Citations

Abstract Brexucabtagene autoleucel (brexu-cel) is a chimeric antigen receptor T-cell therapy approved for relapsed/refractory mantle cell lymphoma (R/R MCL). Here, we report real-world effectiveness and safety outcomes of brexu-cel in a prospective study of patients with R/R MCL, including subgroups based on prior treatment with Bruton's tyrosine kinase inhibitor, bendamustine, or autologous hematopoietic cell transplant (auto-HCT) and number of prior therapy lines, using Center for International Blood and Marrow Transplant Research registry data. A total of 476 patients with R/R MCL who received brexu-cel between July 2020 and December 2022 were included in the analysis. With a median follow-up of 13.5 months, the overall response rate was 91% and complete response rate was 82%. One-year overall survival and progression-free survival rates were 76% and 63%, respectively. One-year cumulative incidence of nonrelapse mortality was 8%. Prior auto-HCT was associated with better duration of response within 6 months after infusion (hazard ratio [HR], 0.49; 95% confidence interval [CI], 0.28-0.85) but greater risk of immune effector cell–associated neurotoxicity syndrome (odds ratio [OR], 1.66; 95% CI, 1.06-2.60). Prior bendamustine was associated with increased risk of prolonged thrombocytopenia (OR, 1.90; 95% CI, 1.13-3.21). In patients with 1 to 2 prior therapy lines, relapse or progression was less frequent compared with those with ≥3 prior lines (HR, 0.64; 95% CI, 0.42-1.00). Collectively, our results suggest that real-world outcomes with brexu-cel were consistent with those of the ZUMA-2 trial, regardless of prior therapy type or number of prior therapy lines.

Objective Cognitive impairment is increasingly recognized in patients with cerebral venous congestion (CVC), yet the cognitive tools used are largely adapted from stroke and dementia research. This review examines current literature on cognitive function in CVC, including conditions such as cerebral venous sinus thrombosis (CVST), idiopathic intracranial hypertension (IIH), and dural arteriovenous fistulas (dAVFs). Special emphasis is placed on the limitations of common screening tools like the Montreal Cognitive Assessment (MoCA) and Mini-Mental State Examination (MMSE). Cognitive dysfunction—primarily affecting executive function, processing speed, and attention—is reported in up to 86% of CVC cases, yet only about 20% of studies use validated cognitive testing tools, most of which may lack sensitivity for CVC-specific deficits. Emerging techniques such as ocular motor testing and physiological markers show promise but require further validation. There is an urgent need for standardized, CVC-specific cognitive assessment protocols that reflect the unique pathophysiology of venous disorders. Future research should prioritize the development of targeted cognitive batteries and integrate objective physiological measures to enhance diagnostic accuracy.

ABSTRACTBackgroundPercutaneous transluminal angioplasty and stenting (PTAS) in patients with carotid stenosis may have potential effects on brain parenchyma. However, current studies on parenchymal changes are scarce due to the need for advanced imaging modalities. Consequently, the alterations in brain parenchyma following PTAS remain an unsolved issue.PurposeTo investigate changes to the brain parenchyma using magnetic resonance elastography (MRE).Study TypeProspective.Population13 patients (6 women and 7 men; 39 MRI imaging sessions) with severe unilateral carotid stenosis patients indicated for PTAS were recruited between 2021 and 2024.Field Strength/SequenceNoncontrast MRI sequences including MRE (spin echo) were acquired using 3 T scanners.AssessmentAll patients underwent MRE before (preprocedural), within 24 h (early postprocedural) and 3 months after (delayed postprocedural) PTAS. Preprocedural and delayed postprocedural ultrasonographic peak systolic velocity (PSV) was recorded. MRE stiffness and damping ratio were evaluated via neural network inversion of the whole brain, in 14 gray matter (GM) and 12 white matter (WM) regions.Statistical TestsStiffness and damping ratio differences between each pair of MR sessions for each subject were identified by paired sample t tests. The correlations of stiffness and damping ratio with stenosis grade and ultrasonographic PSV dynamics were evaluated by Pearson correlation coefficients. The statistical significance was defined as p < 0.05.ResultsThe stiffness of lesion side insula, deep GM, and deep WM increased significantly from preprocedural to delayed postprocedural MRE. Increasing deep GM stiffness on the lesion side was positively correlated with the DSA stenosis grade significantly (r = 0.609). The lesion side insula stiffness increments were positively correlated with PSV decrements significantly (r = 0.664).Data ConclusionRegional brain stiffness increased 3 months after PTAS. Lesion side stiffness was positively correlated with stenosis grades in deep GM and PSV decrements in the insula.Evidence Level2.Technical EfficacyStage 2.

Abstract Front-line pharmaceutical interventions for treating acute graft-versus-host disease (GVHD) are not uniformly effective and have toxic side effects. Myeloid-derived suppressor cells (MDSCs) are a heterogeneous population of immature myeloid cells with potent in vitro and in vivo immunosuppressive functions. Clinical translation of in vitro–generated MDSCs has been limited because of requirements for multiple, high infusion doses, the relatively low yield from peripheral blood–sourced MDSCs (PB-MDSCs), and inconsistent product quality. To circumvent these obstacles, we developed a methodology to generate MDSCs using human induced pluripotent stem cell (iPSC)–derived CD34+ cells. Compared with PB-MDSCs, iPSC-derived MDSCs (iMDSCs) shared similar morphology, phenotype, and suppressive function. We found that the CD14+ iMDSC subset possessed the highest suppressor function. In previous studies, we reported that MDSCs transferred into mice with GVHD lost suppressor function because of inflammasome activation and immature myeloid cell maturation. In striking contrast to human PB-MDSCs, we show herein that iMDSCs retained 95% of suppressor function in vitro despite exposure to lipopolysaccharide (LPS) plus adenosine triphosphate (ATP), which are stimuli that activate the inflammasome via danger-associated molecular patterns released during early posttransplant conditioning and GVHD-induced injury. In an in vivo xenogenic GVHD model with PB mononuclear cells, iMDSCs significantly increased recipient survival without loss of antileukemia effects. iMDSC RNA sequencing and gene knockdown studies revealed that the maintenance of the purine metabolizing enzyme, phosphoglycerate dehydrogenase, during LPS plus ATP treatment, was linked to iMDSC inflammasome resistance. Taken together, these findings provide a platform for translating in vitro–generated, off-the-shelf iMDSCs into the clinic for suppressing a spectrum of adverse immune responses, including GVHD.

Background : The COVID-19 pandemic profoundly impacted healthcare, emphasizing the need to strengthen future pandemic responses and optimize resource allocation planning and deployment during times of disruption and crisis. Methods : This retrospective, single-center, cross-sectional study included participants ≤17 years-old admitted to the Children’s Hospital (CH) between 01/01/2017 and 12/31/2021. Clinical data was abstracted using Vizient ® Clinical Data Base and the internal data warehouse. Using the International Classification of Disease, 10 th Revision, Clinical Modification (ICD-10-CM) admit diagnosis, frequency and pattern of total admissions during the pre-pandemic phase (2017 Q1-2019 Q4) and intra-pandemic phase (2020 Q1-2021 Q4) were compared. Results : The study included 33,158 admissions. CH SARS-CoV-2 prevalence rate was 0.1% in 2020 and 0.5% in 2021. There was a decrease in overall admissions to the CH (p <0.01) and PICU (p <0.01) at the start of the pandemic. There were significant and variable differences in admission patterns for certain infectious, mental health, and seizure related diagnoses. Seasonality was noted for viral bronchiolitis during the pre-pandemic phase but was disrupted during the intra-pandemic phase with significantly lower admission rates for viral bronchiolitis in 2020 Q4 (p <0.05) and 2021 Q1 (p <0.01), followed by a significant early increase in viral bronchiolitis admissions in 2021 Q3 (p <0.01). Conclusion : The COVID-19 pandemic significantly impacted the number and pattern of admissions despite low SARS-CoV-2 prevalence in our hospital. These changes may be secondary to COVID-19 mitigation strategies implemented in the community. Results can inform anticipated patterns during future pandemics.

Abstract Background Methylation class pleomorphic xanthoastrocytoma (mcPXA) comprises tumors with the DNA methylation signature of classical PXA but with a wider histologic spectrum, including overlap with glioblastoma (GBM). Methods To clarify the histologic and molecular scope of mcPXA and characterize its clinical behavior, a cohort of 469 tumor samples from 458 patients matching to mcPXA by the DKFZ classifier (v12.6 score ≥0.85) was interrogated. Results Patient median age was 23 years (range 1-73 years) with a female predominance (259 female/199 male). CDKN2A/B homozygous deletion was observed in 406 of 469 (87%) samples. In samples tested for BRAF p.V600E mutations (n = 279), 240 (86%) harbored the mutation. A chr7+/chr10− pattern was observed in 103 of 469 (22%) samples. Among samples tested for TERT promoter mutations (n = 143), 32 (22%) harbored the mutation. Progression-free and overall survival of patients with mcPXA were comparable to patients with methylation class IDH-mutant astrocytoma, low grade, but a GBM-like subset (ie, cases with a pre-methylation working diagnosis of GBM) showed shorter survival. Histologic features of high grade, including palisading necrosis and microvascular proliferation, were prognostic in mcPXA. Compared to patients with BRAF p.V600E-altered GBM, patients with mcPXA were younger and had a lower frequency of TERT promoter mutations. Conclusion Tumors in mcPXA share molecular characteristics with histologically defined PXA, and high-grade histologic features can help predict their clinical behavior. The use of an epigenetic classification of PXA reveals that this group of tumors is more common than previously appreciated and warrants in-depth study to identify efficacious therapeutic options.

The Doppler twinkling artifact (TA) plays a crucial role in detecting some biopsy markers including those made of polymethyl methacrylate (PMMA), facilitating precise lymph node localization in diagnostic and therapeutic procedures. This study presents comprehensive signal processing analysis methods to quantify and characterize the TA phenomenon using raw, per-channel radiofrequency (RF) data acquired from PMMA markers scanned with an L7-4 linear array transducer. We evaluated signals at different stages along the image reconstruction pipeline including (1) beamforming, (2) beamformed RF signal conversion into in-phase/quadrature (IQ) signals, and (3) Doppler velocity calculations and image reconstruction. We analyzed changes of pulses within an ensemble and between ensembles (i.e., frames). We also evaluated the impact of wall filters with various cutoff frequencies on color and power Doppler image reconstruction. Comparative analysis between PMMA markers and a non-twinkling control sample demonstrated distinct TA signatures or lack thereof in color and power Doppler images. The IQ data from PMMA marker locations exhibiting TA signatures showed substantially higher variability compared to non-twinkling samples, with standard deviations approximately 20 times higher between ensembles and 5 times higher within ensembles. This quantitative analysis framework provides valuable insight into the TA signal, potentially leading to more reliable and accurate diagnostic interpretations.

The color Doppler twinkling artifact has been attributed to existing microbubbles or cavitation has been reported for objects with rough surfaces like kidney stones, sandpaper, and polymethyl methacrylate (PMMA) bone cement. Passive cavitation detection (PCD) is a method for determining the presence of bubble oscillation from subharmonic, ultraharmonic, and inharmonic components in the Fourier domain. We evaluated multiple PMMA samples with varying twinkling amounts as well as a non-twinkling metal rod. Ultrasound scans were conducted using a Verasonics L11-4v probe on a V1 system from 3–9 MHz Doppler transmit frequency. A Sonic Concepts Y-107 PCD probe connected to a JSR DPR300 pulser/receiver collected data during Doppler ultrasound transmission. The Fourier spectra showed increased magnitude trends in the midband frequency range between the fundamental, f, and second harmonic, 2f, on the twinkling samples compared to non-twinkling metal rod. The midband increase was highest at frequencies that showed the most twinkling. This work indicates that the presence of color Doppler twinkling signal on PMMA gives rise to additional peaks in the Fourier domain, particularly in the midband range. Additionally, as there were no distinct subharmonic peaks, the increased midband magnitudes could be due to cavitation on the rough surfaces of the PMMA.