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1.
N Engl J Med ; 391(6): 504-514, 2024 Aug 08.
Artículo en Inglés | MEDLINE | ID: mdl-38828955

RESUMEN

BACKGROUND: Adrenal insufficiency in patients with classic 21-hydroxylase deficiency congenital adrenal hyperplasia (CAH) is treated with glucocorticoid replacement therapy. Control of adrenal-derived androgen excess usually requires supraphysiologic glucocorticoid dosing, which predisposes patients to glucocorticoid-related complications. Crinecerfont, an oral corticotropin-releasing factor type 1 receptor antagonist, lowered androstenedione levels in phase 2 trials involving patients with CAH. METHODS: In this phase 3 trial, we randomly assigned adults with CAH in a 2:1 ratio to receive crinecerfont or placebo for 24 weeks. Glucocorticoid treatment was maintained at a stable level for 4 weeks to evaluate androstenedione values, followed by glucocorticoid dose reduction and optimization over 20 weeks to achieve the lowest glucocorticoid dose that maintained androstenedione control (≤120% of the baseline value or within the reference range). The primary efficacy end point was the percent change in the daily glucocorticoid dose from baseline to week 24 with maintenance of androstenedione control. RESULTS: All 182 patients who underwent randomization (122 to the crinecerfont group and 60 to the placebo group) were included in the 24-week analysis, with imputation of missing values; 176 patients (97%) remained in the trial at week 24. The mean glucocorticoid dose at baseline was 17.6 mg per square meter of body-surface area per day of hydrocortisone equivalents; the mean androstenedione level was elevated at 620 ng per deciliter. At week 24, the change in the glucocorticoid dose (with androstenedione control) was -27.3% in the crinecerfont group and -10.3% in the placebo group (least-squares mean difference, -17.0 percentage points; P<0.001). A physiologic glucocorticoid dose (with androstenedione control) was reported in 63% of the patients in the crinecerfont group and in 18% in the placebo group (P<0.001). At week 4, androstenedione levels decreased with crinecerfont (-299 ng per deciliter) but increased with placebo (45.5 ng per deciliter) (least-squares mean difference, -345 ng per deciliter; P<0.001). Fatigue and headache were the most common adverse events in the two trial groups. CONCLUSIONS: Among patients with CAH, the use of crinecerfont resulted in a greater decrease from baseline in the mean daily glucocorticoid dose, including a reduction to the physiologic range, than placebo following evaluation of adrenal androgen levels. (Funded by Neurocrine Biosciences; CAHtalyst ClinicalTrials.gov number, NCT04490915.).


Asunto(s)
Hiperplasia Suprarrenal Congénita , Aminas , Androstenodiona , Tiazoles , Adulto , Femenino , Humanos , Masculino , Adulto Joven , Hiperplasia Suprarrenal Congénita/sangre , Hiperplasia Suprarrenal Congénita/complicaciones , Hiperplasia Suprarrenal Congénita/tratamiento farmacológico , Androstenodiona/sangre , Relación Dosis-Respuesta a Droga , Método Doble Ciego , Glucocorticoides/administración & dosificación , Glucocorticoides/efectos adversos , Hidrocortisona/sangre , Aminas/administración & dosificación , Aminas/efectos adversos , Tiazoles/administración & dosificación , Tiazoles/efectos adversos , Receptores de Hormona Liberadora de Corticotropina/antagonistas & inhibidores , Quimioterapia Combinada/efectos adversos , Quimioterapia Combinada/métodos , Fatiga/inducido químicamente , Fatiga/epidemiología , Cefalea/inducido químicamente , Cefalea/epidemiología
2.
Clin Endocrinol (Oxf) ; 94(2): 277-289, 2021 02.
Artículo en Inglés | MEDLINE | ID: mdl-33098107

RESUMEN

CONTEXT: The international GENHYPOPIT network collects phenotypical data and screens genetic causes of non-acquired hypopituitarism. AIMS: To describe main phenotype patterns and their evolution through life. DESIGN: Patients were screened according to their phenotype for coding sequence variations in 8 genes: HESX1, LHX3, LHX4, PROP1, POU1F1, TBX19, OTX2 and PROKR2. RESULTS: Among 1213 patients (1143 index cases), the age of diagnosis of hypopituitarism was congenital (24%), in childhood (28%), at puberty (32%), in adulthood (7.2%) or not available (8.8%). Noteworthy, pituitary hormonal deficiencies kept on evolving during adulthood in 49 of patients. Growth Hormone deficiency (GHD) affected 85.8% of patients and was often the first diagnosed deficiency. AdrenoCorticoTropic Hormone deficiency rarely preceded GHD, but usually followed it by over 10 years. Pituitary Magnetic Resonance Imaging (MRI) abnormalities were common (79.7%), with 39.4% pituitary stalk interruption syndrome (PSIS). The most frequently associated extrapituitary malformations were ophthalmological abnormalities (16.1%). Prevalence of identified mutations was 7.3% of index cases (84/1143) and 29.5% in familial cases (n = 146). Genetic analysis in 449 patients without extrapituitary phenotype revealed 36 PROP1, 2 POU1F1 and 17 TBX19 mutations. CONCLUSION: This large international cohort highlights atypical phenotypic presentation of constitutional hypopituitarism, such as post pubertal presentation or adult progression of hormonal deficiencies. These results justify long-term follow-up, and the need for systematic evaluation of associated abnormalities. Genetic defects were rarely identified, mainly PROP1 mutations in pure endocrine phenotypes.


Asunto(s)
Hipopituitarismo , Adulto , Estudios de Cohortes , Proteínas de Homeodominio/genética , Humanos , Hipopituitarismo/genética , Imagen por Resonancia Magnética , Mutación , Factores de Transcripción/genética
3.
Arch Toxicol ; 95(5): 1671-1681, 2021 05.
Artículo en Inglés | MEDLINE | ID: mdl-33638691

RESUMEN

Dichlorodiphenyltrichloroethane (p,p'DDT) is an endocrine-disrupting chemical (EDC). Several studies showed an association between p,p'DDT exposure and reprotoxic effects. We showed that p,p'DDT was a positive allosteric modulator of human follitropin receptor (FSHR). In contrast, we demonstrated that p,p'DDT decreased the cyclic AMP (cAMP) production induced by human choriogonadotropin (hCG). This study evaluated further the effects of p,p'DDT on Gs-, ß-arrestin 2- and steroidogenesis pathways induced by hCG or luteinizing hormone (LH). We used Chinese hamster ovary cells line stably expressing hCG/LHR. The effects of 10-100 µM p,p'DDT on cAMP production and on ß-arrestin 2 recruitment were measured using bioluminescence and time-resolved resonance energy transfer technology. The impact of 100 µM of p,p'DDT on steroid secretion was analysed in murine Leydig tumor cell line (mLTC-1). In cAMP assays, 100 µM p,p'DDT increased the EC50 by more than 300% and reduced the maximum response of the hCG/LHR to hCG and hLH by 30%. This inhibitory effect was also found in human granulosa cells line and in mLTC-1 cells. Likewise, 100 µM p,p'DDT decreased the hCG- and hLH-promoted ß-arrestin 2 recruitment down to 14.2 and 26.6%, respectively. Moreover, 100 µM p,p'DDT decreased by 30 and 47% the progesterone secretion induced by hCG or hLH, respectively, without affecting testosterone secretion. This negative effect of p,p'DDT was independent of cytotoxicity. p,p'DDT acted as a negative allosteric modulator of the hCG/LHR signalling. This emphasizes the importance of analyzing all receptor-downstream pathways to fully understand the deleterious effects of EDC on human health.


Asunto(s)
DDT/toxicidad , Disruptores Endocrinos/toxicidad , Animales , Células CHO , Gonadotropina Coriónica , Cricetinae , Cricetulus , AMP Cíclico , Femenino , Humanos , Células Intersticiales del Testículo , Hormona Luteinizante/metabolismo , Masculino , Ratones , Receptores Acoplados a Proteínas G , Receptores de HL , Transducción de Señal
4.
Int J Mol Sci ; 22(23)2021 Nov 30.
Artículo en Inglés | MEDLINE | ID: mdl-34884794

RESUMEN

Differentiated thyroid cancers are more frequent in women than in men. These different frequencies may depend on differences in patient's behavior and in thyroid investigations. However, an impact on sexual hormones is likely, although this has been insufficiently elucidated. Estrogens may increase the production of mutagenic molecules in the thyroid cell and favor the proliferation and invasion of tumoral cells by regulating both the thyrocyte enzymatic machinery and the inflammatory process associated with tumor growth. On the other hand, the worse prognosis of thyroid cancer associated with the male gender is poorly explained.


Asunto(s)
Hormonas Esteroides Gonadales/metabolismo , Razón de Masculinidad , Neoplasias de la Tiroides/epidemiología , Estrógenos/metabolismo , Femenino , Humanos , Masculino , Pronóstico , Receptores de Estrógenos/metabolismo , Factores Sexuales , Glándula Tiroides/patología , Neoplasias de la Tiroides/mortalidad , Neoplasias de la Tiroides/patología
5.
Cancer Immunol Immunother ; 69(10): 2053-2061, 2020 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-32445029

RESUMEN

OBJECTIVE: To explore the programmed death-ligand 1 (PD-L1) expression in varied subtypes of pituitary neuroendocrine tumors with assessment of their clinical behavior at diagnosis and follow-up. METHODS: We conducted a retrospective monocentric study, including all patients operated in the Academic Hospital of Angers (France) for a pituitary neuroendocrine tumor between 2012 and 2018. PDL-1 immunostaining was performed using a European Conformity-In Vitro Diagnostic-labeled anti-PDL1 antibody (clone 22C3). PD-L1 immunostaining was evaluated as the percentage of tumor cells showing positive membrane staining, into four grades: grade 0 = < 1%, grade 1 = 1 to 5%, grade 2 = 6 to 49% and grade 3 = ≥ 50%. PD-L1 expression was compared with tumor features (secretion, proliferation, invasion) and outcome. RESULTS: The study included 139 pituitary neuroendocrine tumors, including 84 (60%) nonfunctioning adenomas. Twenty-five pituitary neuroendocrine tumors were PD-L1 positive (18%), including 3 grade 3, 8 grade 2 and 14 grade 1. PD-L1 expression was not different between functioning and nonfunctioning adenomas (p = 0.26). Among 16 tumors with proliferative markers (Ki-67 ≥ 3% and p53 positive), only one was PD-L1 positive. CONCLUSION: In our series, PD-L1 was expressed in a rather small proportion of PitNET (18%), and this immune marker was not associated with any biological characteristic or behavior of the pituitary tumors. Thus, PD-L1 staining may be necessary before considering PD-L1 blockage in pituitary neuroendocrine tumors, in case of therapeutic impasse.


Asunto(s)
Antígeno B7-H1/metabolismo , Biomarcadores de Tumor/metabolismo , Recurrencia Local de Neoplasia/patología , Tumores Neuroendocrinos/patología , Neoplasias Hipofisarias/patología , Femenino , Estudios de Seguimiento , Humanos , Masculino , Persona de Mediana Edad , Recurrencia Local de Neoplasia/metabolismo , Tumores Neuroendocrinos/metabolismo , Neoplasias Hipofisarias/metabolismo , Pronóstico , Estudios Retrospectivos , Tasa de Supervivencia
7.
Proteins ; 82(9): 2141-56, 2014 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-24677372

RESUMEN

Covariation between positions in a multiple sequence alignment may reflect structural, functional, and/or phylogenetic constraints and can be analyzed by a wide variety of methods. We explored several of these methods for their ability to identify covarying positions related to the divergence of a protein family at different hierarchical levels. Specifically, we compared seven methods on a model system composed of three nested sets of G-protein-coupled receptors (GPCRs) in which a divergence event occurred. The covariation methods analyzed were based on: χ2 test, mutual information, substitution matrices, and perturbation methods. We first analyzed the dependence of the covariation scores on residue conservation (measured by sequence entropy), and then we analyzed the networking structure of the top pairs. Two methods out of seven--OMES (Observed minus Expected Squared) and ELSC (Explicit Likelihood of Subset Covariation)--favored pairs with intermediate entropy and a networking structure with a central residue involved in several high-scoring pairs. This networking structure was observed for the three sequence sets. In each case, the central residue corresponded to a residue known to be crucial for the evolution of the GPCR family and the subfamily specificity. These central residues can be viewed as evolutionary hubs, in relation with an epistasis-based mechanism of functional divergence within a protein family.


Asunto(s)
Evolución Molecular , Receptores Acoplados a Proteínas G/genética , Alineación de Secuencia , Algoritmos , Secuencia de Aminoácidos , Biología Computacional , Humanos , Modelos Moleculares , Filogenia
8.
Rev Prat ; 64(6): 828-34, 2014 Jun.
Artículo en Francés | MEDLINE | ID: mdl-25090772

RESUMEN

Genetic and environmental determinants inducing Graves' disease are still poorly defined, especially those leading to the appearance of TSH receptor antibodies, which are both the hallmark of the disease and the keystone of its diagnosis. The treatment of Graves' disease is based on the use of antithyroid drugs and no therapeutic protocol has proven superior to the other. Surgical or radiometabolic treatments, largely restricted to relapses and to patients with comorbidities could be considered earlier provided we had reliable predictive markers for relapse. The treatment of Graves' orbitopathy relies first on a rigorous analysis of severity and activity of the disease. Intravenous steroids appear as a reference treatment in active forms. Evaluation of new therapeutics is in process. Graves' disease during pregnancy requires a multidisciplinary approach and an expert ultrasound evaluation of the fetus. Because of a suspected teratogenicity of carbimazole and methimazole, propylthiouracyl is the preferred drug used during early pregnancy.


Asunto(s)
Enfermedad de Graves/diagnóstico , Enfermedad de Graves/terapia , Antitiroideos/uso terapéutico , Femenino , Predisposición Genética a la Enfermedad , Enfermedad de Graves/etiología , Humanos , Embarazo , Complicaciones del Embarazo , Recurrencia , Glándula Tiroides/patología
9.
Artículo en Inglés | MEDLINE | ID: mdl-39193719

RESUMEN

INTRODUCTION: The clinical manifestations of Cushing's syndrome are variable, but an important number of patients present a metabolic syndrome, strongly associated with hepatic steatosis. The aim of this study was to determine the prevalence of Metabolic Dysfunction Associated Steatotic Liver Disease (MASLD) at the diagnosis of Cushing's syndrome. METHODS: We conducted a single-center retrospective study at Angers Hospital (France) between 2010 and 2020. Forty-nine patients followed for Cushing's syndrome with available abdominal imaging at diagnosis were included. A mean liver/spleen (L/S) density ratio < 1 on CT scan was diagnostic of hepatic steatosis. Simple clinicobiological scores predictive of hepatic fibrosis (FIB4, NAFLD Fibrosis Score and e-lift) were calculated for patients with hepatic steatosis. RESULTS: Thirteen of the 49 patients (26.5%) had hepatic steatosis at diagnosis of Cushing's syndrome. All 13 had MASLD. These patients had a higher prevalence of type 2 diabetes and higher triglyceride levels in multivariate analysis. There was no difference according to the intensity or duration of Cushing's syndrome. Among the 13 patients with MASLD, 2 (15.4%) had a significant fibrosis predictive score. Of the 4 patients with follow-up imaging after remission of Cushing's syndrome, 3 had remission of steatosis between 1 and 5 years after remission of Cushing's syndrome. No patient without MASLD at diagnosis had a worsening L/S ratio after remission. CONCLUSION: We estimated the prevalence of hepatic steatosis at the diagnosis of Cushing's syndrome at 26.5%. The presence of metabolic factors was associated with the occurrence of hepatic steatosis.

10.
Eur Thyroid J ; 13(4)2024 Aug 01.
Artículo en Inglés | MEDLINE | ID: mdl-38963712

RESUMEN

Impaired sensitivity to thyroid hormones encompasses disorders with defective transport of hormones into cells, reduced hormone metabolism, and resistance to hormone action. Mediated by heritable single-gene defects, these rare conditions exhibit different patterns of discordant thyroid function associated with multisystem phenotypes. In this context, challenges include ruling out other causes of biochemical discordance, making a diagnosis using clinical features together with the identification of pathogenic variants in causal genes, and managing these rare disorders with a limited evidence base. For each condition, the present guidelines aim to inform clinical practice by summarizing key clinical features and useful investigations, criteria for molecular genetic diagnosis, and pathways for management and therapy. Specific, key recommendations were developed by combining the best research evidence available with the knowledge and clinical experience of panel members, to achieve a consensus.


Asunto(s)
Hormonas Tiroideas , Humanos , Hormonas Tiroideas/sangre , Hormonas Tiroideas/metabolismo , Europa (Continente) , Enfermedades de la Tiroides/genética , Enfermedades de la Tiroides/terapia , Enfermedades de la Tiroides/diagnóstico , Enfermedades de la Tiroides/metabolismo , Sociedades Médicas , Síndrome de Resistencia a Hormonas Tiroideas/genética , Síndrome de Resistencia a Hormonas Tiroideas/diagnóstico , Síndrome de Resistencia a Hormonas Tiroideas/terapia
11.
Eur J Endocrinol ; 190(4): 266-274, 2024 Mar 30.
Artículo en Inglés | MEDLINE | ID: mdl-38578777

RESUMEN

PURPOSE: The purpose of this study was to characterize the phenotype associated with a de novo gain-of-function variant in the GUCY1A2 gene. METHODS: An individual carrying the de novo heterozygous variant c.1458G>T p.(E486D) in GUCY1A2 was identified by exome sequencing. The effect of the corresponding enzyme variant α2E486D/ß1 was evaluated using concentration-response measurements with wild-type enzyme and the variant in cytosolic fractions of HEK293 cells, UV-vis absorbance spectra of the corresponding purified enzymes, and examination of overexpressed fluorescent protein-tagged constructs by confocal laser scanning microscopy. RESULTS: The patient presented with precocious peripheral puberty resembling the autonomous ovarian puberty seen in McCune-Albright syndrome. Additionally, the patient displayed severe intellectual disability. In vitro activity assays revealed an increased nitric oxide affinity for the mutant enzyme. The response to carbon monoxide was unchanged, while thermostability was decreased compared to wild type. Heme content, susceptibility to oxidation, and subcellular localization upon overexpression were unchanged. CONCLUSION: Our data define a syndromic autonomous ovarian puberty likely due to the activating allele p.(E486D) in GUCY1A2 leading to an increase in cGMP. The overlap with the ovarian symptoms of McCune-Albright syndrome suggests an impact of this cGMP increase on the cAMP pathway in the ovary. Additional cases will be needed to ensure a causal link.


Asunto(s)
Displasia Fibrosa Poliostótica , Pubertad Precoz , Femenino , Humanos , Displasia Fibrosa Poliostótica/diagnóstico , Mutación con Ganancia de Función , Células HEK293 , Ovario , Pubertad Precoz/etiología
12.
J Hazard Mater ; 479: 135619, 2024 Nov 05.
Artículo en Inglés | MEDLINE | ID: mdl-39217935

RESUMEN

Halogenated bisphenol A (BPA) derivatives are produced during disinfection treatment of drinking water or are synthesized as flame retardants (TCBPA or TBBPA). BPA is considered as an endocrine disruptor especially on human follicle-stimulating hormone receptor (FSHR). Using a global experimental approach, we assessed the effect of halogenated BPA derivatives on FSHR activity and estimated the risk of halogenated BPA derivatives to the reproductive health of exposed populations. For the first time, we show that FSHR binds halogenated BPA derivatives, at 10 nM, a concentration lower than those requires to modulate the activity of nuclear receptors and/or steroidogenesis enzymes. Indeed, bioluminescence assays show that FSHR response is lowered up to 42.36 % in the presence of BPA, up to 32.79 % by chlorinated BPA derivatives and up to 27.04 % by brominated BPA derivatives, at non-cytotoxic concentrations and without modification of basal receptor activity. Moreover, molecular docking, molecular dynamics simulations, and site-directed mutagenesis experiments demonstrate that the halogenated BPA derivatives bind the FSHR transmembrane domain reducing the signal transduction efficiency which lowers the cellular cAMP production and in fine disrupts the physiological effect of FSH. The potential reproductive health risk of exposed individuals was estimated by comparing urinary concentrations (through a collection of human biomonitoring data) with the lowest effective concentrations derived from in vitro cell assays. Our results suggest a potentially high concern for the risk of inhibition of the FSHR pathway. This global approach based on FSHR activity could enable the rapid characterization of the toxicity of halogenated BPA derivatives (or other compounds) and assess the associated risk of exposure to these halogenated BPA derivatives.


Asunto(s)
Compuestos de Bencidrilo , Disruptores Endocrinos , Simulación del Acoplamiento Molecular , Fenoles , Receptores de HFE , Humanos , Fenoles/toxicidad , Fenoles/química , Compuestos de Bencidrilo/toxicidad , Compuestos de Bencidrilo/química , Receptores de HFE/metabolismo , Medición de Riesgo , Disruptores Endocrinos/toxicidad , Disruptores Endocrinos/química , Halogenación , Células HEK293 , Simulación de Dinámica Molecular
13.
Front Endocrinol (Lausanne) ; 15: 1403687, 2024.
Artículo en Inglés | MEDLINE | ID: mdl-39015176

RESUMEN

Background: Nintedanib is a triple-angiokinase inhibitor with potential activity in patients with advanced thyroid cancers, as radioiodine refractory differentiated thyroid cancer (RAIR DTC) and medullary thyroid cancer (MTC). Design: EORTC-1209 (NCT01788982) was a double-blind randomized (2:1 ratio) placebo-controlled phase II, multi-cohort study exploring the efficacy and safety of nintedanib in patients with progressive, locally advanced, and/or metastatic RAIR DTC and MTC. The primary endpoint was progression-free survival (PFS) in the per-protocol (PP) population for both cohorts. Secondary endpoints included response rate, duration of response, overall survival (OS), and safety. Results: RAIR DTC cohort: Seventy out of the 75 planned patients with RAIR DTC (median age, 66 years; 39 women) who had progressed after one (76%) or two lines (24%) of previous systemic therapy were randomized to receive either nintedanib (N = 45) or placebo (N = 25). Of these, 69 patients started treatment and 56 met all inclusion criteria (PP). At data cutoff, the median duration of follow-up was 26.3 months in the nintedanib arm and 19.8 months in the placebo arm. In the PP population, the median PFS was 3.7 months [80% confidence interval (CI), 1.9-6.5] in the nintedanib arm and 2.9 months (80% CI, 2.0-5.6) in the placebo arm (HR = 0.65; 80% CI, 0.42-0.99; one-sided log-rank test P = 0.0947). No objective response was observed. The median OS was 29.6 months [80% CI, 15.2-not reached (NR)] in the nintedanib arm and not reached in the placebo arm. Grade 3-4 adverse events of any attribution occurred in 50% of patients receiving nintedanib and in 36% of patients receiving placebo. MTC cohort: Thirty-one out of the 67 planned patients with MTC (median age, 57 years; eight women) who had progressed after one (68%) or two (32%) lines of previous systemic therapy were randomized to receive either nintedanib (N = 22) or placebo (N = 9). Of these, 20 patients (15 in the nintedanib arm and five in the placebo arm) started treatment and met all inclusion criteria (PP). The median PFS was 7.0 months (80% CI, 1.9-8.7) in the nintedanib arm and 3.9 months (80% CI, 3.0-5.5) in the placebo arm (HR = 0.49; 95% CI, 0.16-1.53). No objective response was reported. The median OS was 16.4 months (80% CI, 12.1-24.9) in the nintedanib arm and 12.3 months (80% CI, 7.1-NR) in the placebo arm. Grade 3-4 adverse events of any attribution during the blinded period occurred in 59.1% of patients receiving nintedanib and in 33.3% of patients receiving placebo. Conclusion: This study did not suggest a clinically significant improvement of PFS with nintedanib over placebo in patients with pretreated RAIR DTC and MTC.


Asunto(s)
Carcinoma Neuroendocrino , Indoles , Neoplasias de la Tiroides , Humanos , Neoplasias de la Tiroides/tratamiento farmacológico , Neoplasias de la Tiroides/patología , Femenino , Masculino , Indoles/uso terapéutico , Indoles/efectos adversos , Indoles/administración & dosificación , Persona de Mediana Edad , Anciano , Método Doble Ciego , Carcinoma Neuroendocrino/tratamiento farmacológico , Carcinoma Neuroendocrino/patología , Adulto , Progresión de la Enfermedad , Anciano de 80 o más Años , Antineoplásicos/uso terapéutico , Antineoplásicos/efectos adversos , Resultado del Tratamiento
14.
Ann Endocrinol (Paris) ; 84(3): 346-350, 2023 May.
Artículo en Inglés | MEDLINE | ID: mdl-36963755

RESUMEN

Immune checkpoint inhibitors (ICIs) are currently the key therapy for several cancers. Among immune-related adverse events, thyroid dysfunction is the most frequent. We review this thyroid dysfunction, with recent data on epidemiology, diagnostic considerations, management and risk factors.


Asunto(s)
Inhibidores de Puntos de Control Inmunológico , Enfermedades de la Tiroides , Humanos , Inhibidores de Puntos de Control Inmunológico/efectos adversos , Enfermedades de la Tiroides/inducido químicamente , Enfermedades de la Tiroides/terapia
15.
Ann Endocrinol (Paris) ; 84(4): 407-412, 2023 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-36716819

RESUMEN

Thyrotropic adenomas (TSH-PitNET) are the rarest pituitary tumours. Most TSH-PitNETs are secreting adenoma, with a biological picture of inappropriate TSH secretion (moderately elevated TSH, elevated FT3 and FT4). Patients present most often clinical hyperthyroidism, but with more moderate symptoms than in peripheral hyperthyroidism. Biological diagnosis is not always easy. The main differential diagnoses are interfering antibody assay interactions, dysalbuminemia and thyroid hormone resistance syndrome. Misdiagnosis is common. However, the diagnosis is easier when macroadenomas are involved (80% of cases), with symptoms of optic chiasm compression, headache and signs of hypopituitarism. Treatment is initially based on surgery. In case of failure, somatostatin analogues are very effective in controlling tumor volume and secretion, although there is a risk of thyroid insufficiency, which is usually transient.


Asunto(s)
Adenoma , Antineoplásicos , Hipertiroidismo , Neoplasias Hipofisarias , Humanos , Tirotropina , Neoplasias Hipofisarias/terapia , Neoplasias Hipofisarias/tratamiento farmacológico , Adenoma/terapia , Adenoma/tratamiento farmacológico , Hipertiroidismo/diagnóstico
16.
Trials ; 24(1): 298, 2023 Apr 28.
Artículo en Inglés | MEDLINE | ID: mdl-37118818

RESUMEN

BACKGROUND: Prophylactic central neck dissection in clinically low-risk cT1bT2N0 papillary thyroid carcinoma is controversial, due to a large number of conflicting retrospective studies, some showing an advantage in terms of locoregional recurrence, others showing no advantage. These previous studies all show high rates of excellent response. We aim to demonstrate the non-inferiority of thyroidectomy alone as compared to total thyroidectomy with prophylactic central neck dissection in conjunction with adjuvant RAI 30 mCi with rTSH stimulation in terms of excellent response at 1 year. TRIAL DESIGN AND METHODS: Prospective randomized open multicenter phase III trial including patients with 11-40-mm papillary thyroid carcinoma (Bethesda VI) or suspicious cytology (Bethesda V) confirmed malignant on intra-operative frozen section analysis, with no suspicious lymph nodes on a specialized preoperative ultrasound examination. Patients will be randomized 1:1 into two groups: the reference group total thyroidectomy with bilateral prophylactic central neck dissection, and the comparator group total thyroidectomy alone. All patients will receive an ablative dose of 30mCi of radioactive iodine (RAI) within 4 months of surgery. The primary outcome is to compare the rate of excellent response at 1 year after surgery between the groups, as defined by an unstimulated serum thyroglobulin (Tg) level ≤ 0.2 ng/mL with no anti-Tg antibodies, an normal neck ultrasound and no ectopic uptake on the post-RAI scintiscan. Non-inferiority will be demonstrated if the rate of patients with excellent response at 1 year after randomization does not differ by more than 5%. Setting the significance level at 0.025 (one-sided) and a power of 80% requires a sample size of 598 patients (299 per group). Secondary outcomes are to compare Tg levels at 8 +/- 2 postoperative weeks, before RAI ablation, the rate of excellent response at 3 and 5 years, the rate of other responses at 1, 3, and 5 years (biochemical incomplete, indeterminate, and structurally incomplete responses), complications, quality of life, and cost-utility. DISCUSSION (POTENTIAL IMPLICATIONS): If non-inferiority is demonstrated with this high-level evidence, prophylactic neck dissection will have been shown to not be necessary in clinically low-risk papillary thyroid carcinoma. TRIAL REGISTRATION: NCT03570021. June 26,2018.


Asunto(s)
Carcinoma Papilar , Neoplasias de la Tiroides , Humanos , Neoplasias de la Tiroides/diagnóstico por imagen , Neoplasias de la Tiroides/cirugía , Disección del Cuello/efectos adversos , Cáncer Papilar Tiroideo/cirugía , Radioisótopos de Yodo , Estudios Retrospectivos , Estudios Prospectivos , Calidad de Vida , Carcinoma Papilar/patología , Carcinoma Papilar/cirugía , Recurrencia Local de Neoplasia/patología , Tiroidectomía/efectos adversos
17.
Cells ; 11(4)2022 02 17.
Artículo en Inglés | MEDLINE | ID: mdl-35203352

RESUMEN

BACKGROUND: Many studies link G protein-coupled receptors (GPCRs) to cancer. Some endocrine tumors are unresponsive to standard treatment and/or require long-term and poorly tolerated treatment. This study explored, by bioinformatics analysis, the tumoral profiling of the GPCR transcriptome to identify potential targets in these tumors aiming at drug repurposing. METHODS: We explored the GPCR differentially expressed genes (DEGs) from public datasets (Gene Expression Omnibus (GEO) database and The Cancer Genome Atlas (TCGA)). The GEO datasets were available for two medullary thyroid cancers (MTCs), eighty-seven pheochromocytomas (PHEOs), sixty-one paragangliomas (PGLs), forty-seven pituitary adenomas and one-hundred-fifty adrenocortical cancers (ACCs). The TCGA dataset covered 92 ACCs. We identified GPCRs targeted by approved drugs from pharmacological databases (ChEMBL and DrugBank). RESULTS: The profiling of dysregulated GPCRs was tumor specific. In MTC, we found 14 GPCR DEGs, including an upregulation of the dopamine receptor (DRD2) and adenosine receptor (ADORA2B), which were the target of many drugs. In PGL, seven GPCR genes were downregulated, including vasopressin receptor (AVPR1A) and PTH receptor (PTH1R), which were targeted by approved drugs. In ACC, PTH1R was also downregulated in both the GEO and TCGA datasets and was the target of osteoporosis drugs. CONCLUSIONS: We highlight specific GPCR signatures across the major endocrine tumors. These data could help to identify new opportunities for drug repurposing.


Asunto(s)
Biología Computacional , Neoplasias de la Tiroides , Perfilación de la Expresión Génica , Humanos , Receptores Acoplados a Proteínas G/genética , Receptores Acoplados a Proteínas G/metabolismo , Neoplasias de la Tiroides/genética , Transcriptoma
18.
J Clin Endocrinol Metab ; 107(9): e3548-e3552, 2022 08 18.
Artículo en Inglés | MEDLINE | ID: mdl-35689814

RESUMEN

CONTEXT: Resistance to thyroid hormone ß syndrome (RTHß) is caused by pathogenic variants in the THRB gene, but such variants are found in only 85% of cases. We report the case of a patient with RTHß phenotype but for whom we found a pathogenic variant of the THRB gene in a mosaic state. CASE DESCRIPTION: The patient is a 52-year-old woman with clinical and biological signs of RTHß. Symptoms included asthenia, cardiac palpitations, and diarrhea. Repeated thyroid function tests showed an elevated serum TSH, elevated serum free T4, and variably normal or slightly elevated serum fT3. Pituitary magnetic resonance imaging was normal, and the thyrotropin-releasing hormone test result was compatible with the diagnosis of RTHß syndrome. Initial Sanger sequencing on blood samples could not highlight the presence of a mosaic variant because of insufficient sensitivity. When next-generation sequencing became accessible, blood samples were retested and we found a known pathogenic variant: c.949G > A; p.(ala317Thr), with an allelic frequency of 12%. Other samples from tissues of different embryological origin were also tested and found an allelic frequency of 5.7%, 17.9%, 9.9%, 6.4%, and 0% on urine tests, oral swab, nasal mucosa swab, skin biopsy, and conjunctival swab, respectively. Cloning confirmed the allelic frequency observed. CONCLUSIONS: We highlight that a pathogenic variant in a mosaic state in the THRB gene may be the cause of an authentic RTHß syndrome. High-throughput sequencing of multiple tissues eases the detection of pathogenic variant in a mosaic state and allows the correct diagnosis of patients with true RTHß, thus avoiding patient mismanagement.


Asunto(s)
Genes erbA , Síndrome de Resistencia a Hormonas Tiroideas , Humanos , Mosaicismo , Mutación , Receptores beta de Hormona Tiroidea/genética , Síndrome de Resistencia a Hormonas Tiroideas/diagnóstico , Síndrome de Resistencia a Hormonas Tiroideas/genética , Hormonas Tiroideas
19.
J Clin Med ; 11(2)2022 Jan 13.
Artículo en Inglés | MEDLINE | ID: mdl-35054098

RESUMEN

About half of patients with Graves' disease develop an orbitopathy related to an inflammatory expansion of the periorbital adipose tissue and muscles. We used a targeted metabolomic approach measuring 188 metabolites by mass spectrometry to compare the metabolic composition of tears in patients with active (n = 21) versus inactive (n = 24) thyroid-associated orbitopathy. Among the 44 metabolites accurately measured, 8 showed a significant alteration of their concentrations between the two groups. Two short-chain acylcarnitines, propionylcarnitine and butyrylcarnitine, and spermine showed increased concentrations in the tears of patients with active orbitopathy, whereas ornithine, glycine, serine, citrulline and histidine showed decreased concentrations in this group. In addition, the ratio putrescine/ornithine, representing the activity of ornithine decarboxylase, was significantly increased in patients with active compared to inactive orbitopathy (p = 0.0011, fold change 3.75). The specificity of this candidate biomarker was maintained when compared to a control group with unclassified dry eye disease. Our results suggest that the stimulation of ornithine decarboxylase by TSH receptor autoantibodies in orbital fibroblasts could lead to increased synthesis of spermine, through the increased activity of ornithine decarboxylase, that may contribute to periorbital expansion in Graves' ophthalmopathy.

20.
J Clin Oncol ; 40(17): 1870-1878, 2022 06 10.
Artículo en Inglés | MEDLINE | ID: mdl-35192411

RESUMEN

PURPOSE: Selumetinib can increase radioactive iodine (RAI) avidity in RAI-refractory tumors. We investigated whether selumetinib plus adjuvant RAI improves complete remission (CR) rates in patients with differentiated thyroid cancer (DTC) at high risk of primary treatment failure versus RAI alone. METHODS: ASTRA (ClinicalTrials.gov identifier: NCT01843062) is an international, phase III, randomized, placebo-controlled, double-blind trial. Patients with DTC at high risk of primary treatment failure (primary tumor > 4 cm; gross extrathyroidal extension outside the thyroid gland [T4 disease]; or N1a/N1b disease with ≥ 1 metastatic lymph node(s) ≥ 1 cm or ≥ 5 lymph nodes [any size]) were randomly assigned 2:1 to selumetinib 75 mg orally twice daily or placebo for approximately 5 weeks (no stratification). On treatment days 29-31, recombinant human thyroid-stimulating hormone (0.9 mg)-stimulated RAI (131I; 100 mCi/3.7 GBq) was administered, followed by 5 days of selumetinib/placebo. The primary end point (CR rate 18 months after RAI) was assessed in the intention-to-treat population. RESULTS: Four hundred patients were enrolled (August 27, 2013-March 23, 2016) and 233 randomly assigned (selumetinib, n = 155 [67%]; placebo, n = 78 [33%]). No statistically significant difference in CR rate 18 months after RAI was observed (selumetinib n = 62 [40%]; placebo n = 30 [38%]; odds ratio 1.07 [95% CI, 0.61 to 1.87]; P = .8205). Treatment-related grade ≥ 3 adverse events were reported in 25/154 patients (16%) with selumetinib and none with placebo. The most common adverse event with selumetinib was dermatitis acneiform (n = 11 [7%]). No treatment-related deaths were reported. CONCLUSION: Postoperative pathologic risk stratification identified patients with DTC at high risk of primary treatment failure, although the addition of selumetinib to adjuvant RAI failed to improve the CR rate for these patients. Future strategies should focus on tumor genotype-tailored drug selection and maintaining drug dosing to optimize RAI efficacy.


Asunto(s)
Adenocarcinoma , Neoplasias de la Tiroides , Adenocarcinoma/tratamiento farmacológico , Bencimidazoles/efectos adversos , Método Doble Ciego , Humanos , Radioisótopos de Yodo/efectos adversos , Neoplasias de la Tiroides/tratamiento farmacológico , Neoplasias de la Tiroides/radioterapia
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