We assess the severity and frequency of diabetic ketoacidosis (DKA) in new-onset type 1 diabetes mellitus (T1D) patients and in patients with previous diagnosis of T1D in a referral Brazilian university hospital in the first five months of the COVID-19 pandemic. We also compare the data with data from pre-pandemic periods. Forty-three new-onset T1D patients were diagnosed between April and August of the years 2017, 2018, 2019, and 2020. During the COVID-19 pandemic, the number of newonset T1D was over twice the number of new-onset T1D in the same period in the three previous years. All the 43 patients survived and are now on outpatient follow-up. We also compared the characteristics of the T1D patients hospitalized between April and August of the years 2017, 2018, and 2019 (32 hospitalizations) to the characteristics of the T1D patients hospitalized between April and August/2020 (35 hospitalizations; 1 patient was hospitalized twice in this period). Fourteen of the 34 patients admitted during the pandemic presented with COVID-19-related symptoms (any respiratory symptom, fever, nausea, vomiting, and diarrhea), but only one had positive SARS-CoV-2 RT-PCR test. Samples from 32 out of these 34 patients were assayed for SARS-CoV-2 antibodies, and four patients were positive for total antibodies (IgM and IgG). In agreement with recent reports from European countries, we observed increased frequency of DKA and severe DKA in new-onset and previously diagnosed T1D children and adolescents in a large referral public hospital in Brazil in the first five months of the COVID-19 pandemic. The reasons for this outcome might have been fear of SARS-CoV-2 infection in emergency settings, the more limited availability of primary healthcare, and the lack of school personnel's attention toward children's general well-being.

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BackgroundDistinct genome-wide methylation patterns have consistently clustered pituitary neuroendocrine tumors (PT) into molecular groups associated with specific clinicopathological features. Here we aim to identify, characterize and validate the methylation signatures that objectively classify PT into those molecular groups.MethodsCombining in-house and publicly available data, we conducted an analysis of the methylome profile of a comprehensive cohort of 177 tumor and 20 non-tumor specimens from the pituitary gland. We also retrieved methylome data from an independent pituitary tumor (PT) cohort (N=86) to validate our findings.ResultsWe identified three methylation clusters associated with functional status and adenohypophyseal cell lineages using an unsupervised approach. We also identified signatures based on differentially methylated CpG probes (DMP), some of which overlapped with pituitary-specific transcription factors genes (SF1 and Tpit), that significantly distinguished pairs of clusters related to functional status and adenohypophyseal cell lineage. These findings were reproduced in an independent cohort, validating these methylation signatures. The DMPs were mainly annotated in enhancer regions associated with pathways and genes involved in cell identity and tumorigenesis.ConclusionsWe identified and validated methylation signatures that distinguished PT by distinct functional status and adenohypophyseal cell lineages. These signatures, annotated in enhancer regions, indicate the importance of these elements in pituitary tumorigenesis. They also provide an unbiased approach to classify pituitary tumors according to the most recent classification recommended by the WHO 2017 using methylation profiling.Key-pointsDistinct methylation landscapes define PT groups with specific functional status/subtypes and adenohypophyseal lineages subtypes.Methylation abnormalities in each cluster mainly occur in CpG annotated in distal regions overlapping predicted enhancers regions associated with pathways and genes involved in cell identity and tumorigenesis.DNA methylation signatures provide an unbiased approach to classify PT.Importance of the studyThis study harnessed the largest methylome data to date from a comprehensive cohort of pituitary specimens obtained from four different institutions. We identified and validated methylation signatures that distinguished pituitary tumors into molecular groups that reflect the functionality and adenohypophyseal cell lineages of these tumors. These signatures, mainly located in enhancers, are associated with pathways and genes involved in cell identity and tumorigenesis. Our results show that methylome profiling provides an objective approach to classify PT according to the most recent classification of PT recommended by the 2017 WHO.

The aim of the study was to clarify the relationship and the time of aldosterone and renin recoveries at immediate and long-term follow-up in aldosterone-producing adenoma (APA) patients who underwent adrenalectomy. Prospective and longitudinal protocol in a cohort of APA patients was followed in a single center. Among 43 patients with primary aldosteronism (PA), thirteen APA patients were enrolled in this study. Blood was collected for aldosterone, renin, potassium, creatinine, cortisol, and ACTH before and 1, 3, 5, 7, 15, 30, 60, 90, 120, 180, 270, 360 days after adrenalectomy. At diagnosis, most patients (84%) had hypokalemia and high median aldosterone levels (54.8; 24.0–103 ng/dl) that decreased to undetectable (<2.2) or very low (<3.0) levels between fifth to seventh days after surgery; then, between 3–12 months, its levels gradually increased to the lower normal range. The suppressed renin (2.3; 2.3–2.3 mU/l) became detectable between the fifteen and thirty days after surgery, remaining normal throughout the study. The aldosterone took longer than renin to recover (60 vs.15 days; p<0.002) and patients with higher aldosterone had later recovery (p=0.03). The cortisol/ACTH levels remained normal despite the presence of a post-operative hypoaldosteronism. Blood pressure and antihypertensive requirement decreased after adrenalectomy. In conclusion, our prospective study shows the borderline persistent post-operative hypoaldosteronism in the presence of early renin recovery indicating incapability of the zona glomerulosa of the remaining adrenal gland to produce aldosterone. These findings contribute to the comprehension of differences in renin and aldosterone regulation in APA patients, although both are part of the same interconnected system.

Children diagnosed with adrenocortical tumors (pACT) have variable outcomes and, to date, the disease lacks robust prognostic biomarkers. The prognostic potential of tumor methylation has been demonstrated in several cancers. We aimed to evaluate the pACT methylation profile and its association with disease presentation and survival. In this cross-sectional study, we accessed the DNA methylation (MethylationEPIC Array, Illumina) of 57 primary pACT from Southeastern Brazil and the respective patients’ clinicopathological features. We also applied our analysis in an independent 48 pACT methylation data-set. Unsupervised learning whole-methylome analysis showed two groups with distinct methylation signatures: pACT-1 and pACT-2. Compared to pACT-2, pACT-1 tumors were enriched for higher methylation in CpG islands, mainly in gene promoter regions. The top-most hypermethylated gene in these samples was shown to be under-expressed. Patients in the pACT-1 group were older at diagnosis and were more likely to have carcinomas, non-localized/advanced and recurrent/metastatic disease. Univariate and bivariate regressions showed that pACT-1 methylation signature confers superior hazard-ratio of disease progression and death than known prognostic features. The methylation groups had similar frequencies of germline mutations in the TP53 gene, including the regionally frequent p.R337H. Our analysis replication validated our findings and reproduced those recently described in pACT. Conclusions: We demonstrated the existence of different tumor methylation signatures associated with pACT presentation and clinical evolution, even in the context of germline TP53 mutations. Our data support tumor methylation profiling as a robust and independent prognostic biomarker for pACT and suggest a list of candidate genes for further validation.

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Pediatric adrenocortical tumors (ACT) are rare malignancies and in advanced disease the treatment has a small impact on overall survival. Previous study from our group suggests that AURKA and AURKB overexpression in pediatric ACT may be related to more aggressive disease. These genes are involved in the maintenance of the genome integrity during cell cycle division and they have been considered as new targets to cancer treatment. The present study shows the previous results of the effects of the new Aurora kinase inhibitor AMG900, associated or not with standard chemotherapeutic agents on adrenocortical carcinoma cell line H295A. Cell proliferation was assessed by Giemsa staining and apoptosis was performed by flow cytometry. Quantitative RT-PCR assays were used to determine the mRNA expression after AMG900 exposition. Drug combination analysis was made based on Chou-Talalay method. Hormones dosage assay was carried out to evaluate the effects of the Aurora kinase inhibitor on hormone secretion. AMG900 inhibited cell proliferation and caused apoptosis in a dose dependent manner in H295A cells. Moreover, it acted synergistically with doxorubicin, cisplatin and etoposide in the apoptosis induction, but only with doxorubicin in the proliferation inhibition. AMG900 treatment induced the mRNA expression of the genes p53, p21, and GDF15 and effectively inhibited dehydroepiandrosterone, androstenedione, cortisol and testosterone secretion. These data suggest that Aurora kinase inhibition by AMG900 may be a new therapeutic approach to adrenocortical carcinoma treatment. Financial Support: FAPESP (10/07020-9 and 12/09391-0) Citation Information: Mol Cancer Ther 2013;12(11 Suppl):A294. Citation Format: Kleiton S. Borges, Augusto F. Andrade, Vanessa S. Silveira, David S.M Antonio, Elton J.R. Vasconcelos, Sonir R.R. Antonini, Luiz G. Tone, Carlos A. Scrideli. Antitumor activity of AMG900, an Aurora kinase inhibitor, alone or in combination with chemotherapeutic agents on H295A adrenocortical carcinoma cell line. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr A294.

Mesmo entre os especialistas mais dedicados, a prática clínica da Neuroendocrinologia é conhecida por sua larga complexidade. Os temas e subtemas a partir dos quais se pode dividir a especialidade são inúmeros e precisam ser tratados com o devido cuidado, assegurando aos profissionais médicos referências confiáveis para as abordagens e aplicações mais adequadas em sua rotina. O Guia Prático em Neuroendocrinologia é o resultado da reunião dos principais nomes da área e uma iniciativa do Departamento de Neuroendocrinologia da Sociedade Brasileira de Endocrinologia e Metabologia (SBEM). Em 28 capítulos escritos em uma linguagem acessível, o guia oferece uma literatura que, ao assimilar a complexidade da Neuroendocrinologia, enfoca as lacunas de conhecimento de endocrinologistas de todo o país, visando transformá-las em informações consistentes e atualizadas para o melhor atendimento dos pacientes.