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ABSTRACT Objective: Sorafenib significantly prolonged progression-free survival in patients with iodine-refractory advanced thyroid cancer. The present study was initiated before sorafenib was approved in Colombia and therefore represents an effort by an oncology institution to evaluate its efficacy and safety in this population. Subjects and methods: This phase II clinical trial had a single treatment arm. We included adult patients with progressive metastatic iodine-refractory thyroid cancer who received treatment with sorafenib 800 mg/day (400 mg every 12 hours) up to a maximum of 24 months or until the occurrence of limiting related toxicity, the progression of the disease, or voluntary withdrawal. Results: Nineteen patients received the treatment and were included in the safety analysis. However, for the efficacy analysis, 6 patients were excluded because they received only one month of therapy. Thirteen (68%) patients were women, and the mean age at diagnosis was 61.8 years. No complete responses were observed; 5 patients had a partial response (35.7%), 6 patients had stable disease, and 3 showed progression. Mean progression-free survival was calculated at 18 months (95% CI 10.7-20.3). Overall survival was estimated at 21.3 months (95% CI 17.8-24.8). Conclusion: For the first time in Colombia, the efficacy of sorafenib was evaluated in patients with advanced and progressive thyroid carcinoma refractory to radioactive iodine, with an efficacy and a safety profile similar to those previously reported.

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ABSTRACT Objective: The aim of this study was to describe the real-world experience multikinase inhibitors (MKI) in the treatment advanced differentiated thyroid carcinoma (DTC) refractory to radioactive iodine (RAIR) therapy. Subjects and methods: We reviewed the records of all patients with MKI-treated DTC from 2010 to 2018. Progression free survival (PFS), response rates (RR) and adverse events (AE) profiles were assessed. Clinical parameters were compared between groups with different outcomes (disease progression and death) to identify possible prognostic factors and benefit from treatment. Results: Forty-four patients received MKI for progressive RAIR DTC. Median PFS was 24 months (10.2-37.7) and median overall survival (OS) was 31 months. Best overall response was complete response in one patient (4.5%), partial response in nine (20.4%), stable disease in twenty-two (50%), and progressive disease (PD) in twelve (27.3%). Seventy-two point 7 percent patients had clinical benefit and AE were mild in most cases (82.7%). Progressive patients were more likely to have FDG positive target lesion than those who did not progress (p = 0.033) and higher maximum SUV on target lesions (p = 0.042). Presence of lung-only metastasis and lower thyroglobulin (Tg) during treatment was associated with stable disease (p = 0.015 and 0,049, respectively). Patients with shorter survival had larger primary tumor size (p = 0.015) and higher maximum SUV on target lesions (p = 0.023). Conclusion: Our findings demonstrate safety and effectiveness of MKI in patients with advanced RAIR DTC. We were able to identify as possible prognostic markers of better outcomes: absence of FDG uptake on target lesions, lower maximum SUV on PET-CT, presence of lung-only metastasis and lower Tg during treatment.

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ABSTRACT Objective: To evaluate the effect of beinaglutide on weight loss and plasma protein patterns of inflammation/obesity relevant cytokines and biomarkers. Materials and methods: This study involved 36 adult patients with a body mass index (BMI) of ≥ 24 kg/m2 and T2DM. Beinaglutide was administered for three months. Changes in body weight, fasting plasma glucose (FPG) level, 2 h postprandial plasma glucose (2h-PG) level, glycosylated hemoglobin (HbA1c) level, BMI and visceral and subcutaneous fat areas were measured at baseline and after three months of treatment. In addition, relevant inflammation/obesity cytokines and biomarkers were measured. Results: After three months, beinaglutide treatment led to significant changes, including in body weight, BMI, FPG level, HbA1c level, visceral and subcutaneous fat areas. In addition, serpin E1, leptin, C-reaction protein (CRP) and tumor necrosis factor-α (TNF-α) also decreased significantly. The plasma protein concentrations of CRP (Log2 transformed) were found to be positively correlated with the percentage of weight loss (R = 0.514 and p-value = 0.021). Conclusion: Beinaglutide treatment resulted in weight loss, plasma glucose control and anti-inflammatory effects in patients with T2DM and overweight/obesity.

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ABSTRACT Objective: Thyrotropin-stimulated thyroglobulin (STg) after total thyroidectomy is a prognosis marker for differentiated thyroid carcinoma (DTC). As Tg level is influenced by thyrotropin (TSH), perhaps the STg/TSH ratio is also a prognosis marker for these tumours. We aimed to compare STg/TSH ratio and first STg level in differentiated thyroid carcinoma patients for their ability to predict the long-term response to initial treatment. Subjects and methods: This retrospective study evaluated data from 181 DTC patients for first (1st) STg and STg/TSH ratio, at 1-3 months post-total thyroidectomy and before iodine-131 therapy, according to response to initial therapy [Excellent/Indeterminate or Incomplete (Biochemical/Structural)] observed at final evaluation, and with the survival time with excellent/indeterminate response. Results: Cases with incomplete response presented higher STg level [225.13 ± 585.26 ng/mL versus (vs) 20.4 ± 192.9 ng/mL; p < 0.001] and STg/TSH ratio (3.01 ± 7.8 vs 0.27 ± 2.58; p < 0.001). Cutoffs of 5 ng/mL for STg and 0.085 for STg/TSH displayed sensitivities of 76.7% and 76.9%, and specificities of 79.2% and 82.6%, respectively, in predicting response to therapy. Values below these cutoffs were associated with longer survival time in excellent/indeterminate response (140.4 vs 15.9 and 144.6 vs 15.9 months, respectively). Conclusion: STg/TSH ratio has a similar performance to the 1st STg in predicting long-term response to initial therapy.

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ABSTRACT Objective: The aim of the study was to assess the autoimmunity in first degrees relatives (FDR) of patients with type 1 diabetes (T1DM) and the progression to T1DM after 10 years of follow up in the Brazilian population. Subjects and methods: Non-diabetic FDR of T1DM patients were interviewed and blood was drawn for autoantibodies measurement (GADA, IA-2A, IAA, ZnT8A). Serum samples were analyzed by standard radioligand binding assays performed at the Federal University of Rio de Janeiro (GADA, IAA and IA2A), and at the Skäne University Hospital, Sweden (ZnT8A). The FDR were interviewed by phone after 10 years to determine if they had developed T1DM. Descriptive statistical analysis was performed and results were described as means and standard deviation (SD). Results: 81 individuals were analyzed. Thirteen subjects had positive autoantibodies associated with T1DM.10 were positive for 1 autoantibody and 3 subjects were positive for multiple autoantibodies (1 of them showed positivity for 2 autoantibodies – GADA, ZnT8A – and the other two were positive for 3 autoantibodies – GADA, IA2A, ZnT8A). The 3 subjects with multiple positive autoantibodies developed T1DM within 10 years. Conclusions: In Brazilian FDR of T1DM patients, the positivity for multiple autoantibodies indicate a greater chance of progression to T1DM, similar to observed in Caucasians. ZnT8A was helpful in the risk assessment for T1DM development.

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ABSTRACT Objective: Globally developing metabolic syndrome (MetS) prevalence as a major health problem can be related to multiple factors of genetic and environmental. Dimethylaminohydrolase 2 (DDAH2) is the main enzyme implicated in the cardiovascular system, which regulates the nitric oxide pathway. This study investigated the association of DDAH2 polymorphism −499C/G (rs805305) with the risk of MetS among the Azar-Cohort population. Subjects and methods: The occurrence of SNP rs805305 in the DDAH2 gene was tested using the PCR-RFLP method in 332 MetS cases and 294 healthy controls. Afterward, the association of the allele and genotypes with the risk of MetS and its components were examined. Results: The G allele and GC genotype were significantly associated with a reduced risk of MetS (P ≤ 0.001). Also, the dominant genetic model (GG+GC) significantly decreased the risk of MetS (P = 0.001), however, in sex subtypes MetS risk was significantly reduced in males before and in females after adjustment for age (P ≤ 0.02). Conclusion: The −499C/G polymorphism of DDAH2 may play a protective role and reduce MetS risk among the Azar-Cohort population.

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ABSTRACT Objective: The effects of maternal thyroid hormone levels on the course of pregnancy and birth weight have attracted interest. The aim of the present study was to consider FT3 and FT3/FT4 ratio in the evaluation of the effects of maternal thyroid functions in gestational transient thyrotoxicosis (GTT). Materials and methods: This case-control study included 45 patients with GTT and 45 healthy pregnant women. Maternal history before pregnancy, thyroid function tests, thyroid autoantibodies, and thyroid ultrasonography results in 6th to 10th weeks of pregnancy were used in the differential diagnosis of GTT. In both groups, the effects of FT3, FT4 and FT3/FT4 ratios on gestational age and birth weight were evaluated. Results: There was no significant difference in the gestational age between the GTT and control groups (39,3±1,0 weeks and 39,2±1,2 weeks, respectively). Birth weights were similar in both groups (3205,2±4899 g and 3196,6±309,3 g, respectively). When maternal weight was adjusted, a positive correlation was observed between maternal FT3/FT4 ratio and birth weight (r=0,317, p=0,017). Additionally there was a positive correlation between the gestational age and the birth weight in the control group (ρ=0,726, p=0,001). Conclusion: GTT had no significant effect on the gestational age and the birth weight. On the other hand an increase in the maternal FT3/FT4 ratio had a positive effect on the birth weight in the patient with GTT. Maternal characteristics (age, weight, BMI) and FT3/FT4 ratio should be taken into consideration in future impact assessment studies on this issue.

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ABSTRACT Objective: Obesity and diabetes are the risk factors for cancer development including differentiated thyroid cancer (DTC). Contradictory accumulated data indicates the possible negative effects of obesity and hyperglyceamia as a factor for aggressiveness of DTC. The aim of the present study is to investigate the association of high body mass index (BMI) and presence of type 2 diabetes mellitus (T2DM) on the histological aggressiveness and clinical outcomes in DTC patients followed for over 4 years in a single center. Materials and methods: Consequative 526 DTC patients who had undergone total thyroidectomy and/or radioactive iodine (RAI) ablation were reviewed retrospectively. Patients were divided into groups based on their BMI: normal weight, overweight, obese and also were evalauted in 3 groups presence of diabetes, prediabetes and nomoglyceamia. Histological aggressiveness of DTC at the time of diagnosis and clinical response at the time of last clinical visit were reassessed according to the criteria suggested by ATA 2015 guideline. Results: No differences in histopathologic features, risk of recurrence, cumulative dose of RAI ablation and prevalence of 131I avid metastatic disease were demonstrated among the groups both classified according to BMI and hyperglycemia. Mean of 3.4 year follow-up also showed no differences in the clinial repsonse to therapy and percentage of nonthyroid primary cancer in DTC patients. Conclusion: In this retrospective study we demonstrated that obesity and T2DM have no additive effect on DTC aggressiveness and response to therapy. DTC patients with obesity and diabetes can be treated according to present guidelines without requirement for spesific attention.

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ABSTRACT Objective: Describe the demographic, clinical, and biochemical characteristics of overweight or obese people with severe COVID-19 pneumonia and evaluate its association with mechanical ventilation requirements in a Mexican cohort. Subjects and methods: Data were obtained from medical electronic records. Patients were divided in three groups according to the World Health Organization (WHO) classification of body mass index (BMI): lean, overweight and obese. Baseline characteristics and clinical course were compared among these 3 groups. Results: The study included a total of 355 patients with confirmed COVID-19 diagnoses. Patients with obesity and overweigh, according to the WHO classification, had no significantly increased risk of requiring intubation and invasive mechanical ventilation (IMV) compared to lean subjects, with an odds ratio (OR) of 1.82 (95% CI, 0.94-3.53). A post hoc and multivariate analysis using a BMI > 35 kg/m2 to define obesity revealed that subjects above this cut off had as significantly increased risk of requiring IMV after with an OR of 2.86 (95% CI, 1.09-7.05). Conclusion: We found no higher risk of requiring IMV in patients with overweight or obesity while using conventional BMI cutoffs. According to our sensitivity analyses, the risk of IMV increases in patients with a BMI over 35 kg/m2.

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ABSTRACT Objective: To evaluate incidence of subclinical and overt hyperthyroidism and hypothyroidism. Subjects and methods: The Brazilian Longitudinal Study of Adult Health (ELSA-Brasil) is a prospective cohort study of 15,105 civil servants, examined at baseline and over a 4-year follow-up. This analysis included 9,705 participants with normal thyroid function at baseline, follow-up information about thyroid function and with no report of using drugs that may interfere in the thyroid function. Thyroid function was defined by TSH/FT4 levels or routine use of thyroid hormones/anti-thyroid medications. Annual and cumulative (over 4-year) incidence rates were presented as percentages (95% Confidence Intervals). Results: The incidence of all overt and subclinical thyroid disease was 6.7% (1.73%/year): 0.19% for overt hyperthyroidism (0.048%/year), 0.54% for subclinical hyperthyroidism (0.14%/year), 1.98% for overt hypothyroidism (0.51%/year), and 3.99% for subclinical hypothyroidism (1.03%/year). The incidence of all thyroid diseases was higher in women, when compared to men, with a low women:men ratio (1.36). For Blacks the highest incidence was for overt hyperthyroidism, while for Whites, the highest incidence was for overt hypothyroidism. However, the highest incidence of overt hyperthyroidism was detected in Asian descendants. The presence of antithyroperoxidase antibodies at baseline was associated with higher incidence of overt thyroid diseases. Conclusion: These results showed a high incidence of hypothyroidism, which is compatible with a country with a more-than-adequate iodine intake. The low women:men ratio of the incidence of thyroid dysfunction highlights the importance of the diagnosis of thyroid diseases among men in Brazil.

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ABSTRACT Objective: Galanin is a neuropeptide which has effects not only on metabolic syndrome but also on reproduction. Glypican-4 is an adipokine associated with insulin sensitivity by interacting directly with the insulin receptor. This study evaluated serum concentrations of galanin and glypican-4 in relation with the hormonal profile as well as metabolic and cardiovascular risk factors in patients with and without polycystic ovary syndrome (PCOS). Subjects and methods: A total of 44 women with PCOS and 44 age-matched controls were eligible. Hirsutism scores, hormonal profile, metabolic and cardiovascular risk factors as well as galanin and glypican-4 levels were evaluated in each subject. Results: Women with PCOS exhibited lower levels of galanin (20.2 pg/mL versus 26.4 pg/mL, p = 0.002) and higher concentrations of glypican-4 (3.1 ng/mL versus 2.6 ng/mL, p < 0.001) than controls. Both adipokines were correlated positively with body mass index (BMI), insulin, triglyceride and Homeostasis Model Assessment (HOMA) index; glypican-4 also showed positive correlations with fasting blood glucose, free testosterone, modified Ferriman-Gallwey scores (p < 0.05). Multiple Linear Regression analyses showed that PCOS and BMI were the best predictors affecting galanin levels with a decreasing and increasing effect respectively; however BMI was the best predictor affecting glypican-4 levels with an increasing effect (p < 0.001). Conclusion: Galanin levels were lower and glypican-4 levels were higher in women with PCOS than controls. Further studies are needed to determine whether these adipokines could be used as additional markers for insulin sensitivity and lipid profile and whether they might play a role in the pathogenesis of PCOS, in which metabolic cardiovascular risks are increased.

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ABSTRACT Primary adrenal insufficiency (PAI) is characterized by the inability of the adrenal cortex to produce sufficient amounts of glucocorticoids and/or mineralocorticoids. Addison's disease (AD) and congenital adrenal hyperplasia (CAH) are the most frequent disorders in adults and children, respectively. Despite the diagnostic advances and the availability of glucocorticoid and mineralocorticoid replacements, adrenal crisis (AC) is still a potentially lethal condition contributing to the increased mortality, not only during the first year of life, but also throughout life. Failure in increasing glucocorticoid doses during acute stress, when greater amounts of glucocorticoids are required, can lead to AC and an increase morbimortality rate of PAI. Considering a mortality rate of 0.5 per 100 patient years, up to 1,500 deaths from AC are expected in Brazil in the coming decade, which represents an alarming situation. The major clinical features are hypotension and volume depletion. Nonspecific symptoms such as fatigue, lack of energy, anorexia, nausea, vomiting, and abdominal pain are common. The main precipitating factors are gastrointestinal diseases, other infectious disease, stressful events (e.g., major pain, surgery, strenuous physical activity, heat, and pregnancy), and withdrawal of glucocorticoid therapy. Suspected AC requires immediate therapeutic action with intravenous (iv) hydrocortisone, fluid infusion, monitoring support, and antibiotics if necessary. AC is best prevented through patient education, precocious identification and by adjusting the glucocorticoid dosage in stressor situations. The emergency card, warning about acute glucocorticoid replacement, has high value in reducing the morbidity and mortality of AC.

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SUMMARY Collision tumors are rare and may comprise components with different behavior, treatments, and prognosis. We report an unprecedented case of aggressive thyroid collision tumor containing widely invasive oncocytic carcinoma (OC), classical and hobnail (HPTC) variants of papillary carcinoma, and poorly differentiated carcinoma (PDTC). The patient underwent total thyroidectomy, radioactive iodine therapy, and within months progressed with local recurrence, and pulmonary metastases requiring neck dissection, external radiotherapy and systemic treatment with sorafenib. The rapid progression, dedifferentiated metastatic lesions, and failure to treatments resulted in the patient´s death. The great variety of histological types and the evolution of this case were a challenge for the management of metastatic disease. Widely invasive OC, HPTC and PDTC are considered to have a worse prognosis. HPTC has never been reported as a component of a collision tumor. HPTC and PDTC should call attention to a possible higher-grade transformation.

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SUMMARY The occurrence of fractures in young individuals is frequently overlooked by physicians, especially when associated with exercise or trauma. Nevertheless, multiple fractures should always be investigated since underlying conditions can predispose to such events. We describe here the case of a young, healthy woman who sustained multiple fractures in the lower limbs, which were initially considered to be “stress fractures”. Further investigation, including a panel of genes associated with osteogenesis imperfecta, revealed that the patient is a heterozygous carrier of a SERPINF1 variant. According to criteria recommended by the American College of Medical Genetics and Genomics and the Association for Molecular Pathology, this variant is classified as likely benign (PM2, PP3, PP4, BP1, and BP4). The patient's mother and brother were also asymptomatic carriers of the variant and had sustained previous minor fractures. The patient had normal biochemical profile and bone density. This condition has been rarely described and is not associated with low bone mineral density or altered bone turnover markers. This case highlights the importance of investigating multiple fractures in young patients who are otherwise healthy since these may be a warning sign of rare genetic conditions associated with fragility fractures.

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ABSTRACT Objective: To evaluate changes in bone density and architecture in postmenopausal women with breast cancer (BC) and use of aromatase inhibitor (AI). Subjects and methods: Thirty-four postmenopausal women with BC, without bone metastasis, renal function impairment and who were not receiving bone-active drugs were selected from a population of 523 outpatients treated for BC. According to the presence of hormonal receptors, HER2 and Ki67, seventeen had positive hormonal receptors and received anastrozole (AI group), and seventeen were triple-negative receptors (non-AI group), previously treated with chemotherapy. Areal bone mineral density (aBMD) and vertebral fracture assessment (VFA) analyses were performed by DXA; vBMD and bone microarchitecture were evaluated by HR-pQCT. Fracture risk was estimated using the FRAX tool. Results: No patient referred previous low-impact fracture, and VFA detected one moderate vertebral fracture in a non-AI patient. AI patients showed lower aBMD and BMD T-scores at the hip and 33% radius and a higher proportion of osteoporosis diagnosis on DXA (47%) vs non-AI (17.6%). AI group had significantly lower values for vBMD at the entire, cortical and trabecular bone compartments, cortical and trabecular thickness and BV/TV. They also had a higher risk for major fractures and for hip fractures estimated by FRAX. Several HR-pQCT parameters evaluated at distal radius and distal tibia were significantly associated with fracture risk. Conclusion: AI is associated with alterations in bone density and microarchitecture of both the cortical and trabecular compartments. These findings explain the overall increase in fracture risk in this specific population.

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SUMMARY Cyclic Cushing's syndrome (CS) due to thymic carcinoid is a rare disorder. We report a case of cyclic CS due to ectopic adrenocorticotropic hormone (ACTH)-secreting atypical thymic carcinoid tumor and reviewed similar cases published in the literature. Our patient had hypercortisolemia lasting approximately one month, followed by normal cortisol secretion, with relapse one year later. Histopathology revealed an atypical ACTH-positive thymic carcinoid. Ectopic CS can be derived from atypical thymic carcinoids, which can be aggressive tumors with early relapse, suggesting that this type of tumor probably needs aggressive treatment.

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ABSTRACT We conducted a cross-sectional study to evaluate the impact of social distancing determined by the COVID-19 pandemic on treatment adherence using the Self-Care Inventory-revised in adults with diabetes mellitus. In type 1 diabetes, the adherence score was lower during than before social distancing.