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Featured researches published by Laura Agate.


The Lancet | 1998

Prevalence of thyroid autoantibodies in children and adolescents from Belarus exposed to the Chernobyl radioactive fallout

Furio Pacini; Tatiana Vorontsova; Eleonora Molinaro; Elvira Kuchinskaya; Laura Agate; Elena Shavrova; Larisa Astachova; Luca Chiovato; Aldo Pincheia

BACKGROUND The long-term effects of ionising radiation, including radioiodine, on thyroid function are not well known. We compared thyroid immunity and function in two groups of children from Belarus, one of whom was exposed to the radioactive fallout of Chernobyl. METHODS We measured serum free thyroxine 4 (free T4), free T3, and thyrotropin hormone (TSH) and the prevalence of thyroid autoantibodies (antithyroglobulin and antithyroperoxidase), in 287 children or adolescents living in Hoiniki (average caesium contamination of 5.4 Ci/km2). We also studied 208 children and adolescents living in Braslav (average contamination <0.1 Ci/km2), who were age 12 years or less at the time of the Chernobyl accident. FINDINGS The prevalence of antithyroglobulin or antithyroperoxidase, or both, was significantly higher (p=0.0001) in individuals living in Hoiniki (56 [19.5%] of 287) than in those living in Braslav (eight [3.8%] of 208). In both villages, no sex differences were found in the antibody prevalence before age 13 years. Thereafter, a significantly higher prevalence of thyroid autoantibodies was found in girls from Hoiniki. The increase in the prevalence of circulating antibodies in the contaminated group was already apparent in individuals who, at the time of the accident, were in utero or newborn (15.7%), and was even more pronounced in children of 9 years or more (35.1%). No major alterations of serum FT-4, FT-3, or TSH were found. INTERPRETATION 6-8 years after the Chernobyl accident, a significant increase in thyroid autoimmunity was found in children exposed to radioactive fallout. Pubertal age in girls is a risk factor for increased prevalence of thyroid autoimmunity. The autoimmune phenomena are limited to an increased prevalence of circulating thyroid autoantibodies without evidence of significant thyroid dysfunction. The future development of clinically relevant thyroid autoimmune diseases, especially hypothyroidism, is a possibility.


Clinical Endocrinology | 2011

RET genetic screening of sporadic medullary thyroid cancer (MTC) allows the preclinical diagnosis of unsuspected gene carriers and the identification of a relevant percentage of hidden familial MTC (FMTC)

Cristina Romei; Barbara Cosci; G. Renzini; Valeria Bottici; Eleonora Molinaro; Laura Agate; P. Passannanti; David Viola; Agnese Biagini; Fulvio Basolo; Clara Ugolini; Gabriele Materazzi; Aldo Pinchera; Paolo Vitti; Rossella Elisei

Objective  This study was aimed to demonstrate the clinical benefits of rearranged during transfection (RET) genetic screening in patients with apparently sporadic medullary thyroid cancer (MTC) not only to identify the hereditary nature of the disease in the index case but also to discover family members harbouring the same germline mutations (i.e. gene carriers) who are unaware of their condition.


Cancer | 2014

Treatment of advanced thyroid cancer with axitinib: Phase 2 study with pharmacokinetic/pharmacodynamic and quality-of-life assessments.

Laura D. Locati; Lisa Licitra; Laura Agate; Sai-Hong Ignatius Ou; Andrée Boucher; Barbara Jarzab; Shukui Qin; Madeleine A. Kane; Lori J. Wirth; Connie Chen; Sinil Kim; Antonella Ingrosso; Yazdi K. Pithavala; Paul Bycott; Ezra E.W. Cohen

In a previous phase 2 trial, axitinib was active and well tolerated in patients with advanced thyroid cancer. In this second phase 2 trial, the efficacy and safety of axitinib were evaluated further in this population, and pharmacokinetic/pharmacodynamic relationships and patient‐reported outcomes were assessed.


Endocrine-related Cancer | 2016

Treatment of advanced thyroid cancer with targeted therapies: ten years of experience

David Viola; Laura Valerio; Eleonora Molinaro; Laura Agate; Valeria Bottici; Agnese Biagini; Loredana Lorusso; Virginia Cappagli; Letizia Pieruzzi; Carlotta Giani; Elena Sabini; Paolo Passannati; Luciana Puleo; Antonio Matrone; Benedetta Pontillo-Contillo; Valentina Battaglia; Salvatore Mazzeo; Paolo Vitti; Rossella Elisei

Thyroid cancer is rare, but it is the most frequent endocrine malignancy. Its prognosis is generally favorable, especially in cases of well-differentiated thyroid cancers (DTCs), such as papillary and follicular cancers, which have survival rates of approximately 95% at 40 years. However, 15-20% of cases became radioiodine refractory (RAI-R), and until now, no other treatments have been effective. The same problems are found in cases of poorly differentiated (PDTC) and anaplastic (ATC) thyroid cancers and in at least 30% of medullary thyroid cancer (MTC) cases, which are very aggressive and not sensitive to radioiodine. Tyrosine kinase inhibitors (TKIs) represent a new approach to the treatment of advanced cases of RAI-R DTC, MTC, PDTC, and, possibly, ATC. In the past 10 years, several TKIs have been tested for the treatment of advanced, progressive, and RAI-R thyroid tumors, and some of them have been recently approved for use in clinical practice: sorafenib and lenvatinib for DTC and PDTC and vandetanib and cabozantinib for MTC. The objective of this review is to present the current status of the treatment of advanced thyroid cancer with the use of innovative targeted therapies by describing both the benefits and the limits of their use based on the experiences reported so far. A comprehensive analysis and description of the molecular basis of these therapies, as well as new therapeutic perspectives, are reported. Some practical suggestions are given for both the choice of patients to be treated and their management, with particular regard to the potential side effects.


Acta Paediatrica | 1999

Thyroid consequences of the Chernobyl nuclear accident

Furio Pacini; T Vorontsova; Eleonora Molinaro; E Shavrova; Laura Agate; E Kuchinskaya; Rossella Elisei; Ep Demidchik; Aldo Pinchera

It is well recognized that the use of external irradiation of the head and neck to treat patients with various non‐thyroid disorders increases their risk of developing papillary thyroid carcinoma years after radiation exposure. An increased risk of thyroid cancer has also been reported in survivors of the atomic bombs in Japan, as well as in Marshall Island residents exposed to radiation during the testing of hydrogen bombs. More recently, exposure to radioactive fallout as a result of the Chernobyl nuclear reactor accident has clearly caused an enormous increase in the incidence of childhood thyroid carcinoma in Belarus, Ukraine, and, to a lesser extent, in the Russian Federation, starting in 1990. When clinical and epidemiological features of thyroid carcinomas diagnosed in Belarus after the Chernobyl accident are compared with those of naturally occurring thyroid carcinomas in patients of the same age group in Italy and France, it becomes apparent that the post‐Chernobyl thyroid carcinomas were much less influenced by gender, virtually always papillary (solid and follicular variants), more aggressive at presentation and more frequently associated with thyroid autoimmunity. Gene mutations involving the RET proto‐oncogene, and less frequently TRK, have been shown to be causative events specific for papillary cancer. RET activation was found in nearly 70% of the patients who developed papillary thyroid carcinomas following the Chernobyl accident. In addition to thyroid cancer, radiation‐induced thyroid diseases include benign thyroid nodules, hypothyroidism and autoimmune thyroiditis, with or without thyroid insufficiency, as observed in populations after environmental exposure to radioisotopes of iodine and in the survivors of atomic bomb explosions. On this basis, the authors evaluated thyroid autoimmune phenomena in normal children exposed to radiation after the Chernobyl accident. The results demonstrated an increased prevalence of circulating thyroid antibodies not associated with significant thyroid dysfunction. This finding is consistent with the short period of follow‐up, but it is highly likely that these children will develop clinical thyroid autoimmune diseases in the future. Therefore, screening programmes for this at‐risk population should focus, not only on the detection of thyroid nodules and cancer, but also on the development of thyroid autoimmune diseases.


Endocrine-related Cancer | 2011

In silico and in vitro analysis of rare germline allelic variants of RET oncogene associated with medullary thyroid cancer

Barbara Cosci; Agnese Vivaldi; Cristina Romei; Federica Gemignani; Stefano Landi; Raffaele Ciampi; Alessia Tacito; Eleonora Molinaro; Laura Agate; Valeria Bottici; Virginia Cappagli; David Viola; Paolo Piaggi; Paolo Vitti; Aldo Pinchera; Rossella Elisei

Germline and somatic RET oncogene mutations are found in 98% hereditary and 40% sporadic medullary thyroid carcinomas. Our aim was to analyse by in silico and in vitro assays the transforming activity of six rare RET mutations (T338I, V648I, M918V, A883T, S904F and M848T). Six known RET mutations were used as controls. The in silico analysis showed the highest score value (i.e. 65) for S904F, M848T, M918T and C634R, whereas L790F, G691S, T338I and V648I had 0 score. Intermediate score values were obtained by A883T (score=55), M918V, V804M and Y791F (score=15). The in vitro focus formation assay showed that cells transfected with S904F, M918T, M848T or C634R generated the largest number of focus formation units (FFU). Intermediate numbers of FFU were observed in cells transfected with M918V, V804M, Y791F or A883T, while cells transfected with L790F, G691S, T338I or V648I showed a number of FFU similar to control cells. A positive correlation between the in silico score and in vitro FFU was found (P=0.0005). Only cells transfected with M918T or C634R grew faster and generated higher number of colonies in soft agar than control cells. However, the cells that were transfected with V804M produced an intermediate number of colonies. In conclusion, two of the six rare RET mutations, S904F and M848T possessed a relatively high transforming activity but a low aggressiveness; the other four mutations T338I, V648I, M918V and A883T were low or non-transforming, and their ability to induce tumoural transformation might be related to particular genetic conditions.


Molecular and Cellular Endocrinology | 2009

Re-differentiation of thyroid carcinoma cell lines treated with 5-Aza-2′-deoxycytidine and retinoic acid.

Agnese Vivaldi; Fy Miasaki; Raffaele Ciampi; Laura Agate; Paola Collecchi; Alessandra Capodanno; Aldo Pinchera; Rossella Elisei

We studied cell growth rate, mechanisms of growth inhibition, phenotype re-differentiation, expression of RARalpha, beta, gamma and differentiation thyroid genes before and after combined treatment with 5-Aza-CdR and RA (5-Aza/RA) of human thyroid carcinoma cell lines (FRO, WRO, TT). Furthermore, the activity and localization of the re-expressed sodium-iodide-symporter (NIS) protein was analyzed. After 5-Aza/RA treatment, all cell lines showed a significant reduction in cell growth. This was associated with apoptosis in the TT, with inhibition of cell proliferation in the WRO, and with cell cycle impairment in FRO and WRO. FRO and WRO treated with 5-Aza/RA lost the ability to grow in soft agar. FRO re-expressed thyroid transcription factor-1 and thyroglobulin, TT and WRO re-expressed PAX-8 and FRO and TT re-expressed RARbeta and NIS mRNA. Despite this expression, they were unable to take up iodine: a cytoplasmic localization of NIS protein was demonstrated in FRO. In conclusion, besides a significant reduction in cell growth rate and in the ability to grow in soft agar, treatment with 5-Aza/RA partially re-differentiated FRO and induced expression of NIS mRNA and protein in FRO and TT, but this treatment was unable to restore the functional activity of NIS, likely because it was located into the cytoplasm without reaching the plasma membrane.


The Journal of Clinical Endocrinology and Metabolism | 2008

Thyroid autoantibodies and thyroid function in subjects exposed to Chernobyl fallout during childhood: evidence for a transient radiation-induced elevation of serum thyroid antibodies without an increase in thyroid autoimmune disease.

Laura Agate; Stefano Mariotti; Rossella Elisei; Paola Mossa; Furio Pacini; Eleonora Molinaro; Lucia Grasso; Lucio Masserini; Tatiana Mokhort; Tatiana Vorontsova; Alexander Arynchyn; Mycola D. Tronko; A. F. Tsyb; Ulla Feldt-Rasmussen; Anders Juul; Aldo Pinchera

CONTEXT An increase in the prevalence of thyroid autoantibodies (ATAs) was reported 6-8 yr after the Chernobyl accident in radiation-exposed children and adolescents. OBJECTIVE Our objective was to reassess the effects of childhood radiation exposure on ATAs and thyroid function 13-15 yr after the accident. DESIGN AND SETTING We measured the antithyroglobulin (TgAbs) and antithyroperoxidase (TPOAbs) antibodies and TSH in 1433 sera collected between 1999 and 2001 from 13- to 17-yr-old adolescents born between January 1982 and October 1986 in paired contaminated and noncontaminated villages of Belarus, Ukraine, and Russia. A total of 1441 sera was collected from age- and sex-matched controls living in Denmark and Sardinia (Italy). Free T(4) and free T(3) were measured when TSH was abnormal. RESULTS TPOAb prevalence was higher in contaminated than in noncontaminated Belarusian children (6.4 vs. 2.4%; P = 0.02) but lower than previously reported (11%) in a different contaminated Belarus village. No difference in TPOAb prevalence was found in Ukrainian and Russian villages. TgAbs showed no difference between contaminated and noncontaminated Belarus and Ukraine, whereas in Russia they showed a relative increase in the exposed subjects with respect to the unexposed, who showed an unexpectedly lower prevalence of TgAbs. Besides radiation exposure, female gender was the only variable significantly correlated with ATAs in all groups. ATA prevalence in nonexposed villages of Belarus, Ukraine, and Russian Federation did not differ from that found in Sardinia and Denmark. With few exceptions, thyroid function was normal in all study groups. CONCLUSIONS TPOAb prevalence in adolescents exposed to radioactive fallout was still increased in Belarus 13-15 yr after the Chernobyl accident. This increase was less evident than previously reported and was not accompanied by thyroid dysfunction. Our data suggest that radioactive fallout elicited a transient autoimmune reaction, without triggering full-blown thyroid autoimmune disease. Longer observation periods are needed to exclude later effects.


Journal of Endocrinological Investigation | 2004

Video assisted prophylactic thyroidectomy and central compartment nodes clearance in two RET gene mutation adult carriers

Paolo Miccoli; Rossella Elisei; Piero Berti; Gabriele Materazzi; Laura Agate; Mg Castagna; Barbara Cosci; Pinuccia Faviana; Clara Ugolini; Aldo Pinchera

Activating point mutations of RET gene have been demonstrated to be causative of the familial form of medullary thyroid cancer (MTC), both isolated (FMTC) and associated to other endocrine neoplasia [multiple endocrine neoplasia (MEN) 2A and 2B]. In RET gene mutation carriers, who are prone to developing MTC, prophylactic thyroidectomy is recommended to obtain their definitive cure. The simultaneous excision of the central node compartment is mandatory when the stimulation pentagastrin test for serum calcitonin is positive. Although the minimally invasive video assisted thyroidectomy (MIVAT) is nowadays currently adopted in many centers, it has never been employed for the prophylactic thyroidectomy of RET gene mutation carriers. The fear of obtaining an incomplete lymphadenectomy of the central compartment was the main reason for this reluctance. Since RET gene mutation carriers have often normal thyroid volume and, if involved, small lymph nodes, they indeed represent the best candidates to this approach especially when considering that they are usually young and concerned about the cosmetic results and the period of hospitalization. The excellent results obtained by MIVAT in the last few years induced us to propose this procedure together with a central compartment lymphadenectomy to 2 RET gene mutation carriers recently found by genetic screening. As assessed by a negative pentagastrin stimulation test performed after 6 months from the MIVAT, they were definitively cured without any surgical complication with the exception of a transient hypoparathyroidism. They showed a great satisfaction for both the cosmetic results and the very short period of hospitalization, thus supporting the idea that MIVAT can be used in association with the central node dissection for the prophylactic treatment of RET mutation gene carriers whose thyroid volume is still normal.


Clinical Endocrinology | 2015

Twenty years of lesson learning: how does the RET genetic screening test impact the clinical management of medullary thyroid cancer?

Cristina Romei; Alessia Tacito; Eleonora Molinaro; Laura Agate; Valeria Bottici; David Viola; Antonio Matrone; Agnese Biagini; Francesca Casella; Raffaele Ciampi; Gabriele Materazzi; Paolo Miccoli; Liborio Torregrossa; Clara Ugolini; Fulvio Basolo; Paolo Vitti; Rossella Elisei

Medullary thyroid carcinoma (MTC) is a rare disease that can be inherited or sporadic; its pathogenesis is related to activating mutations in the RET gene.

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