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ABSTRACT The indolent evolution of low-risk papillary thyroid microcarcinoma (mPTC) in adult patients and the consequences of thyroidectomy require a revision of the management traditionally recommended. Aiming to spare patients unnecessary procedures and therapies and to optimize the health system in Brazil, we suggest some measures. Fine-needle aspiration of nodules ≤ 1 cm without extrathyroidal extension on ultrasonography should be performed only in nodules classified as “very suspicious” (i.e., high suspicion according to ATA, high risk according to AACE, TI-RADS 5) and in selected cases [age < 40 years, nodule adjacent to the trachea or recurrent laryngeal nerve (RLN), multiple suspicious nodules, presence of hypercalcitoninemia or suspicious lymph nodes]. Active surveillance (AS) rather than immediate surgery should be considered in adult patients with low-risk mPTC. Lobectomy is the best option in patients with unifocal low-risk mPTC who are not candidates for AS because of age, proximity of the tumor to the trachea or RLN, or because they opted for surgery. The same applies to patients who started AS but had a subsequent surgical indication not due to a suspicion of tumor extension beyond the gland or multicentricity. Molecular tests are not necessary to choose between AS and surgery or, in the latter case, between lobectomy and total thyroidectomy. The presence of RAS or other RAS-like mutations or BRAFV600E or other BRAF V600E-like mutations should not modify the management cited above; however, the rare cases of mPTC exhibiting high-risk mutations, like in the TERT promoter or p53, are not candidates for AS.

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ABSTRACT Objectives To determine the percentage of patients with papillary thyroid carcinoma (PTC) who accepted active surveillance as an alternative to surgery in our clinical practice and to describe the clinical characteristics and outcomes of patients with Bethesda category V and VI thyroid nodules who chose active surveillance. Subjects and methods We included 136 PTC patients from the Hospital de Clínicas, University of Buenos Aires without (i) US extrathyroidal extension, (ii) tumors adjacent to the recurrent laryngeal nerve or trachea, and/or (iii) US regional lymph-node metastasis or clinical distant metastasis. PTC progression was defined as the presence of i) a tumor larger than ≥ 3 mm, ii) novel appearance of lymph-node metastasis, and iii) serum thyroglobulin doubling time in less than one year. For patients with these features, surgery was recommended. Results Only 34 (25%) of 136 patients eligible for active surveillance accepted this approach, and around 10% of those who accepted abandoned it due to anxiety. The frequency of patients with tumor enlargement was 17% after a median of 4.6 years of follow-up without any evidence of nodal or distant metastases. Ten patients who underwent surgical treatment after a median time of 4 years of active surveillance (AS) had no evidence of disease after a median of 3.8 years of follow-up after surgery. Conclusion Although not easily accepted in our cohort of patients, AS would be safe and easily applicable in experienced centers.

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ABSTRACT Objective We analyzed the clinical, biochemical, and imaging findings of adrenalectomized patients with Cushing’s disease (CD) in order to compare the characteristics of those who developed Nelson’s syndrome (NS) versus those who did not develop this complication (NNS), aiming to identify possible predictive factors for its occurrence. Subjects and methods We performed a retrospective review of the clinical records of a group of patients with CD who underwent TBA between 1974 and 2011. Results Out of 179 patients with CD, 13 (7.3%) underwent TBA. NS occurred in 6 of them (46%) after a mean of 24 months from the total bilateral adrenalectomy (TBA). Age at diagnosis, duration of Cushing’s syndrome (CS) until TBA, and steroid replacement doses were similar in both groups. Initial urinary cortisol levels (24-hour urinary free cortisol [UFC]) were significantly higher in the NS group than in the NNS group (p = 0.009). Four patients in the NS group and three of those in the NNS group received radiotherapy before TBA (p = 0.26). Three patients in the NS group presented residual tumors before TBA, compared with none in the NNS group (p = 0.04). At 1 year after TBA, the median ACTH level was 476 ng/L (240-1500 ng/L) in the NS group and 81 ng/L (48-330 ng/L) in the NNS group (p = 0.0007). Conclusion In conclusion, a residual tumor before TBA, higher 24-hour UFC at diagnosis, and increasing ACTH levels within 1 year after TBA emerged as predictive factors of development of NS.

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ABSTRACT Objectives To provide a meta-analysis of the clinical efficacy and safety of sodium glucose co-transporter 2 inhibitors (SGLT2-i), as a combination treatment with metformin in type 2 diabetes mellitus (T2DM) patients with inadequate glycemic control with metformin alone. Materials and methods We have searched randomized controlled trials (RCTs) in the database: MEDLINE, Embase and Cochrane Collaborative database. We used mean differences (MD) to assess the efficacy of glycemic and other clinical parameters, and risk ratios (RR) to evaluate the adverse events for safety endpoints. The heterogeneity was evaluated by I2. Results Finally 9 studies were included. SGLT2-i plus metformin had higher reduction level in HbA1C [MD = -0.50, 95% CI (-0.62, -0.38), p < 0.00001], FPG [MD = -1.12, 95%CI (-1.38, -0.87), p < 0.00001], body weight [MD = -1.72, 95% CI (-2.05, -1.39), p < 0.00001], SBP [MD = -4.44, 95% CI (-5.45, -3.43), p < 0.00001] and DBP [MD = -1.74, 95% CI (-2.40, -1.07), p < 0.00001] compared with metformin monotherapy. However, SGLT2-i plus metformin group had higher risk of genital infection [RR = 3.98, 95% CI (2.38, 6.67), p < 0.00001]. No significant difference was found in the risk of hypoglycemia, urinary tract infection or volume related adverse events. Conclusions Although the risk of genital infection may increase, SGLT2-i plus metformin may provide an attractive treatment option to those T2DM patients who are unable to achieve glycemic control with metformin alone, based on its effects on glycemic control, reducing body weight and lowering blood pressure.

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ABSTRACT Objective Different pathways may lead from night work to metabolic diseases, including type 2 diabetes. This study aimed to explore the direct and indirect pathways from night work to glycemic levels, considering the role of physical activity, waist circumference and snacking using data from ELSA-Brasil. Materials and methods A structural equation model was used to confirm the pathways from night work to glycemic levels. The latent variable, “glycemic levels”, included fasting glucose, glycated hemoglobin and 2-hour plasma glucose. Results A total of 10.396 participants were included in the analyses. The final model showed that among women, night work was associated with increased glycemic levels. A statistical significant association between night work and glycemic levels mediated by waist circumference was observed among women and men. Conclusions The association between night shift and glycemic levels can be interpreted as an important step toward understanding the pathways that could explain night work as a risk factor for diabetes using epidemiological data.

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ABSTRACT Objectives The differentiation between the various etiologies of thyrotoxicosis, including those with hyperthyroidism (especially Graves’ disease [GD], the most common cause of hyperthyroidism) and without hyperthyroidism (like thyroiditis), is an important step in planning specific therapy. Technetium-99m (99mTc) pertechnetate thyroid scanning is the gold standard in differentiating GD from thyroiditis. However, this technique has limited availability, is contraindicated in pregnancy and lactation, and is not helpful in cases with history of recent exposure to excess iodine. The aim of this study was to identify the diagnostic value of the peak systolic velocity of the inferior thyroid artery (PSV-ITA) assessed by color-flow Doppler ultrasound (CFDU) and compare the sensitivity and specificity of this method versus 99mTc pertechnetate thyroid uptake. Subjects and methods We prospectively analyzed 65 patients (46 with GD and 19 with thyroiditis). All patients were evaluated with clinical history and physical examination and underwent 99mTc pertechnetate scanning and measurement of TRAb levels and PSV-ITA values by CFDU. The diagnosis was based on findings from signs and symptoms, physical examination, and 99mTc pertechnetate uptake. Results Patients with GD had significantly higher mean PSV-ITA values than those with thyroiditis. At a mean PSV-ITA cutoff value of 30 cm/sec, PSV-ITA discriminated GD from thyroiditis with a sensitivity of 91% and specificity of 89%. Conclusion Measurement of PSV-ITA by CFDU is a good diagnostic approach to discriminate between GD and thyroiditis, with sensitivity and specificity values comparable to those of 99mTc pertechnetate thyroid uptake.

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ABSTRACT Objective To investigate the association of the genetic variants of the folate metabolism genes (MTHFR C677T; MTHFR A1298C; MTR A2756G; MTRR A66G and RFC-1 A80G) with the development of polycystic ovary syndrome (PCOS). Subjects and methods This study included 203 women (99 women with PCOS and 104 controls). The genotyping was performed by PCR-RFLP. Chi-squared test and multiple logistic regression were used in the statistical analysis. Haplotype analysis was conducted using the SNPstat program. The results were presented in odds ratio (OR) and confidence interval of 95% (CI-95%), with a significance level of 5% (p ≤ 0.05). Results The genotypic distribution of the RFC-1 A80G polymorphism showed significant difference between the two groups, showing that the heterozygous genotype (AG genotype) was most frequent in controls. The polymorphic homozygous (GG genotype) of MTRR A66G polymorphism were most frequent in controls. The T-C haplotype MTHFR C677T and A1298C polymorphisms were more frequent in the control group (OR = 0.19; CI 95% — 0.04 to 0.93 e p = 0.042). The multivariate analysis evidenced that family history of PCOS was more frequent in the PCOS group (OR = 3.29; CI 95% — 1.48 to 7.31; p = 0.003). Conclusion In our casuistry, the polymorphic homozygous of MTRR A66G polymorphism gene and heterozygous of RFC-1 A80G polymorphism gene, the haplotype T-C C677T and A1298C polymorphisms of MTHFR gene, can be associated with protective factors for the disease.

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ABSTRACT Objective We denote the four major factors related to the development of type 2 diabetes (T2D) as “diabetes factor” (DF); increased insulin resistance (IR); decreased glucose effectiveness (GE); and the first-and-second-phase of insulin secretion (FPIS, SPIS). The level of hemoglobin (Hb) was found to be related to IR and FPIS, but no-known studies focused on its role in relation to SPIS and GE. In this study, we aim to evaluate the relationships between Hb and all four DFs in the same individual. Subjects and methods We randomly enrolled 24,407 men and 24,889 women between 30 and 59 years old. IR, FPIS, SPIS and GE were measured according to equations published in our previous studies. To compare the slopes between Hb and the four DFs with different units, we converted their units to percent of change per unit of increased Hb. Results Age, HDL-cholesterol and GE were higher in women; BMI, blood pressure, LDL-cholesterol, TG, Hb, FPIS, SPIS and IR were higher in men. After they were converted into percentage, the closeness of their relationships to Hb, from the highest to the lowest, were GE, IR, FPIS and SPIS for women and IR, GE, FPIS and SPIS for men. GE was the only one negatively related to Hb. Conclusions Our data showed that IR, FPIS and SPIS were both positively and, GE negatively, related to the Hb in adult Chinese. For women, GE had the closest association with Hb; for men, it was IR. Both phases of insulin secretion had relatively weaker relationships than IR and GE.

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ABSTRACT Objective To describe the prevalence, clinical characteristics and outcome of adrenal lesions in long-term follow-up of Multiple endocrine neoplasia type 1 (MEN1) patients. Subjects and methods We retrospectively studied sixteen patients from six families of individuals with MEN1. Adrenal involvement was evaluated using clinical, biochemical and imaging data. Results Adrenal lesions were identified in nine of sixteen (56.3%) patients: seven women and two men (mean age: 52.2 years). Adrenal involvement was detected at MEN1 diagnosis in more than half of the patients. Eighteen adrenal nodules were founded (median of two nodules per patient) with mean adrenal lesion diameter of 17.4 mm. Three patients had unilateral adrenal involvement. Hormonal hypersecretion (autonomous cortisol secretion) was found in two patients. None of the patients was submitted to adrenalectomy, presented an aldosterone-secreting lesion, a pheochromocytoma, an adrenal carcinoma or metastatic disease during the follow-up. A predominance of stable adrenal disease, in terms of size and hormonal secretion, was observed. Adrenal lesions were evenly distributed between the germline mutations. Conclusion Adrenal tumours are a common feature of MEN1 that can affect more than half of the patients. Most of the tumours are bilateral non-functional lesions, but hormonal secretion may occur and should be promptly identified to reduce the morbidity/mortality of the syndrome. Periodic surveillance of these patients should be performed.

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ABSTRACT Objective The aim of the study is to describe a portable and convenient software to facilitate the diagnostics of gestational (GDM) and pre-gestational diabetes (PGDM). Materials and methods An open source software, d-GDM, was developed in Java. The integrated development environment Android Studio was used as the Android operational system. The software for GDM diagnosis uses the criteria endorsed by the International Association of Diabetes and Pregnancy Study Group, modified by the World Health Organization. Results GDM diagnosis criteria is not simple to follow, therefore, errors or inconsistencies in diagnosis are expected and could delay the appropriate treatment. The d-GDM, was developed to assist GDM diagnosis with precision and consistency diagnostic reports. The open source software can be manipulated conveniently. The operator requires information regarding the gestational period and selects the appropriate glycaemic marker options from the menu. During operation, pressing the button “diagnosticar” on the screen will present the diagnosis and information for the follow up. d-GDM is available in Portuguese or English and can be downloaded from the Google PlayStore. A responsive web version of d-GDM is also available. The usefulness and accuracy of d-GDM was verify by field tests involving 22 subjects and 5 mobile phone brands. The approval regards user-friendliness and efficiency were 95% or higher. The GDM diagnosis were 100% correct, in this pilot test. d-GDM is a user-friendly, free software for diagnosis that was developed for mobile devices. It has the potential to contribute and facilitate the diagnosis of gestational diabetes for healthcare professionals.

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ABSTRACT Objective The purpose of this study is to examine risk factors for recurrence of diabetic ketoacidosis and determine interventions to prevent future admissions. Materials and methods Review article. Results Recurrent diabetic ketoacidosis is a serious and not uncommon health problem. Diabetic ketoacidosis is associated with severe morbidity and mortality and hospital admissions due to this problem constitute a serious economic burden on the healthcare system. Younger age at diabetic ketoacidosis onset, poor baseline glycemic control and elevated HbA1C, patient comorbidities, depression, alcohol or substance abuse, particularly active cocaine use, have been associated with recurrent diabetic ketoacidosis. In addition, socioeconomic factors (such as ethnic minority status, use of public health insurance and underinsurance), psychosocial, economic, and behavioral factors (including financial constraint, stretching a limited insulin supply, and homelessness) have been all reported to be associated with readmission among diabetic ketoacidosis patients. Conclusions Identifying high-risk patients during the first diabetic ketoacidosis admission and performing relevant interventions (repeated instructions of insulin use, social help and involvement of family members in medical treatment, collaboration with the patient’s primary care physician in order to establish a close and frequent follow up program) may help prevent future admissions. Further studies need to take place to determine whether early interventions with those factors prevent future admissions.

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ABSTRACT Thyroid cancer has been rapidly increasing in prevalence among humans in last 2 decades and is the most prevalent endocrine malignancy. Overall, thyroid-cancer patients have good rates of long-term survival, but a small percentage present poor outcome. Thyroid cancer aggressiveness is essentially related with thyroid follicular cell loss of differentiation and metastasis. The discovery of oncogenes that drive thyroid cancer (such as RET, RAS, and BRAF), and are aligned in the MAPK/ERK pathway has led to a new perspective of thyroid oncogenesis. The uncovering of additional oncogene-modulated signaling pathways revealed an intricate and active signaling cross-talk. Among these, microRNAs, which are a class of small, noncoding RNAs, expanded this cross-talk by modulating several components of the oncogenic network – thus establishing a new layer of regulation. In this context, TGFβ signaling plays an important role in cancer as a dual factor: it can exert an antimitogenic effect in normal thyroid follicular cells, and promote epithelial-to-mesenchymal transition, cell migration, and invasion in cancer cells. In this review, we explore how microRNAs influence the loss of thyroid differentiation and the increase in aggressiveness of thyroid cancers by regulating the dual function of TGFβ. This review provides directions for future research to encourage the development of new strategies and molecular approaches that can improve the treatment of aggressive thyroid cancer.