Genotype and phenotype landscape of MEN2 in 554 medullary thyroid cancer patients : the BrasMEN study

Multiple endocrine neoplasia type 2 (MEN2) is an autosomal dominant genetic disease caused by RET gene germline mutations that is characterized by medullary thyroid carcinoma (MTC) associated with other endocrine tumors. Several reports have demonstrated that the RET mutation profile may vary according to the geographical area. In this study, we collected clinical and molecular data from 554 patients with surgically confirmed MTC from 176 families with MEN2 in 18 different Brazilian centers to compare the type and prevalence of RET mutations with those from other countries. The most frequent mutations, classified by the number of families affected, occur in codon 634, exon 11 (76 families), followed by codon 918, exon 16 (34 families: 26 with M918T and 8 with M918V) and codon 804, exon 14 (22 families: 15 with V804M and 7 with V804L). When compared with other major published series from Europe, there are several similarities and some differences. While the mutations in codons C618, C620, C630, E768 and S891 present a similar prevalence, some mutations have a lower prevalence in Brazil, and others are found mainly in Brazil (G533C and M918V). These results reflect the singular proportion of European, Amerindian and African ancestries in the Brazilian mosaic genome

Método e kit para predição prognóstico de câncer e uso do método em oncologia clínica

Universidade Federal do Rio Grande do SulMedicinaDepositad

Impact of the updated TNM staging criteria on prediction of persistent disease in a differentiated thyroid carcinoma cohort

Objective: The 8th TNM system edition (TNM-8) released in 2018 presents significant changes when compared to the 7th edition (TNM-7). The aim of this study was to assess the impact of changing the TNM staging criteria on the outcomes in a Brazilian cohort of differentiated thyroid carcinoma (DTC). Subjects and methods: DTC patients, attending a tertiary, University-based hospital, were classified by TNM-7 and TNM-8. Prediction of disease outcomes status of the two systems was compared in a retrospective cohort study design. Results: Four hundred and nineteen DTC patients were evaluated, comprised by 82% (345/419) women, with mean age at diagnosis of 46.4 ± 15.6 years, 89% (372/419) papillary thyroid carcinoma, with a median tumor size of 2.3 cm (P25-P75, 1.3-3.5). One hundred and sixty patients (38%) had lymph node metastases and 47 (11%) distant metastases at diagnosis. Using the TNM-7 criteria, 236 (56%) patients were classified as Stage I, 50 (12%) as Stage II, 75 (18%) as Stage III and 58 (14%) as Stage IV. When evaluated by the TNM-8, 339 (81%) patients were classified as Stage I, 64 (15%) as Stage II, 2 (0.5%) as Stage III and 14(3%) as Stage IV. After a median followup of 4.4years (P25-P75 2.6-6.6), the rate of incomplete biochemical and/or structural response was 54% vs. 92% (P = 0.004) and incomplete structural response was 42% vs. 86% (P = 0.009) for patients classified as stage IV by TNM-7 vs TNM-8, respectively. Only 4 (1%) disease-related deaths were recorded. Conclusions: In our cohort, 37% of DTC patients were down staged with the application of TNM-8 (vs. TNM-7). Additionally, TNM-8 seems to better stratify the risk of structural incomplete response at follow-up

Increasing diagnostic effectiveness of thyroid nodule evaluation by implementation of cell block preparation in routine US-FNA analysis

Objective: Ultrasound-guided fine-needle aspiration (US-FNA) biopsy has proven to be an accurate and efficient tool in thyroid nodule evaluation. We evaluated whether cell block adds to the diagnostic accuracy of US-FNA. Subjects and methods: Three hundred twenty-eight consecutive patients underwent US-FNA, cytology and cell block evaluation. Six slides were prepared for each patient and stained by Papanicolaou and Giemsa techniques. The residual hemorrhagic aspirate in the syringe and needle was fixed in 10% formalin and paraffin-embedded (cell block). The histological sections were examined as a complementary diagnostic tool to US-FNA. Results: The study population comprised 89% females and the mean age was 57.4 ± 13.7 years. The mean nodule size was 2.3 ± 1.2 cm. US-FNA cytological results were as follows: Bethesda I, 17.1% (n = 56); Bethesda II, 61.6% (n = 202); Bethesda III, 9.5% (n = 31); Bethesda IV, 5.8% (n = 19); Bethesda V, 2.4% (n = 8), and Bethesda VI, 3.6% (n = 12). Cell blocks were obtained in 100% of cases and were considered diagnostic in 89.6%. Combined cytological and cell block (cyto-cell block) results were as follows: unsatisfactory, 4.3% (n = 14); benign, 72.6% (n = 238); indeterminate, 11.3% (n = 37); follicular lesion, 5.8% (n = 19); suspicious for malignancy, 2.4% (n = 8), and malignant, 3.6% (n = 12). The sensitivity and specificity for cyto-cell block was 100% and 90%, respectively, and the accuracy was 94%. Cyto-cell block analysis reduced the rate of unsatisfactory samples (p < 0.001). Conclusions: The cyto-cell block interpretation improved the efficiency of US-FNA. This simple, fast and low-cost technique should be used as an adjunctive test in thyroid nodule evaluation

Management of hereditary medullary thyroid carcinoma : clinical implications of molecular diagnosis

O carcinoma medular de tireóide (CMT) hereditário pode apresentar-se como componente das síndromes de Neoplasia Endócrina Múltipla (NEM 2A e 2B) ou Carcinoma Medular de Tireóide Familiar (CMTF). Diferentes mutações no RET foram identificadas como responsáveis pelo CMT e estudos recentes sugerem uma correlação entre o genótipo-fenótipo, podendo existir uma grande variabilidade de síndromes clínicas associadas às diferentes mutações. O presente estudo realizou a análise molecular do RET em indivíduos com CMT e avaliou a correlação entre fenótipo-genótipo nos afetados e seus familiares. Foram incluídos 57 indivíduos com diagnóstico histopatológico/imunohistoquímico de CMT (10 esporádicos e 47 hereditários, provenientes de 16 famílias). O DNA genômico foi extraído de leucócitos periféricos e os exons 10, 11, 13, 14, 15 e/ou 16 do RET amplificados por PCR com primers específicos. A presença de mutações foi determinada por SSCP, restrição enzimática e/ou sequenciamento. Das famílias com CMT hereditário, 7 apresentavam NEM 2A, 3 NEM 2A associada à Líquen Amilóide Cutânea (CLA), 3 NEM 2B, 2 CMTF e 1 outras formas hereditárias. Em 6 famílias com NEM 2A, nas 3 com NEM 2A+CLA e nas 2 com CMTF a mutação estava presente códon 634. Enquanto que a outra família com NEM 2A apresentava a mutação no códon 618. Nos indivíduos com NEM 2B foi detectada uma mutação de novo no códon M918T. Na família classificada como outros, a mutação também localizava-se no códon 634. O diagnóstico molecular identificou mutações em todos indivíduos com doença hereditária, em 23 indivíduos carreadores sem evidência clínica da neoplasia e em 3 indivíduos com CMT aparentemente esporádico, destacando a importância do rastreamento genético como método diagnóstico.Hereditary MTC can occur either alone – familial MTC (FMTC) – or as the thyroid manifestation of multiple endocrine neoplasia type 2 (MEN 2) syndromes (MEN 2A and MEN 2B) or others. Three phenotypic subtypes have been reported. MEN 2A(1), MEN 2A(2) and MEN 2A(3). Germline mutations in the RET proto-oncogene cause MEN 2 and recent studies suggest a relationship between specific mutations and different phenotypes in MEN 2 syndromes. The purpose of this study was to identify RET proto-oncogene mutations and analyze a possible relationship between genotype-phenotype in Brazilian kindred with MTC. A total of 57 patients with histopathological and immunohistochemistry diagnosis of MTC were included. This sample was formed from index cases and affected members of 16 families with hereditary MTC and 10 individuals with sporadic tumors. DNA was extracted from leukocytes of the affected individuals and relatives. Exons 10, 11, 13, 14, 15 and 16 were amplificated by PCR, using specific primers. The presence of mutation was determined by SSCP, enzymatic restriction analysis and/or automatic sequencing. The phenotypes of hereditary MTC were as follows: 7 MEN 2A, 3 MEN 2A associated with CLA, 3 MEN 2B, 2 FMTC and 1 other forms. We identified mutations at codon 634 in 6 families with MEN 2A, only one kindred had the mutation at codon 618. The 3 kindred with MEN 2A+CLA, both cases of FMTC and the only family classified as other hereditary forms of the MTC presented the mutation in codon 634. A mutation at codon M918T was identified in the 3 individuals with MEN 2B. The genetic screening was able to identified 23 assymtomatic carriers and determine the hereditary MCT pattern in 3 individuals with apparently sporadic tumors. In conclusion, genetic testing can identify affected and assymtomatic individuals with hereditary disease, allowing early diagnosis and treatment

Novel aspects in graves' disease therapy

O hipertireoidismo da doença de Graves é a forma mais comum de hipertireoidismo em pacientes entre 20-50 anos. Três abordagens terapêuticas são atualmente utilizadas, drogas antitireoidiana, cirurgia e iodo radioativo (131I). O iodo radioativo tem sido cada vez mais aceito como primeira escolha terapêutica, porque é um tratamento seguro, definitivo e de fácil administração. O risco de piora do quadro de tireotoxicose após administração do 131I, os fatores prognósticos de falência e o cálculo da dose administrada têm sido alguns dos aspectos discutidos na literatura recentemente, e constituem o foco desta artigo. Em pacientes com bócios pequenos (<30g), crianças e adolescentes, e em situações especiais como na gravidez, as drogas antitireoidianas ainda é a primeira escolha no tratamento para a maioria dos autores. O tratamento cirúrgico é, atualmente, quase um tratamento de exceção, com indicação restrita para os casos em que as terapias anteriores não possam ser utilizadas.Graves’ disease is the most frequent cause of hyperthyroidism and current treatment options are antithyroid drugs, radioiodine (131I) and surgery. Radiactive iodine is increasingly being used as definitive therapy, because it long has proven to be a safe, cheap and effective treatment. The risk of exacerbation of hyperthyroidism after 131I administration, factors that may predict the response to radioiodine and the dose to be administrated have been discussed in the literature and we comment the controversies in this review. In patients with mild disease, small goiters, children, adolescents and in special situations, as pregnancy, antityhyroid drugs are still the first choice of treatment for most authors. Surgery is rarely employed, and it is indicated only in cases where antithyroid drugs have not been effective and radioiodine is contraindicated or not acceptable by the patients

Association between PCOS and autoimmune thyroid disease : systematic review and meta-analysis

Polycystic ovary syndrome (PCOS) is the most prevalent endocrine disorder affecting women of reproductive age. PCOS has been associated with distinct metabolic and cardiovascular diseases and with autoimmune conditions, predominantly autoimmune thyroid disease (AITD). AITD has been reported in 18–40% of PCOS women, depending on PCOS diagnostic criteria and ethnicity. The aim of this systematic review and metaanalysis was to summarize the available evidence regarding the likelihood of women with PCOS also having AITD in comparison to a reference group of non-PCOS women. We systematically searched EMBASE and MEDLINE for non-interventional case control, cross-sectional or cohort studies published until August 2017. The Ottawa–Newcastle Scale was used to assess the methodological quality of studies. Statistical meta-analysis was performed with R. Thirteen studies were selected for the present analysis, including 1210 women diagnosed with PCOS and 987 healthy controls. AITD was observed in 26.03 and 9.72% of PCOS and control groups respectively. A significant association was detected between PCOS and chance of AITD (OR = 3.27, 95% CI 2.32–4.63). Notably, after geographical stratification, the higher risk of AITD in PCOS women persisted for Asians (OR = 4.56, 95% CI 2.47–8.43), Europeans (OR = 3.27, 95% CI 2.07–5.15) and South Americans (OR = 1.86, 95% CI 1.05–3.29). AIDT is a frequent condition in PCOS patients and might affect thyroid function. Thus, screening for thyroid function and thyroidspecific autoantibodies should be considered in patients with PCOS even in the absence of overt symptoms. This systematic review and meta-analysis is registered in PROSPERO under number CRD42017079676