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PURPOSE: Time to antibiotic administration (TTA) in <60 minutes for children with neutropenic fever presenting to an emergency room is associated with reduced incidence of sepsis and intensive care admission. As such, TTA is used as a national quality metric for pediatric oncology patients. At our center, in 2020, 19% of the hospitalized patients with a new fever encounter were receiving antibiotics in <60 minutes, prompting a multidisciplinary approach to reach a goal of >90% in all pediatric patients with cancer with a new fever. METHODS: A multidisciplinary team completed four Plan-Do-Study-Act cycles between March 2021 and September 2023. We implemented education initiatives, an updated handoff smartphrase guiding the on-call team, an antibiotic champion (AC) nursing role, a revised fever plan for handoff, a rapid-response team to address new fevers, and an algorithm for blood culture collection. Data were collected, analyzed, and reported biweekly with feedback sought for delays in TTA. RESULTS: There was a total of 639 new fevers in 329 unique oncology patients. As of September 4, 2023, average TTA decreased from 89 minutes at baseline to 46.4 minutes for more than 12 months. The percentage of patients receiving first dose of antibiotic in <60 minutes also increased from 19% to 93.7%, which was sustained as well. The most effective interventions were creation of the AC role and streamlining the blood culture collection process. CONCLUSION: This project demonstrates the importance of multidisciplinary involvement for providing optimal care. Specific implementation of targeted education, an AC role, and development of an algorithm streamlining the processes led to meaningful targeted improvements. Further analyses will explore the impact of these interventions on patient outcomes.
Assuntos
Antibacterianos , Febre , Neoplasias , Humanos , Antibacterianos/administração & dosagem , Antibacterianos/uso terapêutico , Criança , Febre/tratamento farmacológico , Neoplasias/complicações , Neoplasias/tratamento farmacológico , Feminino , Masculino , Pré-Escolar , Adolescente , Tempo para o TratamentoRESUMO
Blinatumomab, a bispecific T cell engager that binds CD19 in leukemic cells and CD3 in cytotoxic T cells and leads to leukemic blast lysis, is often used in pediatric patients with relapsed/refractory (R/R) B cell acute lymphoblastic leukemia (B-ALL) prior to allogeneic hematopoietic cell transplantation (allo-HCT). Concerns about the potential risk of blinatumomab-related immune-mediated toxicities after allo-HCT have not been adequately addressed. These include graft-versus-host disease (GVHD), delayed engraftment, and graft failure or rejection. Pediatric-specific data reporting post-HCT outcomes of patients treated with blinatumomab are scarce and limited to small cohorts. We sought to investigate the clinical outcomes of pediatric patients with R/R B-ALL who received blinatumomab therapy pre-HCT, focusing on overall survival (OS), leukemia-free survival (LFS), cumulative incidence of relapse (CIR), and nonrelapse mortality (NRM), as well as the incidence of immune-mediated post-HCT complications including GVHD, delayed neutrophil or platelet engraftment, graft failure, and graft rejection. We also investigated blinatumomab's effects on B cell reconstitution based on achievement of i.v. immunoglobulin (IVIG) independence post-HCT. This single-center, retrospective study included patients with B-ALL receiving blinatumomab therapy before undergoing allo-HCT, with transplantation performed between 2016 and 2021 at our institution. Patients receiving blinatumomab for relapse after allo-HCT were excluded. Patients receiving chemotherapy alone before allo-HCT during the same period composed the control group. Seventy-two patients were included, 31 of whom received blinatumomab before allo-HCT. Survival estimates were obtained using the Kaplan-Meier method, and the log-rank test was used to analyze differences between groups. Categorical variables were compared between groups using the chi-square test or Fisher exact test, and continuous variables were compared using the Wilcoxon rank-sum test. Cumulative incidences were estimated using the competing risks method, and Gray's test was used to analyze differences between groups. A Cox proportional hazards regression model was used for univariate and multivariable analyses for OS. Landmark analysis was performed at the set time points of 30 days and 100 days post-allo-HCT. Most patients in the study cohort had high-risk relapsed B-ALL. Blinatumomab therapy induced minimal residual disease (MRD)-negative remissions in all patients, whereas 5 patients (12.2%) receiving chemotherapy alone had persistent MRD pre-allo-HCT. Time from the start of therapy to the date of allo-HCT was shorter for patients who received blinatumomab compared with those who received chemotherapy (P < .0001). Blinatumomab therapy was associated with greater LFS compared to chemotherapy alone (P = .049), but when limited to 1 year, LFS was not significantly different from control (P = .066). There appeared to be higher OS, lower CIR, and lower NRM in patients receiving blinatumomab compared to the control group; however, the differences were not significant. None of the variables assessed in multivariable analysis was associated with differences in OS. When compared to the controls, blinatumomab therapy did not result in a higher incidence of acute or chronic GVHD, delayed neutrophil or platelet engraftment, or graft failure or rejection. The time to IVIG infusion independence post-allo-HCT was similar in the 2 groups. This study supports the use of blinatumomab salvage therapy for R/R B-ALL before allo-HCT given its efficacy in inducing MRD-negative remissions and optimizing LFS, as well as its lack of association with an increased incidence of post-allo-HCT adverse immune-mediated toxicities. Larger, prospective studies are needed to confirm these findings and to investigate blinatumomab's effects in long-term post-allo-HCT events.
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Anticorpos Biespecíficos , Linfoma de Burkitt , Doença Enxerto-Hospedeiro , Transplante de Células-Tronco Hematopoéticas , Leucemia-Linfoma Linfoblástico de Células Precursoras B , Leucemia-Linfoma Linfoblástico de Células Precursoras , Humanos , Criança , Estudos Retrospectivos , Imunoglobulinas Intravenosas , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Leucemia-Linfoma Linfoblástico de Células Precursoras B/tratamento farmacológico , Leucemia-Linfoma Linfoblástico de Células Precursoras B/etiologia , Doença Enxerto-Hospedeiro/etiologia , Doença Enxerto-Hospedeiro/prevenção & controle , Leucemia-Linfoma Linfoblástico de Células Precursoras/terapia , Linfoma de Burkitt/etiologia , RecidivaRESUMO
Chimeric antigen receptor (CAR) T cell (CAR-T) therapy represents a revolutionary treatment for patients with relapsed/refractory hematologic malignancies. However, its use can result in significant toxicities, including cytokine release syndrome (CRS), a potentially life-threatening clinical syndrome resulting from the release of proinflammatory cytokines upon T cell activation. In addition, patients who develop CRS often experience prolonged cytopenias, and those with the most severe CRS also have the longest delays in full marrow recovery. Although an association between CRS and delayed bone marrow recovery has been established, the precise mechanism underlying this phenomenon remains unknown. This study was conducted to test our hypothesis that delayed bone marrow recovery following CAR-T therapy is caused by elevation of proinflammatory cytokines, leading to apoptosis and depletion of hematopoietic stem and progenitor cells (HSPCs). SCID-beige mice bearing intraperitoneal CD19+ Raji cell tumors were treated with injection of human CD19.28z CAR T cells. Bone marrow was then harvested for analysis by flow cytometry, and HSPCs were isolated for whole-transcriptome analysis by RNA sequencing. Complete blood counts and serum cytokine levels were measured as well. A second model was developed in which SCID-beige mice were treated with murine IFN-γ (mIFN-γ), murine IL-6 (mIL-6), or both. Bone marrow was harvested, and flow cytometry assays were conducted to evaluate the degree of apoptosis and proliferation on specific HSPC populations. SCID-beige mice bearing intraperitoneal Raji cell tumors that were treated with CAR-T therapy developed CRS, with elevations of several proinflammatory cytokines, including profound elevation of human IFN-γ. Gene set enrichment analysis of RNA sequencing data revealed that genes associated with apoptosis were significantly upregulated in HSPCs from mice that developed CRS. Endothelial protein C receptor (EPCR)-negative HSCs, a subset of HSCs that is poised for terminal differentiation, was found to be specifically decreased in mice that were treated with CAR T cells. Furthermore, HSPCs were found to have increased levels of apoptosis upon treatment with mIFN-γ and mIL-6, whereas short-term HSCs and multipotent progenitors exhibited increases in proliferation with mIFN-γ treatment alone. The results from this study provide evidence that the elevation of proinflammatory cytokines following CAR-T therapy impacts the bone marrow through a combined mechanism: pluripotent HSCs that are exposed to elevated levels of IFN-γ and IL-6 undergo increased cell death, while more committed progenitor cells become more proliferative in response to elevated IFN-γ. These combined effects lead to depleted stores of repopulating HSCs and ultimately cytopenias. © 2023 American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc.
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Doenças da Medula Óssea , Imunoterapia Adotiva , Neoplasias , Receptores de Antígenos Quiméricos , Animais , Humanos , Camundongos , Apoptose , Medula Óssea/patologia , Doenças da Medula Óssea/metabolismo , Doenças da Medula Óssea/patologia , Citocinas/metabolismo , Células-Tronco Hematopoéticas , Interleucina-6/metabolismo , Camundongos SCID , Imunoterapia Adotiva/efeitos adversosRESUMO
Wnt/ß-catenin signaling is active in small subpopulations of Ewing sarcoma cells, and these cells display a more metastatic phenotype, in part due to antagonism of EWS-FLI1-dependent transcriptional activity. Importantly, these ß-catenin-activated Ewing sarcoma cells also alter secretion of extracellular matrix (ECM) proteins. We thus hypothesized that, in addition to cell-autonomous mechanisms, Wnt/ß-catenin-active tumor cells might contribute to disease progression by altering the tumor microenvironment (TME). Analysis of transcriptomic data from primary patient biopsies and from ß-catenin-active versus -nonactive tumor cells identified angiogenic switch genes as being highly and reproducibly upregulated in the context of ß-catenin activation. In addition, in silico and in vitro analyses, along with chorioallantoic membrane assays, demonstrated that ß-catenin-activated Ewing cells secreted factors that promote angiogenesis. In particular, activation of canonical Wnt signaling leads Ewing sarcoma cells to upregulate expression and secretion of proangiogenic ECM proteins, collectively termed the angiomatrix. Significantly, our data show that induction of the angiomatrix by Wnt-responsive tumor cells is indirect and is mediated by TGF-ß. Mechanistically, Wnt/ß-catenin signaling antagonizes EWS-FLI1-dependent repression of TGF-ß receptor type 2, thereby sensitizing tumor cells to TGF-ß ligands. Together, these findings suggest that Wnt/ß-catenin-active tumor cells can contribute to Ewing sarcoma progression by promoting angiogenesis in the local TME.
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Regulação Neoplásica da Expressão Gênica/genética , Sarcoma de Ewing/metabolismo , Microambiente Tumoral/fisiologia , Via de Sinalização Wnt/fisiologia , Linhagem Celular Tumoral , Humanos , Proteínas de Fusão Oncogênica/genética , Proteína Proto-Oncogênica c-fli-1/genética , Proteína EWS de Ligação a RNA/genética , Sarcoma de Ewing/genética , Sarcoma de Ewing/patologia , Regulação para CimaRESUMO
BACKGROUND: Patients with DLBCL exhibit widely divergent outcomes despite harboring histologically identical tumors. Currently, GEP and IHC algorithms assign patients to 1 of 2 main subtypes: germinal center B cell-like (GCB), or activated B cell-like (ABC), the latter of which historically carries a less favorable prognosis. However, it remains controversial as to whether these prognostic groupings remain valid in the era of rituximab therapy. MATERIALS AND METHODS: A systematic literature review identified 24 articles from which meta-analyses were conducted, comparing survival outcomes for patients assigned to either GCB or ABC/non-GCB subtype using GEP and/or Hans, Choi, or Muris IHC algorithms. RESULTS: Patients designated as GCB DLBCL using GEP fared significantly better in terms of overall survival than those with ABC DLBCL (hazard ratio, 1.85; P < .0001). In contrast, the Hans and Choi algorithms failed to identify significant differences in overall survival (P = .07 and P = .76, respectively) between GCB and non-GCB groups. CONCLUSIONS: Our study illustrates a lack of evidence supporting the use of the Hans and Choi algorithms for stratifying patients into distinct prognostic groups. Rather, GEP remains the preferred method for predicting the course of a patient's disease and informing decisions regarding treatment options.
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Perfilação da Expressão Gênica , Imuno-Histoquímica , Linfoma Difuso de Grandes Células B/genética , Linfoma Difuso de Grandes Células B/metabolismo , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Humanos , Linfoma Difuso de Grandes Células B/diagnóstico , Linfoma Difuso de Grandes Células B/tratamento farmacológico , Linfoma Difuso de Grandes Células B/mortalidade , Estadiamento de Neoplasias , Prognóstico , Modelos de Riscos Proporcionais , Resultado do TratamentoRESUMO
[reaction: see text] A chemoenzymatic synthesis of ADP-D-glycero-beta-D-manno-heptose (ADP-D,D-Hep) is described in which D,D-Hep 7-phosphate is converted to ADP-D,D-Hep by two biosynthetic enzymes. This strategy allows access to the 6''-deuterated analogue, which upon incubation with the epimerase showed complete retention of the isotopic label at the 6''-position. This provides evidence for a direct oxidation mechanism in which the hydride initially transferred to the NADP+ cofactor is subsequently returned to the same carbon in a nonstereospecific manner.