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ABSTRACT Differentiated thyroid carcinoma (DTC) accounts for most cases of thyroid cancer, and the heterogeneity of DTC requires that management decisions be taken by a multidisciplinary team involving endocrinologists, head and neck surgeons, nuclear medicine physicians, pathologists, radiologists, radiation oncologists, and medical oncologists. It is important for nonspecialists to recognize and refer patients with DTC who will benefit from a specialized approach. Recent advances in knowledge and changes in management of DTC call for the need to raise awareness on the part of these nonspecialist physicians, including general endocrinologists and medical oncologists at large. We provide an overview of diagnostic and therapeutic principles in DTC, especially those that bear direct implication on day-to-day management of these patients by generalists. Patients with DTC may be broadly categorized as having localized, locally persistent/recurrent, or metastatic disease. Current recommendations for DTC include a three-tiered system that classifies patients with localized disease into low, intermediate, or high risk of persistent or recurrent disease. Risk stratification should be performed at baseline and repeated on an ongoing basis, depending on clinical evolution. One of the overarching goals in the management of DTC is the need to personalize treatment by tailoring its modality and intensity according to ongoing prognostic stratification, evolving knowledge about the disease, and patient characteristics and preference. In metastatic disease that is refractory to radioactive iodine, thyroid tumors are being reclassified into molecular subtypes that better reflect their biological properties and for which molecular alterations can be targeted with specific agents.

ABSTRACT Objective: A primary medical relevance of thyroid nodules consists of excluding thyroid cancer, present in approximately 5% of all thyroid nodules. Fine-needle aspiration biopsy (FNAB) has a paramount role in distinguishing benign from malignant thyroid nodules due to its availability and diagnostic performance. Nevertheless, intraoperative frozen section (iFS) is still advocated as a valuable tool for surgery planning, especially for indeterminate nodules. Subjects and methods: To compare the FNAB and iFS performances in thyroid cancer diagnosis among nodules in Bethesda Categories (BC) I to VI. The performance of FNAB and iFS tests were calculated using final histopathology results as the gold standard. Results: In total, 316 patients were included in the analysis. Both FNAB and iFS data were available for 272 patients (86.1%). The overall malignancy rate was 30.4%% (n = 96). The FNAB sensitivity, specificity, and accuracy for benign (BC II) and malignant (BC V and VI) were 89.5%, 97.1%, and 94.1%, respectively. For all nodules evaluated, the iFS sensitivity, specificity, and accuracy were 80.9%, 100%, and 94.9%, respectively. For indeterminate nodules and follicular lesions (BC III and IV), the iFS sensitivity, specificity, and accuracy were 25%, 100%, and 88.7%, respectively. For BC I nodules, iFS had 95.2% of accuracy. Conclusion: Our results do not support routine iFS for indeterminate nodules or follicular neoplasms (BC III and IV) due to its low sensitivity. In these categories, iFS is not sufficiently accurate to guide the intraoperative management of thyroidectomies. iFS for BC I nodules could be an option and should be specifically investigated

IntroductionThe COVID-19 pandemic delayed the diagnosis, treatment, and follow-up visits of patients with thyroid cancer. However, the magnitude with which these restrictions affected the Brazilian health care is still unknown.MethodsRetrospective analysis of thyroid cancer-related procedures performed in the Brazilian public health system from 2019 to 2021. Data were retrieved from the Department of Informatics of the Unified Health System (DATASUS). The following procedures were evaluated: fine-needle aspiration biopsies (FNABs), oncologic thyroidectomies, and radioiodine (RAI) therapies for thyroid cancer. The year of 2019 served as baseline control.ResultsCompared with 2019, FNABs, oncologic thyroidectomies, and RAI therapies performed in 2020 decreased by 29%, 17% and 28%, respectively. In 2021, compared with 2019, FNABs increased by 2%, and oncologic thyroidectomies and RAI therapies decreased by 5% and 25%, respectively. Most pronounced reductions were observed in the first months of the pandemic. In April 2020, FNABs decreased by 67%, oncologic thyroidectomies by 45%, and RAI therapies by 75%. In 2021, RAI therapies were the only procedure with a statistically significant decrease.ConclusionThe restrictions to public health care during the COVID-19 pandemic resulted in a significant reduction in diagnostic and treatment procedures for thyroid cancer in Brazil. The effects of these transitory gaps in thyroid cancer care, due to COVID-19, are still unclear.

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 (

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.

A transformação neoplásica resulta de uma série de alterações genéticas, envolvendo ativação de proto-oncogenes e inativação de genes supressores tumorais. Ativação do protooncogene ras por mutações em ponto é a alteração genética mais freqüente em tumores espontâneos da tireóide. Mutações no ras são prevalentes em neoplasias benignas e malignas da tireóide, sugerindo que possam ser um evento inicial no processo de transformação da célula tireoidiana. O bócio multinodular é considerado uma neoplasia benigna e um interessante modelo para o estudo das alterações nesse proto-oncogene na tumorogênese da tireóide. De acordo, observamos aumento da expressão dos proto-oncogenes H-ras e K-ras no tecido nodular de bócio em comparação com o tecido normal. A revisão da literatura e os nossos resultados sugerem que o controle da expressão do ras tenha um importante papel nas etapas iniciais da transformação neoplásica da glândula tireóide.

ABSTRACT Objective: Choosing Wisely (CW) is an initiative that aims to advance the dialogue between physicians and patients about low-value health interventions. Given that thyroid conditions are frequent in clinical practice, we aimed to develop an evidence-based list of thyroid CW recommendations. Materials and methods: The Thyroid Department of the Brazilian Society of Endocrinology and Metabolism (SBEM) named a Task Force to conduct the initiative. The Task Force work was based on an electronic Delphi approach. The 10 recommendations that received the highest scores by the Task Force were submitted for voting by all SBEM associates. The 5 recommendations that received the highest scores by SBEM associates are presented herein. Results: The Task Force was composed of 14 thyroidologists from 10 tertiary-care, teaching-based Brazilian institutions. The brainstorming/ideation phase resulted in 69 recommendations. After the removal of duplicates and recommendations that did not adhere to the initiative's scope, 35 remained. Then the Task Force voted to attribute a grade (0 [lowest agreement] to 10 [highest agreement]) for each recommendation. The 10 recommendations that received the highest scores by the Task Force were submitted to all SBEM associates. A total of 683 associates voted electronically, attributing a grade (0 to 10) for each recommendation. The 5 recommendations that received the highest scores by the SBEM associates compose our final list. Conclusion: A set of recommendations to avoid unnecessary medical tests, treatments, or procedures for thyroid conditions are offered with a transparent methodology. This initiative aims to foster productive interactions between physicians and patients, stimulating shared decision-making.

ABSTRACT Objective: This study aimed to explore the patterns of radioactive iodine (RAI) use for differentiated thyroid cancer (DTC) in Brazil over the past 20 years. Materials and methods: A retrospective analysis of the DTC-related RAI prescriptions, from 2000 to 2018, retrieved from the Department of Informatics of the Unified Health System (Datasus) and National Supplementary Health Agency (ANS) database was performed. RAI activities prescriptions were re-classified as low (30-50 mCi), intermediate (100 mCi), or high activities (>100 mCi). Results: The number of DTC-related RAI prescriptions increased from 0.45 to 2.28/100,000 inhabitants from 2000 to 2015, declining onwards, closing 2018 at 1.87/100,000. In 2018, population-adjusted RAI prescriptions by state ranged from 0.07 to 4.74/100,000 inhabitants. Regarding RAI activities, in the 2000 to 2008 period, the proportion of high-activities among all RAI prescriptions increased from 51.2% to 74.1%. From 2009 onwards, there was a progressive reduction in high-activity prescriptions in the country, closing 2018 at 50.1%. In 2018, the practice of requesting high-activities varied from 16% to 82% between Brazilian states. Interestingly, variability of RAI use do not seem to be related to RAI referral center volume nor state socio-economic indicators. Conclusion: In recent years, there has been a trend towards the lower prescription of RAI, and a reduction of high-activity RAI prescriptions for DTC in Brazil. Also, significative inter-state and inter-institutional variability on RAI use was documented. These results suggest that actions to advance DTC healthcare quality surveillance should be prioritized.

Abstract Thyroid hormones (THs) are critical regulators of cellular processes, while changes in their levels impact all the hallmarks of cancer. Disturbed expression of type 3 deiodinase (DIO3), the main TH-inactivating enzyme, occurs in several human neoplasms and has been associated with adverse outcomes. Here, we investigated the patterns of DIO3 expression and its prognostic significance in breast cancer. DIO3 expression was evaluated by immunohistochemistry in a primary cohort of patients with breast cancer and validated in a second cohort using RNA sequencing data from the TCGA database. DNA methylation data were obtained from the same database. DIO3 expression was present in normal and tumoral breast tissue. Low levels of DIO3 expression were associated with increased mortality in the primary cohort. Accordingly, low DIO3 mRNA levels were associated with an increased risk of death in a multivariate model in the validation cohort. DNA methylation analysis revealed that the DIO3 gene promoter is hypermethylated in tumors when compared to normal tissue. In conclusion, DIO3 is expressed in normal and tumoral breast tissue, while decreased expression relates to poor overall survival in breast cancer patients. Finally, loss of DIO3 expression is associated with hypermethylation of the gene promoter and might have therapeutic implications.

ABSTRACT Objective: Although the prognostic role of BRAFV600E mutation in papillary thyroid carcinoma (PTC) is controversial, the American Thyroid Association (ATA) includes the mutational status in their risk stratification system. To evaluate the impact of the BRAFV600E mutation status on PTC risk stratification. Subjects and methods: PTC patients attending a university-based hospital who had the analysis of the BRAFV600E mutation were included. Persistent disease was defined as the presence of biochemical or structural disease. The performance of the ATA risk stratification system on predicting persistent disease with or without the BRAFV600E mutation status information was evaluated. Results: Of the 134 patients evaluated, 44 (32.8%) carried BRAFV600E mutation. The median tumor size was 1.7 cm (P25-75 1.0-3.0), 64 (47.8%) patients had lymph node, and 11 (8.2%) distant metastases. According to the ATA risk stratification system, patients were classified as low, intermediate, and high risk in 55 (41%), 59 (44%), and 20 (14%) patients, respectively. The data on BRAFV600E mutation reclassified 12 (8.9%) patients from low to intermediate risk. After a median follow-up of 8.5 years, the prevalence of persistent disease was similar in patients with and without BRAFV600E mutation (P = 0.42). Multivariate analysis failed to demonstrate an association between the BRAFV600E mutation and persistent disease status (RR 0.96; 95%CI 0.47-1.94). Notably, none of the patients reclassified from low to intermediate risk showed persistent disease on follow-up. Conclusion: Inclusion of BRAFV600E mutational status has a limited impact on risk stratification and does not add to the prediction of outcomes in PTC patients.

Suppressive levothyroxine therapy (sT4) is a cornerstone in the management of differentiated thyroid cancer (DTC). Long-term sT4 may affect bone mineral density (BMD). We evaluated the effect of sT4 on the bone mass of young DTC patients. In this cross-sectional study, BMD was evaluated via dual-energy X-ray absorptiometry in DTC patients younger than 25 years at diagnosis and undergoing sT4 for ≥1 year. The two control groups comprised patients matched for sex, age, and body-mass-index who were thyroidectomized for indications other than DTC and undergoing L-T4-replacement therapy, and healthy individuals with no prior known thyroid disease. Ninety-three participants were included (thirty-one in each group). There were no differences in the mean age, female sex (77.4% in all groups), or BMI between the sT4 group and each control group. The median TSH level was lower (0.4 [0.04–6.5] vs. 2.7 [0.8–8.5] mIU/mL, p = 0.01) and the mean L-T4 mcg/Kg levels were higher (2.4 ± 0.6 vs. 1.6 ± 0.3, p = 0.01) in the sT4 group compared to the L-T4-replacement therapy group. Lumbar spine, femoral neck, and total femur BMD were all similar among the groups. sT4 does not impact BMD in young DTC patients after a median time of suppression of 8 years. These findings may help in the decision-making and risk/benefit evaluation of sT4 for this population.

Thyroid hormone (TH) signaling controls muscle progenitor cells differentiation. However, inflammation can alter muscle TH signaling by modulating the expression of TH transporters (Slc16a2), receptors (Thra1), and deiodinase enzymes (Dio2 and Dio3). Thus, a proinflammatory environment could affect myogenesis. The role of a low-grade inflammatory milieu in TH signaling during myogenesis needs further investigation. Herein, we aimed to study the impact of the bacterial lipopolysaccharide (LPS)-induced inflammatory stimulus on the TH signaling during myogenesis. C2C12 myoblasts differentiation was induced without (CTR) or with 10 ng/mL LPS presence. The myoblasts under LPS stimulus release the proinflammatory cytokines (IL-6 and IL-1β) and chemokines (CCL2 and CXCL-1). LPS decreases Myod1 expression by 28% during the initial myogenesis, thus reducing the myogenic stimulus. At the same time, LPS reduced the expression of Dio2 by 41% but doubled the D2 enzymatic activity. The late differentiation was not affected by inflammatory milieu, which only increased the Slc16a2 gene expression by 38%. LPS altered the intracellular metabolism of TH and reduced the initial myogenic stimulus. However, it did not affect late differentiation. Increased intracellular TH activation may be the compensatory pathway involved in the recovery of myogenic differentiation under a low-grade inflammatory milieu.

Background: Type 2 Deiodinase (DIO2) converts thyroxine (T4) into the active hormone triiodothyronine (T3). Thr92Ala DIO2 polymorphism has been associated with reduced conversion of T4 into T3 and central nervous system hypothyroidism. However, how Thr92Ala DIO2 polymorphism affects cognitive function is still unclear. Objective: To assess the association between Thr92Ala DIO2 polymorphism and cognitive performance in older adults. Design: Cross-sectional study. Setting: University-based tertiary hospital in Brazil. Patients: > 65-year-old with no limiting clinical disease. Interventions: All participants answered a standard questionnaire before undergoing thyroid function laboratory evaluation and genotyping of the Thr92Ala DIO2 polymorphism. Main Outcomes: Cognitive impairment measured by the Word List Memory task from the Consortium to Establish a Registry for Alzheimer’s Disease Neuropsychological Battery (CERAD-NB) and the Brief Cognitive Screening Battery (BCSB). Results: A hundred individuals were included. Clinical and laboratory characteristics were similar among DIO2 genotypes (all p > 0.05). No differences were found in the Word List Memory, recall, or recognition tests of the CERAD-NB assuming a recessive model for the Ala/Ala vs. Thr/Ala-Thr/Thr genotypes. Results of Clock Drawing Test, Animal Fluency Test, Mini-Mental State Exam, and Figure Memory Test of the BCSB were similar between groups. Conclusions: These findings suggest that Thr92Ala DIO2 polymorphism is not associated with relevant cognitive impairment in older adults.

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 meta-analysis 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 thyroid-specific 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.

Background: Papillary thyroid carcinoma (PTC) is the most common and less aggressive thyroid cancer, but some patients may display locally advanced disease. Therapeutic options are limited in these cases, particularly for those patients with unresectable tumors. Neoadjuvant therapy is not part of the recommended work up.Methods: Report a case of an unresectable grossly locally invasive PTC successfully managed with neoadjuvant therapy and provide a systematic review (SR) using the terms “Neoadjuvant therapy” AND “Thyroid carcinoma.”Results: A 32-year-old man with a 7.8 cm (in the largest dimension) PTC was referred to total thyroidectomy, but tumor resection was not feasible due to extensive local invasion (trachea, esophagus, and adjacent structures). Sorafenib, a multikinase inhibitor (MKI), was initiated; a 70% tumor reduction was observed after 6 months, allowing new surgical intervention and complete resection. Radioactive iodine (RAI) was administered as adjuvant therapy, and whole body scan (WBS) shows uptake on thyroid bed. One-year post-surgery the patient is asymptomatic with a status of disease defined as an incomplete biochemical response. The SR retrieved 123 studies on neoadjuvant therapy use in thyroid carcinoma; of them, 6 were extracted: 4 case reports and 2 observational studies. MKIs were used as neoadjuvant therapy in three clinical cases with 70–84% of tumor reduction allowing surgery.Conclusion: Our findings, along with other reports, suggest that MKIs is an effective neoadjuvant therapy and should be considered as a therapeutic strategy for unresectable grossly locally invasive thyroid carcinomas.

O presente artigo trata da sucessão hereditária com bens situados no exterior. Analisa-se a competência do Brasil para conhecer de bens da pessoa falecida situados em países estrangeiros, bem como a incidência de imposto de transmissão causa mortis sobre ditos bens. O texto aborda, ainda, questões pertinentes aos testamentos celebrados no exterior com efeitos no Brasil, ponderando sobre a importância dos acordos e tratados internacionais para dar conta do crescente número de sucessões hereditárias com elementos internacionais diante do mundo globalizado.

The role of serum TSH concentrations as a predictor of malignancy of thyroid nodule remains unclear.To prospectively evaluate the usefulness of serum TSH levels as a predictor of malignancy in thyroid nodules.Patients with thyroid nodule(s) who underwent fine-needle aspiration biopsy under ultrasonographic guidance in a tertiary, university-based hospital were consecutively evaluated. Patients with known thyroid cancer and/or patients receiving thyroid medication were excluded. Serum TSH levels were measured by two differents methodologies, chemiluminescent (CLIA) and electrochemiluminscent immunoassay (ECLIA). Anatomopathological exam of tissue samples obtained at thyroidectomy was considered the gold standard for the diagnosis of thyroid cancer.A total of 615 patients participated in the study. The mean age was 55.9±14.7 years, and 544(88.5%) were female. The median TSH values were 1.48 and 1.55 μU/mL, using CLIA and ECLIA, respectively. One-hundred-sixty patients underwent thyroidectomy and the final diagnoses were malignant in 47(29.4%) patients. TSH levels were higher in patients with malignant than in those with benign nodules in both TSH assays: 2.25 vs. 1.50; P = 0.04 (CLIA) and 2.33 vs. 1.27; P = 0.03 (ECLIA). Further analysis using binary logistic regression identified elevated TSH levels, a family history of thyroid cancer, the presence of microcalcifications, and solitary nodule on US as independent risk factors for malignancy in patients with thyroid nodules. Additional analyses using TSH levels as a categorical variable, defined by ROC curve analysis, showed that the risk of malignancy was approximately 3-fold higher in patients with TSH levels ≥2.26 μU/mL than in patients with lower TSH levels (P = 0.00).Higher serum TSH levels are associated with an increased risk of thyroid cancer in patients with thyroid nodules. Using TSH levels as an adjunctive diagnostic test for stratifying the risk of malignancy associated with a thyroid nodule may help on defining the best therapeutic approaches.

O objetivo da imposição do regime de separação obrigatória de bens é proteger centros de interesses que poderiam conflitar com a comunhão de bens. O verbete 377 da Súmula do Supremo Tribunal Federal viola a proteção da lei, contrariando o objetivo do legislador. Propõe-se, assim, a possibilidade de previsão de pacto antenupcial prevendo exatamente o que a lei determina.

Pheochromocytoma (PHEO), a rare catecholamine producing tumor arising from the chromaffin cells, may occurs sporadically (76%–80%) or as part of inherited syndromes (20%–24%). Angiogenesis is a fundamental step in tumor proliferation and vascular endothelial growth factor (VEGF-A) is the most well-characterized angiogenic factor. The role of angiogenic markers in PHEO is not fully understood; investigations were therefore made to evaluate the expression of VEGF-A and its receptors in PHEO and correlate to clinical parameters. Twenty-nine samples of PHEO were evaluated for VEGF-A, VEGF receptor-1 (VEGFR-1) VEGFR-2 expression and microvessel density (MVD) by immunohistochemistry. Clinical data were reviewed in medical records. The mean age of patients was 38 ± 14 years, and 69% were woman. VEGF-A, VEGFR-1 and VEGFR-2 staining were detected in nearly all PHEO samples. No significant correlation was observed between VEGF-A, VEGFR-1, VEGFR-2 expression or MVD and age at diagnosis, tumor size or sporadic and hereditary PHEO. However, the levels of expression of these molecules were significantly higher in malignant PHEO samples (p = 0.027, p = 0.003 and p = 0.026, respectively).VEGF-A and its receptors were shown to be up-regulated in malignant PHEO, suggesting that these molecules might be considered as therapeutic targets for unresectable or metastatic tumors.

O que uma pessoa é capaz de fazer por um filho? Apesar de os casos concretos serem diferentes entre si, é preciso apontar o que todos têm em comum: a reflexão de que o melhor interesse da criança e do adolescente deve nortear as questões que dizem respeito à filiação. Não se pode agir de forma individualista e egoísta. A atenção deve estar voltada para essa terceira pessoa, que deve ter os seus direitos preservados e garantidos, por serem pessoas em desenvolvimento, que precisam de proteção.

BACKGROUND:The RET S836S variant has been associated with early onset and increased risk for metastatic disease in medullary thyroid carcinoma (MTC). However, the mechanism by which this variant modulates MTC pathogenesis is still open to discuss. Of interest, strong linkage disequilibrium (LD) between RET S836S and 3'UTR variants has been reported in Hirschsprung's disease patients. OBJECTIVE:To evaluate the frequency of the RET 3'UTR variants (rs76759170 and rs3026785) in MTC patients and to determine whether these variants are in LD with S836S polymorphism. METHODS:Our sample comprised 152 patients with sporadic MTC. The RET S836S and 3'UTR (rs76759170 and rs3026785) variants were genotyped using Custom TaqMan Genotyping Assays. Haplotypes were inferred using the phase 2.1 program. RET mRNA structure was assessed by Vienna Package. RESULTS:The mean age of MTC diagnosis was 48.5±15.5 years and 57.9% were women. The minor allele frequencies of RET polymorphisms were as follows: S836S, 5.6%; rs76759170, 5.6%; rs3026785, 6.2%. We observed a strong LD among S836S and 3'UTR variants (|D'| = -1, r2 = 1 and |D'| = -1, r2 = 0,967). Patients harboring the S836S/3'UTR variants presented a higher percentage of lymph node and distant metastasis (P = 0.013 and P

Medullary thyroid carcinoma is a rare malignant tumor originating in parafollicular C cells. It accounts for 5 to 8% of all thyroid cancers. MTC develops in either sporadic (75%) or hereditary form (25%). Genetic and molecular studies have demonstrated the involvement of the RET proto-oncogene in hereditary MTC and, less often, in its sporadic form. Although a strong genotype-phenotype correlation has been described, wide clinical heterogeneity is observed among families with the same RET mutation or even in carriers of the same kindred. In recent years, several single nucleotide polymorphisms of the RET gene have been described in the general population as well as in patients with MTC. Some studies have reported associations between the presence of polymorphisms and development or progression of MTC. Nonetheless, other studies failed to demonstrate any effect of the RET variants. Differences in the genetic background of distinct populations or methodological approaches have been suggested as potential reasons for the conflicting results. Here, we review current knowledge concerning the molecular pathogenesis of sporadic and hereditary MTC. In particular, we analyze the role of RET polymorphisms in the clinical presentation and prognosis of MTC based on the current literature.

The Thr92Ala (rs225014) polymorphism in the type 2 deiodinase (DIO2) gene has been associated with insulin resistance (IR) and decreased enzyme activity in human tissues but kinetic studies failed to detect changes in the mutant enzyme, suggesting that this variant might be a marker of abnormal DIO2 expression. Thus, we aimed to investigate whether other DIO2 polymorphisms, individually or in combination with the Thr92Ala, may contribute to IR. The entire coding-region of DIO2 gene was sequenced in 12 patients with type 2 diabetes mellitus (T2DM). Potentially informative variants were evaluated in 1077 T2DM patients and 516 nondiabetic subjects. IR was evaluated using the homeostasis model assessment (HOMA-IR) index. DIO2 gene sequencing revealed no new mutation but 5 previously described single nucleotide polymorphisms (SNPs). We observed that all T2DM patients displaying high HOMA-IR index (n = 6) were homozygous for the rs225017 (T/A) polymorphism. Further analysis showed that the median fasting plasma insulin and HOMA-IR of T2DM patients carrying the T/T genotype were higher than in patients carrying the A allele (P = 0.013 and P = 0.002, respectively). These associations were magnified in the presence of the Ala92Ala genotype of the Thr92Ala polymorphism. Moreover, the rs225017 and the Thr92Ala polymorphisms were in partial linkage disequilibrium (|D'| = 0.811; r2 = 0.365). In conclusion, the rs225017 polymorphism is associated with greater IR in T2DM and it seems to interact with the Thr92Ala polymorphism in the modulation of IR.

Objective. It is generally accepted that higher doses of radioiodine (131I) improve cure rates in Graves’ disease (GD). In this trial we sought to evaluate whether very high 131I doses increase the efficacy of treatment in severe GD. Design. Clinical trial with historical control. Patients with GD and a goiter ≥48 mL were eligible for the study. The patients in the contemporaneous intervention cohort were treated with 250 μCi of 131I/mL thyroid tissue, corrected by 24-RAIU values (Group 1; n=15). A subgroup of patients with GD and a goiter ≥48 mL who were treated with 200 μCi of 131I/mL/24-RAIU in a previously published randomized controlled trial served as a historical control group (Group 2; n=15). The primary outcome evaluated was the one-year cure rate. Results. There were no significant baseline differences regarding age, gender, body mass index, smoking status, pretreatment with methimazole, thyroid volume, or thyroid hormone levels of the two treatment groups. The cumulative 12-month cure rate for the patients in Group 1 was 66.6%, a figure similar to the 12-month cure rate observed in Group 2 (60.0%; P=0.99). Conclusions. Our results suggest that increasing the 131I dose does not improve cure rates in severe GD. This trial is registered with ClinicalTrials.gov NCT01039818.

Cushing’s syndrome is a condition characterized by elevated cortisol levels that can result from either augmented endogenous production or exogenous administration of corticosteroids. The predisposition to fungal infections among patients with hypercortisolemia has been noted since Cushing’s original description of the disease. We describe here a patient with endo-genous Cushing’s syndrome secondary to an adrenocortical carcinoma, who developed concomitant disseminated cryptococcosis and candidiasis in the course of his disease.

O bócio multinodular (BMN) é definido como um aumento da glândula tireóide secundário à proliferação multifocal de tireócitos e caracteriza-se pela heterogeneidade no crescimento e função das células foliculares. O BMN é considerado uma neoplasia benigna da tireóide. É uma patologia comum, com aumento da prevalência em áreas com deficiência de iodo, sendo este o principal fator etiológico ambiental. A patogênese desta disfunção tireoidiana ainda não está inteiramente elucidada. Nesta revisão serão abordados os principais mecanismos envolvidos na patogênese, seguidos das implicações clínicas dessa patologia.

O crescimento tumoral está diretamente relacionado com a neovascularização, a qual decorre do desequilíbrio entre os fatores pró-angiogênicos e antiangiogênicos, secretados pelas células neoplásicas O fator de crescimento endotelial vascular (VEGF) desempenha papel chave na angiogênese tumoral, estimulando a proliferação, migração e sobrevivência das células endoteliais. Atua através da ligação a receptores tirosina quinase específicos: VEGFR-1/Flt-1, VEGFR-2/KDR e VEGFR-3. O aumento da expressão do VEGF e de seus receptores tem sido associado à progressão, metastatização e pior prognóstico em diversos tumores malignos. A compreensão das vias moleculares que envolvem o mecanismo de indução da angiogênese tumoral por fatores de crescimento como o VEGF aumentam as possibilidades de novas terapêuticas a serem utilizadas no tratamento de tumores malignos humanos. Evidências indicam um importante papel do VEGF nas neoplasias da tireóide e a utilização de inibidores do VEGF ou de seus receptores pode constituir um importante recurso terapêutico, já tendo sido utilizado em determinados tipos de tumores humanos. O presente artigo tem como objetivo fazer uma revisão da atuação do VEGF no crescimento tumoral com enfoque nas neoplasias malignas da tireóide.

ABSTRACT 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 follow-up 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.

ABSTRACT 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. Arch Endocrinol Metab. 2016;60(4):367-73