RESUMO
BACKGROUND: Spine surgery accounts for a large proportion of neurosurgical procedures, with approximately 313 million spine surgeries conducted annually worldwide. Considering delayed recovery and postoperative complications that are commonly reported, there has been a recent shift toward minimally invasive spine procedures conducted under local anesthesia. Despite proven success, there exists a limited body of literature on the use of awake surgery in spinal procedures. METHODS: A bibliometric analysis was conducted to map the current landscape of work in this field. 190 articles were identified from the Web of Science (Clarivate, NY) database. A comprehensive bibliometric analysis was performed on a narrowed list of the most relevant articles using Bibliometrix, an R-based programming tool. RESULTS: There has been a rise in academic papers published on the topic of awake spine surgery since 2016, with an increase in publication count by approximately 18% annually and each article cited approximately ten times on average to date. The year 2022 saw an uptick in publications, with 9 throughout the entire year. The most impactful article, with a total of 95 citations, was published by Sairyo et al.1 Thematic analysis revealed that the terms "lumbar spine" and "stenosis" are well-developed topics in the literature, whereas the topics of "complications," "fusion," and "cost-analysis" are less well-developed topics. CONCLUSIONS: This study provides a comprehensive overview of the most-cited articles in the field of awake spine surgery. Specifically, it identifies areas that are well represented in the literature and those which are underrepresented and should be areas of continued future research.
Assuntos
Bibliometria , Procedimentos Neurocirúrgicos , Vigília , Humanos , Procedimentos Neurocirúrgicos/métodos , Coluna Vertebral/cirurgia , Doenças da Coluna Vertebral/cirurgiaRESUMO
Chimeric antigen receptor (CAR) T cells induce impressive responses in patients with hematologic malignancies but can also trigger cytokine release syndrome (CRS), a systemic toxicity caused by activated CAR T cells and innate immune cells. Although IFNγ production serves as a potency assay for CAR T cells, its biologic role in conferring responses in hematologic malignancies is not established. Here we show that pharmacologic blockade or genetic knockout of IFNγ reduced immune checkpoint protein expression with no detrimental effect on antitumor efficacy against hematologic malignancies in vitro or in vivo. Furthermore, IFNγ blockade reduced macrophage activation to a greater extent than currently used cytokine antagonists in immune cells from healthy donors and serum from patients with CAR T-cell-treated lymphoma who developed CRS. Collectively, these data show that IFNγ is not required for CAR T-cell efficacy against hematologic malignancies, and blocking IFNγ could simultaneously mitigate cytokine-related toxicities while preserving persistence and antitumor efficacy. SIGNIFICANCE: Blocking IFNγ in CAR T cells does not impair their cytotoxicity against hematologic tumor cells and paradoxically enhances their proliferation and reduces macrophage-mediated cytokines and chemokines associated with CRS. These findings suggest that IFNγ blockade may improve CAR T-cell function while reducing treatment-related toxicity in hematologic malignancies. See related content by McNerney et al., p. 90 (17). This article is highlighted in the In This Issue feature, p. 85.
Assuntos
Neoplasias Hematológicas , Imunoterapia Adotiva , Síndrome da Liberação de Citocina , Citocinas/metabolismo , Neoplasias Hematológicas/terapia , Humanos , Imunoterapia Adotiva/efeitos adversos , Interferon gama/metabolismo , Ativação de Macrófagos , Linfócitos T/metabolismoRESUMO
BACKGROUND: Adoptive cell therapy with chimeric antigen receptor T cells (CAR-T) has become a standard treatment for patients with certain aggressive B cell malignancies and holds promise to improve the care of patients suffering from numerous other cancers in the future. However, the high manufacturing cost of CAR-T cell therapies poses a major barrier to their broader clinical application. Among the key cost drivers of CAR-T production are single-use reagents for T cell activation and clinical-grade viral vector. The presence of variable amounts of contaminating monocytes in the starting material poses an additional challenge to CAR-T manufacturing, since they can impede T cell stimulation and transduction, resulting in manufacturing failure. METHODS: We created K562-based artificial antigen-presenting cells (aAPC) with genetically encoded T cell stimulation and costimulation that represent an inexhaustible source for T cell activation. We additionally disrupted endogenous expression of the low-density lipoprotein receptor (LDLR) on these aAPC (aAPC-ΔLDLR) using CRISPR-Cas9 gene editing nucleases to prevent inadvertent lentiviral transduction and avoid the sink effect on viral vector during transduction. Using various T cell sources, we produced CD19-directed CAR-T cells via aAPC-ΔLDLR-based activation and tested their in vitro and in vivo antitumor potency against B cell malignancies. RESULTS: We found that lack of LDLR expression on our aAPC-ΔLDLR conferred resistance to lentiviral transduction during CAR-T production. Using aAPC-ΔLDLR, we achieved efficient expansion of CAR-T cells even from unpurified starting material like peripheral blood mononuclear cells or unmanipulated leukapheresis product, containing substantial proportions of monocytes. CD19-directed CAR-T cells that we produced via aAPC-ΔLDLR-based expansion demonstrated potent antitumor responses in preclinical models of acute lymphoblastic leukemia and B-cell lymphoma. CONCLUSIONS: Our aAPC-ΔLDLR represent an attractive approach for manufacturing of lentivirally transduced T cells that may be simpler and more cost efficient than currently available methods.