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As metas de hemoglobina glicada (A1C) em pacientes com diabetes tipo 2 devem ser adaptadas ao indivíduo, equilibrando a melhora das complicações microvasculares com o risco de hipoglicemia. Uma meta razoável da terapia pode ser um valor de A1C ≤ 7% para a maioria dos pacientes. As metas glicêmicas geralmente são definidas um pouco mais altas para pacientes com histórico de hipoglicemia grave, pacientes com expectativa de vida limitada, crianças muito pequenas ou adultos mais velhos e indivíduos com comorbidades. Melhor controle glicêmico melhora o risco de complicações microvasculares em pacientes com diabetes tipo 2. O tratamento intensivo da glicose no sangue está associado a um risco aumentado de hipoglicemia, bem como a sobrecarga de polifarmácia, efeitos colaterais adicionais e custo. Dependendo dos agentes prescritos, o ganho de peso também pode ocorrer com o tratamento intensivo.

A pandemia da COVID-19 impôs desafios para o acesso e a continuidade da oferta de cuidados aos usuários na Atenção Primária à Saúde (APS). Uma das estratégias propostas pelo município de Belo Horizonte foi a telessaúde, que consiste na utilização de recursos tecnológicos, como os atendimentos por áudio-vídeo, para a oferta de serviços de saúde. O objetivo deste artigo é apresentar a experiência da estruturação do teleatendimento na APS de Belo Horizonte, no contexto da pandemia. Como metodologia utilizou-se o relato de experiência. Foram apresentados processos estruturantes e aspectos de destaque na oferta dessa modalidade. Dois grandes grupos beneficiados, inicialmente, com o teleatendimento e telemonitoramento foram os usuários com condições crônicas e os casos suspeitos de COVID-19. Embora tenham sido identificados desafios e aspectos que necessitam de maior atenção, investimento e readequações, os resultados alcançados refletem a complexidade do cuidado à saúde e as perspectivas práticas na organização e ampliação da capacidade de resposta dos serviços. Destaca-se que a telessaúde representa benefícios para a prática assistencial e para a gestão dos serviços de saúde.

AURORA aims to study the processes of relapse in metastatic breast cancer (MBC) by performing multi-omics profiling on paired primary tumors and early-course metastases. Among 381 patients (primary tumor and metastasis pairs: 252 targeted gene sequencing, 152 RNA sequencing, 67 single nucleotide polymorphism arrays), we found a driver role for GATA1 and MEN1 somatic mutations. Metastases were enriched in ESR1, PTEN, CDH1, PIK3CA, and RB1 mutations; MDM4 and MYC amplifications; and ARID1A deletions. An increase in clonality was observed in driver genes such as ERBB2 and RB1. Intrinsic subtype switching occurred in 36% of cases. Luminal A/B to HER2-enriched switching was associated with TP53 and/or PIK3CA mutations. Metastases had lower immune score and increased immune-permissive cells. High tumor mutational burden correlated to shorter time to relapse in HR+/HER2− cancers. ESCAT tier I/II alterations were detected in 51% of patients and matched therapy was used in 7%. Integration of multi-omics analyses in clinical practice could affect treatment strategies in MBC.Significance:The AURORA program, through the genomic and transcriptomic analyses of matched primary and metastatic samples from 381 patients with breast cancer, coupled with prospectively collected clinical data, identified genomic alterations enriched in metastases and prognostic biomarkers. ESCAT tier I/II alterations were detected in more than half of the patients.This article is highlighted in the In This Issue feature, p. 2659

File with the supplementary material & methods, supplementary tables and supplementary figure.

Supplementary file with the listing of the liver genes excluded from transcriptomic analyses.

Introdução: O termo telemedicina refere-se ao uso de tecnologias de informação para atenção à saúde, expandindo a cobertura do cuidado quando a distância é um empecilho. Inicialmente, a simples transferência de informações médicas via aparatos tecnológicos como o rádio, eram consideradas como desempenho dessa prática. Posteriormente, a avaliação médico-paciente e o compartilhamento de resultados foram instituídos no cuidado remoto. Apesar de estar vigente há mais de um século, a telemedicina ainda enfrenta empecilhos para sua aplicação ampla. Todavia, a pandemia desencadeada pela COVID-19 gerou um novo cenário, propiciando avanços no que tange essa prática. Apesar de não substituir a relação médico-paciente presencial, essa prática pode constituir um importante instrumento para aumentar a eficiência global em saúde, aprimorar o serviço ofertado, propiciar redução de custo e a democratização do acesso, devendo ser utilizada de forma complementar e coordenada. Metodologia: Este estudo trata-se de uma revisão integrativa da literatura, por meio da pesquisa dos descritores “telemedicine”, “legislation in telemedicine” e “telemedicine and COVID-19” nas bases de dados Pubmed e Lilacs. Artigos publicados nas línguas portuguesa, inglesa e espanhola, disponíveis na íntegra e que estivessem relacionados aos aspectos legislativos e burocráticos da telemedicina, bem como seu uso durante a pandemia foram selecionados. Pesquisas com data de publicação com períodos superiores a 15 anos, disponibilizadas apenas na forma de resumo, publicados em periódicos de baixo fator de impacto ou com metodologias inconclusivas foram excluídos. Sendo assim, após a realização da análise criteriosa descrita, foram selecionados 13 estudos. Desenvolvimento: A Resolução CFM nº 1.643, de 26 de agosto de 2002 conceitua a telemedicina, reforça a responsabilidade que o médico possui ao assistir seus pacientes, e a obrigação de pessoas jurídicas se inscreverem no Cadastro de Pessoa Jurídica do Conselho Regional de Medicina do estado onde estão situadas. Se o prestador for pessoa física, deverá ser médico e devidamente inscrito no Conselho Regional de Medicina. Também estabelece a necessidade de constante vigilância e avaliação das técnicas de Telemedicina. Todavia, as limitações e lacunas impostas pela Res. nº 1.643 figuravam como empecilhos para a plena e efetiva aplicação do atendimento médico remoto, de modo que os hospitais, médicos e planos de saúde não podiam utilizar esse atendimento como parte de seus serviços. Diante da pandemia de COVID-19 e da consequente necessidade de se realizar o isolamento social, o ofício CRM n° 1756/2020 reconheceu a possibilidade e a eticidade do uso da telemedicina, além do disposto na Resolução CFM nº 1.643, em caráter excepcional, enquanto durar a pandemia da COVID-19. A Portaria nº 467/2020 do Ministério da Saúde contemplou, ainda, o atendimento pré-clínico, de suporte assistencial e consultas. Diante do cenário pandêmico a telemedicina tornou-se uma ferramenta fácil e de baixo custo, usada para ajudar a solucionar quadros menos complexos, evitando a sobrecarga do sistema de saúde. Além dos atendimentos de urgência para infecções respiratórias, a telemedicina também é eficiente no gerenciamento de condições crônicas, como diabetes, pois permite um acompanhamento contínuo de maneira simples. Outro benefício da telemedicina é o maior acesso a cuidados nas áreas rurais e diferentes regiões do Brasil, tendo em vista que o acesso à internet torna-se cada vez mais comum (apesar de ainda ser um limitador). Porém, o atendimento médico prestado de forma remota carrega limitações, que podem dificultar o alcance do diagnóstico e da prescrição terapêutica adequados, como a falta de exame físico, essencial em diversos casos. Ademais, os dados obtidos durante uma consulta de telemedicina devem ser protegidos para evitar acesso não autorizado. A falta de políticas de remuneração para o médico que presta serviço na área de telemedicina também é um problema que pode cercear o desenvolvimento dessa modalidade. Conclusão: Mesmo com alguns problemas, a telemedicina mostrou resultados favoráveis no Brasil e no mundo. Torna-se necessário a realização de mais estudos sobre a temática, além de uma atuação firme do poder legislativo, em vista de criar legislações mais seguras e eficazes para regulamentação desse tipo de medicina.

AURORA aims to study the processes of relapse in metastatic breast cancer (MBC) by performing multi-omics profiling on paired primary tumors and early-course metastases. Among 381 patients (primary tumor and metastasis pairs: 252 TGS, 152 RNA-Seq, 67 SNP Arrays), we found a driver role for GATA1 and MEN1 somatic mutations. Metastases were enriched in ESR1, PTEN, CDH1, PIK3CA and RB1 mutations; MDM4, MYC amplifications; ARID1A deletions. An increase in clonality was observed in driver genes like ERBB2 and RB1. Intrinsic subtype switching occurred in 36% of cases. Luminal A/B to HER2-Enriched switching was associated with TP53 and/or PIK3CA mutations. Metastases had lower immune score and increased immune permissive cells. High TMB correlated to shorter time to relapse in HR+/HER2- cancers. ESCAT tier I/II alterations were detected in 51% of patients and matched therapy was used in 7%. Integration of multi-omics analyses in clinical practice could impact treatment strategies in MBC., info:eu-repo/semantics/published

Introduction Gene fusions (GFs) are genomic alterations with oncogenic potential. This class of alterations is highly actionable with targeted therapies showing high rates of durable responses in agnostic settings such as tumors with NTRK fusions. Recurrent GFs are rare in metastatic breast cancer (mBC) and ESR1 fusions drive endocrine resistance. AURORA is a molecular screening program for patients with mBC early in the course of their disease, collecting primary tumors, metastatic samples, liquid samples and longitudinal clinical follow-up data. Experimental procedures Patients are enrolled at the diagnosis of metastatic disease or after 1 line of therapy. Targeted gene sequencing of 411 BC genes is performed on the primary tumor, a metastatic sample, whole blood for germline variants and, for a subset of these genes, on tumor DNA from a baseline plasma sample. RNA-seq is performed on primary and metastatic tumor tissue samples. GFs were identified by rnafusion, a pipeline implementing 5 widely-used tools. Only GFs detected by at least 3 tools or 2 tools and 1 GF database match were considered for downstream analysis. Selected GFs were validated in-silico by FusionInspector. GFs detected in independent human normal tissue datasets were filtered out. Findings were correlated to available genomics, transcriptomics and clinical data. Results GFs data were generated from 316 paired primary/metastatic samples from 158 patients with curated clinical and genomic data: 97 ER+/HER2- (61.4%), 37 triple-negative (23.4%) and 24 HER2+ (15.2%). A total of 538 fusions were called in the primary samples (mean = 3.4 per sample) and 707 in the metastatic samples (mean = 4.5) with a validation rate of 72%. The gene fusion burden in metastatic samples was higher than in the primary (p Conclusions We report on the characterization of GFs in a large cohort of patients with mBC. Through the analysis of matched primary and metastatic tumor samples from 158 patients, we delineated the landscape of acquired gene fusions in BC. We observed a significant increase of gene fusion burden in metastatic compared to corresponding primary samples, involving key BC genes. Fusions involving actionable genes were associated with shorter PFS. Additional integrative analyses combining detected GFs and available genomics, gene expression and/or patients' treatments and outcomes are ongoing and will be presented during the meeting. Citation Format: Matteo Benelli, Chiara Biagioni, Danai Fimereli, Florentine S. Hilbers, Claudia De Angelis, Ana Vivancos, David Venet, Andrea Vingiani, Alexandre Irrthum, Veerle Van Dooren, Peter Willem Vuylsteke, Sonia Servitja, Jorge Reis-Filho, Giuseppe Curigliano, Mafalda Oliveira, Martine Piccart, Philippe Aftimos. Characterization of gene fusions in paired primary and metastatic samples of breast cancer in the AURORA molecular screening program [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 2488.

Reconstructing gene regulatory networks from high-throughput data is a long-standing challenge. Through the Dialogue on Reverse Engineering Assessment and Methods (DREAM) project, we performed a comprehensive blind assessment of over 30 network inference methods on Escherichia coli, Staphylococcus aureus, Saccharomyces cerevisiae and in silico microarray data. We characterize the performance, data requirements and inherent biases of different inference approaches, and we provide guidelines for algorithm application and development. We observed that no single inference method performs optimally across all data sets. In contrast, integration of predictions from multiple inference methods shows robust and high performance across diverse data sets. We thereby constructed high-confidence networks for E. coli and S. aureus, each comprising ~1,700 transcriptional interactions at a precision of ~50%. We experimentally tested 53 previously unobserved regulatory interactions in E. coli, of which 23 (43%) were supported. Our results establish community-based methods as a powerful and robust tool for the inference of transcriptional gene regulatory networks.

Several studies have demonstrated the feasibility of molecular screening of tumour samples for matching patients with cancer to targeted therapies. However, most of them have been carried out at institutional or national level. Herein, we report on the pilot phase of AURORA (NCT02102165), a European multinational collaborative molecular screening initiative for advanced breast cancer patients. Forty-one patients were prospectively enroled at four participating centres across Europe. Metastatic tumours were biopsied and profiled using an Ion Torrent sequencing platform at a central facility. Sequencing results were obtained for 63% of the patients in real-time with variable turnaround time stemming from delays between patient consent and biopsy. At least one clinically actionable mutation was identified in 73% of patients. We used the Illumina sequencing technology for orthogonal validation and achieved an average of 66% concordance of substitution calls per patient. Additionally, copy number aberrations inferred from the Ion Torrent sequencing were compared to single nucleotide polymorphism arrays and found to be 59% concordant on average. Although this study demonstrates that powerful next generation genomic techniques are logistically ready for international molecular screening programs in routine clinical settings, technical challenges remain to be addressed in order to ensure the accuracy and clinical utility of the genomic data., info:eu-repo/semantics/published

Lymphedema is caused by dysfunction of lymphatic vessels, leading to disabling swelling that occurs mostly on the extremities. Lymphedema can be either primary (congenital) or secondary (acquired). Familial primary lymphedema commonly segregates in an autosomal dominant or recessive manner. It can also occur in combination with other clinical features. Nine mutated genes have been identified in different isolated or syndromic forms of lymphedema. However, the prevalence of primary lymphedema that can be explained by these genetic alterations is unknown. In this study, we investigated 7 of these putative genes. We screened 78 index patients from families with inherited lymphedema for mutations in FLT4, GJC2, FOXC2, SOX18, GATA2, CCBE1, and PTPN14. Altogether, we discovered 28 mutations explaining 36% of the cases. Additionally, 149 patients with sporadic primary lymphedema were screened for FLT4, FOXC2, SOX18,CCBE1, and PTPN14. Twelve mutations were found that explain 8% of the cases. Still unidentified is the genetic cause of primary lymphedema in 64% of patients with a family history and 92% of sporadic cases. Identification of those genes is important for understanding of etiopathogenesis, stratification of treatments and generation of disease models. Interestingly, most of the proteins that are encoded by the genes mutated in primary lymphedema seem to act in a single functional pathway involving VEGFR3 signaling. This underscores the important role this pathway plays in lymphatic development and function and suggests that the unknown genes also have a role.

Traditionally, intertumour heterogeneity in breast cancer has been documented in terms of different histological subtypes, treatment sensitivity profiles, and clinical outcomes among different patients. Results of high-throughput molecular profiling studies have subsequently revealed the true extent of this heterogeneity. Further complicating this scenario, the heterogeneous expression of the oestrogen receptor (ER), progesterone receptor (PR), and HER2 has been reported in different areas of the same tumour. Furthermore, discordance, in terms of ER, PR and HER2 expression, has also been reported between primary tumours and their matched metastatic lesions. High-throughput molecular profiling studies have confirmed that spatial and temporal intratumour heterogeneity of breast cancers exist at a level beyond common expectations. We describe the different levels of tumour heterogeneity, and discuss the strategies that can be adopted by clinicians to tackle treatment response and resistance issues associated with such heterogeneity, including a rationally selected combination of agents that target driver mutations, the targeting of deleterious passenger mutations, identifying and eradicating the 'lethal' clone, targeting the tumour microenvironment, or using adaptive treatments and immunotherapy. The identification of the most-appropriate strategies and their implementation in the clinic will prove highly challenging and necessitate the adoption of radically new practices for the optimal clinical management of breast malignancies.

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