HLA-G 3' untranslated region polymorphic sites associated with increased HLA-G production are more frequent in patients exhibiting differentiated thyroid tumours.

BACKGROUND: HLA-G is a nonclassical class I histocompatibility molecule implicated on the immune escape mechanism of tumour cells. We evaluated the genetic diversity of HLA-G 3' untranslated region (3'UTR) and associated polymorphic sites with clinical presentation and with the magnitude of HLA-G thyroid expression. PATIENTS AND METHODS: Polymorphic sites at 3'UTR (14bpINS/DEL, +3003C/T, +3010C/G, +3027A/C, +3035C/T, +3142C/G, +3187A/G, +3196C/G) were characterized by sequencing analyses in blood samples of 72 patients exhibiting papillary thyroid carcinoma (PTC), 22 follicular thyroid carcinomas (FTC), 19 follicular adenomas (FA), 21 colloid goitres and 156 healthy controls. RESULTS: Compared to goitre and/or controls, patients with PTC exhibited higher frequency of 14bpDEL (P = 0·030), +3010G (P = 0·034), +3010CG (P = 0·044), +3142CG (P = 0·040), +3035C (P = 0·050) and +3187GG (P = 0·032). Patients with FTC presented higher frequency of 14bpINS/DEL (P = 0·020). The UTR-5 haplotype was underrepresented in PTC (P = 0·050). The +3003TT was more frequent in patients with PTC older than 45 years (P = 0·030). Male patients had a higher frequency of +3196GG (P = 0·040). Tumour multicentricity was associated with UTR-2 (P = 0·030). The following associations were observed in PTC and FTC combined: i) tumour size <2 cm with 14bpINS/INS (P = 0·030); ii) multicentricity with +3035CC (P = 0·030) and +3196GG (P = 0·030); iii) decreased thyroid HLA-G expression with +3196C and +3196CC; and iv) moderate HLA-G thyroid staining with UTR-2. CONCLUSIONS: HLA-G 3'UTR polymorphisms associated with a greater magnitude of HLA-G production were associated with differentiated thyroid tumours and with variables implicated in poor prognosis. These findings corroborate the unfavourable role of HLA-G in thyroid cancer.

Assessment of Cardiometabolic Risk Factors and Insulin Sensitivity by Hyperinsulinemic-Euglycemic Clamp in Resistance to Thyroid Hormone ß Syndrome.

Background: Resistance to thyroid hormone beta (RTHß) is a rare disease resulting from mutations in the THRB gene, characterized by reduced T3 action in tissues with high thyroid hormone receptor ß expression. Thyroid hormones regulate body composition and metabolism in general, and increased or decreased hormone levels are associated with insulin resistance. This study evaluated the presence of cardiometabolic risk factors and insulin sensitivity in patients with RTHß. Methods: In all, 16 patients, 8 adults (52.3 ± 16.3 years of age) and 8 children (10.9 ± 3.9 years of age), were compared to 28 control individuals matched for age, sex, and body mass index (BMI). Anthropometry evaluation and blood samples were collected for glycemia, lipids, insulin, interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-α), leptin, adiponectin, ultrasensitive C-reactive protein (CRPus), free thyroxine, total triiodothyronine, thyrotropin, and anti-thyroid peroxidase measurements. Body composition was assessed using dual-emission X-ray absorptiometry and bioimpedance. Insulin sensitivity was evaluated in adult patients and controls using the hyperinsulinemic-euglycemic clamp (HEC), whereas homeostasis model assessment of insulin resistance (HOMA-IR) was calculated in all individuals studied. Results: Patients and controls presented similar weight, BMI, abdominal perimeter, and total fat body mass. Patients with RTHß demonstrated higher total cholesterol (TC), p = 0.04, and low-density lipoprotein cholesterol (LDL-C), p = 0.03, but no alteration was observed in other parameters associated with metabolic risk, such as leptin, TNF-α, and CRPus. Two adult patients met the criteria for metabolic syndrome. There was no evidence of insulin resistance assessed by HEC or HOMA-IR. Elevated IL-6 levels were observed in patients with RTHß. Conclusion: Using HEC as the gold standard method, no evidence of reduced insulin sensitivity in skeletal muscle was documented in RTHß adult patients; however, higher levels of TC and LDL-C were observed in these patients, which suggest the need for active monitoring of this abnormality to minimize cardiometabolic risk. In addition, we demonstrated, for the first time, that the increase in IL-6 levels in patients with RTHß is probably secondary to metabolic causes as they have normal levels of TNF-α and CRPus, which may contribute to an increase in cardiovascular risk. A larger number of patients must be studied to confirm these results.

Impact of lead exposure on the thyroid glands of individuals living in high- or low-lead exposure areas.

Ecuador was an endemic area for iodine deficiency; however, due to the population consumption of iodized table salt, the country is nowadays considered iodine sufficient. Despite the population consumption of iodized salt for more than 50 years, the prevalence of hypothyroidism has increased in recent years. A similar increment has been reported for thyroid cancer (TC) becoming the second most common cancer in women and seventh most common cancer in men. High blood lead (BPb) level is a controversial causal factor for impaired thyroid function as well as a debated environmental cause for the increased incidence of TC. To study the association between BPb and thyroid function, anti-thyroid peroxidase (anti-TPO) and anti-thyroglobulin (anti-Tg) antibodies, and the presence of benign and malignant thyroid nodules in Ecuadorian individuals living in high lead exposure (HE) areas compared with those living in low lead exposure (LE) area. We evaluated 197 euthyroid individuals: 70 from Esmeraldas (close to a petrol refinery) and 27 from La Victoria de Pujilí (Pb-glazing ceramics), considered HE areas, and 100 from Quito, considered the LE area. In parallel, we evaluated 187 patients with hypothyroidism (60, 27, and 100 patients from Esmeraldas, Pujilí, and Quito, respectively). BPb was detected using atomic absorption spectroscopy, while thyroid-stimulating hormone (TSH), free-thyroxine (FT4), and autoantibodies were measured using chemiluminescence assays. Thyroid ultrasonography was performed in 300 individuals and fine-needle aspiration biopsy (FNA) was performed only when required based on the guidelines of the American Thyroid Association. The BPb levels (mean ±â€…SD) in the HE areas were increased (8.5 ±â€…7.4) than those in the LE area (3.2 ±â€…2.4, P < .001). No significant associations were observed between BPb and TSH, FT4, or thyroid antibody levels. Enlarged thyroid glands and larger thyroid nodules were primarily observed in HE areas. Just 1 TC was observed. High BPb levels detected in HE areas were not associated with thyroid function or thyroid autoantibodies; however, increased thyroid size and numbers of thyroid nodules were observed, demanding further actions to control lead contamination in these Ecuadorian areas.

Polymorphisms at the IL17A and IL17RA Genes are Associated with Prognosis of Papillary Thyroid Carcinoma.

BACKGROUND: Interleukin (IL)-17A has a dual role in tumor immunity, promotes anti-tumor responses and facilitates angiogenesis by interacting with IL-17 receptor A (IL-17RA). Although IL-17A has been associated with the pathogenesis of papillary thyroid carcinoma (PTC), the nucleotide variability at the IL17A and IL17RA genes is still poorly characterized. AIM: To assess the contribution of the IL17A (-197 G >A, rs2275913) and IL17RA (-947 A >G, rs4819554) single nucleotide polymorphisms (SNP) on the development and progression of PTC and on IL-17 plasma levels. METHODS: We studied 188 PTC patients and 170 healthy controls. SNPs were identified using PCR-amplified DNA and restriction fragment length polymorphism (RFLP) techniques. Plasma levels of IL-17A was evaluated in 83 PTC patients using ELISA. Statistical analyses were performed to evaluate the associations between SNPs and clinicohistopathological features of PTC and IL-17A levels. RESULTS: No significant difference was observed regarding the allele and genotype distributions of both SNPs between PTC patients and controls. The IL17A GA was associated with poor biochemical and structural incomplete response to therapy, whereas no influence over the IL-17A expression was observed. The IL17RA AG was significantly associated with small-sized tumors, initial tumor stage at diagnosis and better response to therapy. CONCLUSIONS: The IL17A SNP may predict an aggressive manifestation of PTC, whereas the IL17RA SNP was associated with a more favorable clinical outcome.

Evaluation of thyroid nodules in the Brazilian Public Health Care System, Supplementary Health System, and Private Health System in the northeastern region of the State of São Paulo.

OBJECTIVE: To obtain data about the evaluation of thyroid nodules (TNs) in the northeastern of the State of São Paulo, compared by health care type, and measure the performance of cytology as a screening test for thyroid cancer (TC). METHODS: We collected data of 597 patients treated in the Brazilian public health care system (SUS), supplementary health (SH) and in private health system (PHS) in 2014. A total of 803 TNs were aspirated, and 125 patients underwent surgery. RESULTS: The distribution of all cytologic results according to the Bethesda system was: I, 135 (16.8%); II, 475 (59.2%); III, 107 (13.3%); IV, 32 (4.0%); V, 20 (2.5%); VI, 34 (4.2%). The time between cytologic analysis and surgery was longer in the SUS than in the SH for TNs in general (p < 0.001) and for TNs with Bethesda V and VI cytology (p = 0.01). The sizes of the TNs and resected malignant TNs was larger in the SUS than in the SH (p = 0.001 and p = 0.02, respectively). The number of PHS surgeries was too small and was not compared. The prevalence of TC was 9.2% and 23.6% of them were treated in the SUS. Cytology showed a 93.6% sensitivity, 95.8% specificity, and 94.7% accuracy when Bethesda III and IV were excluded. CONCLUSION: Cytology was a good screening test for TC categories Bethesda II, V, and VI. The differences between the SUS and SH indicate a need for improved access to consultations and specialized tests in the SUS.

Structural insights revealed by two novel THRB mutations.

PURPOSE: Among the inheritable forms of impaired sensitivity to thyroid hormone, resistance to thyroid hormone (RTH) due to mutations in the thyroid hormone receptor beta gene (THRB) is the first and best known described defect, revealing a wide phenotypic variability with an incompletely understood physiopathology. The objective of this study was to evaluate two novel mutations in THRB, N331H and L346R, in an attempt to provide a rational understanding of the harmful effects caused by them. METHODS: The mutations of two patients with RTHß were reproduced for analysis of gene transactivation by dual-luciferase reporter assay, and for molecular modeling for crystallography-based structural assessment. Serum measurements of TSH and FT4 were performed to compare the thyrotrophic resistance to thyroid hormone between RTHß patients and controls. RESULTS: Both mutants showed impaired gene transactivation, with greater damage in L346R. Molecular modeling suggested that the damage occurring in N331H is primarily due to reduced strength of the hydrogen bonds that stabilize T3 in its ligand-binding cavity (LBC), whereas in L346R, the damage is more marked and is mainly due to changes in hydrophobicity and molecular volume inside the LBC. Hormonal dosages indicated that the L346R mutant exhibited greater thyrotrophic resistance than N331H. CONCLUSIONS: This study provides a rational understanding of the effects of mutations, indicating deleterious structural changes in the LBC in both THR, and discloses that not only the position of the mutation but, notably, the nature of the amino acid exchange, has a cardinal role in the functional damage of the receptor.

The first five-year evaluation of cystic fibrosis neonatal screening program in São Paulo State, Brazil.

The Hospital of the Ribeirão Preto Medical School, University of São Paulo is one of the three screening centers in São Paulo State, Brazil, and has included a test for cystic fibrosis (CF) since February 6, 2010, by a court order. We evaluated the first five years of this CF-newborn screening program. The original immunoreactive trypsinogen (IRT)/IRT screening protocol was adopted in Brazil. A total of 173,571 newborns were screened, 1,922 (1.1%) of whom showed IRT1 ≥ 70ng/mL. Of these, 1,795 (93.4%) collected IRT2, with elevated results (IRT2 ≥ 70ng/mL) in 102 of them (5.2%). We identified a total of 26 CF cases during this period, including three CF cases that were not detected by the CF-newborn screening. The incidence of the disease among the screened babies was 1:6,675 newborns screened. Median age at the initial evaluation was 42 days, comparable to that of neonates screened with the IRT/DNA protocol. Almost all infants with CF already exhibited some manifestations of the disease during the neonatal period. The mutation most frequently detected in the CF cases was F508del. These findings suggest the early age at the beginning of treatment at our center was due to the effort of the persons involved in the program regarding an effective active search. Considering the false negative results of CF-newborn screening and the early onset of clinical manifestations of the disease in this study, pediatricians should be aware of the diagnosis of CF even in children with negative test.

Preoperative detection of TERT promoter and BRAFV600E mutations in papillary thyroid carcinoma in high-risk thyroid nodules.

OBJECTIVES: This observational study analyzed telomerase reverse transcriptase (pTERT) mutations in 45 fine-needle aspiration (FNA) specimens obtained from thyroid nodules followed by postoperatively confirmation of papillary thyroid cancer (PTC) diagnosis, examining their relationship with clinicopathologic aspects and the BRAFV600E mutation. SUBJECTS AND METHODS: Clinical information was collected from patients who presented to Ribeirao Preto University Hospital for surgical consultation regarding a thyroid nodule and who underwent molecular testing between January 2010 to October 2012. Tests included a DNA-based somatic detection of BRAFV600E and pTERT mutations. RESULTS: We found coexistence of pTERTC228T and BRAFV600E mutations in 8.9% (4/45) of thyroid nodules. All nodules positive for pTERT mutations were BRAFV600E positives. There was a significant association between pTERTC228T/BRAFV600E with older age and advanced stage compared with the group negative for either mutation. CONCLUSIONS: This series provides evidence that FNA is a reliable method for preoperative diagnosis of high-risk thyroid nodules. pTERTC228T/BRAFV600E mutations could be a marker of poor prognosis. Its use as a personalized molecular medicine tool to individualize treatment decisions and follow-up design needs to be further studied.

Hypothalamic-pituitary axis and peripheral tissue responses to TRH stimulation and liothyronine suppression tests in normal subjects evaluated by current methods.

OBJECTIVE: To reevaluate the responses of thyrotropin-releasing hormone (TRH) stimulation test in baseline condition as well as after the administration of graded supraphysiological doses of liothyronine (L-T(3)) in normal subjects. DESIGN: To assess various parameters related to the hypothalamic-pituitary axis and peripheral tissue responses to L-T(3) in 22 normal individuals (median age: 30.5 years). Subjects were submitted to an intravenous TRH test at baseline condition and also to the oral administration of sequential and graded doses of L-T(3) (50, 100, and 200 microg/day), each given over 3 days, at an outpatient clinic. Blood samples were obtained for thyrotropin (TSH) and prolactin (PRL) at basal and then 15, 30, and 60 minutes after the TRH injection. Effects of L-T(3) administration on cholesterol, creatine kinase, retinol, ferritin, and sex hormone-binding globulin (SHBG) were also measured at basal and after the oral administration of L-T(3). MAIN OUTCOME: TRH administration resulted in an increase of 4- to 14-fold rise in serum TSH (8.3 +/- 2.5-fold), and in a slight rise in serum PRL concentrations (3.8 +/- 1.5-fold). Administration of graded doses of triiodothyronine (T(3)) resulted in a dose-dependent suppression of TSH and PRL. Basal thyroxine-binding globulin (TBG) and cholesterol levels decreased, and ferritin and SHBG increased after L-T(3) administration, while creatine kinase and retinol did not change throughout the study. There was a positive correlation between basal TSH and TSH peak response to TRH at basal condition and after each sequential L-T(3) doses. On the other hand, TSH peak response to the TRH test did not predict cholesterol, TBG, ferritin, or SHBG values. CONCLUSION: Using the current methods on hormone and biochemical analysis, we standardized the response of many parameters to TRH stimulation test after sequential and graded T(3) suppression test in normal subjects. Our data suggest that the evaluation of the responses of the hypothalamus-pituitary axis to TRH test as well as the impact of L-T(3) on peripheral tissues were not modified by the current methods.

The role of major histocompatibility complex alleles in the susceptibility of Brazilian patients to develop the myogenic type of Graves' orbitopathy.

OBJECTIVE: To assess the frequency of the genetic markers HLA-DRB1 and DQB1 in patients with Graves' orbitopathy (GO) with and without extraocular muscle involvement. DESIGN: The frequencies of class II HLA-DRB1 and DQB1 allele groups were determined for 81 Brazilian patients with GO and 161 normal subjects. The patients were divided into myogenic and nonmyogenic groups based on the clinical characteristics of the orbitopathy and quantitative computed tomography analysis of the extraocular muscle (EOM) dimensions. MAIN OUTCOME: Compared to the frequency obtained for samples of normal subjects of the Brazilian population, HLA-DRB1 16 ( pc=0.008) was overrepresented in myogenic and HLA-DRB1 03 ( pc=0.02) in nonmyogenic patients. CONCLUSIONS: The association between the HLA-DRB1 16 and the myogenic subtype of GO suggests that EOM involvement in GO may be genetically predisposed.

Effects of drying and storage conditions on the stability of TSH in blood spots.

OBJECTIVE: To evaluate the influence of sample drying and storage temperature on TSH stability in neonatal screening. SUBJECTS AND METHODS: Blood samples from 29 adult volunteers as a surrogate for neonatal blood (10 with normal TSH, 9 with overt hypothyroid and 10 with subclinical hypothyroidism) were spotted on filter paper and dried at 22°C or 35°C for 3 hours. The samples were then stored at 22°C, -4°C, or -20°C, and TSH measurements were performed at day 0 (D0), D7, D30, D60, D180, and D360 of storage. RESULTS: The drying temperature did not interfere with TSH measurement on D0. TSH values remained stable up to D30 when stored at 22°C and were stable up to D60 when stored in a refrigerator or freezer. Samples stored at 22°C had a greater decrease in TSH values than samples stored in a refrigerator or a freezer. CONCLUSIONS: Freezer storage is not advantageous compared to storage in the refrigerator. At the end of one year, if confirmation of the initial result is required, a reduction of TSH concentrations should be taken into account.

Assessment of thyroid function, ioduria and oxidative stress in women in the first trimester of pregnancy.

INTRODUCTION: adequate iodine intake during pregnancy is essential for the synthesis of thyroid hormones, which are important for the physiological functions of the mother and appropriate maturation of the central nervous system of the fetus. OBJECTIVE: the objective of the present study was to determine the levels of urinary iodine excretion and thyroid function, antioxidants and oxidative stress markers in pregnant women. METHODS: the study was conducted on 191 pregnant women and 62 non-pregnant women who were evaluated regarding nutritional status. Analyses of urinary iodine, of oxidative stress markers and thyroid function were performed, revealing iodine insufficiency in 81 pregnant women. RESULTS: there was no change in the thyroid stimulating hormone concentration in 89% of the pregnant women. Antithyroperoxidase antibody values were higher in the control group compared to the pregnant women's group (64.5% and 12.6%, respectively) and antithyroglobulin antibody values were also higher in the control group (11.6%). Assessment of oxidative stress revealed higher levels of advanced oxidation protein products, of total antioxidant capacity and of superoxide dismutase antioxidants in pregnant women. Classification of ioduria with respect to oxidative stress markers revealed lower α-tocopherol levels for the pregnant women with iodine insufficiency. CONCLUSION: on this basis, the results suggest that iodine insufficiency did not induce changes in thyroid stimulating hormone levels or antibodies and those pregnant women with adequate urinary iodine excretion had a better profile of the α-tocopherol antioxidant, indicating that iodine may play a significant role in antioxidant capacity during gestation.

[Genetic polymorphisms: implications in the pathogenesis of medullary thyroid carcinoma]. / Polimorfismos genéticos: implicações na patogênese do carcinoma medular de tireóide.

Medullary thyroid carcinoma (MTC) is a rare malignant neoplasia, which may occur on sporadic form or on a hereditary basis. Germ line mutations in the RET proto-oncogene is responsible for hereditary MTC. However, most MTC occur in individuals without family history where the pathogenesis is still unclear. Single nucleotide polymorphisms (SNPs) of the RET gene have been described in the general population as well as in patients with MTC. Even though these allelic variants do not seem to confer any transforming activity to the tyrosine kinase domain of the RET protein, cumulative studies suggest that they could modify disease susceptibility and clinical phenotype in patients with sporadic or hereditary MTC. Polymorphisms located in exons 11 (G691S), 13 (L769L), 14 (S836S), and 15 (S904S) seem to be over-represented in sporadic MTC patients from American and European countries. Here, we discuss the results obtained in different studies as well as describe the frequency of RET polymorphisms in Brazilian patients with sporadic MTC.

Medullary thyroid carcinoma - Adverse events during systemic treatment: risk-benefit ratio.

Medullary thyroid carcinoma (MTC) is a rare neuroendocrine tumor originating from parafollicular C cells of the thyroid and associated with mutations in the proto-oncogene REarranged during Transfection (RET). The prognosis of MTC depends on clinical stage, with a 95.6% 10-year survival rate among patients with localized disease and 40% among patients with advanced disease. Standard chemotherapy and radiotherapy have no significant impact on the overall survival of these patients and two tyrosine kinase receptor inhibitors (TKIs), vandetanib and cabozantinib, have been recently approved for the systemic treatment of locally advanced or metastatic MTC. However, since patients with MTC and residual or recurrent disease may have an indolent course with no need for systemic treatment, and since these drugs are highly toxic, it is extremely important to select the patients who will receive these drugs in a correct manner. It is also essential to carefully monitor patients using TKI regarding possible adverse effects, which should be properly managed when occurring.

Graves' disease, myxedema, and papillary thyroid carcinoma / Doença de Graves, mixedema e carcinoma papilífero de tireoide

Graves' disease (GD) is the leading cause of hyperthyroidism and diffuse toxic goiter in iodine-sufficient geographi-cal areas. GD is associated with classical manifestations such as ophthalmopathy and thyroid dermopathy, in addi-tion to diffuse goiter, which may be the site of carcinomas, as a complication. Case report: A 52-year-old woman presented with goiter and symptoms compatible with hyperthyroidism, such as heat intolerance, weight loss, fati-gue, increased sweat, tachycardia, fine tremors, increased intestinal transit, anxiety, emotional lability, insomnia, exophthalmos, and pretibial myxedema. A complementary investigation confirmed the diagnosis of hyperthyroidism (high free T4 and total T3 levels and low thyroid-stimulating hormone - TSH levels). Ultrasound images showed dif-fuse enlargement of the thyroid lobes by approximately 10 times and the presence of three thyroid nodules, one of which was larger than 2 cm with heterogeneous echogenicity and vascularization throughout the nodule; ultrasoun-d-guided fine needle aspiration revealed cytology compatible with Bethesda IV; scintigraphy revealed a low uptake area (cold nodule) amid a diffuse high-uptake goiter. A thyroidectomy was performed, and the anatomical specimen diagnosis revealed papillary thyroid carcinoma in the right lobe, with adjacent parenchyma compatible with GD. Histopathological examination of the skin showed the presence of myxedema compatible with Graves' dermopathy. The patient evolved with the normalization of TSH levels and a reduction of cutaneous manifestations. Conclusion:GD abnormalities may not be restricted to the classic clinical manifestations, and a careful investigation may reveal the coexistence of carcinomas. (AU)

A doença de Graves (DG) é a principal causa de hipertireoidismo e bócio difuso tóxico em áreas geográficas com iodo suficiente. DG está associada a manifestações clínicas clássicas como oftalmopatia e dermopatia da tireoide, além do bócio difuso, que pode ser sítio de carcinomas, como uma complicação. Relato de caso: Mulher de 52 anos apresentou bócio e sintomas compatíveis com hipertireoidismo como intolerância ao calor, emagrecimento, fadiga, sudorese aumentada, taquicardia, tremores finos, trânsito intestinal aumentado, ansiedade, labilidade emocional, insônia, exoftalmia e mixedema pré-tibial. A investigação complementar confirmou o diagnóstico de hipertireoidis-mo (níveis elevados de T4 livre e T3 total; níveis baixos de hormônio estimulante da tireoide - TSH). As imagens ultrassonográficas mostraram aumento difuso dos lobos tireoidianos em aproximadamente 10 vezes e a presença de três nódulos tireoidianos, um dos quais, maior que 2 cm, com ecogenicidade e vascularização heterogêneas em todo o nódulo, cuja punção aspirativa por agulha fina guiada por ultrassom revelou citologia compatível com Bethesda IV; e a cintilografia evidenciou uma área de baixa captação (nódulo frio) em meio a um bócio difuso de alta captação. Foi realizada tireoidectomia e o diagnóstico da peça anatômica revelou carcinoma papilífero de tir-eoide em lobo direito, com parênquima adjacente compatível com DG. O exame histopatológico da pele mostrou a presença de mixedema compatível com dermopatia de Graves. A paciente evoluiu com normalização dos níveis de TSH e redução das manifestações cutâneas. Conclusão: As anormalidades da DG podem não estar restritas às manifestações clínicas clássicas, e uma investigação criteriosa pode revelar a coexistência de carcinomas, (AU)

The first five-year evaluation of cystic fibrosis neonatal screening program in São Paulo State, Brazil / Uma avaliação dos primeiros cinco anos do programa de triagem neonatal da fibrose cística no Estado de São Paulo, Brasil / Una evaluación de los primeros cinco años del programa de cribado neonatal de fibrosis cística en el Estado de São Paulo, Brasil

The Hospital of the Ribeirão Preto Medical School, University of São Paulo is one of the three screening centers in São Paulo State, Brazil, and has included a test for cystic fibrosis (CF) since February 6, 2010, by a court order. We evaluated the first five years of this CF-newborn screening program. The original immunoreactive trypsinogen (IRT)/IRT screening protocol was adopted in Brazil. A total of 173,571 newborns were screened, 1,922 (1.1%) of whom showed IRT1 ≥ 70ng/mL. Of these, 1,795 (93.4%) collected IRT2, with elevated results (IRT2 ≥ 70ng/mL) in 102 of them (5.2%). We identified a total of 26 CF cases during this period, including three CF cases that were not detected by the CF-newborn screening. The incidence of the disease among the screened babies was 1:6,675 newborns screened. Median age at the initial evaluation was 42 days, comparable to that of neonates screened with the IRT/DNA protocol. Almost all infants with CF already exhibited some manifestations of the disease during the neonatal period. The mutation most frequently detected in the CF cases was F508del. These findings suggest the early age at the beginning of treatment at our center was due to the effort of the persons involved in the program regarding an effective active search. Considering the false negative results of CF-newborn screening and the early onset of clinical manifestations of the disease in this study, pediatricians should be aware of the diagnosis of CF even in children with negative test.

O Hospital das Clínicas da Faculdade de Medicina de Ribeirão Preto, Universidade de São Paulo é um dos três centros de triagem da fibrose cística (FC) no estado de São Paulo, tendo incluído esse teste desde 6 de fevereiro de 2010, a partir de uma liminar judicial. O estudo avalia os primeiros cinco anos desse programa de triagem neonatal da FC. O Brasil adota o protocolo de triagem original, com o tripsinogênio imunorreativo (IRT)/IRT. Foram triados um total de 173.571 recém-nascidos, dos quais 1.922 (1,1%) mostraram IRT ≥ 70ng/mL. Destes, 1.795 (93,4%) tiveram amostras coletadas para IRT2, com resultados elevados (IRT2 ≥ 70ng/mL) em 102 deles (5,2%). Identificamos um total de 26 casos de FC durante esse período, inclusive 3 casos de FC que não foram detectados com a triagem neonatal. A incidência da FC foi de 1 caso em cada 6.675 recém-nascidos triados. A idade mediana na avaliação inicial foi 42 dias, comparável à idade de recém-nascidos triados com o protocolo IRT/DNA. Quase todos os lactentes com FC já exibiam algumas manifestações da doença durante o período neonatal. A mutação mais comum nos casos de FC foi a F508del. Os resultados em nosso centro indicam que a idade precoce no início do tratamento foi devido aos esforços do programa na implementação de uma busca ativa eficaz. Considerando os resultados falsos-negativos no programa de triagem neonatal para FC e o início precoce das manifestações clínicas da doença neste estudo, os pediatras devem estar cientes da possibilidade de diagnóstico de FC, mesmo em crianças com teste negativo.

El Hospital das Clínicas de la Facultad de Medicina de Ribeirão Preto, São Paulo Universidad es uno de los tres centros de cribado de fibrosis cística (FC) en el estado de São Paulo, incluyendo este test desde el 6 de febrero de 2010, debido a una medida cautelar judicial. El estudio evalúa los primeros cinco años de este programa de cribado neonatal de FC. Brasil adopta el protocolo de cribado original, con el tripsinógeno inmunorreactivo (TIR)/IRT. Se cribaron un total de 173.571 recién nacidos, de los cuales 1.922 (1,1%) mostraron IRT ≥ 70ng/mL. De estos, se obtuvieron 1.795 (93,4%) muestras recogidas para IRT2, con resultados elevados (IRT2 ≥ 70ng/mL) en 102 de ellos (5,2%). Identificamos un total de 26 casos de FC durante ese período, inclusive 3 casos de FC que no fueron detectados con el cribado neonatal. La incidencia de la FC fue de 1 caso por cada 6.675 recién-nacidos cribados. La edad media en la evaluación inicial fue 42 días, comparable a la edad de recién nacidos cribados con el protocolo IRT/DNA. Casi todos los lactantes con FC ya manifestaban algunos síntomas de la enfermedad durante el período neonatal. La mutación más común en los casos de FC era el F508del. Los resultados en nuestro centro indican que la edad precoz en el inicio del tratamiento se debía a los esfuerzos del programa en la implementación de una búsqueda activa eficaz. Considerando los resultados falsos-negativos en el programa de cribado neonatal para FC, y el inicio precoz de las manifestaciones clínicas de la enfermedad en este estudio, los pediatras deben ser conscientes de la posibilidad de diagnóstico de FC, incluso en niños con test negativo.

Iodine insufficiency in pregnant women from the State of São Paulo.

OBJECTIVE: The intake of adequate amounts of iodine during pregnancy is essential for the neurological development of the fetus. The aim of this study was to assess iodine nutrition status in pregnant women from the state of São Paulo, Brazil. MATERIAL AND METHODS: We analyzed urinary iodine concentration (UIC) in 191 pregnant and 58 non-pregnant women matched by age. We used the World Health Organization criteria to define sufficient iodine supply (median UIC: 150-249 µg/L among pregnant women, and 100-199 µg/L for non-pregnant women). RESULTS: Median UIC of the pregnant women studied was lower than the recommended value (median = 137.7 µg/L, 95% CI = 132.9 - 155.9), while non-pregnant women had UIC levels within the appropriate range (median = 190 µg/L; 95% IC = 159.3-200.1). UIC was below 150 µg/L in 57% of the pregnant women. CONCLUSIONS: Although a larger sample is needed to consolidate these findings, these results raise concerns about the adequacy of the iodine supply of pregnant women in Brazil, especially considering the new determinations of the Brazilian government, which have recently reduced the concentrations of iodine in table salt to 15-45 mg/kg of salt.

Role of RET genetic variants in MEN2-associated pheochromocytoma.

BACKGROUND: RET polymorphisms have been involved in the clinical presentation and prognosis of multiple endocrine neoplasia type 2 (MEN2)-associated medullary thyroid carcinoma. OBJECTIVE: To investigate the effect of RET variants on the penetrance of pheochromocytoma (PHEO) in MEN2 patients. METHODS: The RET variants L769L, S836S, and G691S/S904S were evaluated in a cohort of 153 MEN2 patients attending a tertiary teaching hospital. A comparison of RET variant frequencies between patients with and without PHEO was performed. Kaplan-Meier curves and Cox regression analysis were used to estimate the effect of RET variants on the age-dependent penetrance. RESULTS: A total of 48 (31.4%) patients presented with MEN2-associated PHEOs. The mean age at diagnosis was 35.5±13.4 years, 60.4% of patients were women, and 92.8% had RET mutations at codon 634. The frequencies of RET polymorphisms were as follows: 20.1% L769L, 4.75% S836S, and 17.3% S904S/G691S. We did not observe any association between the frequencies of L769L, S836S, or S904S/G691S variants and PHEO development (all P>0.05). However, individuals carrying two RET polymorphic alleles had an increased estimated risk of PHEO (2.63; 95% CI, 1.4-5.0; P=0.004) and were younger at diagnosis when compared with those with one or no polymorphism (29.6±6.3 and 39.3±14.4 years respectively; P=0.006). Accordingly, additional analysis using Cox proportional hazard models demonstrated that the presence of two RET variants was associated with an increased risk for early PHEO development (hazard ratio, 5.99 (95% CI, 2.24-16.03); P<0.001). CONCLUSIONS: RET polymorphic alleles have an additive effect on the estimated risk of age-related PHEO penetrance in MEN2 patients.

HLA-G is differentially expressed in thyroid tissues.

BACKGROUND: HLA-G is a nonclassical major histocompatibility complex molecule that has well-recognized immunomodulatory properties. The expression of HLA-G in tumor cells has been considered to be detrimental, permitting tumor spreading and decreased survival. We evaluated the expression of HLA-G in histologically normal thyroid tissue, goiter, and benign and malignant thyroid tumors, and studied the relationship between HLA-G expression and patient clinical variables. PATIENTS AND METHODS: The immunohistochemistry expression of HLA-G was performed on 72 specimens of papillary thyroid carcinoma (PTC), 19 follicular thyroid carcinomas (FTC), 22 follicular adenomas (FA), 22 colloid goiters (CG), and 14 histologically normal thyroid glands (NT). The percentage of HLA-G staining was graded from absent (-) to intense (+++). RESULTS: HLA-G was faintly expressed in areas of hyperplasia in NT and CG. In PTC, FTC, and FA, the percentage of cell staining was significantly higher than in NT and CG (p<0.001 for each comparison). The tumor area with HLA-G expression was greater in FTC (p=0.0059) and PTC (p=0.0330) compared to FA. According to the magnitude of HLA-G staining, PTC tumors >1 cm exhibited increased HLA-G staining when compared to smaller tumors (p=0.03). Aggressive histologic subtypes of PTC have a higher median stained tumor area. No association was found between HLA-G expression and tumoral staging or patient disease-free survival. CONCLUSIONS: The gradual increase of HLA-G expression from hyperplasia to carcinomas, and the association of strong HLA staining with some variables implicated in poor prognosis corroborate the unfavorable role of HLA-G in tumor thyroid cells, inhibiting cytotoxic immune system cells and facilitating tumor evasion and progression.

Preoperative detection of TERT promoter and BRAFV600E mutations in papillary thyroid carcinoma in high-risk thyroid nodules

ABSTRACT Objectives: This observational study analyzed telomerase reverse transcriptase (pTERT) mutations in 45 fine-needle aspiration (FNA) specimens obtained from thyroid nodules followed by postoperatively confirmation of papillary thyroid cancer (PTC) diagnosis, examining their relationship with clinicopathologic aspects and the BRAFV600E mutation. Subjects and methods: Clinical information was collected from patients who presented to Ribeirao Preto University Hospital for surgical consultation regarding a thyroid nodule and who underwent molecular testing between January 2010 to October 2012. Tests included a DNA-based somatic detection of BRAFV600E and pTERT mutations. Results: We found coexistence of pTERTC228T and BRAFV600E mutations in 8.9% (4/45) of thyroid nodules. All nodules positive for pTERT mutations were BRAFV600E positives. There was a significant association between pTERTC228T/BRAFV600E with older age and advanced stage compared with the group negative for either mutation. Conclusions: This series provides evidence that FNA is a reliable method for preoperative diagnosis of high-risk thyroid nodules. pTERTC228T/BRAFV600E mutations could be a marker of poor prognosis. Its use as a personalized molecular medicine tool to individualize treatment decisions and follow-up design needs to be further studied.