Risk Factors of Venous Thromboembolic Disease in Cancer Patients Treated with Immune Checkpoint Inhibitor.

BACKGROUND: Immune checkpoint inhibitors (ICIs) have revolutionized the management of cancers. The risk factors and pathophysiological mechanisms of venous thromboembolic events (VTEs) of this new therapeutic class are still to be specified. METHODS: The included patients had to have cancer and should be treated with ICI. Data analyzed included demographic data, biological data, and immune-related adverse events (IRAEs). We studied the prevalence of VTEs and the factors associated with VTEs. RESULTS: Of 374 patients on ICI, over a median follow-up period of 15.2 months, the number of VTE was 50 (13.4%). The majority of patients were treated for metastatic melanoma or nonsmall cell lung cancer. There was no difference in prevalence or survival between cancer types. Patients with combined therapy composed of nivolumab and ipilimumab had higher 1-year cumulative VTE occurrence (29.3% [95% confidence interval [CI]: 9.7; 44.6]) than patients with pembrolizumab (14.9%, [95%CI: 2.5; 25.8], p = 0.03) or nivolumab (9.1%, [95% CI: 5.0; 12.9], p < 0.01). The presence of IRAE was associated with a higher risk of VTE occurrence compared with patients without any IRAE (1-year VTE cumulative incidence: 17.42% [95% CI: 9.5; 24.65] vs. 9.46% [95% CI: 5.18; 13.55], p = 0.04). There was a higher risk of VTE in patients treated with the combination of nivolumab and ipilimumab (adjusted subdistribution hazard ratio [SHR]: 3.71 [95% CI: 1.74; 7.90], p < 0.001) and in patients with IRAE (adjusted SHR: 2.14 [95% CI: 1.22; 3.75], p < 0.01). CONCLUSION: The prevalence of VTE was 14.2% under ICIs. IRAE and combine treatment of nivolumab and ipilimumab were associated with VTE. The pathophysiological mechanisms are multiple and complex with a possible link to aberrant activation of the immune system.

Cobrança pelo uso da água para o saneamento: mecanismos para incentivo a eficiência e atendimento ao uso mínimo / Freshwater use charging for sanitation: mechanisms to encourage efficiency and meet the basic needs

RESUMO A cobrança pelo uso da água como instrumento econômico de gestão deve orientar os usuários quanto ao valor do recurso hídrico e incentivar o combate ao uso perdulário. Metodologias recentes inserem mecanismos relacionados às boas práticas no uso da água, mensurado no saneamento por meio do indicador de perdas percentuais na distribuição. Contudo, desprezam-se as perdas ocorridas nas etapas anteriores, bem como a essencialidade do serviço para a sociedade. Usando variáveis que abarcam todo o sistema de abastecimento desde a captação, este trabalho propôs uma metodologia de cobrança que amplia e penaliza as perdas reais, ao mesmo tempo em que permite descontos decorrentes da retirada para atendimento às necessidades mais fundamentais da população. Revela-se como resultado uma equação simples e transparente, com homogeneidade nas parcelas precificadas, que pode ter a punição e os privilégios ajustados às especificidades da bacia em que seja aplicada.

Abstract Freshwater use charging as an economic instrument must guide users as to the value of water resources and encourage the struggle against wasteful use. Recent methodologies include mechanisms related to good practices in the use of water resources, measured in sanitation sector by the indicator of percentage losses in distribution. However, leakages that occurred in the previous stages are ignored, as well as the essentiality of the service for society. Using variables that cover the entire supply system since withdrawn point, this paper proposes a freshwater charging methodology that conceptually expand and penalizes real losses, while imputing discounts resulting from the water use to supply a minimum volume to meet basic needs of the population. The result is a simple and transparent equation, with homogeneity in the variables charged, which might have the punishment and privileges adjusted to the specificities of the watershed in which it is applied.

A comparative study of endothelial cell markers expressed in chronically inflamed human tissues: MECA-79, Duffy antigen receptor for chemokines, von Willebrand factor, CD31, CD34, CD105 and CD146.

Endothelial cells play a central role in chronic inflammation: for example, they express adhesion molecules and present chemokines leading to enhanced leukocyte recruitment into tissues. Numerous markers of endothelial cells have been reported but there has been a lack of comparative data on their specificity. The present study compared the specificity of seven endothelial cell markers in the rheumatoid synovium and the colon of patients with Crohn's disease. These markers were: the sulphated epitope MECA-79, the Duffy antigen receptor for chemokines (DARC), von Willebrand factor, CD31 (PECAM-1), CD34, CD105 (endoglin) and CD146. MECA-79, DARC and von Willebrand factor showed a specific endothelial cell distribution. MECA-79, which recognizes sulphated ligands for leukocyte adhesion receptor L-selectin (CD62L), was selective for a subset of venules in highly inflamed tissue and was present in rheumatoid but not control osteoarthritic synovia. DARC was also specific for venules but had a more widespread distribution than MECA-79, and was present in rheumatoid and control synovia. The other markers all labelled endothelial cells in venules, arterioles and capillaries. However, they also localized to other cell types. For example, CD34 stained fibroblasts, CD146 was expressed by the pericytes and smooth muscle cells of vessel walls and CD31 and CD105 labelled a broad range of cell types.

Endothelial cell phenotypes in the rheumatoid synovium: activated, angiogenic, apoptotic and leaky.

Endothelial cells are active participants in chronic inflammatory diseases. These cells undergo phenotypic changes that can be characterised as activated, angiogenic, apoptotic and leaky. In the present review, these phenotypes are described in the context of human rheumatoid arthritis as the disease example. Endothelial cells become activated in rheumatoid arthritis pathophysiology, expressing adhesion molecules and presenting chemokines, leading to leukocyte migration from the blood into the tissue. Endothelial cell permeability increases, leading to oedema formation and swelling of the joints. These cells proliferate as part of the angiogenic response and there is also a net increase in the turnover of endothelial cells since the number of apoptotic endothelial cells increases. The endothelium expresses various cytokines, cytokine receptors and proteases that are involved in angiogenesis, proliferation and tissue degradation. Associated with these mechanisms is a change in the spectrum of genes expressed, some of which are relatively endothelial specific and others are widely expressed by other cells in the synovium. Better knowledge of molecular and functional changes occurring in endothelial cells during chronic inflammation may lead to the development of endothelium-targeted therapies for rheumatoid arthritis and other chronic inflammatory diseases.