RESUMO
Loss-of-function mutations in KMT2D are a striking feature of germinal center (GC) lymphomas, resulting in decreased histone 3 lysine 4 (H3K4) methylation and altered gene expression. We hypothesized that inhibition of the KDM5 family, which demethylates H3K4me3/me2, would reestablish H3K4 methylation and restore the expression of genes repressed on loss of KMT2D. KDM5 inhibition increased H3K4me3 levels and caused an antiproliferative response in vitro, which was markedly greater in both endogenous and gene-edited KMT2D mutant diffuse large B-cell lymphoma cell lines, whereas tumor growth was inhibited in KMT2D mutant xenografts in vivo. KDM5 inhibition reactivated both KMT2D-dependent and -independent genes, resulting in diminished B-cell signaling and altered expression of B-cell lymphoma 2 (BCL2) family members, including BCL2 itself. KDM5 inhibition may offer an effective therapeutic strategy for ameliorating KMT2D loss-of-function mutations in GC lymphomas.
Assuntos
Proteínas de Ligação a DNA/metabolismo , Inibidores Enzimáticos/farmacologia , Mutação com Perda de Função , Linfoma Difuso de Grandes Células B/tratamento farmacológico , Proteínas de Neoplasias/metabolismo , Proteína 2 de Ligação ao Retinoblastoma/antagonistas & inibidores , Animais , Linhagem Celular Tumoral , Proteínas de Ligação a DNA/genética , Humanos , Linfoma Difuso de Grandes Células B/enzimologia , Linfoma Difuso de Grandes Células B/genética , Camundongos , Proteínas de Neoplasias/genética , Proteína 2 de Ligação ao Retinoblastoma/genética , Proteína 2 de Ligação ao Retinoblastoma/metabolismo , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
BACKGROUND: Virtual patient simulations are interactive, computer-based cases. We designed scenarios based on the McGill Simulation Complexity Score (MSCS), a previously described objective complexity score. We aimed to establish validity of the MSCS and introduce a novel learning tool in trauma education at our institution. METHODS: After design of an easy and difficult patient scenario, we randomized medical students and residents to each perform 1 of the 2 scenarios. We conducted a 2-way analysis of variance of training level (medical student, resident) and scenario complexity (easy, difficult) to assess their effects on virtual time, the number of steps taken in the scenario, beneficial and harmful actions, and the ratio of beneficial over harmful actions. RESULTS: Virtual patient scenarios were successfully designed using the MSCS. Twenty-four medical students and 12 residents participated in the easy scenario (MSCS = 3), and 27 medical students and 12 residents did the difficult scenario (MSCS = 18). Though beneficial actions were similar between students and residents, sudents performed more harmful actions, particularly when the scenario was difficult. One virtual patient died in the easy scenario and 3 died in the difficult one (all medical students). Performance varied with level of complexity and there was significant interaction between level of training and number of steps, as well as with number of harmful actions. Decreasing performance with increasing level of complexity, as defined by the MSCS, suggests this score can accurately quantify difficulty. CONCLUSION: We established validity of the MSCS and showed its successful application on virtual patient scenario design.
Assuntos
Internato e Residência , Estudantes de Medicina , Humanos , Competência Clínica , Simulação por Computador , Aprendizagem , Simulação de PacienteRESUMO
BACKGROUND: In medical education, simulation can be defined as an activity in which an individual demonstrates skills, procedures and critical thinking using interactive mannequins in a setting closely resembling the clinical environment. To our knowledge, the complexity of trauma simulations has not previously been assessed. We aimed to develop an objective trauma simulation complexity score and assess its interrater reliability. METHODS: The McGill Simulation Complexity Score (MSCS) was designed to address the need for objective evaluation of the complexity of trauma scenarios. Components of the score reflected the Advanced Trauma Life Support approach to trauma. The score was developed to take into account the severity of trauma injuries and the complexity of their management. We assessed interrater reliability at 5 high-fidelity simulation events. Interrater reliability was calculated using the Pearson correlation coefficient (PCC) and the intraclass correlation coefficient (ICC). RESULTS: The MSCS has 5 categories: airway, breathing, circulation, disability, and extremities or exposure. The scale has 5 levels for each category, from 0 to 4; level increases with complexity, with 0 corresponding to normal or absent. Cases designed to lead to cardiac arrest, regardless of whether or not the trainee has the ability to resuscitate the simulated patient and regardless of the level of each category, are automatically assigned the maximum score. Between 3 and 9 raters used the MSCS to grade the level of complexity of 26 scenarios at the 5 events. The mean MSCS was 10.2 (range 3.0-20.0). Mean PCC and ICC values were both above 0.7 and therefore statistically significant. CONCLUSION: The MSCS for trauma is an innovative scoring system with high interrater reliability.
Assuntos
Educação Médica , Internato e Residência , Humanos , Reprodutibilidade dos TestesRESUMO
BACKGROUND: Nutritional assessment can be challenging in patients with traumatic brain injury (TBI), and indirect calorimetry may be a more suitable method than predictive equations. We compared the Penn State equation versus the gold standard of indirect calorimetry for the nutritional assessment of patients with TBI, and quantified the difference between nutritional requirements and actual patient intake. METHODS: This single-centre, prospective cohort study included patients with moderate (Glasgow Coma Scale score 9-12) and severe (Glasgow Coma Scale score 3-8) TBI admitted to the Montreal General Hospital intensive care unit (ICU) between June 2018 and March 2019. Penn State equation estimates and indirect calorimetry measurements were collected, and actual intake was drawn from medical records. We compared the 2 assessment methods using a Spearman correlation coefficient. RESULTS: Twenty-three patients with TBI (moderate in 7 and severe in 16) were included in the study. Overall, there was a moderate positive correlation between the Penn State equation estimate and indirect calorimetry readings (correlation coefficient 0.457, p = 0.03); however, the correlation was weaker in severe TBI (correlation coefficient 0.174, p = 0.5) than in moderate TBI (correlation coefficient 0.929, p = 0.003). When compared to indirect calorimetry assessment, patients received 5.4% (p = 0.5) of required intake on the first day and 43.9% (p = 0.8) of required daily intake throughout their ICU stay. CONCLUSION: Patients with moderate or severe TBI in the ICU received less than 50% of their nutritional requirements. The difference between the Penn State equation and indirect calorimetry assessments was most noticeable for patients with severe TBI, which indicates that indirect calorimetry may be a more suitable tool for assessment of nutritional needs in this population.
Assuntos
Lesões Encefálicas Traumáticas , Avaliação Nutricional , Lesões Encefálicas Traumáticas/complicações , Lesões Encefálicas Traumáticas/diagnóstico , Calorimetria Indireta/métodos , Humanos , Necessidades Nutricionais , Estudos ProspectivosRESUMO
Donor T-cell immune responses can eradicate lymphomas after allogeneic hematopoietic stem cell transplantation (AHSCT), but can also damage healthy tissues resulting in harmful graft-versus-host disease (GVHD). Next-generation sequencing has recently identified many new genetic lesions in follicular lymphoma (FL). One such gene, tumor necrosis factor receptor superfamily 14 (TNFRSF14), abnormal in 40% of FL patients, encodes the herpes virus entry mediator (HVEM) which limits T-cell activation via ligation of the B- and T-lymphocyte attenuator. As lymphoma B cells can act as antigen-presenting cells, we hypothesized that TNFRSF14 aberrations that reduce HVEM expression could alter the capacity of FL B cells to stimulate allogeneic T-cell responses and impact the outcome of AHSCT. In an in vitro model of alloreactivity, human lymphoma B cells with TNFRSF14 aberrations had reduced HVEM expression and greater alloantigen-presenting capacity than wild-type lymphoma B cells. The increased immune-stimulatory capacity of lymphoma B cells with TNFRSF14 aberrations had clinical relevance, associating with higher incidence of acute GVHD in patients undergoing AHSCT. FL patients with TNFRSF14 aberrations may benefit from more aggressive immunosuppression to reduce harmful GVHD after transplantation. Importantly, this study is the first to demonstrate the impact of an acquired genetic lesion on the capacity of tumor cells to stimulate allogeneic T-cell immune responses which may have wider consequences for adoptive immunotherapy strategies.
Assuntos
Doença Enxerto-Hospedeiro/genética , Transplante de Células-Tronco Hematopoéticas , Ativação Linfocitária/genética , Linfoma Folicular/genética , Linfoma Folicular/terapia , Membro 14 de Receptores do Fator de Necrose Tumoral/genética , Adulto , Idoso , Aloenxertos , Células Apresentadoras de Antígenos/metabolismo , Células Apresentadoras de Antígenos/patologia , Linfócitos B/metabolismo , Linfócitos B/patologia , Feminino , Doença Enxerto-Hospedeiro/metabolismo , Doença Enxerto-Hospedeiro/patologia , Humanos , Linfoma Folicular/patologia , Masculino , Pessoa de Meia-Idade , Membro 14 de Receptores do Fator de Necrose Tumoral/metabolismo , Linfócitos T/metabolismo , Linfócitos T/patologiaRESUMO
In-depth molecular investigation of familial leukemia has been limited by the rarity of recognized cases. This study examines the genetic events initiating leukemia and details the clinical progression of disease across multiple families harboring germ-line CEBPA mutations. Clinical data were collected from 10 CEBPA-mutated families, representing 24 members with acute myeloid leukemia (AML). Whole-exome (WES) and deep sequencing were performed to genetically profile tumors and define patterns of clonal evolution. Germline CEBPA mutations clustered within the N-terminal and were highly penetrant, with AML presenting at a median age of 24.5 years (range, 1.75-46 years). In all diagnostic tumors tested (n = 18), double CEBPA mutations (CEBPAdm) were detected, with acquired (somatic) mutations preferentially targeting the C-terminal. Somatic CEBPA mutations were unstable throughout the disease course, with different mutations identified at recurrence. Deep sequencing of diagnostic and relapse paired samples confirmed that relapse-associated CEBPA mutations were absent at diagnosis, suggesting recurrence was triggered by novel, independent clones. Integrated WES and deep sequencing subsequently revealed an entirely new complement of mutations at relapse, verifying the presentation of a de novo leukemic episode. The cumulative incidence of relapse in familial AML was 56% at 10 years (n = 11), and 3 patients experienced ≥3 disease episodes over a period of 17 to 20 years. Durable responses to secondary therapies were observed, with prolonged median survival after relapse (8 years) and long-term overall survival (10-year overall survival, 67%). Our data reveal that familial CEBPA-mutated AML exhibits a unique model of disease progression, associated with favorable long-term outcomes.
Assuntos
Proteínas Estimuladoras de Ligação a CCAAT/genética , Mutação em Linhagem Germinativa , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/patologia , Recidiva Local de Neoplasia/genética , Recidiva Local de Neoplasia/patologia , Adolescente , Adulto , Criança , Pré-Escolar , Progressão da Doença , Feminino , Predisposição Genética para Doença , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Lactente , Leucemia Mieloide Aguda/mortalidade , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/mortalidade , Linhagem , Adulto JovemRESUMO
Chronic lymphocytic leukemia (CLL) is a disease of an accumulation of mature B cells that are highly dependent on the microenvironment for maintenance and expansion. However, little is known regarding the mechanisms whereby CLL cells create their favorable microenvironment for survival. High-mobility group protein B-1 (HMGB1) is a highly conserved nuclear protein that can be actively secreted by innate immune cells and passively released by injured or dying cells. We found significantly increased HMGB1 levels in the plasma of CLL patients compared with healthy controls, and HMGB1 concentration is associated with absolute lymphocyte count. We therefore sought to determine potential roles of HMGB1 in modulating the CLL microenvironment. CLL cells passively released HMGB1, and the timing and concentrations of HMGB1 in the medium were associated with differentiation of nurse-like cells (NLCs). Higher CD68 expression in CLL lymph nodes, one of the markers for NLCs, was associated with shorter overall survival of CLL patients. HMGB1-mediated NLC differentiation involved internalization of both receptor for advanced glycation end products (RAGE) and Toll-like receptor-9 (TLR9). Differentiation of NLCs can be prevented by blocking the HMGB1-RAGE-TLR9 pathway. In conclusion, this study demonstrates for the first time that CLL cells might modulate their microenvironment by releasing HMGB1.
Assuntos
Proteína HMGB1/metabolismo , Leucemia Linfocítica Crônica de Células B/patologia , Linfonodos/patologia , Recidiva Local de Neoplasia/patologia , Receptor para Produtos Finais de Glicação Avançada/metabolismo , Microambiente Tumoral , Western Blotting , Estudos de Casos e Controles , Diferenciação Celular , Proliferação de Células , Técnicas de Cocultura , Meios de Cultivo Condicionados , Ensaio de Imunoadsorção Enzimática , Citometria de Fluxo , Imunofluorescência , Seguimentos , Humanos , Imunoprecipitação , Leucemia Linfocítica Crônica de Células B/metabolismo , Leucemia Linfocítica Crônica de Células B/mortalidade , Linfonodos/metabolismo , Recidiva Local de Neoplasia/metabolismo , Recidiva Local de Neoplasia/mortalidade , Plasmócitos/metabolismo , Plasmócitos/patologia , Prognóstico , Transdução de Sinais , Taxa de Sobrevida , Análise Serial de Tecidos , Receptor Toll-Like 9/metabolismo , Células Tumorais CultivadasRESUMO
Distinct patterns of DNA methylation characterize the epigenetic landscape of promyelocytic leukemia/retinoic acid receptor-α (PML-RARα)-associated acute promyelocytic leukemia (APL). We previously reported that the microRNAs (miRNAs) clustered on chromosome 14q32 are overexpressed only in APL. Here, using high-throughput bisulfite sequencing, we identified an APL-associated hypermethylation at the upstream differentially methylated region (DMR), which also included the site motifs for the enhancer blocking protein CCCTC-binding factor (CTCF). Comparing the profiles of diagnostic/remission paired patient samples, we show that hypermethylation was acquired in APL in a monoallelic manner. The cytosine guanine dinucleotide status of the DMR correlated with expression of the miRNAs following a characteristic position-dependent pattern. Moreover, a signature of hypermethylation was also detected in leukemic cells from an established transgenic PML-RARA APL mouse model at the orthologous region on chromosome 12, including the CTCF binding site located upstream from the mouse miRNA cluster. These results, together with the demonstration that the region does not show DNA methylation changes during myeloid differentiation, provide evidence that 14q32 hypermethylation is implicated in the pathogenesis of APL. We propose a model in which loss of imprinting at the 14q32 domain leads to overexpression of the miRNAs in APL.
Assuntos
Cromossomos Humanos Par 14/genética , Impressão Genômica , Leucemia Promielocítica Aguda/genética , MicroRNAs/genética , Animais , Células Cultivadas , Metilação de DNA , Regulação Leucêmica da Expressão Gênica , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Camundongos , Análise em Microsséries , TranscriptomaRESUMO
CD4(+) T-helper cells (THs) dominate the classical Hodgkin lymphoma (CHL) microenvironment, but their role is poorly understood. Advances in flow cytometry and immunohistochemistry permit more detailed investigation of this aspect of CHL pathophysiology. To address the hypothesis that the TH-infiltrate, rather than being TH2-enriched, senescent and hypofunctional, is TH1 and activation marker-rich, cytokine-secretory and proliferative, we applied comprehensive flow cytometric immunophenotyping and functional assays of cytokine secretion/proliferation to TH cells from 18 CHL-derived single-cell suspensions (SCSs) compared to reactive lymph nodes (RLNs). CHL-derived TH cells express TH1-associated CXCR3/CCR5 and TNFα/IFNγ/interleukin-2 (IL-2) and less TH2-associated CCR3/CCR4, with no IL-4/IL-13. They lack exhaustion-/suppression-associated PD1, CD57 and terminally differentiated effector memory cells, with more central memory cells, activation-associated partners of Hodgkin Reed Sternberg (HRS) cell-expressed CD30/OX40-L/ICOS-L, and other activation markers. TH cell lines established from CHL and RLN-derived SCSs remain cytokine-secretory. We confirmed and extended these studies using tissue microarray immunohistochemistry (TMA-IHC) from a large CHL tissue bank (n = 122) and demonstrate TH1-associated TBET is abundant in CHL, and TH2-associated CMAF/GATA3 and exhaustion-associated PD1 expressed at significantly lower levels. These molecular insights into the CHL-associated TH offer potential diagnostic, prognostic and pharmacologically modifiable therapeutic targets and do not support the established view of a TH2-enriched, senescent/exhausted, hypofunctional, hypoproliferative infiltrate.
Assuntos
Doença de Hodgkin/sangue , Linfócitos T Auxiliares-Indutores/citologia , Linfócitos T Auxiliares-Indutores/metabolismo , Microambiente Tumoral , Adolescente , Adulto , Idoso , Proliferação de Células , Senescência Celular , Citocinas/metabolismo , Feminino , Citometria de Fluxo , Humanos , Imuno-Histoquímica , Imunofenotipagem , Imunossupressores/uso terapêutico , Masculino , Pessoa de Meia-Idade , Resultado do Tratamento , Adulto JovemRESUMO
Phosphoinositide-3 kinase (PI3K) pathway activation contributes to mantle cell lymphoma (MCL) pathogenesis, but early-phase studies of the PI3K p110δ inhibitor GS-1101 have reported inferior responses in MCL compared with other non-Hodgkin lymphomas. Because the relative importance of the class IA PI3K isoforms p110α, p110ß, and p110δ in MCL is not clear, we studied expression of these isoforms and assessed their contribution to PI3K signaling in this disease. We found that although p110δ was highly expressed in MCL, p110α showed wide variation and expression increased significantly with relapse. Loss of phosphatase and tensin homolog expression was found in 16% (22/138) of cases, whereas PIK3CA and PIK3R1 mutations were absent. Although p110δ inhibition was sufficient to block B-cell receptor-mediated PI3K activation, combined p110α and p110δ inhibition was necessary to abolish constitutive PI3K activation. In addition, GDC-0941, a predominantly p110α/δ inhibitor, was significantly more active compared with GS-1101 against MCL cell lines and primary samples. We found that a high PIK3CA/PIK3CD ratio identified a subset of primary MCLs resistant to GS-1101 and this ratio increased significantly with relapse. These findings support the use of dual p110α/p110δ inhibitors in MCL and suggest a role for p110α in disease progression.
Assuntos
Linfoma de Célula do Manto/tratamento farmacológico , Fosfatidilinositol 3-Quinases/metabolismo , Inibidores de Fosfoinositídeo-3 Quinase , Inibidores de Proteínas Quinases/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Linhagem Celular Tumoral , Classe I de Fosfatidilinositol 3-Quinases , Análise Mutacional de DNA , Resistencia a Medicamentos Antineoplásicos/genética , Regulação Enzimológica da Expressão Gênica/fisiologia , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica/genética , Regulação Neoplásica da Expressão Gênica/fisiologia , Humanos , Linfoma de Célula do Manto/genética , Linfoma de Célula do Manto/metabolismo , Linfoma de Célula do Manto/patologia , Fosfatidilinositol 3-Quinases/genética , Fosfatidilinositol 3-Quinases/fisiologia , Inibidores de Proteínas Quinases/administração & dosagem , Inibidores de Proteínas Quinases/farmacologia , Purinas/administração & dosagem , Purinas/farmacologia , Purinas/uso terapêutico , Quinazolinonas/administração & dosagem , Quinazolinonas/farmacologia , Quinazolinonas/uso terapêutico , Recidiva , Transdução de Sinais/fisiologia , Especificidade por Substrato , Resultado do TratamentoRESUMO
T-cell exhaustion, originally described in chronic viral infections, was recently reported in solid and hematologic cancers. It is not defined whether exhaustion contributes to T-cell dysfunction observed in chronic lymphocytic leukemia (CLL). We investigated the phenotype and function of T cells from CLL patients and age-matched controls. CD8+ and CD4+ T cells from CLL patients had increased expression of exhaustion markers CD244, CD160, and PD1, with expansion of a PD1+BLIMP1HI subset. These molecules were most highly expressed in the expanded population of effector T cells in CLL. CLL CD8+ T cells showed functional defects in proliferation and cytotoxicity, with the cytolytic defect caused by impaired granzyme packaging into vesicles and nonpolarized degranulation. In contrast to virally induced exhaustion, CLL T cells showed increased production of interferon-γ and TNFα and increased expression of TBET, and normal IL2 production. These defects were not restricted to expanded populations of cytomegalovirus (CMV)specific cells, although CMV seropositivity modulated the distribution of lymphocyte subsets, the functional defects were present irrespective of CMV serostatus. Therefore, although CLL CD8+ T cells exhibit features of T-cell exhaustion, they retain the ability to produce cytokines. These findings also exclude CMV as the sole cause of T-cell defects in CLL.
Assuntos
Citocinas/metabolismo , Leucemia Linfocítica Crônica de Células B/imunologia , Linfócitos T/metabolismo , Linfócitos T/fisiologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Antígenos CD/metabolismo , Complexo CD3/metabolismo , Linfócitos T CD8-Positivos/metabolismo , Linfócitos T CD8-Positivos/patologia , Estudos de Casos e Controles , Células Cultivadas , Proteínas Ligadas por GPI/metabolismo , Humanos , Leucemia Linfocítica Crônica de Células B/metabolismo , Leucemia Linfocítica Crônica de Células B/patologia , Pessoa de Meia-Idade , Receptor de Morte Celular Programada 1/metabolismo , Receptores Imunológicos/metabolismo , Família de Moléculas de Sinalização da Ativação Linfocitária , Linfócitos T/imunologia , Linfócitos T/patologiaRESUMO
Gain of function mutations in the H3K27 methyltransferase EZH2 represent a promising therapeutic target in germinal center lymphomas. In this study, we assessed the frequency and distribution of EZH2 mutations in a large cohort of patients with follicular lymphoma (FL) (n = 366) and performed a longitudinal analysis of mutation during the disease progression from FL to transformed FL (tFL) (n = 33). Mutations were detected at 3 recurrent mutation hot spots (Y646, A682, and A692) in 27% of FL cases with variant allele frequencies (VAF) ranging from 2% to 61%. By comparing VAF of EZH2 with other mutation targets (CREBBP, MLL2, TNFRSF14, and MEF2B), we were able to distinguish patients harboring clonal EZH2 mutation from rarer cases with subclonal mutations. Overall, the high incidence of EZH2 mutations in FL and their stability during disease progression makes FL an appropriate disease to evaluate EZH2 targeted therapy.
Assuntos
Biomarcadores Tumorais/genética , Linfoma Folicular/genética , Mutação , Complexo Repressor Polycomb 2/genética , Proteína de Ligação a CREB/genética , Estudos de Coortes , Análise Mutacional de DNA , Progressão da Doença , Proteína Potenciadora do Homólogo 2 de Zeste , Perfilação da Expressão Gênica , Frequência do Gene , Humanos , Estimativa de Kaplan-Meier , Linfoma Folicular/patologia , Fatores de Transcrição MEF2/genética , Membro 14 de Receptores do Fator de Necrose Tumoral/genética , Fatores de TempoRESUMO
INTRODUCTION: Characterised by chronic inflammation of the gastrointestinal tract, inflammatory bowel disease (IBD) symptoms including diarrhoea, abdominal pain and fatigue can significantly impact patient's quality of life. Therapeutic developments in the last 20 years have revolutionised treatment. However, clinical trials and real-world data show primary non-response rates up to 40%. A significant challenge is an inability to predict which treatment will benefit individual patients.Current understanding of IBD pathogenesis implicates complex interactions between host genetics and the gut microbiome. Most cohorts studying the gut microbiota to date have been underpowered, examined single treatments and produced heterogeneous results. Lack of cross-treatment comparisons and well-powered independent replication cohorts hampers the ability to infer real-world utility of predictive signatures.IBD-RESPONSE will use multi-omic data to create a predictive tool for treatment response. Future patient benefit may include development of biomarker-based treatment stratification or manipulation of intestinal microbial targets. IBD-RESPONSE and downstream studies have the potential to improve quality of life, reduce patient risk and reduce expenditure on ineffective treatments. METHODS AND ANALYSIS: This prospective, multicentre, observational study will identify and validate a predictive model for response to advanced IBD therapies, incorporating gut microbiome, metabolome, single-cell transcriptome, human genome, dietary and clinical data. 1325 participants commencing advanced therapies will be recruited from ~40 UK sites. Data will be collected at baseline, week 14 and week 54. The primary outcome is week 14 clinical response. Secondary outcomes include clinical remission, loss of response in week 14 responders, corticosteroid-free response/remission, time to treatment escalation and change in patient-reported outcome measures. ETHICS AND DISSEMINATION: Ethical approval was obtained from the Wales Research Ethics Committee 5 (ref: 21/WA/0228). Recruitment is ongoing. Following study completion, results will be submitted for publication in peer-reviewed journals and presented at scientific meetings. Publications will be summarised at www.ibd-response.co.uk. TRIAL REGISTRATION NUMBER: ISRCTN96296121.
Assuntos
Colite Ulcerativa , Doença de Crohn , Doenças Inflamatórias Intestinais , Humanos , Colite Ulcerativa/terapia , Doença de Crohn/tratamento farmacológico , Doenças Inflamatórias Intestinais/tratamento farmacológico , Estudos Multicêntricos como Assunto , Estudos Observacionais como Assunto , Medicina de Precisão , Estudos Prospectivos , Qualidade de VidaRESUMO
Inherited risk determinants for follicular lymphoma (FL) have recently been described in the immune gene-rich human leukocyte antigen region on chromosome 6p. The known importance of host immune response to FL survival led us to evaluate these germline factors in FL outcome. We confirm the association of single nucleotide polymorphisms rs10484561 (P = 3.5 × 10â»9) and rs6457327 (P = .008) with risk of FL and demonstrate that rs6457327 predicts both time to (P = .02) and risk of (P < .01) FL transformation independently of clinical variables, including the Follicular Lymphoma International Prognostic Index.
Assuntos
Transformação Celular Neoplásica/genética , Transformação Celular Neoplásica/patologia , Cromossomos Humanos Par 6/genética , Antígenos HLA/genética , Linfoma Folicular/genética , Linfoma Folicular/patologia , Polimorfismo de Nucleotídeo Único/genética , Humanos , Pessoa de Meia-Idade , Fatores de Risco , Fatores de Tempo , Reino UnidoRESUMO
BACKGROUND: Discordance between dialysis registry and death certificate reported death has been demonstrated. Since cause of death is measured using registry data in dialysis patients and death certificate data in the general population, comparisons of cause of death proportions between dialysis patients and the general population may be biased. Our aim was to compare the proportion of deaths attributed to cardiovascular disease (CVD), malignancy, and infections between patients receiving dialysis and the general population using death certificates for both, and to quantify the magnitude of discrepancy between registry and death certificate estimates in dialysis patients. METHODS: A retrospective cohort study of 5858 patients initiating maintenance dialysis between 2001 and 2007 was conducted. Cause of death was obtained from both registry and death certificate data for dialysis patients, and from death certificate data for the general population. RESULTS: Compared to the general population, use of death certificate data in dialysis patients resulted in smaller differences in the proportion of deaths attributed to CVD or infection than that from the registry. In the general population, the proportion of deaths due to CVD is 29.3% for men and 28.2% for women, and the proportion of deaths due to infection is 3.3% for men and 3.6% for women. For men, the proportion of deaths in dialysis patients due to CVD using registry data is 41.5%, compared with a proportion of 32.1% using death certificate data. Similarly for women, the proportion of deaths due to CVD using registry data is 35.2% and that using death certificate data 24.3%. The proportion of deaths due to infection in dialysis patients follows the same pattern: for men, the proportion of deaths due to infection using registry data is 9.9% and that from death certificate data at 5.0%; while for women the proportions are 11.6% and 4.8%, respectively. CONCLUSIONS: While absolute cause-specific mortality rates did differ, evaluation of causes of death using death certificate in dialysis patients in Quebec revealed that they do not have substantially different proportion of death due to CVD or infections than the general population. Infections appeared to be a frequent complication leading to death, suggesting that infections are an important target to consider for reducing mortality in dialysis populations.
Assuntos
Doenças Cardiovasculares/mortalidade , Causas de Morte , Atestado de Óbito , Neoplasias/mortalidade , Sistema de Registros , Diálise Renal/estatística & dados numéricos , Idoso , Doenças Cardiovasculares/complicações , Doenças Cardiovasculares/epidemiologia , Estudos de Coortes , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Neoplasias/complicações , Neoplasias/epidemiologia , Vigilância da População , Quebeque/epidemiologia , Estudos Retrospectivos , Distribuição por Sexo , Análise de SobrevidaRESUMO
BACKGROUND: With various types of complex patients being treated in a mixed medical- surgical- trauma intensive care unit (ICU), we hypothesized that there should be no difference in patient mortality with respect to the core training of the intensivist. METHODS: We reviewed the cases of all patients admitted to a mixed medical-surgical-trauma ICU at a Canadian university teaching hospital in 2007. Patients were assigned to 1 of 2 treatment groups (internal medicine, surgery/anesthesiology) based on the treating intensivist's training. Our primary outcome was to compare patient mortality in the ICU between the groups. We used generalized estimating equations to determine 10-day mortality after admission to the ICU. A multivariate Cox hazard model was used to determine statistical significance and 95% confidence intervals (CIs) for 11- to 60-day mortality in the ICU. RESULTS: A total of 961 patients were admitted from January to December, 2007. We found no significant difference between the groups in 10-day mortality (odds ratio 0.73, 95% CI 0.46-1.18, p = 0.20) and 11- to 60-day mortality (hazard ratio 1.43, 95% CI 0.62-3.30, p = 0.40) after admission to the ICU. CONCLUSION: In a large university trauma centre that operates a mixed medicine- surgical-trauma ICU, there was no significant difference in mortality between patients managed by intensivists with core training in internal medicine and those managed by intensivists with training in surgery/anesthesiology.
CONTEXTE: Compte tenu de la variété de cas complexes traités dans les unités de soins intensifs (USI) mixtes de médecinechirurgietraumatologie, nous avons émis l'hypothèse selon laquelle il ne devrait y avoir aucune différence en ce qui concerne la mortalité chez les patients selon la formation de base de l'intensiviste. MÉTHODES: Nous avons passé en revue les dossiers de tous les patients admis dans l'USI mixte de médecinechirurgietraumatologie d'un centre hospitalier universitaire canadien en 2007. Les patients ont été assignés à l'un de 2 groupes (médecine interne ou chirurgie/anesthésie) selon la formation de l'intensiviste traitant. Notre paramètre principal visait à comparer la mortalité des patients des USI selon leur groupe. Nous avons utilisé des équations d'estimation généralisées pour déterminer la mortalité à 10 jours suivant l'admission à l'USI. Et nous avons utilisé un modèle de risque multivarié de Cox pour déterminer la portée statistique et les intervalles de confiance (IC) de 95 % en ce qui concerne la mortalité dans les 11 à 60 jours d'hospitalisation à l'USI. RÉSULTANTS: En tout, 961 patients ont été admis entre janvier et décembre 2007. Nous n'avons observé aucune différence significative entre les 2 groupes pour ce qui est de la mortalité à 10 jours (rapport des cotes 0,73, IC de 95 % 0,461,18, p = 0,20) et de la mortalité dans les 11 à 60 jours (rapport des risques 1,43, IC de 95 % 0,623,30, p = 0,40) suivant l'admission à l'USI. CONCLUSIONS: Dans un important centre universitaire de traumatologie doté d'une USI mixte médecinechirurgietraumatologie, on n'a noté aucune différence significative quant à la mortalité entre les patients soignés par des intensivistes ayant une formation de base en médecine interne et les patients soignés par des intensivistes ayant une formation de base en chirurgie/anesthésie.
Assuntos
Mortalidade Hospitalar , Unidades de Terapia Intensiva , Corpo Clínico Hospitalar , APACHE , Centros Médicos Acadêmicos , Adolescente , Adulto , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Anestesiologia , Feminino , Cirurgia Geral , Hospitais de Ensino , Humanos , Medicina Interna , Tempo de Internação , Masculino , Pessoa de Meia-Idade , Modelos de Riscos Proporcionais , Quebeque , Estudos Retrospectivos , Adulto JovemRESUMO
While most myelodysplastic syndrome/acute myeloid leukemia cases are sporadic, rare familial cases occur and provide some insight into leukemogenesis. The most clearly defined familial cases result from inherited mutations in RUNX1 or CEBPA. Recently, novel germline mutations in GATA2 have been reported. We, therefore, investigated individuals from families with one or more first-degree relatives with myelodysplastic syndrome/acute myeloid leukemia with wild-type RUNX1 and CEBPA, for GATA2 mutations. Screening for other recurrent mutations was also performed. A GATA2 p.Thr354Met mutation was observed in a pedigree in which 2 first-degree cousins developed high-risk myelodys-plastic syndrome with monosomy 7. They were also observed to have acquired identical somatic ASXL1 mutations and both died despite stem cell transplantation. These findings confirm that germline GATA2 mutations predispose to familial myelodysplastic syndrome/acute myeloid leukemia, and that monosomy 7 and ASXL1 mutations may be recurrent secondary genetic abnormalities triggering overt malignancy in these families.
Assuntos
Fator de Transcrição GATA2/genética , Leucemia Mieloide Aguda/genética , Síndromes Mielodisplásicas/genética , Proteínas Repressoras/genética , Adolescente , Adulto , Idade de Início , Sequência de Bases , Deleção Cromossômica , Cromossomos Humanos Par 7/genética , Análise Mutacional de DNA , Feminino , Predisposição Genética para Doença , Mutação em Linhagem Germinativa , Humanos , Leucemia Mieloide Aguda/mortalidade , Masculino , Dados de Sequência Molecular , Síndromes Mielodisplásicas/mortalidade , Linhagem , Taxa de SobrevidaRESUMO
AIM: The aim of this study was to determine the midterm functional quality of life in octogenarians after open valvular surgery. METHODS: One hundred and eighty-five consecutive patients above age 80 had valvular surgery with or without coronary artery bypass grafting (CABG). Using the Karnofsky Performance score and Barthel Index, patients were evaluated for functional autonomy, living disposition, and leisure activity by a single telephone interview. Subgroup analysis was performed on the 49 cases of isolated aortic valve replacement (AVR). RESULTS: Mean age of octogenarians undergoing valvular surgery was 82.7 years (range 80 to 92 years). Actuarial survival at one and three years was 71% and 59%, respectively, for the entire group, compared to 84% and 71%, respectively, for isolated AVRs. After a mean follow-up of 38 months there were 110 survivors (59.5%). Among survivors, 66% were autonomous, 26% semiautonomous, and 8% deemed dependent. Seventy-two percent were living at home, 19% in a residence, and 9% in a supervised nursing facility. Over 90% of patients pursued leisure activities in the social, cognitive, and physical domains. CONCLUSIONS: Valvular surgery in high-risk octogenarians, can be performed with acceptable mortality rates, and provide patients with functional autonomy and an excellent quality of life.
Assuntos
Atividades Cotidianas , Doenças das Valvas Cardíacas/cirurgia , Implante de Prótese de Valva Cardíaca/reabilitação , Qualidade de Vida , Fatores Etários , Idoso de 80 Anos ou mais , Feminino , Seguimentos , Doenças das Valvas Cardíacas/mortalidade , Doenças das Valvas Cardíacas/reabilitação , Implante de Prótese de Valva Cardíaca/mortalidade , Humanos , Vida Independente , Entrevistas como Assunto , Atividades de Lazer , Masculino , Readmissão do Paciente/estatística & dados numéricos , Autonomia Pessoal , Instituições Residenciais , Estudos Retrospectivos , Risco , Resultado do TratamentoRESUMO
BACKGROUND: Ongoing gastrointestinal bleeding (GIB) following endoscopic therapy and deciding between mesenteric angiography and surgery often challenge surgeons. We sought to identify predictors of positive angiographic study (active contrast medium extravasation) and characterize outcomes of embolization for acute GIB. METHODS: We retrospectively analyzed angiographies for GIB at 2 teaching hospitals from January 2005 to December 2008. The χ2, Wilcoxon rank sum and t tests determined significance. A Cox proportional hazards model was used for multivariate analyses. RESULTS: Eighteen of 83 (22%) patients had active extravasation on initial angiography and 25 (30%) were embolized. Patients with active extravasation had more packed red blood cell (PRBC; 5.3 v. 2.8 units, p < 0.001) and fresh frozen plasma (4.8 v. 1.7 units, p = 0.005) transfusions 24 hours preangiography and were more likely to be hemodynamically unstable at the time of the procedure (67% v. 28%, p = 0.001) than patients without active extravasation. Each unit of PRBC transfused increased the risk of a positive study by 30% (hazard ratio [HR] 1.3, 95% confidence interval [CI] 1.2-1.6 per unit). Embolization did not decrease recurrent bleeding (53% v. 52%) or length of stay in hospital (28.1 v. 27.5 d, p = 0.95), but was associated with a trend toward fewer emergency surgical interventions (13% v. 26%, p = 0.31) and greater 30-day mortality (33% v. 7%, p = 0.006) than nonembolization. Blind embolization was performed in 10 of 83 (12%) patients and was found to be an independent predictor of death in patients without active extravasation (HR 9.2, 95% CI 1.5-55.9). CONCLUSION: The number of PRBC units transfused correlates with greater likelihood of a positive study. There was a significant increase in mortality in patients who underwent angioembolization. Large prospective studies are needed to further characterize the indications for angiography and blind embolization.
Assuntos
Angiografia , Embolização Terapêutica , Transfusão de Eritrócitos , Extravasamento de Materiais Terapêuticos e Diagnósticos/diagnóstico por imagem , Hemorragia Gastrointestinal/etiologia , Hemorragia Gastrointestinal/terapia , Artérias Mesentéricas/diagnóstico por imagem , Doença Aguda , Adulto , Idoso , Idoso de 80 Anos ou mais , Comorbidade , Embolização Terapêutica/mortalidade , Extravasamento de Materiais Terapêuticos e Diagnósticos/mortalidade , Feminino , Hemorragia Gastrointestinal/diagnóstico por imagem , Hemorragia Gastrointestinal/mortalidade , Hospitais de Ensino , Humanos , Masculino , Artéria Mesentérica Inferior/diagnóstico por imagem , Artéria Mesentérica Superior/diagnóstico por imagem , Pessoa de Meia-Idade , Análise Multivariada , Valor Preditivo dos Testes , Modelos de Riscos Proporcionais , Estudos RetrospectivosRESUMO
OBJECTIVE: To compare quality-of-care indicators for management of patients with chronic kidney disease (CKD) and type 2 diabetes among the James Bay Cree of Northern Quebec with those among residents of Montreal, Que. DESIGN: A cross-sectional survey using medical records from patients seen between 2002 and 2008. SETTING: Predialysis clinics of the McGill University Health Centre in Montreal. PARTICIPANTS: Thirty Cree and 51 nonaboriginal patients older than 18 years of age with type 2 diabetes mellitus and estimated glomerular filtration rates of less than 60 mL/min/1.73 m2. MAIN OUTCOME MEASURES: Rates of anemia, iron deficiency, obesity, and renoprotective medication use among aboriginal and nonaboriginal patients. RESULTS: Overall, the Cree patients were younger (59 vs 68 years of age, P < .0035) and weighed more (101 vs 77 kg,P < .001). The 2 groups were prescribed medication to control blood pressure, lipids, and phosphate levels at similar rates, but the Cree patients were more likely to receive renoprotective agents (87% vs 65%, P = .04). Despite similar rates of erythropoietin supplementation, the Cree patients were at greater risk of anemia, with an adjusted risk ratio of 2.80 (95% CI 1.01 to 7.87). CONCLUSION: Cree patients with CKD were younger, weighed more, and were more likely to receive renoprotective agents. With the exception of the management of anemia, quality of CKD care was similar between the 2 groups.Anemia education for family physicians and continuous monitoring of quality indicators must be implemented in northern Quebec.