors, and the presence of thyroid antibodies does not always coincide with the presence of thyroid disease or its future development. In addition, the incidence of autoimmune diseases shows a general increasing trend in the last decades. For all these reasons, available data are quite heterogeneous and difficult to analyze and compare. In conclusion, available data from long-term population surveys show that a higher than adequate population iodine intake due to a poorly controlled program of iodine prophylaxis could induce thyroid dysfunction, including thyroid autoimmunity mostly represented by euthyroid or subclinical hypothyroid autoimmune thyroiditis. Close monitoring iodine prophylaxis is therefore advised to ensure that effects of both iodine deficiency and iodine excess are avoided.
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Enfermedades Autoinmunes/epidemiología , Yodo/efectos adversos , Cloruro de Sodio Dietético/efectos adversos , Enfermedades de la Tiroides/epidemiología , Animales , Autoinmunidad/efectos de los fármacos , Humanos , Glándula Tiroides/efectos de los fármacos , Glándula Tiroides/inmunologíaRESUMEN
Papillary thyroid cancer (PTC) often co-occurs with Hashimoto's thyroiditis, an association that has long been reported in clinical studies yet remains controversial. Some studies, in fact, have suggested a protective effect of thyroiditis while others have not. We generated a mouse model where PTC and thyroiditis develop in a predictable manner, combining the oncogenic drive of the BRAFv600E mutation (inducible by tamoxifen) to the thyroiditis susceptibility of the NOD.H2h4 strain (inducible by iodine). A total of 113 NOD.H2h4_TPO-CRE-ER_BRAFV600E mice (50 followed throughout lifetime and 63 sacrificed at 16 weeks post tamoxifen) were used to determine whether the PTC phenotype differs when thyroiditis precedes or coincides with the onset of PTC. Mice with pre-existing thyroiditis lived longer (median survival of 28.2 weeks post tamoxifen) than those with concomitant (25.6 weeks) or no (24.5 weeks) thyroiditis (Pâ <â 0.01 by Laplace regression). PTC developed less frequently (33%) in the pre-existing thyroiditis group than the concomitant (100%) or no (100%) thyroiditis groups (Pâ <â 0.001 by chi-squared) and showed less aggressive histopathological features. The intratumoral mononuclear cell infiltration was more prominent in mice with pre-existing thyroiditis (Pâ =â 0.002 vs the other groups) and sustained by a significant expansion of effector memory CD8â +â T cells and CD19â +â B cells. These findings shed light on the controversial PTC-thyroiditis association and emphasize the contribution of intratumoral T and B lymphocytes to the evolution of PTC.
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Enfermedad de Hashimoto/complicaciones , Cáncer Papilar Tiroideo/complicaciones , Neoplasias de la Tiroides/complicaciones , Animales , Antígenos CD19/biosíntesis , Linfocitos T CD8-positivos/citología , Cruzamientos Genéticos , Modelos Animales de Enfermedad , Femenino , Genotipo , Enfermedad de Hashimoto/metabolismo , Enfermedad de Hashimoto/terapia , Humanos , Sistema Inmunológico , Masculino , Ratones , Ratones Endogámicos NOD , Mutación , Fenotipo , Proteínas Proto-Oncogénicas B-raf/genética , Análisis de Regresión , Tamoxifeno/farmacología , Cáncer Papilar Tiroideo/terapia , Glándula Tiroides/metabolismo , Neoplasias de la Tiroides/terapia , Tiroiditis Autoinmune/metabolismo , Tiroxina/metabolismoRESUMEN
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.
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Antineoplásicos/uso terapéutico , Accesibilidad a los Servicios de Salud , Compuestos de Fenilurea/uso terapéutico , Inhibidores de Proteínas Quinasas/uso terapéutico , Calidad de Vida , Quinolinas/uso terapéutico , Neoplasias de la Tiroides/tratamiento farmacológico , Anciano , Anciano de 80 o más Años , Antineoplásicos/efectos adversos , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos/diagnóstico , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos/epidemiología , Femenino , Humanos , Italia/epidemiología , Masculino , Persona de Mediana Edad , Compuestos de Fenilurea/efectos adversos , Prevalencia , Inhibidores de Proteínas Quinasas/efectos adversos , Quinolinas/efectos adversos , Neoplasias de la Tiroides/epidemiología , Neoplasias de la Tiroides/patología , Factores de Tiempo , Resultado del TratamientoRESUMEN
OBJECTIVES: The thymus plays a central role in immune tolerance, which prevents autoimmunity. Myasthenia gravis (MG) is commonly associated with thymoma or thymus hyperplasia, and it can coexist with autoimmune thyroid diseases. However, the role of the thymus in thyroid autoimmunity remains to be clarified, which we investigated here. STUDY DESIGN: The study design entailed the inclusion of consecutive MG patients and the measurement of anti-thyroid autoantibodies at baseline and, limited to autoantibody-positive patients, also at 24 and 48 weeks. One hundred and seven MG patients were studied. The main outcome measure was the behaviour of anti-thyroglobulin autoantibodies (TgAbs) and anti-thyroperoxidase autoantibodies (TPOAbs) over time in relation to thymectomy. RESULTS: Serum TgAbs and/or TPOAbs were detected in â¼20% of patients in the absence of thyroid dysfunction. The prevalence of positive serum TgAbs and/or TPOAbs decreased significantly (p = 0.002) over the follow-up period in patients who underwent thymectomy, but not in patients who were not thymectomized. When the analysis was restricted to TgAbs or TPOAbs, findings were similar. On the same line, there was a general trend towards a reduction in the serum concentrations of anti-thyroid autoantibodies in patients who underwent thymectomy, which was significant for TPOAbs (p = 0.009). CONCLUSIONS: Our findings suggest a role of the thymus in the maintenance of humoral thyroid autoimmunity.
RESUMEN
BACKGROUND: Using recombinant human monoclonal thyroglobulin antibodies expressed as Fab molecules (TgAb-Fab), we have recently confirmed the restriction of Tg epitopes in Hashimoto's thyroiditis (HT). OBJECTIVE: To investigate Tg epitopes of serum TgAb in HT adults and HT juveniles from a geographically isolated area (Sardinia). DESIGN AND PATIENTS: Serum TgAb of 39 Sardinian HT adults, 53 Sardinian HT juveniles and 45 non-Sardinian HT adults were evaluated. The binding of serum TgAb to Tg in ELISA was inhibited by four recombinant human TgAb-Fab, identifying Tg epitopic regions A-D. The percentage of Tg binding inhibition was calculated comparing the binding of serum TgAb in presence of each TgAb-Fab with that in its absence. RESULTS: In the whole cohort of 137 patients, A region TgAb-Fab induced the highest levels of inhibition (55.3 +/- 17.8%) (mean +/- SD). Lower levels of inhibition were induced by TgAb-Fab of regions B (27.8 +/- 25.8%), C (26.8 +/- 24.6%) and D (17.5 +/- 18.4%). In Sardinian HT adults inhibition by TgAb-Fab of regions A, B and C were comparable to Sardinian HT juveniles; the marginal D region TgAb-Fab induced a slightly higher inhibition (22.1 vs. 13.8%; P = 0.034) in the former than in the latter group. In Sardinian and non-Sardinian HT adults inhibitions by the four TgAb-Fab were similar. CONCLUSIONS: In HT, the Tg epitope pattern of serum TgAb was similar in juveniles and adults from a geographically restricted area and in two adult populations from different geographical areas. Thus, in HT, neither age nor genetic background appear to influence B-cell epitopes.
Asunto(s)
Epítopos de Linfocito B/inmunología , Enfermedad de Hashimoto/inmunología , Tiroglobulina/inmunología , Adolescente , Adulto , Reacciones Antígeno-Anticuerpo/efectos de los fármacos , Autoantígenos/inmunología , Niño , Etnicidad/genética , Femenino , Humanos , Fragmentos Fab de Inmunoglobulinas/farmacología , Yoduro Peroxidasa/inmunología , Proteínas de Unión a Hierro/inmunología , Italia , Masculino , Población Blanca/genéticaRESUMEN
BACKGROUND: Very few studies on glucose abnormalities in European overweight/obese children and adolescents are available, and scientific evidence on the value of standard oral glucose tolerance test (OGTT) in childhood is lacking. We therefore aimed to establish prevalence and features of impaired fasting glucose (IFG), impaired glucose tolerance (IGT) and type 2 diabetes (T2D) in a large cohort of Italian overweight/obese children and adolescents and to assess the validity of standard OGTT in the paediatric population. METHODS: This is a 1-year observational study conducted on 736 (535 overweight/obese and 201 normal weight) consecutive paediatric patients attending the outpatient clinic of Paediatric Endocrine Unit. Clinical and biochemical parameters were collected for all participants. All overweight/obese subjects underwent OGTT. RESULTS: We observed a high prevalence of IFG (7.66%), more than twice that observed in other European children, but a low prevalence of IGT (3.18%) and T2D (0.18%). IFG was useless to predict IGT, having very low predictive value (7.3%) and sensitivity (17.6%). Compared to normal weight children, overweight/obese subjects showed significant differences in most metabolic and clinical parameters. In the overweight/obese group, having hyperglycaemia was associated to significantly higher blood pressure, homeostasis model assessment for insulin resistance, insulin and triglycerides. CONCLUSIONS: In our children, the prevalence of IFG is higher than that reported in other European cohorts, whereas T2D is rare. IFG appears not useful to detect IGT in childhood. Paediatric diagnostic cut-points, glucose load and timing of sampling need to be further validated to define glucose abnormalities in obese children that, compared with normal weight subjects, already are characterised by a different metabolic phenotype.