Background CD19-directed CAR T-cell therapy (CAR-T) has emerged as an effective therapy for relapsed/refractory large B-cell lymphoma (R/R LBCL). The neurologic toxicity seen with CAR-T, referred to as Immune Effector Cell-Associated Neurotoxicity Syndrome (ICANS), is poorly understood. To better elucidate the clinical characteristics, treatment outcomes, and correlative biomarkers of ICANS, we review here a single-center analysis of ICANS after CAR-T therapy in R/R LBCL. Methods Patients (n=45) with R/R LBCL treated with axicabtagene ciloleucel (axi-cel) were identified. Data regarding treatment course, clinical outcomes, and correlative studies were collected. Patients were monitored and graded for ICANS via CARTOX-10 scoring and CTCAE v4.03 criteria, respectively. Results Twenty-five (56%) patients developed ICANS, eighteen (72%) of which had severe (grade 3-4) ICANS. Median time to development of ICANS of 5 days (range 3-11). Elevated pre-infusion (D0) fibrinogen (517 vs. 403 mg/dL, ULN 438mg/dL, p=0.01) and D0 LDH (618 vs. 506 units/L, ULN 618 units/L, p=0.04) were associated with ICANS. A larger drop in fibrinogen was associated with ICANS (393 vs 200, p<0.01). Development of ICANS of any grade had no effect on complete remission (CR), progression-free survival (PFS) or overall survival (OS). Duration and total dose of steroid treatment administered for ICANS did not influence CR, PFS, or OS. Conclusions ICANS after CAR-T with axi-cel for R/R LBCL was seen in about half of patients, majority of which was high grade. Contrary to previous reports, neither development of ICANS nor its treatment were associated with inferior CR, PFS, or OS. The novel finding of high D0 fibrinogen level can identify patients at higher risk for ICANS.
Tumor cell metastasis to the brain involves cell migration through biochemically and physically complex microenvironments at the blood-brain barrier (BBB). The current understanding of tumor cell migration across the BBB is limited. We hypothesize that an interplay between biochemical cues and physical cues at the BBB affects the mechanisms of brain metastasis. We found that astrocyte conditioned medium (ACM) applied directly to tumor cells increased tumor cell velocity, induced elongation, and promoted actin stress fiber organization. Notably, treatment of the extracellular matrix with ACM led to even more significant increases in tumor cell velocity in comparison with ACM treatment of cells directly. Furthermore, inhibiting matrix metalloproteinases in ACM reversed ACM's effect on tumor cells. The effects of ACM on tumor cell morphology and migration also depended on astrocytes' activation state. Finally, using a microfluidic device, we found that the effects of ACM were abrogated in confinement. Overall, our work demonstrates that astrocyte-secreted factors alter migration and morphology of metastatic breast tumor cells, and this effect depends on the cells' mechanical microenvironment. Metastasis to the brain is one of the most deadly aspects of breast cancer, leading to a particularly poor prognosis for patients (1). During metastasis, breast tumor cells break away from the primary tumor, travel through the circulatory system, preferentially infiltrate the brain, and form secondary tumors that are notoriously difficult to treat (1). During metastasis, tumor cells encounter many heterogeneous microenvironments containing an array of biochemical and physical cues (2), both of which regulate the migration, mechanobiology, and signaling mechanisms used by tumor cells to navigate these environments (3). It has been shown that astrocytes in the brain microenvironment promote brain metastasis and facilitate tumor cell invasion (4-8). We hypothesize that astrocyte-secreted biochemical cues regulate the morphology and migration of metastatic breast tumor cells and that this effect depends on the astrocyte activation state, as well as the mechanical microenvironment of the tumor cells.In healthy physiology, astrocytes provide support for neurons by maintaining an ionic, neurotransmitter, amino acid, and water balance in the brain (9). The endfeet of astrocytes support the blood-brain barrier (BBB) by assisting with the exchange of chemical signals between the circulatory system and the brain (9) and modulating the physiology of brain endothelial cells (9, 10). Although astrocytes are important regulators of brain homeostasis, they also play a role in brain metastasis. It has been reported that astrocyte-secreted serpins are involved in tumor cell survival during metastasis across the BBB in vivo (4). Another report demonstrated an increased invasiveness of tumor cells in response to astrocyte-conditioned medium (ACM), and they attributed this response to astrocyte-secreted matrix metalloproteinases (MMPs) (...
Background and ObjectivesPerioperative exposure to opioids is associated with adverse outcomes. We aim to determine the associations between surgery and subsequent opioid overdose, an acute event, and a new diagnosis of opioid use disorder (OUD), a chronic relapsing disease, in parallel.MethodsThis retrospective cohort study of US veterans used surgery as exposure and the two outcomes were (1) occurrence of overdose and (2) new diagnosis of OUD in the first postoperative year. Surgical group was matched to the reference controls based on the propensity score of having surgery, and matched logistic regression was used to calculate the odds ratio (OR).ResultsA total of 261 208 surgical patients were matched to 479 531 controls. Overdose occurred in 1893 (0.7%) of the surgical patients and in 518 (0.1%) of the matched controls in the first postoperative year (OR, 6.71; 95% confidence interval [CI], 5.80‐7.75; P < .001). Among patients with no history of OUD, surgery was also associated with a new diagnosis of OUD in the first postoperative year (OR, 1.13; 95% CI, 1.02‐1.24; P = .015).Discussion and ConclusionsThe postoperative period is strongly associated with opioid overdose, but only weakly associated with new diagnosis of OUD. This is likely due to the difficulty of diagnosing OUD in the postoperative period.Scientific SignificanceThis is the first study that has examined opioid overdose and new‐onset OUD in the postoperative period in parallel. Our analysis suggests different risk factors for each, as well as different strengths of association with surgery. More sensitive diagnostic criteria for postoperative OUD are needed to promptly diagnose and treat this condition. (Am J Addict 2020;00:00–00)
In light of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) variants potentially undermining humoral immunity, it is important to understand the fine specificity of the antiviral antibodies. We screened 20 COVID-19 patients for antibodies against 9 different SARS-CoV-2 proteins observing responses against the spike (S) proteins, the receptor-binding domain (RBD), and the nucleocapsid (N) protein which were of the IgG1 and IgG3 subtypes. Importantly, mutations which typically occur in the B.1.351 “South African” variant, significantly reduced the binding of anti-RBD antibodies. Nine of 20 patients were critically ill and were considered high-risk (HR). These patients showed significantly higher levels of transforming growth factor beta (TGF-β) and myeloid-derived suppressor cells (MDSC), and lower levels of CD4+ T cells expressing LAG-3 compared to standard-risk (SR) patients. HR patients evidenced significantly higher anti-S1/RBD IgG antibody levels and an increased neutralizing activity. Importantly, a large proportion of S protein-specific antibodies were glycosylation-dependent and we identified a number of immunodominant linear epitopes within the S1 and N proteins. Findings derived from this study will not only help us to identify the most relevant component of the anti-SARS-CoV-2 humoral immune response but will also enable us to design more meaningful immunomonitoring methods for anti-COVID-19 vaccines.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.