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Importance Although adding immune checkpoint inhibitors to neoadjuvant chemotherapy improves outcomes in high-risk early-stage breast cancer, opportunities remain to further enhance response. Dual checkpoint blockade offers a potential strategy to further enhance efficacy. Objective To evaluate the combination of anti−programmed cell death 1 protein (PD-1) cemiplimab and anti−lymphocyte activation gene 3 (LAG-3) added to neoadjuvant therapy in ERBB2 -negative early-stage, high-risk breast cancer. Design, Setting, and Participants The I-SPY2 (Investigation of Serial Studies to Predict Your Therapeutic Response With Imaging and Molecular Analysis 2) is an ongoing randomized clinical platform trial being conducted at multiple US clinical sites including patients with early-stage (II or III) ERBB2 -negative, high-risk breast cancer. Participants, continuously enrolled since 2010, were adaptively randomized from February 2, 2020, to December 9, 2021, to one of several experimental neoadjuvant therapies or control groups based on receptor subtypes defined by hormone receptor (HR), ERBB2 status, and MammaPrint (Agendia Inc) molecular risk, categorized as high (MP1) or ultrahigh (MP2). Data were analyzed from January 1, 2022, to August 5, 2025. Interventions Both groups received weekly paclitaxel for 12 weeks, then doxorubicin and cyclophosphamide followed by surgery; concomitant with paclitaxel, the intervention group also received 4 doses of cemiplimab and fianlimab (PCF) every 3 weeks. Main Outcomes and Measures Pathologic complete response (pCR). Treatments graduated when they achieved 85% bayesian probability of success in a subtype-specific phase 3 trial. Pathway-specific biomarkers were assessed for response prediction. Results A total of 78 participants (mean [SD] age, 47 [39-54] years) were randomized to the intervention group, with 350 participants (mean [SD] age, 48 [39-57] years) randomized to the historical control population. PCF graduated in all clinical signatures, with pCR rates vs control of 44% (95% CI, 34%-53%) vs 21% (95% CI, 17%-25%) in all ERBB2 , 53% (95% CI, 39%-67%) vs 29% (95% CI, 22%-36%) in triple-negative, and 36% (95% CI, 23%-49%) vs 14% (95% CI, 9%-19%) in HR-positive and ERBB2 -negative disease. Among the total participants, 16 (21%) experienced adrenal insufficiency, including hypophysitis (11% grade 3 or 4), mostly occurring after immunotherapy completion. PCF was found to be highly effective in the subset of patients with immune signature positive status (ImPrint positive). Conclusions and Relevance In this randomized clinical trial, the combination of PD-1 and anti−LAG-3 inhibition with standard NAC was effective in early-stage ERBB2 -negative breast cancer, particularly in patients displaying a positive ImPrint immune signature. These results warrant further definitive trials. Trial Registration ClinicalTrials.gov Identifier: NCT01042379

Background Subjective cognitive decline (SCD) is a preclinical condition associated with an increased risk of dementia and Alzheimer’s disease, with no consensus regarding effective therapeutic interventions to date. As the global burden of aging-related neurodegenerative diseases continues to rise, early intervention has become increasingly critical. Cognitive training has been proposed as a promising behavioral intervention; however, few studies have integrated multimodal assessments to elucidate its underlying neurobiological and psychological mechanisms, particularly within the educational system that shapes cognitive reserve and learning strategies across the lifespan. This pilot study aims to estimate effect sizes for future definitive trials, assess the feasibility and acceptability of the intervention and multimodal evaluations, and generate hypotheses regarding the relationship between recitation practice and clinical biomarkers. Methods A total of 60 individuals with subjective cognitive decline will be enrolled in a randomized, assessor-blinded, controlled pilot study. Participants will be randomly assigned to either an intervention group or a non-active control group prior to baseline assessment. The intervention group will undergo a six-month structured recitation training program. Both groups will undergo short-term follow-up after the intervention, and long-term follow-up annually post-intervention. Multimodal assessments will include neuropsychological testing, functional magnetic resonance imaging (fMRI), electroencephalography (EEG), blood biomarker profiling, gut microbiota analysis, and fecal metabolomics. Discussion This study protocol outlines a randomized, assessor-blinded, controlled pilot study designed to advance understanding of the feasibility of Chinese Classics recitation training on both physiological and psychological outcomes in individuals with subjective cognitive decline. The findings are expected to provide mechanistic insights into non-pharmacological interventions and to address the current underrepresentation of Asian populations in neuroscience research. Clinical trial registration We registered this randomized controlled trial on ClinicalTrials.gov on March 11, 2026, under the identifier NCT07463391.

Abstract Objective To evaluate whether thyroid dysfunction, including hypothyroidism and hyperthyroidism, is associated with migraine across racial and age groups using a large, multinational electronic health record database. Background Thyroid disorders are highly prevalent worldwide, with hypothyroidism affecting over 200 million individuals and hyperthyroidism affecting approximately 2.5% of adults. Migraine is a leading cause of disability globally. Prior studies have suggested potential links between thyroid dysfunction and migraine, but evidence has been limited by small sample sizes, restricted population diversity, and inadequate control of confounding. Whether associations differ by thyroid subtype, race, or age remains unclear. Methods We performed two parallel retrospective cohort analyses within the TriNetX Global Collaborative Network, comprising over 200 million patients across 21 countries, using patient records from January 2004 to December 2024. Adults aged 18–100 years with hypothyroidism or hyperthyroidism, defined by ≥3 clinical encounters within 20 years, were identified. Individuals with psychiatric disorders (including mood, anxiety, and stress‐related disorders), sleep disorders, epilepsy or recurrent seizures, or known migraine‐related genetic mutations were excluded. Each thyroid cohort was compared with a control group without thyroid disease, with groups balanced on key demographic and clinical characteristics including age, sex, and hypertension; beta‐blocker use was additionally considered in the hyperthyroidism cohort. The primary outcome was diagnosis of migraine (International Classification of Diseases, 10th Revision, code G43) within 5 years of index date. Subgroup analyses were conducted by race (Caucasian, African American/Black, Asian) and age (18–40, 40–65, 65–100 years). Sensitivity analyses assessed robustness to alternative visit thresholds and expanded covariate adjustment. Results A total of 33,327,750 patients were included in the hypothyroidism analysis and 28,182,377 in the hyperthyroidism analysis. Baseline differences between groups were minimized after cohort balancing. Hypothyroidism was associated with higher odds of migraine across all racial groups, strongest among African American/Black (odds ratio [OR] 2.04; 95% confidence interval [CI] 1.91–2.17), followed by White (OR 1.93; 95% CI 1.89–1.96) and Asian (OR 1.83; 95% CI 1.69–1.98). Hyperthyroidism was similarly associated with increased migraine odds, most prominently among White (OR 1.64; 95% CI 1.59–1.70), with smaller but significant associations in African American/Black (OR 1.28; 95% CI 1.14–1.44) and Asian (OR 1.18; 95% CI 1.07–1.29). Elevated odds were observed across all age strata, generally increasing with age. Findings were consistent in sensitivity analyses. Conclusion In this large, multinational real‐world study, both hypothyroidism and hyperthyroidism were independently associated with increased migraine prevalence across diverse racial and age groups. These results highlight thyroid dysfunction as an important comorbid condition in migraine and support further prospective and mechanistic investigation.

LBA514 Background: Preclinical and clinical data show that antibody-drug conjugates (ADCs) such as T-DXd may synergize with immunotherapy. Rilvegostomig (R) is a monovalent, Fc-reduced, dual checkpoint bispecific IgG1 monoclonal antibody against PD-1 and TIGIT receptors. R + T-DXd was evaluated as neoadjuvant therapy for up to 4 cycles. Methods: I-SPY2.2 is a phase II neoadjuvant trial with three neoadjuvant sequences (Blocks A/B/C). All HER2-negative subtypes were eligible for R + T-DXd in Block A. Predicted responders at the end of Block A or B could undergo surgery; otherwise, they continued to Block B +/- C. Block B pts received paclitaxel +/- carboplatin +/- pembrolizumab and Block C pts doxorubicin + cyclophosphamide (AC) +/- pembrolizumab, HR+ immune+ received IO in Blocks B/C. Results are analyzed by receptor and response predictive subtypes (RPS), that include expression-based immune, and luminal signatures with hormone receptor (HR) and HER2 status. Some pts were randomized to a control regimen (skipping R + T-DXd in block A and starting in block B). To minimize risk of interstitial lung disease (ILD) that could lead to treatment discontinuation, pts underwent pulmonary function tests and high-resolution chest CTs every 6 weeks. Abnormalities were reviewed in real time. The primary endpoint was pathologic complete response (pCR), within each RPS and HR/HER2 signature, with estimated pCR (EpCR) rates compared to subtype-specific block A goal rates and control pts in those groups. Other endpoints included safety and treatment discontinuation. Results: 105 pts were treated with R + T-DXd in block A, while 31 pts were randomized to the control regimen. Block A EpCR rate was 57% in the 12 HR+Immune+ pts vs a pre-specified goal of 15% (posterior probability, PP > .99). In 35 HR-Immune+ pts EpCR was 52% vs a pre-specified goal of 40% (PP = .87). No other groups (Immune-) had a PP > .85 for their respective pCR goal rate. HER2-IHC was 0 (27.6%), 1+ (49.5%) and 2+ (22.9%) in the treatment arm vs. 37.7%, 37.7%, and 24.7% in the control arm, with no difference in distribution between arms in immune subtypes. The most common adverse events in Block A were fatigue (84.8%), nausea (81.0%) and alopecia (58.1%). ILD was the most common adverse event of special interest in Block A and overall, occurring in 12 pts (11.4%; 7G1, 4G2, 1G3) during Block A and in 3 pts (G1, 2.9%) in other Blocks. 8 pts discontinued T-DXd + R due to ILD and proceeded to the next Block. Conclusions: When considering the full treatment strategy including block B and C regimens, experimental strategies had similar EpCR rates vs. controls in immune+ subtypes but block A rates exceeded pre-defined goal thresholds. This infers that treatment beginning with R + T-DXd has equivalent efficacy to standard of care for immune+ pts, but 64% pts with pCR skip chemotherapy (Block B) and 97% avoid AC (Block C). R + T-DXd participants avoided persistent ILD. Clinical trial information: NCT01042379 .

625 Background: I-SPY 2 is a multicenter phase II adaptive platform trial evaluating novel agents for stage II-III high-risk breast cancer using response-predictive subtypes (RPS) and a sequential neoadjuvant treatment design of up to three blocks (A/B/C). Investigational regimens are given in Block A, followed by response-guided escalation to standard-of-care (SOC) therapy (tx) in subsequent blocks or early surgery for responders. Topoisomerase I (TOPO1) inhibition plus PARP inhibition may enhance DNA damage and tumor response. DAN-222 is a tumor-targeted polymeric camptothecin conjugate designed to improve the therapeutic index of TOPO1 inhibition. Based on favorable phase 1 safety and preliminary activity in metastatic breast cancer, DAN-222 plus niraparib was evaluated as Block A tx in HER2− disease. Notably, the neoadjuvant regimen used a higher dose of niraparib (200 mg daily) than the prior phase 1 metastatic study. Methods: Patients (pts) with HER2− breast cancer were randomized to DAN-222 plus niraparib for up to 12 weeks in Block A. Response was assessed by serial MRI and biopsy. Inadequate responders escalated early to SOC tx in Blocks B/C. Primary endpoint was pathologic complete response (pCR). Secondary endpoints included residual cancer burden, safety, early discontinuation, and treatment-strategy performance versus subtype-specific SOC tx controls. Given established PARPi sensitivity in BRCA mut disease, the key objective was to assess clinically meaningful activity of DAN-222 plus niraparib in BRCA wt pts. Accordingly, a prespecified Bayesian interim futility analysis focused on BRCA wt and tested the probability of the true pCR rate after Block A alone exceeded 15% after 50 pts. Results: Fifty pts enrolled from Sep to Dec 2024. In BRCA wt (n=47), estimated Block A pCR was 3%, with posterior probability of 0.02 that that true pCR exceeded 15%, meeting futility criteria and prompting arm closure. Across all blocks, pCR rate was 57% (8/14) for HR-HER2−; 11% (4/36) for HR+ HER2−, largely after SOC tx. 2/3 BRCA mut pts achieved pCR. Treatment strategies initiating with DAN-222 plus niraparib underperformed subtype-specific controls. 68% discontinued Block A early, mainly due to toxicity. Grade ≥3 cytopenias were common: neutropenia (n=25; 50%), anemia (24%), and thrombocytopenia (18%). Cystitis occurred in 36% (1 grade ≥3). Conclusions: Neoadjuvant DAN-222 plus niraparib showed insufficient activity and no treatment-strategy benefit in BRCA wt HER2− breast cancer, underscoring challenges for TOPO1–PARP inhibitor combinations. Although not supported for further development in this setting, these results highlight the strength of I-SPY 2 in rapidly enrolling patients and quickly distinguishing ineffective from promising therapeutic strategies to accelerate progress toward improved outcomes for patients with curable breast cancer. Clinical trial information: NCT01042379 .

Abstract Introduction Sepsis, a dysregulated immune response to infection, accounts for nearly 11 million deaths worldwide each year and remains a major cause of hospital mortality. The absence of precision diagnostics limits efforts to characterize immune dynamics and predict clinical outcomes. We evaluated whether liquid biopsies collected at ICU admission could provide insight into sepsis biology and enable precision diagnostics. Methods We applied cell-free RNA (cfRNA) liquid biopsies as a noninvasive method to highlight signaling networks, identify tissue-specific injury, and predict immune exhaustion. We collected serial samples throughout hospitalization from a cohort of 100 patients admitted with likely sepsis to a medical ICU. Comprehensive clinical data, including inpatient laboratory values and key outcome measures such as survival and ventilator-free days, were curated. Circulating cfRNA was isolated and purified from these samples and prepared for sequencing. We generated data from 254 samples at a minimum sequencing depth of 30x. We then designed a novel deep-learning computational method to enable deconvolution to better analyze and interpret these data. Results In our cohort, a total of 84 patients were adjudicated to have sepsis by the Sepsis-3 criteria, and 25 patients died within 90 days. Differential analysis was performed comparing circulating cfRNA in these septic patients to that of healthy controls, stratified by mortality along with specified subgroups including shock on admission, ventilator dependence, and preexisting immunosuppression. We identified multiple differentially expressed transcripts between septic patients and healthy controls, with significant alterations in signaling cascades associated with mitochondrial signaling, including alterations in oxidative phosphorylation and fatty acid metabolism. Using defined ligand-receptor interaction databases, we identified key pathways associated with immune and endothelial dysfunction in sepsis. Specifically, our analysis identified numerous alterations in CXCL8 (IL-8)-associated signaling cascades (engaging CXCR1, CXCR2, SDC1-3, and ACKR). Our analyses also highlighted key tissue factor pathway inhibitor (TFPI)-associated signaling via interactions with tissue factor and low-density lipoprotein receptor-related protein 1 (LRP1). These analyses are corroborated by our new deep-learning augmented approach to deconvolution, where we demonstrate the identification of rare tissue- and cell-specific signals that are associated with increased mortality in our cohort. Conclusion Liquid biopsy approaches such as cfRNA profiling can provide insight into mechanisms underlying sepsis and may uncover underlying drivers of endothelial dysfunction. These findings support ongoing efforts to develop liquid biopsy-based diagnostics and personalized therapeutic strategies for patients at high risk for sepsis and related mortality. This abstract is funded by: NIH

ABSTRACT Myelodysplastic syndrome (MDS) and chronic myelomonocytic leukemia (CMML) are clonal myeloid neoplasms shaped by genetic lesions and immune dysregulation, both of which contribute to disease progression and poor outcomes. Existing prognostic systems, such as IPSS‐R and IPSS‐M, do not incorporate immune alterations. We assessed the biological and clinical relevance of an immune dysfunction signature (IDS) across multi‐center MDS and CMML cohorts. IDS scores, derived from bulk transcriptomic data, were significantly associated with inferior leukemia‐free and overall survival. In multivariable analyses, IDS retained independent prognostic value alongside IPSS‐R, IPSS‐M, and bi‐allelic TP53 inactivation. Incorporation of IDS into existing models improved prognostic discrimination and time‐dependent predictive accuracy. Longitudinal analyses revealed that rising IDS scores paralleled disease progression and acute transformation, whereas declining scores were observed in remission. Biologically, IDS‐high cases demonstrated reduced cytotoxic T‐cell activity, expansion of regulatory T cells, enrichment of primitive progenitor signals, and increased expression of checkpoint pathway genes. These findings were validated across multiple independent MDS cohorts and consistently reproduced in CMML, where IDS also stratified risk and tracked disease evolution. Finally, integration with drug response signatures from the BeatAMLv2 cohort suggested potential therapeutic vulnerability of IDS‐high cases to multikinase and NF‐κB pathway inhibitors. These results establish IDS as a robust and dynamic biomarker in MDS and CMML, with applications in refined risk stratification, longitudinal disease monitoring, and guiding personalized therapeutic strategies targeting immune dysfunction. Trial Registration: #201709072RINC, #202109078RINB, #202207050RINB

Abstract Background : Traumatic encephalopathy syndrome (TES) is a clinical research construct used to identify individuals at risk for chronic traumatic encephalopathy (CTE) following exposure to repetitive head impacts (RHI). Adjudication of TES relies on clinical features such as progressive cognitive impairment and neurobehavioral dysregulation. Blood-based biomarkers and structural neuroimaging abnormalities have been associated with TES but are not part of the criteria. This study evaluated whether TES identification was associated with the combined contribution of cognitive performance, blood biomarkers, and structural neuroimaging measures across two well-characterized cohorts. Methods : Participants included 158 professional fighters from the Professional Athletes Brain Health Study and 149 former American football players from The DIAGNOSE CTE Research Project. Three indices were constructed representing complementary domains: a cognitive index reflecting cohort-specific cognitive features, a blood biomarker index including plasma neurofilament light chain, glial fibrillary acidic protein, total tau, tau phosphorylated at amino acid 231, and APOE -ε4 carrier status, and an imaging index comprising volumetric MRI measures of subcortical structures, ventricles, and corpus callosum subregions. Grouped weighted quantile sum regression models were estimated within each cohort to evaluate associations between these indices and TES while adjusting for age, race, competition status, and RHI exposure. Results : Multidomain models demonstrated improved model performance compared with single-domain models in both cohorts (PABHS: AUC=0.91, PPV=0.80; DIAGNOSE CTE: AUC=0.84, PPV=0.85). Biomarker and imaging indices contributed additional information across cohorts, although imaging contributions were more prominent in fighters whereas blood biomarker associations were stronger in football players. Conclusion : TES in RHI-exposed athletes was associated with a convergent clinicobiological profile observed across two independent cohorts with distinct exposure patterns. These findings support multidomain analytic frameworks for evaluating correlated biological signals in RHI-exposed populations and may inform future studies of TES and CTE.

Mediastinal radiation potentiates aortic stenosis and complicates its treatment. We compared the short and midterm-outcomes with transcatheter aortic valve replacement (TAVR) versus surgical aortic valve replacement (SAVR) in patients with prior mediastinal radiation. Electronic databases were searched from inception through December 2024. Dichotomous outcomes were pooled as risk ratios (RRs), and continuous outcomes were pooled as mean differences (MDs) with respective 95% confidence intervals (CIs). Six observational studies were identified, including 2458 TAVR patients and 1873 SAVR patients. In the short-term, TAVR was associated with lower rate of mortality (RR: 0.54; 95% CI: 0.34–0.88), atrial fibrillation (RR: 0.31; 95% CI: 0.15–0.65), acute kidney injury (RR: 0.75; 95% CI: 0.59–0.95), bleeding (RR: 0.37, 95% CI: 0.33–0.42), and shorter length of hospital stay (MD: −4.30; 95% CI: −5.45 to −3.15). One-year mortality was comparable between the 2 groups (RR: 1.04; 95% CI: 0.50–2.13). This meta-analysis of observational studies of patients with prior mediastinal radiation demonstrated that TAVR was associated with better short-term outcomes compared to SAVR. While 1-year mortality appeared similar between the 2 interventions, this finding should be interpreted with caution. However, randomized controlled trials are needed to validate these findings.