Assuntos
Anestesia Geral/efeitos adversos , Anestesia Intravenosa/normas , Exposição Ambiental/prevenção & controle , Auditoria Médica/normas , Qualidade da Assistência à Saúde/normas , Anestesia Geral/economia , Anestesia Intravenosa/economia , Anestesia Intravenosa/métodos , Exposição Ambiental/economia , Hospitais de Ensino/economia , Hospitais de Ensino/métodos , Hospitais de Ensino/normas , Humanos , Auditoria Médica/economia , Auditoria Médica/métodos , Qualidade da Assistência à Saúde/economiaAssuntos
COVID-19 , Pandemias , Anestesia por Inalação , Anestesia Intravenosa , Humanos , Oxigênio , SARS-CoV-2RESUMO
We evaluated the outcomes for patients with peripheral T-cell lymphoma (PTCL) undergoing front-line chemotherapy at our institutions between 2002 and 2012. One hundred and fifty-six patients were eligible, comprising PTCL not otherwise specified (NOS) (n = 50, 32.0%), angioimmunoblastic T-cell lymphoma (AITL) (n = 44, 28.2%), anaplastic large-cell lymphoma (ALCL) ALK negative (n = 23, 14.7%), ALCL ALK positive (n = 16, 10.3%), and other (n = 23, 14.7%). Most patients received CHOP (66.0%) and 13.0% received an autologous hematopoietic progenitor cell transplant (HPCT). With a median follow-up of 63.4 months, 5-year overall survival (OS) and progression-free survival (PFS) was 38.8% and 19.8% respectively. Independent risk factors for inferior OS were age >60 years, International Prognostic Index (IPI) ≥ 2 and lack of complete response to induction. When responding patients were compared by receipt of an autologous HPCT versus not, HPCT was associated with improved PFS (p = .001) and OS (p = .046) and remained significant for PFS in multivariate analysis suggesting a possible therapeutic benefit.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Linfoma de Células T Periférico/tratamento farmacológico , Linfoma de Células T Periférico/mortalidade , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Biomarcadores , Terapia Combinada , Quimioterapia de Consolidação , Feminino , Seguimentos , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Transplante de Células-Tronco Hematopoéticas/métodos , Humanos , Quimioterapia de Indução , Linfoma de Células T Periférico/diagnóstico , Masculino , Pessoa de Meia-Idade , Metástase Neoplásica , Estadiamento de Neoplasias , Prognóstico , Recidiva , Análise de Sobrevida , Resultado do Tratamento , Reino Unido , Adulto JovemRESUMO
Glycogen synthase kinase 3 (GSK3), a key regulatory kinase in the wingless-type MMTV integration site family (WNT) pathway, is a therapeutic target of interest in many diseases. Although dual GSK3α/ß inhibitors have entered clinical trials, none has successfully translated to clinical application. Mechanism-based toxicities, driven in part by the inhibition of both GSK3 paralogs and subsequent ß-catenin stabilization, are a concern in the translation of this target class because mutations and overexpression of ß-catenin are associated with many cancers. Knockdown of GSK3α or GSK3ß individually does not increase ß-catenin and offers a conceptual resolution to targeting GSK3: paralog-selective inhibition. However, inadequate chemical tools exist. The design of selective adenosine triphosphate (ATP)-competitive inhibitors poses a drug discovery challenge due to the high homology (95% identity and 100% similarity) in this binding domain. Taking advantage of an Asp133âGlu196 "switch" in their kinase hinge, we present a rational design strategy toward the discovery of paralog-selective GSK3 inhibitors. These GSK3α- and GSK3ß-selective inhibitors provide insights into GSK3 targeting in acute myeloid leukemia (AML), where GSK3α was identified as a therapeutic target using genetic approaches. The GSK3α-selective compound BRD0705 inhibits kinase function and does not stabilize ß-catenin, mitigating potential neoplastic concerns. BRD0705 induces myeloid differentiation and impairs colony formation in AML cells, with no apparent effect on normal hematopoietic cells. Moreover, BRD0705 impairs leukemia initiation and prolongs survival in AML mouse models. These studies demonstrate feasibility of paralog-selective GSK3α inhibition, offering a promising therapeutic approach in AML.
Assuntos
Inibidores Enzimáticos/uso terapêutico , Quinase 3 da Glicogênio Sintase/antagonistas & inibidores , Leucemia Mieloide Aguda/tratamento farmacológico , Dipeptídeos/química , Dipeptídeos/metabolismo , Quinase 3 da Glicogênio Sintase/química , Quinase 3 da Glicogênio Sintase/metabolismo , Humanos , Mutagênese Sítio-Dirigida , Isoformas de Proteínas/antagonistas & inibidores , Isoformas de Proteínas/química , Isoformas de Proteínas/metabolismo , Células U937 , beta Catenina/genética , beta Catenina/metabolismoRESUMO
Recent discoveries have led to the testing of novel targeted therapies for the treatment of acute myeloid leukemia (AML). To better inform the results of clinical trials, there is a need to identify and systematically assess biomarkers of response and pharmacodynamic markers of successful target engagement. Spleen tyrosine kinase (SYK) is a candidate therapeutic target in AML. Small-molecule inhibitors of SYK induce AML differentiation and impair leukemia progression in preclinical studies. However, tools to predict response to SYK inhibition and to routinely evaluate SYK activation in primary patient samples have been lacking. In this study we quantified phosphorylated SYK (P-SYK) in AML cell lines and establish that increasing levels of baseline P-SYK are correlated with an increasing sensitivity to small-molecule inhibitors targeting SYK. In addition, we found that pharmacological inhibition of SYK activity extinguishes P-SYK expression as detected by an immunohistochemical (IHC) test. Quantitative analysis of P-SYK expression by the IHC test in a series of 70 primary bone marrow biopsy specimens revealed a spectrum of P-SYK expression across AML cases and that high P-SYK expression is associated with unfavourable outcome independent of age, cytogenetics, and white blood cell count. This study thus establishes P-SYK as a critical biomarker in AML that identifies tumors sensitive to SYK inhibition, identifies an at-risk patient population, and allows for the monitoring of target inhibition during treatment.