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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.

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ABSTRACT Objective: To analyze the importance of preoperative cytology of thyroid nodules and its relationship with mortality risk, recurrence risk, dynamic stratification, and aggressive characteristics (vascular invasion, aggressive histology, incomplete tumor resection, extrathyroidal extension of the tumor, and presence of lymph node and distant metastases). Subjects and methods: Retrospective evaluation of 153 patients diagnosed with differentiated thyroid carcinoma (DTC) and following up at the Hospital Universitário Presidente Dutra between January 1999 and December 2016. Results: In all, 96% of the patients were female, 79.7% had papillary carcinoma and the most common fine-needle aspiration (FNA) result was Bethesda II (29.4%). The mean age was 43.11 ± 12.8 years. Overall, 85% of the patients progressed without any evidence of disease. There was a statistically significant relationship between the presurgical FNA and the presence of extrathyroidal extension, vascular invasion, and lymph node metastasis. Conclusions: The preoperative cytology of the nodule may have an impact on the follow-up of patients with DTC. Future studies in a larger population are required to confirm this finding.

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ABSTRACT Objective: In this study, we aimed to evaluate serum irisin and apelin levels in patients with subclinical hypothyroidism (SCH) when they were subclinical hypothyroid and become euthyroid after levothyroxine therapy and association of these adipokines with markers of atherosclerosis such as serum homocysteine levels and carotid intima-media thickness (IMT). Subjects and methods: The study included 160 patients with newly diagnosed subclinical hypothyroidism due to Hashimoto's thyroiditis and 86 euthyroid healty subjects. Serum glucose and lipid profile, insulin, HOMA, TSH, free T3, free T4, anti-thyroperoxidase and anti-thyroglobulin antibodies, homocysteine, apelin and irisin levels were measured in all study subjects. Thyroid and carotid ultrasound examinations were performed. The subclinical hypothyroid group was reevaluated after 12-weeks of levothyroxine therapy when they became euthyroid. Results: Clinical characteristics of the patient and control group were similar. Glucose, insulin and HOMA levels, lipid parameters and free T3 were similar between the two groups.. Serum homocystein was higher and apelin was lower in patients with SCH, but irisin levels were similar between the two groups. While thyroid volume was lower, carotid IMT was significantly greater in patients with SCH (pCarotidIMT:0,01). After 12-weeks of levothyroxine therapy, all the studied parameters remained unchanged except, serum freeT4, TSH, homocystein and apelin. While homocystein decreased (p: 0,001), apelin increased significantly (p = 0,049). In multivariate analysis, low apelin levels significantly contributed to carotid IMT (p = 0,041). Conclusions: Apelin-APJ system may play a role in vascular and cardiac dysfunction in patients with SCH and treatment of this condition may improve the risk of cardiovascular disease.

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ABSTRACT Objective: The aim of this study was to evaluate the relationship between inflammatory cytokines, placental weight, glycated hemoglobin and adverse perinatal outcomes (APOs) in women with gestational diabetes mellitus (GDM). Subjects and methods: This was a prospective, longitudinal and observational study conducted from April 2004 to November 2005 in Bauru, Brazil. Included patients had singleton pregnancies and performed a 100 g OGTT and had the levels of C-reactive protein (CRP), interleukin (IL)-6, TNF alfa and glycated hemoglobin (HbA1c) determined at 24-28th gestation weeks. Results: A total of 176 patients were included, of whom 78 had the diagnosis of GDM (44.3%). Multivariate analysis demonstrated that HbA1c, age, body mass index (BMI) and previous history of GDM were independent predictors for GDM diagnosis. ROC curve indicated that HbA1C levels ≥ 5.1% at 24-28 weeks gestation were associated with GDM. No difference was found in IL-6, tumor necrosis factor alpha (TNF-alpha) and CRP serum levels in women with and without GDM. Multivariate analysis showed that placental weight was significantly associated with APOs (p < 0.005), with a cut-off value of 610 grams as demonstrated by the ROC curve. Conclusion: Placental weight ≥ 610 grams and HbA1C ≥ 5.1% were found to be associated with APOs and GDM, respectively, and their evaluation should be part of prenatal care routine.

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ABSTRACT Objective: To identify which anthropometric measurement would be the best predictor of metabolic syndrome (MetS) in Brazilian adolescents. Subjects and methods: Cross-sectional study conducted on 222 adolescents (15-17 years) from a city in southern Brazil. Anthropometric, physical activity, blood pressure and biochemical parameters were investigated. MetS criteria were transformed into a continuous variable (MetS score). Linear regression analyses were performed to assess the associations of BMI, hip circumference, neck circumference (NC), triceps skinfold, subscapular skinfold and body fat percentage with MetS score. ROC curves were constructed to determine the cutoff for each anthropometric measurement. Results: The prevalence of MetS was 7.2%. Each anthropometric measurement was significantly (p < 0.001) associated with MetS score. After adjusting for potential confounding variables (age, sex, physical activity, and maternal education), the standardized coefficients of NC and body fat percentage appeared to have the strongest association (beta = 0.69 standard deviation) with MetS score. The regression of BMI provided the best model fit (adjusted R2 = 0.31). BMI predicted MetS with high sensitivity (100.0%) and specificity (86.4%). Conclusions: Our results suggest that BMI and NC are effective screening tools for MetS in adolescents. The early diagnosis of MetS combined with targeted lifestyle interventions in adolescence may help reduce the burden of cardiovascular diseases and diabetes in adulthood.

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ABSTRACT Objective: To evaluate the influence of obesity on pulmonary function and exercise tolerance in women with obstructive sleep apnea (OSA). Subjects and methods: A descriptive analytic cross- sectional study was carried out. Thirty-nine (39) sedentary climacteric women, aged 45 to 60 years, were evaluated and submitted to polysomnography. The participants were divided into 4 groups: a) ‘eutrophic non-OSA’ (n = 13); b) ‘eutrophic OSA’ (n = 5); c) ‘obese non-OSA’ (n = 6); d) ‘obese OSA’ (n = 15). All subjects underwent clinical and anthropometric evaluation, followed by pulmonary function tests and 6-minute walk test (6MWT). Results: There was a significant difference in the predicted percentage values of FEV1/FVC when comparing ‘eutrophic OSA’ and ‘obese OSA’ (97.6% ± 6.1% vs. 105.7% ± 5.7%, respectively; p = 0.025). The other spirometric variables did not show any differences between the studied groups. There was no significant difference in the maximum distance walked when the ‘eutrophic non-OSA’, ‘eutrophic OSA’, ‘obese non-OSA’ and ‘obese OSA’ groups were compared. Conclusion: Considering the results of this study, OSA itself did not influence pulmonary function or functional capacity parameters compared to eutrophic women. However, not only isolated obesity but also obesity associated with OSA can negatively impact sleep quality and lung function.

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ABSTRACT Objective: The inflammation of the pituitary gland is known as hypophysitis. It is a rare disease accounting for approximately 0.24%-0.88% of all pituitary diseases. The natural course of hypophysitis is variable. Main forms are histologically classified as lymphocytic, granulomatous, IgG4 related and xanthomatous. We aim to present our patients with hypophysitis and compare clinical, laboratory and radiological features. Subjects and methods: We retrospectively reviewed our database of 1.293 patients diagnosed with pituitary diseases between 2010 and 2017. Twelve patients with hypophysitis were identified. Demographical data, clinical features, endocrinological dysfunction, imaging findings, treatment courses and follow-up periods were evaluated. Results: The frequency of hypophysitis was found 0.93% in all cases of the pituitary disease. Twelve patients (nine females and three males), ages between 17-61 years, were evaluated. The characteristic features of our patients tended to be predominantly female and young. Diagnosis of hypophysitis was made after pituitary biopsy in four patients, and in eight patients after pituitary operation due to adenoma. Headache (67%) and visual problems (33%) were the most frequent nonendocrine symptoms. Anterior pituitary hormone deficiencies (63.7%) and/or diabetes insipidus (17%) were seen among patients. According to histopathological forms, four had lymphocytic, seven had granulomatous and one had xanthogranulomatous types. Contrast enhancement heterogeneous and thickened pituitary stalk were the most common radiological alterations. Conclusion: Hypophysitis should be considered in the differential diagnosis of sellar masses. It can mimic pituitary adenomas in radiological and endocrinological aspects. The different patterns of pituitary hormone deficiencies may be seen in the course of the disease.

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ABSTRACT Objectives: The aims of this study are to investigate which of the seven selected predictive equation for estimating basal metabolic rate (BMR) is the best alternative to indirect calorimetry (IC) and to evaluate the dietary energy intake in patients with type 2 diabetes. Subjects and methods: Twenty-one patients with type 2 diabetes participated in this diagnostic test study. Clinical and laboratorial variables were evaluated as well as body composition by absorptiometry dual X-ray emission (DXA) and BMR measured by IC and estimated by prediction equations. Dietary intake was evaluated by a quantitative food frequency questionnaire. Data were analyzed using Bland–Altman plots, paired t-tests, and Pearson's correlation coefficients. Results: Patients were 62 (48-70) years old, have had diabetes for 8 (2-36) yeas, and 52.4% were females. The mean body composition comprised a fat-free mass of 49.8 ± 9.4 kg and a fat mass of 28.3 ± 7.2 kg. The energy intake was 2134.3 ± 730.2 kcal/day and the BMR by IC was 1745 ± 315 kcal/day. There was a wide variation in the accuracy of BMR values predicted by equations when compared to IC BMR measurement. Harris-Benedict, Oxford, FAO/WHO/UNO equations produced the smallest differences to IC, with a general bias of < 8%. The FAO/WHO/UNO equation provided the best BMR prediction in comparison to measured BMR. Conclusion: In patients with type 2 diabetes, the equation of the FAO/WHO/UNO was the one closest to the BMR values as measured by IC.

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ABSTRACT Objective: To assess the relationships between serum dehydroepiandrosterone sulfate (DHEA-S) levels and heart rate variability (HRV) among different age groups. Subjects and methods: Forty-five healthy men were divided into 3 groups: young age (YA; 20-39 yrs; n = 15), middle age (MA; 40-59 yrs; n = 15) and old age (OA; ≥ 60 yrs; n = 15). Hemodynamic parameters, linear analyses of HRV and concentrations of cortisol and DHEA-S were measured at rest. Results: The OA group presented a higher resting heart rate (84.3 ± 4.6 bpm) than the YA group (72.0 ± 4.4 bpm; p < 0.05). The YA group showed an attenuated variance of HRV (2235.1 ± 417.9 ms2) compared to the MA (1014.3 ± 265.2 ms2; p < 0.05) and OA (896.3 ± 274.1 ms2; p < 0.05) groups, respectively. The parasympathetic modulation of HRV was lower in both the MA (244.2 ± 58.0 ms2) and OA (172.8 ± 37.9 ms2) groups in comparison with the YA group (996.0 ± 255.4 ms2; p < 0.05), while serum DHEA-S levels were significantly lower in both the MA (91.2 ± 19.6 mg/dL) and OA (54.2 ± 17.7 mg/dL) groups compared to the YA group (240.0 ± 50.8 mg/dL; p < 0.05). A positive correlation between lower serum concentrations of DHEA-S and attenuated variance of HRV (r = 0.47, p = 0.031), as well as lower serum concentrations of DHEA-S and decreased parasympathetic modulation of HRV (r = 0.54, p = 0.010), were found. Conclusion: The present study demonstrated that the decline of plasma DHEA-S is associated with reduced cardiac autonomic modulation during the aging process.

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ABSTRACT Short stature is a common feature, and frequently remains without a specific diagnosis after conventional clinical and laboratorial evaluation. Longitudinal growth is mainly determined by genetic factors, and hundreds of common variants have been associated to height variability among healthy individuals. Although isolated short stature may be caused by the combination of variants, with a deleterious impact on the growth of individuals with polygenic inheritance, recent studies have pointed out some monogenic defects as the cause of the growth disorder observed in nonsyndromic children. The majority of these defects are in genes related to the growth plate cartilage and in the growth hormone (GH) – insulin-like growth factor 1 (IGF-1) axis. Affected patients usually present the mildest spectrum of some forms of skeletal dysplasia, or subtle abnormalities of laboratory tests, suggesting hormonal resistance or insensibility. The lack of specific characteristics, however, does not allow formulation of a definitive diagnosis without the use of broad genetic studies. Thus, molecular genetic studies including panels of genes or exome analysis will become essential in investigating and identifying the causes of isolated short stature in children, with a crucial impact on treatment and follow-up.

Resumo em Inglês:

SUMMARY Thyroid carcinoma (TC) is rare in children, particularly in those aged < 10 years. Several studies have demonstrated a correlation between neoplasms and hyperinsulinemia and insulin resistance, which are often associated with a higher risk for and/or aggressiveness of the neoplasm. Congenital generalized lipodystrophy (CGL) with autosomal recessive inheritance is a rare disease and is characterized by the lack of adipose tissue, severe insulin resistance, and early metabolic disturbances. Here, we reported a rare case of a type 2 CGL in a girl who presented with a papillary TC (PTC) at the age of 7 years. She had no family history of TC or previous exposure to ionizing radiation. She had a generalized lack of subcutaneous fat, including the palmar and plantar regions, muscle hypertrophy, intense acanthosis nigricans, hepatomegaly, hypertriglyceridemia, severe insulin resistance, and hypoleptinemia. A genetic analysis revealed a mutation in the BSCL2 gene (p.Thr109Asnfs* 5). Ultrasound revealed a hypoechoic solid nodule measuring 1.8 × 1.0 × 1.0 cm, and fine needle aspiration biopsy suggested malignancy. Total thyroidectomy was performed, and a histopathological examination confirmed PTC with vascular invasion and parathyroid lymph node metastasis (pT3N1Mx stage). This is the first report to describe a case of differentiated TC in a child with CGL. Severe insulin resistance that is generally observed in patients with CGL early in life, especially in those with type 2 CGL, may be associated with this uncommon presentation of aggressive PTC during childhood.

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SUMMARY Hyperreninemic hypoaldosteronism due to aldosterone synthase (AS) deficiency is a rare condition typically presenting as salt-wasting syndrome in the neonatal period. A one-month-old Portuguese boy born to non-consanguineous parents was examined for feeding difficulties and poor weight gain. A laboratory workup revealed severe hyponatremia, hyperkaliaemia and high plasma renin with unappropriated normal plasma aldosterone levels, raising the suspicion of AS deficiency. Genetic analysis showed double homozygous of two different mutations in the CYP11B2 gene: p.Glu198Asp in exon 3 and p.Val386Ala in exon 7. The patient maintains regular follow-up visits in endocrinology clinics and has demonstrated a favourable clinical and laboratory response to mineralocorticoid therapy. To our knowledge, this is the first Portuguese case of AS deficiency reported with confirmed genetic analysis.

Resumo em Inglês:

SUMMARY Hypophosphatasia is a rare inborn error of metabolism characterized by low serum alkaline phosphatase activity due to loss-of-function mutations in the gene encoding the tissue-nonspecific isoenzyme of alkaline phosphatase (TNSALP). Extracellular accumulation of TNSALP substrates leads to dento-osseous and arthritic complications featuring tooth loss, rickets or osteomalacia, and calcific arthopathies. Mild hypophosphatasia usually has autosomal dominant inheritance, severe cases are either autosomal recessive or due to a dominant negative effect. Clinical manifestations of hypophosphatasia are extremely variable, ranging from life threatening to asymptomatic clinical presentations. The clinical presentation of the adult-onset hypophosphatasia is highly variable. Fractures, joint complications of chondrocalcinosis, calcifying polyarthritis and multiple pains may reveal minor forms of the disease in adults. It is important to recognize the disease to provide the best supportive treatment and to prevent the use of anti-resorption drugs in these patients. Bone-targeted enzyme-replacement therapy (asfotase alfa) was approved in 2015 to treat pediatric-onset hypophosphatasia. We present a case of a 41-year-old male diagnosed with adult form of hypophosphatasia with a rare ALPL mutation that has been previously described only once and review the literature on the adult form of the disease and its genetic mechanism.