Perfil genômico dos tumores adrenais pediátricos

Orientador : Prof. Dr. Gerard P. ZambettiCo-orientadora : Profª. Drª. Enilze Maria de Souza F. RibeiroTese (doutorado) - Universidade Federal do Paraná, Setor de Ciências Biológicas, Programa de Pós-Graduação em Genética. Defesa: Curitiba, 21/11/2014Inclui referênciasÁrea de concentraçãoResumo: Os tipos histológicos e localizações dos tumores diagnosticados em pacientes portadores de mutação hereditária no gene TP53 são semelhantes aos encontrados nos pacientes com mutação esporádica no TP53. Entretanto, os pacientes com mutação hereditária tendem a desenvolver os tumores mais precocemente. O tecido adrenocortical é aparentemente muito mais sensível à perda da atividade da proteína p53, especialmente nos primeiros anos de vida quando comparado ao córtex adrenal adulto. Em adição, mais de 50% dos tumores do córtex adrenal (TCA) de crianças apresentam algum tipo de mutação no TP53. Células de TCA com mutação no TP53 apresentam mais perdas e ganhos de cromossomos do que TCA sem mutação no TP53. Acredita-se que a mutação isolada no gene TP53 é insuficiente para o desenvolvimento tumoral, sendo necessário contribuições de outros fatores genéticos e/ou ambientais para o inicio da tumorigênese. Carcinoma adrenocortical pediátrico (CCA) é um tumor raro, maligno, e com prognóstico reservado. O objetivo deste trabalho foi analisar 37 TCAs de crianças pelo sequenciamento genômico completo, sequenciamento do exoma e/ou sequenciamento do transcriptoma. O critério de seleção dos TCAs (carcinomas e adenomas) considerou a distribuição dos diferentes tipos histológicos (benigno e maligno), presença ou ausência de mutação no gene TP53, TCAs com a mutação TP53 R337H, ou outras mutações no gene TP53 com elevada penetrância. A perda de heterozigose (LOH) do braço curto do cromossomo 11 (ch11p) ocorreu em 91% dos casos, e em todos os casos analisados a perda foi do cromossomo materno. O gene IGF-2, localizado dentro de um conjunto de genes sob controle de imprinting no ch11p, apresentou elevada expressão em 100% dos tumores analisados. Mutações no gene TP53 em combinação com LOH do cromossomo 17 (ch17) foi observado em 28/37 casos de TCAs (76%), quando comparado com TCAs que apresentaram o p53 selvagem. LOH dos cromossomos ch11p e ch17 ocorreu no início da tumorigênese, sugerindo serem estes eventos iniciadores da formação tumoral. Outras alterações genéticas encontradas nos TCAs incluem mutações somáticas recorrentes nos genes ATRX, CTNNB1, e integração do virus herpes humano-6 (HHV6) na região telomérica do ch11p. O pior prognóstico foi identificado nos pacientes com CCAs que apresentaram mutações no TP53 e ATRX associadas a outras anormalidades genômicas, incluindo as variações estruturais complexas. No conjunto, estes resultados demonstram o caráter, a ordem temporal e o possível significado prognóstico de alterações genéticas fundamentais nos TCAs pediátricos, como também delinearam uma proposta de modelo da tumorigênese no córtex adrenal do grupo pediátrico. Palavras-chave: Tumor de córtex adrenal; criança; genoma; TP53; mutação.Abstract: The spectrum of tumors in patients with TP53 germline mutation is similar to that found in sporadic tumors, but inherited tumors tend to develop much earlier. The adrenocortical tissue of younger children are highly sensitive to the loss of p53 activity, much more than the adult adrenal cortex, and over 50% of the adrenocortical tumours (ACT) of children have some kind of TP53 mutation. ACT cells with TP53 mutations exhibit more deletions and gains of chromosomes than ACTs without TP53 mutation. It is believed that cells with TP53 mutations to undergo transformation require contributions from environmental contaminants and / or other mutations to initiate tumorigenesis. Pediatric adrenocortical carcinoma is a rare malignancy with poor prognosis. Here we analyzed 37 childhood ACTs by whole genome, whole exome and/or transcriptome sequencing. The criteria for selecting ACTs (carcinomas and adenomas) considered the well-known distribution of different ACT types, including benign and malignant tumors, presence or absence of mutations in the TP53 gene, and also ACTs with the TP53 R337H mutation or other mutation in the TP53 gene with higher penetrance. Loss of heterozygosity (LOH) of chromosome 11p occurred in 91% of ACTs and all informative cases selected against the maternal chromosome. IGF2, which is located within a cluster of imprinted genes on chromosome 11p, was overexpressed in 100% of the tumors. TP53 mutations and chromosome 17 LOH with selection against wild-type TP53 were observed in 28 ACT cases (76%). Copy neutral- LOH of chromosomes 11p and 17 occurred early during tumorigenesis, suggestive of tumor driver events. Additional genetic alterations included recurrent somatic mutations in ATRX and CTNNB1, as well as integration of human herpesvirus-6 (HHV6) in the telomeric region of chromosome 11p. A very poor outcome was predicted by concomitant TP53 and ATRX mutations and associated genomic abnormalities, including massive structural variations and a high background mutation rate. Collectively, these findings demonstrate the nature, timing and potential prognostic significance of key genetic alterations in pediatric ACT and outline a hypothetical model of pediatric adrenocortical tumorigenesis. Keywords: Adrenocortical tumour; children; genome, TP53; mutation

Acute myeloid leukemia in children and adolescents in Brazilian institutions : reality and challenges.

Objective: To describe the outcome of acute myeloid leukemia (AML) among children treated in Brazilian institutions. Methods: A structured online questionnaire was sent to pediatric oncologists affiliated to the Brazilian Society of Pediatric Oncology. The physicians and institutions were unidentified. Results: One hundred and four pediatric oncologists in all Brazilian regions answered the questionnaire. The treatment-related mortality rate was reported to be higher than 30% by 29.8% of the participants. Difficulty in accessing the intensive care unit (ICU) was reported by 54.8%. About 85% had access to cytogenetics, 78% to molecular testing, 94% to the measurement of residual disease by flow cytometry. About 90% of participants reported access to HSCT, but 86% of them had difficulties in providing HSCT timely. About 95% of the respondents indicated the need to create a national treatment protocol, and 89.4% are willing to collaborate with a national study group. Conclusion: Our study demonstrated large gaps in the treatment of pediatric AML in Brazil. To improve outcome, a national protocol will have to consider the regional differences and adapt the management according to the local resources

Updated cardiovascular prevention guideline of the Brazilian Society of Cardiology: 2019

Sem informação113478788

Mortality from gastrointestinal congenital anomalies at 264 hospitals in 74 low-income, middle-income, and high-income countries: a multicentre, international, prospective cohort study

Summary Background Congenital anomalies are the fifth leading cause of mortality in children younger than 5 years globally. Many gastrointestinal congenital anomalies are fatal without timely access to neonatal surgical care, but few studies have been done on these conditions in low-income and middle-income countries (LMICs). We compared outcomes of the seven most common gastrointestinal congenital anomalies in low-income, middle-income, and high-income countries globally, and identified factors associated with mortality. Methods We did a multicentre, international prospective cohort study of patients younger than 16 years, presenting to hospital for the first time with oesophageal atresia, congenital diaphragmatic hernia, intestinal atresia, gastroschisis, exomphalos, anorectal malformation, and Hirschsprung’s disease. Recruitment was of consecutive patients for a minimum of 1 month between October, 2018, and April, 2019. We collected data on patient demographics, clinical status, interventions, and outcomes using the REDCap platform. Patients were followed up for 30 days after primary intervention, or 30 days after admission if they did not receive an intervention. The primary outcome was all-cause, in-hospital mortality for all conditions combined and each condition individually, stratified by country income status. We did a complete case analysis. Findings We included 3849 patients with 3975 study conditions (560 with oesophageal atresia, 448 with congenital diaphragmatic hernia, 681 with intestinal atresia, 453 with gastroschisis, 325 with exomphalos, 991 with anorectal malformation, and 517 with Hirschsprung’s disease) from 264 hospitals (89 in high-income countries, 166 in middleincome countries, and nine in low-income countries) in 74 countries. Of the 3849 patients, 2231 (58·0%) were male. Median gestational age at birth was 38 weeks (IQR 36–39) and median bodyweight at presentation was 2·8 kg (2·3–3·3). Mortality among all patients was 37 (39·8%) of 93 in low-income countries, 583 (20·4%) of 2860 in middle-income countries, and 50 (5·6%) of 896 in high-income countries (p<0·0001 between all country income groups). Gastroschisis had the greatest difference in mortality between country income strata (nine [90·0%] of ten in lowincome countries, 97 [31·9%] of 304 in middle-income countries, and two [1·4%] of 139 in high-income countries; p≤0·0001 between all country income groups). Factors significantly associated with higher mortality for all patients combined included country income status (low-income vs high-income countries, risk ratio 2·78 [95% CI 1·88–4·11], p<0·0001; middle-income vs high-income countries, 2·11 [1·59–2·79], p<0·0001), sepsis at presentation (1·20 [1·04–1·40], p=0·016), higher American Society of Anesthesiologists (ASA) score at primary intervention (ASA 4–5 vs ASA 1–2, 1·82 [1·40–2·35], p<0·0001; ASA 3 vs ASA 1–2, 1·58, [1·30–1·92], p<0·0001]), surgical safety checklist not used (1·39 [1·02–1·90], p=0·035), and ventilation or parenteral nutrition unavailable when needed (ventilation 1·96, [1·41–2·71], p=0·0001; parenteral nutrition 1·35, [1·05–1·74], p=0·018). Administration of parenteral nutrition (0·61, [0·47–0·79], p=0·0002) and use of a peripherally inserted central catheter (0·65 [0·50–0·86], p=0·0024) or percutaneous central line (0·69 [0·48–1·00], p=0·049) were associated with lower mortality. Interpretation Unacceptable differences in mortality exist for gastrointestinal congenital anomalies between lowincome, middle-income, and high-income countries. Improving access to quality neonatal surgical care in LMICs will be vital to achieve Sustainable Development Goal 3.2 of ending preventable deaths in neonates and children younger than 5 years by 2030

Reducing the environmental impact of surgery on a global scale: systematic review and co-prioritization with healthcare workers in 132 countries

Abstract Background Healthcare cannot achieve net-zero carbon without addressing operating theatres. The aim of this study was to prioritize feasible interventions to reduce the environmental impact of operating theatres. Methods This study adopted a four-phase Delphi consensus co-prioritization methodology. In phase 1, a systematic review of published interventions and global consultation of perioperative healthcare professionals were used to longlist interventions. In phase 2, iterative thematic analysis consolidated comparable interventions into a shortlist. In phase 3, the shortlist was co-prioritized based on patient and clinician views on acceptability, feasibility, and safety. In phase 4, ranked lists of interventions were presented by their relevance to high-income countries and low–middle-income countries. Results In phase 1, 43 interventions were identified, which had low uptake in practice according to 3042 professionals globally. In phase 2, a shortlist of 15 intervention domains was generated. In phase 3, interventions were deemed acceptable for more than 90 per cent of patients except for reducing general anaesthesia (84 per cent) and re-sterilization of ‘single-use’ consumables (86 per cent). In phase 4, the top three shortlisted interventions for high-income countries were: introducing recycling; reducing use of anaesthetic gases; and appropriate clinical waste processing. In phase 4, the top three shortlisted interventions for low–middle-income countries were: introducing reusable surgical devices; reducing use of consumables; and reducing the use of general anaesthesia. Conclusion This is a step toward environmentally sustainable operating environments with actionable interventions applicable to both high– and low–middle–income countries

Redefor Geografia Módulo 4 Disciplina 7

Temas da disciplina 7 de Geografia. A preocupação central desta disciplina é de analisar o contexto histórico-geográfico que originou e estruturou a hegemonia americana, considerando a relação econômico-financeira e político-militar dos Estados Unidos com os países latino-americanos, europeus, asiáticos e africanos. Em vista dos conflitos regionais, movimentos migratórios internacionais e o aumento da desigualdade regional, os alunos serão desafiados a avaliar diferentes processos que impactam o sistema político internacional