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1.
J Trauma Acute Care Surg ; 90(3): 557-564, 2021 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-33507026

RESUMO

BACKGROUND: The Emergency Surgery Score (ESS) was recently validated as an accurate mortality risk calculator for emergency general surgery. We sought to prospectively evaluate whether ESS can predict the need for respiratory and/or renal support (RRS) at discharge after emergent laparotomies (EL). METHODS: This is a post hoc analysis of a 19-center prospective observational study. Between April 2018 and June 2019, all adult patients undergoing EL were enrolled. Preoperative, intraoperative, and postoperative variables were systematically collected. In this analysis, patients were excluded if they died during the index hospitalization, were discharged to hospice, or transferred to other hospitals. A composite variable, the need for RRS, was defined as the need for one or more of the following at hospital discharge: tracheostomy, ventilator dependence, or dialysis. Emergency Surgery Score was calculated for all patients, and the correlation between ESS and RRS was examined using the c-statistics method. RESULTS: From a total of 1,649 patients, 1,347 were included. Median age was 60 years, 49.4% were men, and 70.9% were White. The most common diagnoses were hollow viscus organ perforation (28.1%) and small bowel obstruction (24.5%); 87 patients (6.5%) had a need for RRS (4.7% tracheostomy, 2.7% dialysis, and 1.3% ventilator dependence). Emergency Surgery Score predicted the need for RRS in a stepwise fashion; for example, 0.7%, 26.2%, and 85.7% of patients required RRS at an ESS of 2, 12, and 16, respectively. The c-statistics for the need for RRS, the need for tracheostomy, ventilator dependence, or dialysis at discharge were 0.84, 0.82, 0.79, and 0.88, respectively. CONCLUSION: Emergency Surgery Score accurately predicts the need for RRS at discharge in EL patients and could be used for preoperative patient counseling and for quality of care benchmarking. LEVEL OF EVIDENCE: Prognostic and epidemiological, level III.


Assuntos
Serviço Hospitalar de Emergência , Hospitalização , Laparotomia/efeitos adversos , Complicações Pós-Operatórias/epidemiologia , Diálise Renal , Respiração Artificial , Idoso , Estudos de Coortes , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Determinação de Necessidades de Cuidados de Saúde , Complicações Pós-Operatórias/terapia , Valor Preditivo dos Testes , Medição de Risco
2.
Am J Surg ; 221(5): 1069-1075, 2021 05.
Artigo em Inglês | MEDLINE | ID: mdl-32917366

RESUMO

INTRODUCTION: We sought to evaluate whether the Emergency Surgery Score (ESS) can accurately predict outcomes in elderly patients undergoing emergent laparotomy (EL). METHODS: This is a post-hoc analysis of an EAST multicenter study. Between April 2018 and June 2019, all adult patients undergoing EL in 19 participating hospitals were prospectively enrolled, and ESS was calculated for each patient. Using the c-statistic, the correlation between ESS and mortality, morbidity, and need for ICU admission was assessed in three patient age cohorts (65-74, 75-84, ≥85 years old). RESULTS: 715 patients were included, of which 52% were 65-74, 34% were 75-84, and 14% were ≥85 years old; 51% were female, and 77% were white. ESS strongly correlated with postoperative mortality (c-statistic:0.81). Mortality gradually increased from 0% to 20%-60% at ESS of 2, 10 and 16 points, respectively. ESS predicted mortality, morbidity, and need for ICU best in patients 65-74 years old (c-statistic:0.81, 0.75, 0.83 respectively), but its performance significantly decreased in patients ≥85 years (c-statistic:0.72, 0.64, 0.67 respectively). CONCLUSION: ESS is an accurate predictor of outcome in the elderly EL patient 65-85 years old, but its performance decreases for patients ≥85. Consideration should be given to modify ESS to better predict outcomes in the very elderly patient population.


Assuntos
Tratamento de Emergência/estatística & dados numéricos , Laparotomia/estatística & dados numéricos , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Tratamento de Emergência/efeitos adversos , Tratamento de Emergência/mortalidade , Feminino , Humanos , Laparotomia/efeitos adversos , Laparotomia/mortalidade , Masculino , Medição de Risco , Índice de Gravidade de Doença , Resultado do Tratamento , Estados Unidos
3.
Am Surg ; 86(4): 369-376, 2020 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-32391762

RESUMO

This study evaluated the safety of early anti-factor Xa assay-guided enoxaparin dosing for chemoprophylaxis in patients with TBI. We hypothesized that assay-guided chemoprophylaxis would be comparable in the risk of intracranial hemorrhage (ICH) progression to fixed dosing. An observational analysis of adult patients with blunt traumatic brain injury (TBI) was performed at a Level I trauma center from August 2016 to September 2017. Patients in the assay-guided group were treated with an initial enoxaparin dose of 0.5 mg/kg, with peak anti-factor Xa activity measured four hours after the third dose. Prophylactic range was defined as 0.2 to 0.5 IU/mL with a dose adjustment of ± 10 mg based on the assay result. The assay-guided group was compared with historical fixed-dose controls and to a TBI cohort from the most recent Trauma Quality Improvement Project dataset. Of 179 patients included in the study, 85 were in the assay-guided group and 94 were in the fixed-dose group. Compared with the fixed-dose group, the assay-guided group had a lower Glasgow Coma Score and higher Injury Severity Score. The proportion of severe (Abbreviated Injury Score, head ≥3) TBI, ICH progression, and venous thromboembolism rates were similar between all groups. The assay-guided and fixed-dose groups had chemoprophylaxis initiated earlier than the Trauma Quality Improvement Project group. The assay-guided group had the highest percentage of low molecular weight heparin use. Early initiation of enoxaparin anti-factor Xa assay-guided venous thromboembolism chemoprophylaxis has a comparable risk of ICH progression to fixed dosing in patients with TBI. These findings should be validated prospectively in a multicenter study.


Assuntos
Anticoagulantes/administração & dosagem , Lesões Encefálicas Traumáticas/complicações , Enoxaparina/administração & dosagem , Tromboembolia Venosa/prevenção & controle , Doença Aguda , Adulto , Idoso , Anticoagulantes/efeitos adversos , Quimioprevenção , Enoxaparina/efeitos adversos , Inibidores do Fator Xa/sangue , Feminino , Humanos , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Tempo para o Tratamento , Índices de Gravidade do Trauma
4.
J Trauma Acute Care Surg ; 89(1): 118-124, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32176177

RESUMO

BACKGROUND: The Emergency Surgery Score (ESS) was recently developed and retrospectively validated as an accurate mortality risk calculator for emergency general surgery. We sought to prospectively validate ESS, specifically in the high-risk nontrauma emergency laparotomy (EL) patient. METHODS: This is an Eastern Association for the Surgery of Trauma multicenter prospective observational study. Between April 2018 and June 2019, 19 centers enrolled all adults (aged >18 years) undergoing EL. Preoperative, intraoperative, and postoperative variables were prospectively and systematically collected. Emergency Surgery Score was calculated for each patient and validated using c-statistic methodology by correlating it with three postoperative outcomes: (1) 30-day mortality, (2) 30-day complications (e.g., respiratory/renal failure, infection), and (3) postoperative intensive care unit (ICU) admission. RESULTS: A total of 1,649 patients were included. The mean age was 60.5 years, 50.3% were female, and 71.4% were white. The mean ESS was 6, and the most common indication for EL was hollow viscus perforation. The 30-day mortality and complication rates were 14.8% and 53.3%; 57.0% of patients required ICU admission. Emergency Surgery Score gradually and accurately predicted 30-day mortality; 3.5%, 50.0%, and 85.7% of patients with ESS of 3, 12, and 17 died after surgery, respectively, with a c-statistic of 0.84. Similarly, ESS gradually and accurately predicted complications; 21.0%, 57.1%, and 88.9% of patients with ESS of 1, 6, and 13 developed postoperative complications, with a c-statistic of 0.74. Emergency Surgery Score also accurately predicted which patients required intensive care unit admission (c-statistic, 0.80). CONCLUSION: This is the first prospective multicenter study to validate ESS as an accurate predictor of outcome in the EL patient. Emergency Surgery Score can prove useful for (1) perioperative patient and family counseling, (2) triaging patients to the intensive care unit, and (3) benchmarking the quality of emergency general surgery care. LEVEL OF EVIDENCE: Prognostic study, level III.


Assuntos
Emergências , Cirurgia Geral , Medição de Risco/métodos , Ferimentos e Lesões/cirurgia , Adulto , Idoso , Feminino , Mortalidade Hospitalar , Humanos , Unidades de Terapia Intensiva/estatística & dados numéricos , Masculino , Pessoa de Meia-Idade , Complicações Pós-Operatórias/mortalidade , Pontuação de Propensão , Estudos Prospectivos , Ferimentos e Lesões/mortalidade
5.
Nat Immunol ; 21(4): 442-454, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32152508

RESUMO

Programmed cell death protein 1 (PD-1) ligation delimits immunogenic responses in T cells. However, the consequences of programmed cell death 1 ligand 1 (PD-L1) ligation in T cells are uncertain. We found that T cell expression of PD-L1 in cancer was regulated by tumor antigen and sterile inflammatory cues. PD-L1+ T cells exerted tumor-promoting tolerance via three distinct mechanisms: (1) binding of PD-L1 induced STAT3-dependent 'back-signaling' in CD4+ T cells, which prevented activation, reduced TH1-polarization and directed TH17-differentiation. PD-L1 signaling also induced an anergic T-bet-IFN-γ- phenotype in CD8+ T cells and was equally suppressive compared to PD-1 signaling; (2) PD-L1+ T cells restrained effector T cells via the canonical PD-L1-PD-1 axis and were sufficient to accelerate tumorigenesis, even in the absence of endogenous PD-L1; (3) PD-L1+ T cells engaged PD-1+ macrophages, inducing an alternative M2-like program, which had crippling effects on adaptive antitumor immunity. Collectively, we demonstrate that PD-L1+ T cells have diverse tolerogenic effects on tumor immunity.


Assuntos
Antígeno B7-H1/imunologia , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD8-Positivos/imunologia , Tolerância Imunológica/imunologia , Macrófagos/imunologia , Tolerância a Antígenos Próprios/imunologia , Animais , Diferenciação Celular/imunologia , Linhagem Celular Tumoral , Feminino , Humanos , Interferon gama/imunologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Receptor de Morte Celular Programada 1/imunologia , Transdução de Sinais/imunologia , Microambiente Tumoral/imunologia
6.
Cancer Cell ; 36(5): 528-544.e10, 2019 11 11.
Artigo em Inglês | MEDLINE | ID: mdl-31631026

RESUMO

H3K27M mutations resulting in epigenetic dysfunction are frequently observed in diffuse intrinsic pontine glioma (DIPGs), an incurable pediatric cancer. We conduct a CRISPR screen revealing that knockout of KDM1A encoding lysine-specific demethylase 1 (LSD1) sensitizes DIPG cells to histone deacetylase (HDAC) inhibitors. Consistently, Corin, a bifunctional inhibitor of HDACs and LSD1, potently inhibits DIPG growth in vitro and in xenografts. Mechanistically, Corin increases H3K27me3 levels suppressed by H3K27M histones, and simultaneously increases HDAC-targeted H3K27ac and LSD1-targeted H3K4me1 at differentiation-associated genes. Corin treatment induces cell death, cell-cycle arrest, and a cellular differentiation phenotype and drives transcriptional changes correlating with increased survival time in DIPG patients. These data suggest a strategy for treating DIPG by simultaneously inhibiting LSD1 and HDACs.


Assuntos
Antineoplásicos/farmacologia , Neoplasias do Tronco Encefálico/tratamento farmacológico , Glioma/tratamento farmacológico , Inibidores de Histona Desacetilases/farmacologia , Histona Desmetilases/antagonistas & inibidores , Animais , Antineoplásicos/uso terapêutico , Neoplasias do Tronco Encefálico/genética , Neoplasias do Tronco Encefálico/mortalidade , Neoplasias do Tronco Encefálico/patologia , Diferenciação Celular/efeitos dos fármacos , Diferenciação Celular/genética , Linhagem Celular Tumoral , Cromatina/metabolismo , Metilação de DNA/efeitos dos fármacos , Metilação de DNA/genética , Epigênese Genética/efeitos dos fármacos , Feminino , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Técnicas de Silenciamento de Genes , Glioma/genética , Glioma/mortalidade , Glioma/patologia , Código das Histonas/efeitos dos fármacos , Inibidores de Histona Desacetilases/uso terapêutico , Histona Desacetilases/metabolismo , Histona Desmetilases/genética , Histona Desmetilases/metabolismo , Histonas/metabolismo , Humanos , Camundongos , Mutação , Ponte/patologia , RNA-Seq , Ensaios Antitumorais Modelo de Xenoenxerto
7.
Cancer Discov ; 9(9): 1288-1305, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31266770

RESUMO

Unconventional T-lymphocyte populations are emerging as important regulators of tumor immunity. Despite this, the role of TCRαß+CD4-CD8-NK1.1- innate αß T cells (iαßT) in pancreatic ductal adenocarcinoma (PDA) has not been explored. We found that iαßTs represent ∼10% of T lymphocytes infiltrating PDA in mice and humans. Intratumoral iαßTs express a distinct T-cell receptor repertoire and profoundly immunogenic phenotype compared with their peripheral counterparts and conventional lymphocytes. iαßTs comprised ∼75% of the total intratumoral IL17+ cells. Moreover, iαßT-cell adoptive transfer is protective in both murine models of PDA and human organotypic systems. We show that iαßT cells induce a CCR5-dependent immunogenic macrophage reprogramming, thereby enabling marked CD4+ and CD8+ T-cell expansion/activation and tumor protection. Collectively, iαßTs govern fundamental intratumoral cross-talk between innate and adaptive immune populations and are attractive therapeutic targets. SIGNIFICANCE: We found that iαßTs are a profoundly activated T-cell subset in PDA that slow tumor growth in murine and human models of disease. iαßTs induce a CCR5-dependent immunogenic tumor-associated macrophage program, T-cell activation and expansion, and should be considered as novel targets for immunotherapy.See related commentary by Banerjee et al., p. 1164.This article is highlighted in the In This Issue feature, p. 1143.


Assuntos
Carcinoma Ductal Pancreático/imunologia , Macrófagos/imunologia , Neoplasias Pancreáticas/imunologia , Receptores de Antígenos de Linfócitos T alfa-beta/metabolismo , Linfócitos T/imunologia , Animais , Carcinoma Ductal Pancreático/terapia , Linhagem Celular Tumoral , Feminino , Humanos , Imunidade Inata , Imunoterapia Adotiva , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Transplante de Neoplasias , Neoplasias Pancreáticas/terapia , Linfócitos T/transplante , Microambiente Tumoral
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