Citations

Abstract SWOG 1318 evaluated the feasibility of combining the tyrosine kinase inhibitor (TKI) dasatinib with prednisone and blinatumomab in older patients (pts) with Philadelphia chromosome positive (Ph+) B-acute lymphoblastic leukemia (ALL). Here, we present longer follow up (median follow up 5.6 years) with outcomes, predictors of response, and translational medicine studies. Methods: This trial was activated through the NCTN in January 2014 and closed to accrual in April 2021. Pt eligibility included: age > 65 years, Ph+ ALL, no evidence of central nervous system (CNS) disease, and adequate organ function. Treatment has been previously described (Blood Adv 2023; 7(7): 1279-85). Statistics: Categorical and quantitative endpoints comparisons used Fisher's exact and Wilcoxon tests. Survival endpoints used the Kaplan-Meier method and Cox regression models and were landmarked for post-baseline events as needed (i.e., number of cycles). Translational medicine studies: Single cell ATAC seq (10x genomics) was performed on 9 archived cryopreserved diagnostic samples from patients with > 500,000 cells. All samples successfully completed library preparation, sequencing, and demonstrated adequate blast clusters for analysis. Briefly, cryopreserved cells were thawed, and transposases were introduced into nuclei in single cell suspension and used to generate GEM beads. ATAC seq libraries were prepared per manufacture instructions. Libraries were then sequenced on a 25B flow cell on Novaseq X plus (Illumina). The data were analyzed with cloupe (version 9.0.0). Results: Twenty-four eligible patients were enrolled. The median age was 73 years (range 65-87). All pts had newly diagnosed Ph+ ALL. Seventy-nine percent of pts had additional cytogenetic abnormalities. Twenty-two pts (92%) achieved a complete remission (CR) during dasatinib and prednisone induction therapy. Most sites also monitored patient's blood or bone marrow with real-time quantitative PCR to quantify the BCR-ABL1 transcript for molecular response. Of 19 patients analyzed 17 (89%) were in a major or complete molecular remission at some point after treatment, with at least 12 of these patients achieving complete molecular remission. Three patients remain on maintenance. The median follow up for patients who are alive is 5.6 years (range 4.4-8.3). Five- year OS and DFS estimates are 63% (95% CI: 40-78%) and 64% (95% CI: 40-80%). Two patients relapsed in the CNS. One pt proceeded to allogeneic hematopoietic stem cell transplant (HSCT) and 1 to autologous HSCT. Increased age was associated with a decreased chance of achieving CR as best response (median age in responder group 73.2 years [range 65-82.9]; median age in non-responder group 85.5 [range 83.8-87.3]; p=0.02). Patients with extramedullary disease had shorter DFS (HR 0.22, 95% CI 0.04-1.15, p=0.07). Increased number of cycles of blinatumomab received was associated with a trend towards improved OS (HR 0.66, 95% CI 0.41-1.08, p=0.10). Translational medicine studies for chromatin accessibility in the blast clusters demonstrated improved OS in patients with homogeneous blast clusters (HR 0.42, 95% CI 0.06-3.04, p=0.39), high DUX4 differential accessibility (HR 0.26, 95% CI 0.03-2.55, p=0.25), and ATAC seq data corresponding to decreased chromatin accessibility in HOXA2 (HR 0.09, 95% CI 0.01-1.05. p=0.06). Conclusions: Despite an elderly population, this trial demonstrated impressive outcomes with longer follow-up for patients with Ph+ ALL. The number of cycles of blinatumomab and the presence of extramedullary disease may be important factors in outcome. Translational studies suggest additional markers may be predictors of overall survival, and these will need to be studied on larger scale studies. Decreased chromatin accessibility to HOXA2 was associated with a trend towards improved OS. Additional translational medicine will also be presented at the meeting.

Abstract Description Hypertensive disorders of pregnancy (HDP) include preeclampsia (PE) and gestational hypertension (gHTN), both suspected to be immune-driven pathologies. Our data shows that both PE and gHTN involve systemic immune cell activation and increased proinflammatory cytokines however it is unclear how these immune profiles play a role in the pathogenesis of disease. We hypothesize that pregnancies complicated with HDP have dysregulated immune profiles, including hyperactive T cells which are activating the vascular endothelium. We have investigated the circulating immune profiles of patients with normotensive (NT), PE or gHTN pregnancies at the RNA, protein and cellular levels, which show significant alterations in T cells, among others. We have seen increased levels of IL-6, CXCL9 and CXCL10 in the plasma of HDP patients vs NT, suggesting the polarization and recruitment of T cells. Using cytometry by time of flight (CyTOF), we have seen changes in expression of CD11a and CXCR3 on CD4+, CD8+ and yd T cells in HDP compared to NT. Single cell RNA sequencing of CD4+ and CD8+ T cells from PE vs NT shows increased expression of genes related to pathways such as allograft rejection, angiogenesis and cytokine signaling. Our in vitro co-culture experiments examine the ability of immune cells, specifically T cells, to activate endothelial cells. These studies will address the functional contribution of T cells to endothelial activation, which is a hallmark of the hypertension seen in HDP. Topic Categories Cellular Adhesion, Migration, and Inflammation (CAM)

Abstract Description Preeclampsia (PE) is a complication of pregnancy characterized by de novo hypertension after 20 weeks of gestation with end-organ damage. Even though symptoms of PE rapidly resolve after delivery, patients have higher incidence of cardiovascular diseases in the years postpartum. Immunological changes have been observed in PE but it is unknown if these are sustained in the postpartum period. Our goal was to address the immune changes in the first year postpartum in PE as compared to normotensive (NT) as well as nulliparous women. We saw that both PE and NT pregnancies had altered immune system, especially decreased CD14+ monocytes and increased circulating pro-inflammatory cytokines when compared to nulliparous patients even one year after delivery. Furthermore, our intracellular cytokine staining analysis following stimulation suggest altered response in the postpartum period in PE with a predominant anti-inflammatory response vs NT. Overall this work suggest that the immune system remains different from nulliparous women at 1 year postpartum, even in cases of normotensive pregnancies, and is further altered following PE-complicated pregnancies. Although further analysis is ongoing, this shows that the immune system does not go back to pre-pregnancy levels in the postpartum period and that changes induced by pregnancy are at least in part sustained. We will further expand this work to address the functional changes in immune cells and the mechanisms underlying these changes. Topic Categories Mucosal and Regional Immunology (MUC)

Purpose: The purpose of this study was to compare the height of velopharyngeal (VP) closure in relation to the palatal plane between individuals with velopharyngeal insufficiency (VPI) with or without cleft palate and individuals without cleft palate and with normal speech, considering the effects of age and sex. Method: Magnetic resonance imaging was used to analyze the height of VP closure in the midsagittal view during phonation of /i/ and /s/ sounds among 105 individuals with VPI and 45 individuals without cleft palate and normal speech. Results: Independent-samples t tests demonstrated that individuals with VPI display a significantly lower mean height of VP closure (3.7 mm) compared to individuals without cleft palate and normal speech during phonation of /i/ and /s/ sounds ( p < .001). Analysis of variance was used to evaluate the impact of age and sex on the height of VP closure. Significant differences were observed between the height of VP closure in individuals with VPI and those without cleft palate and normal speech across the age span during the production of /i/ and /s/ sounds. However, nonsignificant differences were found between the height of VP closure in males and females of the VPI group and those without cleft palate and normal speech during the production of these sounds. Conclusions: The results revealed the variations of the height of VP closure in relation to the palatal plane. These findings provide insights into the presurgical planning for individuals with VPI undergoing palatal surgeries, especially the location of pharyngeal flap insertion.

Abstract The brain avidly consumes glucose to fuel neurophysiology. Cancers of the brain, such as glioblastoma (GBM), relinquish physiological integrity and gain the ability to proliferate and invade healthy tissue. How brain cancers rewire glucose utilization to drive aggressive growth remains elusive. Here, we infused 13C-labeled glucose into patients and mice with brain cancer, coupled with quantitative metabolic flux analysis, to map the fates of glucose-derived carbon in tumor vs. cortex. Through the first direct and comprehensive measurements of carbon and nitrogen labeling in both cortex and glioma tissues, we uncover profound metabolic transformations. In human cortex, glucose carbons fuel essential physiologic processes including TCA cycle oxidation and neurotransmitter synthesis. Conversely, gliomas downregulate these processes and scavenge alternative carbon sources such as amino acids from the environment, repurposing glucose-derived carbons to generate molecules needed for proliferation and invasion. Targeting this metabolic rewiring in mice through dietary amino acid modulation selectively alters GBM metabolism, slows tumor growth, and augments the efficacy of standard-of-care treatments. These findings illuminate how aggressive brain tumors exploit glucose to suppress normal physiological activity in favor of malignant expansion and offer potential therapeutic strategies to enhance treatment outcomes.

Importance Treatment for cognitive dysfunction due to postacute sequelae of long COVID (ie, symptoms of fatigue, malaise, weakness, confusion that persist beyond 12 weeks after an initial COVID infection) remains a significant unmet need. Objective To test evidence-based rehabilitation strategies for improving cognitive symptoms in persons with long COVID. Design, Setting, and Participants This was a 5-arm, multicenter, randomized clinical trial of 3 remotely delivered interventions conducted between August 17, 2023, and June 10, 2024. The study took place at 22 trial sites and included the screening of individuals with cognitive long COVID. Interventions Participants were randomized to 1 of 5 arms: adaptive computerized cognitive training (BrainHQ [Posit Science]), cognitive-behavioral rehabilitation involving both group and individual counseling sessions (PASC-Cognitive Recovery [PASC-CoRE]) paired with BrainHQ, and transcranial direct current stimulation (tDCS) paired with BrainHQ. Two comparator arms were included as follows: unstructured computer puzzles and games (active comparator) and sham tDCS paired with BrainHQ. The interventions occurred 5 times per week over 10 weeks. Main Outcomes and Measures Cognitive and behavioral in-person assessments were performed at baseline, midintervention, at the end of intervention, and 3 months after the end of the intervention. The primary outcome measure was the modified Everyday Cognition Scale 2 (ECog2) completed at the end of the intervention compared to the baseline visit based on participant self-report looking back over the prior 7 days. Results A total of 378 individuals were screened, from which there were 328 participants (median [IQR] age, 48.0 [37.0-58.0] years; 241 female [73.5%]; race: 15 Asian [4.6%], 47 Black [14.3%], and 235 White [71.6%]; ethnicity: 52 Hispanic [15.9%]). None of the 3 active interventions demonstrated benefits on the modified ECog2 in the intention-to-treat population by the end of the intervention period. The adjusted differences in mean change were 0.0 (95% CI, −0.2 to 0.2) for BrainHQ vs active comparator, 0.1 (95% CI, −0.1 to 0.3) for PASC-CoRE + BrainHQ vs active comparator, 0.0 (95% CI, −0.2 to 0.2) for tDCS-active + BrainHQ vs tDCS-sham + BrainHQ, and 0.1 (95% CI, −0.1 to 0.3) for PASC-CoRE + BrainHQ vs BrainHQ alone. Secondary participant-reported outcomes and neuropsychological tests showed no differential benefits for any treatment arm. All 5 arms demonstrated some improvements over time on the modified ECog2 and on secondary outcomes. There were no serious adverse events attributable to the interventions. Conclusions and Relevance This phase 2 randomized clinical trial failed to demonstrate differential benefits for online cognitive training, a structured cognitive rehabilitation program, and tDCS for cognitive long COVID. Trial Registration ClinicalTrials.gov Identifier: NCT05965739 .

Background/Objectives: Family history is a known risk factor for multiple myeloma (MM) and its precursor condition, monoclonal gammopathy of undetermined significance (MGUS). Previous genome-wide association studies (GWASs) have identified 35 common loci associated with MM risk and 21 associated with MGUS. The objective of this study was to identify less common and rare genetic loci predisposing to MM/MGUS through whole-exome sequencing (WES)-based linkage analysis. Methods:Multipoint linkage analysis was conducted using the Multipoint Engine for Rapid Likelihood Inference (MERLIN) with the Lander–Green algorithm on germline WES data from 79 pedigrees with 2 or more affected relatives (120 MM, 86 MGUS, and 21 unaffected). Genome-wide linkage was evaluated using 12,946 independent single-nucleotide variants (linkage disequilibrium r2 < 0.05). Results: Significant linkage was observed at chromosome 6q22.33–q24.2 by the non-parametric model (logarithm-of-odds (LOD) = 3.3) and suggestive linkage by the dominant parametric model (heterogeneity LOD (HLOD) = 2.5). Fourteen rare variants within this region were prioritized using family-specific partial LOD scores and in silico functional prediction tools. Nine of these variants, REPS1, THEMIS, TAAR6, AHI1, VNN1, VNN3, MTFR2/FAM54A, LAMA2, and PHACTR2, overlapped immune-regulatory regions in blood cell lines and were not previously identified in GWASs. Conclusions: This study demonstrates the utility of applying a linkage analysis framework to familial WES data for identifying genomic regions and candidate genes that may contribute to MM/MGUS predisposition. These findings provide new insight into the inherited risk and etiology of familial MM and MGUS.

ABSTRACT Pulmonary hypertension (PH) is a common complication in interstitial lung disease (ILD), but the additional burden it imposes on patients and healthcare systems is not well characterized. This retrospective analysis of claims data from the US Merative MarketScan database assessed hospitalization rates and costs over 2 years in patients with connective tissue disease‐related ILD (CTD‐ILD) and non‐CTD‐ILD with or without PH (between January 2017 and December 2019). Index was the date of first ILD claim; baseline was the 12‐month preindex period. In total, 16,129 patients with non‐CTD‐ILD (1502 [9%] with PH) and 4545 patients with CTD‐ILD (663 [15%] with PH) were identified. A higher proportion of patients with non‐CTD‐ILD with PH, compared with patients without PH, had all‐cause and heart failure (HF)‐related hospitalizations during baseline (all‐cause, 37.0% vs. 22.3%; HF‐related, 14.2% vs. 3.1%), 0–12 months (62.4% vs. 43.0%; 29.0% vs. 7.0%), and 13–24 months (44.7% vs. 18.3%; 21.5% vs. 3.2%) follow‐up ( p < 0.0001 for all). A significantly higher proportion of patients with CTD‐ILD with PH, compared with patients without PH, had all‐cause and HF‐related hospitalizations during baseline (all‐cause: 30.0% vs. 20.6%; HF‐related: 9.1% vs. 1.9%), 0–12 months (41.9% vs. 29.1%; 15.5% vs. 3.9%), and 13–24 months (37.9% vs. 18.9%; 13.9% vs. 2.5%) follow‐up ( p < 0.0001 for all). In both cohorts, total all‐cause and HF‐related costs were significantly higher in patients with PH at baseline, 0–12 months, and 13–24 months follow‐up ( p < 0.05 for all). PH substantially increased hospitalization risks and costs in both types of ILD, underscoring the importance of improving outcomes in patients with ILD‐PH.

ABSTRACT INTRODUCTION Neighborhood deprivation increases dementia risk, although mechanisms remain unclear. We tested a framework in which modifiable risk factors and cerebral small vessel disease (SVD) mediate the link between neighborhood deprivation and cognition. METHODS In 585 cognitively healthy midlife adults (ages 40–59), neighborhood deprivation was derived from postcodes, cognition was assessed using the COGNITO, lifestyle risk factors were measured using clinical assessments, and SVD (white matter hyperintensities, lacunes, microbleeds, perivascular spaces) was assessed on 3T magnetic resonance imaging. Multivariate analyses examined association pathways among these variables. RESULTS Neighborhood deprivation was associated with poorer cognition ( r = 0.36, p < 0.001), greater prevalence of modifiable risk factors ( r = 0.36, p < 0.001), and greater SVD burden ( β = 0.18, p = 0.008). Serial mediation showed that the effects of deprivation on cognition were indirect, possibly operating via lifestyle risk and SVD, explaining 20% of the total effect, whereas SVD alone explained 28%. DISCUSSION Neighborhood disadvantage relates to poorer cognition, possibly mediated through vascular risk factors and cerebrovascular disease. Highlights Neighborhood deprivation linked to poorer cognition in healthy midlife adults Deprivation linked to small vessel disease (SVD) and modifiable risk factors (chiefly cardiovascular risk) Association between deprivation and cognition mediated by modifiable risk and SVD Mediation was exclusive to hypertensive SVD, but not cerebral amyloid angiopathy (CAA)‐related SVD

Background: Breast cancer polygenic risk scores (PRS) and traditional risk models (e.g., the Gail model [Gail]) are known to contribute largely independent information, but it is unclear how the overlap varies by ancestry, age, disease type (invasive breast cancer, DCIS), and risk threshold. Methods: In a retrospective case–control study, we evaluated risk prediction performance in 180,398 women (161,849 of European ancestry; 18,549 of Asian ancestry). Odds ratios (ORs) from logistic regression models and the area under the receiver operating characteristic curve (AUC) were estimated. Results: PRS for invasive disease showed a stronger association in younger (<50 years) women (OR = 2.51, AUC = 0.622) than in women ≥ 50 years (OR = 2.06, AUC = 0.653) of European ancestry. PRS performance in Asians was lower (OR range = 1.62–1.64, AUC = 0.551–0.600). Gail performance was modest across groups and poor in younger Asian women (OR = 0.94–0.99, AUC = 0.523–0.533). Age interactions were observed for both PRS (p < 0.001) and Gail (p < 0.001) in Europeans, whereas in Asians, age interaction was observed only for Gail (invasive: p < 0.001; DCIS: p = 0.002). PRS identified more high-risk individuals than Gail in Asian populations, especially ≥50 years, while Gail identified more in Europeans. Overlap between PRS, Gail, and family history was limited at higher thresholds. Calibration analysis, comparing empirical and model-based ROC curves, showed divergence for both PRS and Gail (p < 0.001), which indicates miscalibration. In Europeans, family history and prior biopsies drove Gail discrimination. In younger Asians, age at first live birth was influential. Conclusions: PRS adds value to risk stratification beyond traditional tools, especially in younger women and Asian ancestry populations.