Citations

Abstract Purpose: Knowledge of prognostic factors and long-term survival in patients with diffuse hemispheric glioma, H3 G34–mutant (DHG, H3 G34), remains limited in this tumor with a poor prognosis. Experimental Design: This retrospective, multi-institutional study investigated prognostic variables for patients with DHG, H3 G34, and their association with progression-free survival (PFS) and overall survival (OS). Uni- and multivariable Cox proportional hazard models were applied with multiple imputed datasets. Results: A total of 153 patients (142 G34R, 9 G34V, 2 via DNA methylation) were included. The median age at diagnosis was 17 years (range, 2–45). Initial gross/near total resection (GTR/NTR) was achieved in 43% of patients. Radiation was given in 91% (85% focal irradiation), and initial chemotherapy was given in 87% [70% temozolomide-based (TMZ), 25% TMZ/lomustine, 5% non-TMZ]. Median OS was 24 months [interquartile range (IQR), 22–28] with a median PFS of 14 months (IQR, 12–19). Twelve patients (8%) were found to be long-term survivors (≥5 years). Exploratory multivariable analysis showed that adjuvant radiotherapy [HR, 0.076; 95% confidence interval (CI), 0.033–0.17] and achieving GTR/NTR compared with < NTR (HR, 0.51; 95% CI, 0.33–0.78) were associated with improved PFS. Multivariable analysis showed improved OS with increasing age at diagnosis (HR, 0.70; 95% CI, 0.57–0.87), initial radiotherapy (HR, 0.38; 95% CI, 0.15–0.96), and initial GTR/NTR compared with < NTR (HR, 0.60; 95% CI, 0.37–0.97). Conclusions: This cohort highlights prognostic factors for patients with DHG, H3 G34, and describes relapse patterns and therapy approaches. Clinical trials and prospective registries are needed to improve outcomes.

Abstract Myocardial infarction (MI) triggers a systemic neutrophil response, yet the roles of distinct neutrophil subsets in cardiac remodeling remain unclear. Studying this requires murine models that accurately mirror human neutrophil dynamics. Here, we show that a minimally invasive intact-chest MI model is more pathophysiologically relevant than the standard open-chest approach for investigating post-MI immune responses. In the open-chest model, surgical trauma disrupts bone marrow homeostasis, releases large numbers of immature neutrophils, and masks MI-specific immune mechanisms. In contrast, the intact-chest model preserves bone marrow integrity and induces only a modest rise in circulating immature neutrophils, closely reflecting MI patient profiles. We further demonstrate that accumulation of immature neutrophils in the infarcted heart exacerbates cardiac dysfunction. Beyond neutrophils, the overall cardiac immune landscape differs markedly between both models. Collectively, our findings establish the intact-chest model as superior for studying post-MI inflammation and reveal immature neutrophils as mediators of adverse cardiac remodeling.

ABSTRACT Polyprenal reductase is an enzyme encoded by the SRD5A3 gene, which is involved in the synthesis of dolichol from polyprenol. Dolichol serves as a carrier for glycan precursors or monosaccharides in N‐linked glycosylation. Pathogenic variants in SRD5A3 can result in a congenital disorder of glycosylation (CDG), SRD5A3‐CDG, which is inherited in an autosomal recessive manner. Most plasma proteins are glycosylated and changes in the glycosylation of several glycoproteins are associated with pathological consequences. Despite the critical role of SRD5A3 in glycosylation, the impact of its deficiency on the glycosylation of serum proteins remains largely unexplored. In this study, we used tandem mass tag‐based multiplexed quantitative approach to analyze serum N‐glycoproteomics and proteomics in SRD5A3‐CDG patients and controls. We quantified 2200 serum N‐glycopeptides from 359 N‐glycosites from 204 serum proteins. Extensive hypoglycosylation of serum proteins was observed in patients, with 245 of 291 altered glycopeptides decreased in SRD5A3‐CDG. Altered glycopeptides included those derived from haptoglobin, plasma serine protease inhibitor, alpha‐1‐B glycoprotein, alpha‐2‐macroglobulin, and ceruloplasmin. Some of these proteins have previously been reported to be associated with liver dysfunction, anemia, and coagulopathy, which could underlie similar clinical features observed in SRD5A3‐CDG patients. Overall, our study provides novel insights into alterations in the glycosylation status of specific serum proteins in SRD5A3‐CDG. Some of these alterations could be further pursued to develop glycopeptide‐based biomarkers as the current diagnosis of SRD5A3‐CDG by screening assays remains challenging. In addition, knowledge of altered glycoproteins could enhance our understanding of the disease spectrum and potentially unveil additional therapeutic avenues.

Abstract INTRODUCTION The tau positron emission tomography (PET) overlap index (OI) has shown promise in maximizing signal‐to‐noise for longitudinal tau PET imaging, particularly for early tau pathology, but requires validation against neuropathology. METHODS Fifty‐seven participants who underwent serial tau PET imaging (flortaucipir) and subsequent autopsy were included. Tau PET OI and standardized uptake value ratios (SUVRs) were compared across neuropathological diagnoses. RESULTS Tau PET OI showed greater concordance with neurofibrillary tangle (NFT) severity in the entorhinal cortex (a key region for Alzheimer's disease [AD] tauopathy) than SUVR, particularly in early Braak tangle stages (positivity: 52.2% for OI vs. 13.0% for SUVR). OI detected overlapping tau voxels that exhibited spatial correspondence with immunohistochemical and autoradiography measures of tau deposition across both AD and non‐AD tauopathies. DISCUSSION These findings demonstrate the enhanced capacity of OI in serial tau PET to robustly detect early and spatially localized tau pathology, supporting its application as a sensitive imaging metric in AD and select non‐AD tauopathies.

ABSTRACT Background Primary lateral sclerosis (PLS) is an ultrarare upper motor neuron syndrome with a prognosis unique from classical ALS. The study of PLS is complicated by its rarity and the difficulty distinguishing PLS from ALS. We present data from a 1‐year prospective follow‐up study on PLS and efforts to distinguish it from ALS. Methods Seventy‐six PLS participants enrolled in this prospective natural history study. EMG studies, blood neurofilament light chain levels (NfLs), and demographic characteristics were obtained at baseline. At 1‐year follow‐up, repeat EMG studies were conducted to determine which participants fulfilled criteria for ALS. Baseline characteristics were then compared to determine features that predict reclassification. Results Seventy participants completed 1‐year follow‐up. Five of the 70 were reclassified to ALS (7.1%). Those reclassified had higher trends in baseline blood NfL levels (91.4 vs. 34.0 pg/mL, p = 0.13) and shorter symptom duration (39 vs. 69 months in the PLS group, p = 0.15). Reclassification was noted in both probable and definite PLS participants. All cases with a symptomatic duration of less than 2 years retained the PLS phenotype (5 of 5). NfL levels over 90 pg/mL predicted reclassification with 94% specificity and 60% sensitivity. No other features predicted reclassification to ALS. Conclusions In our population, reclassification of PLS to ALS occurred at a low frequency at 1 year follow‐up (7.1%). Baseline NfL was the strongest predictor in differentiating UMN dominant ALS from PLS at 1‐year follow‐up. Based on our data, we propose EMG and NfL criteria for enrollment in future PLS trials.

BACKGROUND: Left ventricular (LV) dysfunction is a potential cardioembolic source of ischemic stroke, but its role in recurrent stroke risk and treatment response remains unclear. We explore whether LV injury associates with the risk of recurrent stroke and modifies the association between anticoagulation and stroke recurrence using real-world data. METHODS: We performed a multicenter, retrospective study of Cardiac Abnormalities in Stroke Prevention and Recurrence cohort across 27 US sites. Patients with LV ejection fraction ≥20% were included. LV injury, defined as LV ejection fraction 20% to 40% and wall motion abnormality, was the primary exposure and treatment effect modifier. The treatment of interest was anticoagulant versus antiplatelet therapy. The composite outcome included recurrent stroke, major bleeding, or death. Outcomes were evaluated using unadjusted and inverse probability weighting adjusted Cox proportional hazards models, with treatment effect modification tested by LV injury status. RESULTS: Among 2685 patients enrolled, 2328 with complete data were analyzed (median age, 65 years; 49.8% female; median follow-up, 1.6 years). LV injury was present in 310 patients (13.3%). Overall, 535 events occurred: 258 recurrent ischemic strokes, 28 hemorrhagic strokes, 67 major hemorrhages, and 256 deaths. LV injury was associated with a higher unadjusted risk of the primary outcome (hazard ratio [HR], 1.51 [95% CI, 1.21–1.87]), though nonsignificant after inverse probability weighting adjustment (adjusted HR, 1.29 [95% CI, 0.97–1.70]). In the LV injury subgroup, anticoagulation versus antiplatelet therapy was associated with a lower risk of the primary outcome (adjusted HR, 0.24 [95% CI, 0.10–0.59]), relative to the non-LV injury subgroup (adjusted HR, 1.28 [95% CI, 0.83–1.95]; p[LV-interaction], 0.001). Similar interactions were seen for EF 20% to 40% (versus >40%; adjusted HR, 0.19 [95% CI, 0.04–0.86]; p[LV-interaction], 0.001) and wall motion abnormality (versus no wall motion abnormality; adjusted HR, 0.33 [95% CI, 0.15–0.73]). CONCLUSIONS: After cryptogenic stroke, anticoagulation in those with LV injury was associated with lower rates of recurrent stroke, major bleeding, and death. These findings warrant confirmation in a dedicated randomized controlled trial. REGISTRATION: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT06398366.

ABSTRACT Hospital‐at‐Home (HaH) programs provide acute care in patients' homes, reducing hospitalization and improving patient experience. While crucial in traditional settings, antimicrobial stewardship (AMS) in HaH programs remains understudied. This manuscript explores the potential benefits of AMS in HaH and the role of infectious diseases (ID) pharmacists in optimizing antimicrobial therapy. Key challenges in implementing AMS in HaH include medication delivery logistics, treatment regimen adjustments, and unique administration techniques. ID pharmacists can address these challenges by providing expertise in antimicrobial selection, dosing, and duration, as well as identifying opportunities for de‐escalation and intravenous (IV) to oral conversions. By integrating AMS into HaH programs, health care systems can improve patient outcomes, reduce antimicrobial resistance, and optimize resource utilization. Further research and training programs are needed to fully realize the potential of AMS in this emerging model of care.

Abstract Background While immune checkpoint inhibitors (ICIs) provide durable clinical benefit in a subset of patients, current biomarkers to predict response lack accuracy. Ex vivo cytokine profiling has shown promise for improved accuracy but has been mostly limited to ICIs targeting PD-1 [Voabil et al, 2021]. This poses the question of whether ICIs beyond αPD-1 – such as CTLA4 blockade, which has been reported to act within the draining lymph node – would be amenable to similar approaches. The Elephas platform characterizes response to ICIs in live tumor fragments (LTFs) from core needle biopsies (CNBs) and resections using longitudinal cytokine profiling. Using a panel of 7 clinically relevant ICI regimens, we demonstrate cytokine responses across diverse tumor types, characterize similarities and differences in cytokine response profiles across different ICIs, and explore specimen variability in responses across ICI treatments. Methods CNBs were collected through 3 observational clinical trials (NCT05478538, NCT05520099, NCT0634962) and a biobank collection study, while resections were procured from NCI CHTN. LTFs were generated using an automated cutting device and encapsulated in hydrogel. LTFs were treated with mono (αPD-1, αPD-L1, αCTLA4, αLAG-3) or combination therapy (αPD-1/αCTLA4, αPD-1/αLAG-3, αPD-L1/αCTLA4) using a sequential treatment strategy in which isotype control followed by ICI were added to the same tissue in a single well. This approach enabled the comparison of control and treatment conditions while mitigating the effects of tumor heterogeneity. Production rates for 46 cytokines were measured using a multiplex assay. Remaining T-cell reactivity was also evaluated at the end of the assay to better understand the presence of functional T cells in LTFs. Results Unsupervised hierarchical clustering of cytokine profiling data from CNB LTFs across 129 patients identified defined responder and non-responder clusters. Within the response cluster, 4 subclusters with distinct immune phenotypes were identified. While tight clustering of samples treated with the same ICI was not observed, some enrichment of samples treated with combination ICIs was observed within individual subclusters. Further, cytokine responses to αCTLA4 monotherapy were observed, suggesting that CTLA4 blockade may act beyond the draining lymph node. LTFs from resections enabled the characterization of cytokine response profiles across treatment conditions within individual specimens, including the magnitude of cytokine response and variability in cytokine response profiles. Evaluation of T-cell reactivity provided further insight into the presence of functional T-cells in LTFs and the extent of T-cell activation achieved by ICI treatment. Conclusions This study demonstrates the platform’s ability to recapitulate diverse mechanisms of immune activation ex vivo, enabling the characterization of cytokine responses to clinically relevant ICI mono or combination therapy in live tumor tissue and supporting future efforts to improve ICI response prediction beyond αPD-1. Citation Format: Pichet Adstamongkonkul, Pierre Cunin, Santanu Bhattacharya, Tanmay Kulkarni, Amreen Nasreen, Nathan Marhefke, Nina Chen, T S. Ramasubramanian, Laura Hrycyniak, Julie Zweng, Erika von Euw, Christina Vivelo, Sean Caenepeel, Debabrata Mukhopadhyay, Hinco Gierman, Hilario Ramos. Characterization of αPD1, αPD-L1, αCTLA4, and αLAG3 as mono and combination therapy in live tumor fragments using an ex vivo cytokine profiling platform [abstract]. In: Proceedings of the AACR Immuno-Oncology Conference (AACR IO): Discovery and Innovation in Cancer Immunology: Revolutionizing Treatment through Immunotherapy; 2026 Feb 18-21; Los Angeles, CA. Philadelphia (PA): AACR; Cancer Immunol Res 2026;14(2 Suppl):Abstract nr B032.

Abstract Background PALLAS trial compared palbociclib plus endocrine therapy (ET) vs. ET alone in stage II-III HR+/HER2- breast cancer. SETER/PR index quantifies transcriptional activity related to estrogen and progesterone receptors and serves as a measure of endocrine sensitivity. In CALGB 9741, low SETER/PR (< 0.75) - reflecting endocrine resistance - predicted survival benefit from adjuvant anthracycline/taxane-based treatment. In PALLAS low SETER/PR was associated with worse prognosis and early recurrence. Early recurrences driven by endocrine-resistant tumors may obscure the benefit of palbociclib by disproportionately contributing events from a more resistant population. We hypothesized that palbociclib efficacy might vary by endocrine sensitivity and prior chemotherapy regimen, with greatest benefit in patients with intermediate SETER/PR index. Methods Invasive disease-free survival (iDFS) was summarized with Kaplan-Meier plots and the treatment arms were compared with a log-rank test. Cox models estimated the hazard ratio (HR) with 95% confidence interval (95%CI) (significance level used was a two-sided 0.05). SETER/PR index was successfully obtained for 3,090 PALLAS patients (TransPALLAS ITT cohort, Metzger et al. ASCO 2024). SETER/PR index cut points (0.75 and 1.50) were proposed from previous studies comparing different adjuvant chemotherapy regimens. Results Table 1 summarizes the efficacy of adjuvant palbociclib by prior (neo)adjuvant chemotherapy regimen. Palbociclib was associated with longer iDFS in the group who received prior anthracycline-paclitaxel chemotherapy (AC-P), though the chemo regimen x palbociclib interaction term was not significant (Table 1). In the 1,132 patients from the TransPALLAS cohort who received AC-P chemotherapy, the 518 (46%) patients with intermediate SETER/PR (0.75≤ SETER/PR <1.50) had longer iDFS with palbociclib (HR 0.58; 95% CI: 0.40-0.84; p=0.004; 7-yr iDFS 80.2% vs. 68.4%), but this subset did not predict palbociclib benefit relative to all others, i.e., 206 (18%) patients with low SETER/PR (<0.75) and 408 (36%) high SETER/PR (≥1.50); P interaction=0.11. Exploratory analysis of SETER/PR index as a continuous variable in patients who received prior AC-P chemotherapy revealed a non-linear relationship with the hazard ratio favoring palbociclib observed in the subset with SETER/PR values between 1.1 and 1.8, compared to all others (P interaction=0.01). Conclusions In PALLAS, we observed a numerical benefit favoring palbociclib among pts treated with adjuvant AC-P; in this subset a moderate level of endocrine transcriptional activity (SETER/PR index between 1.1 and 1.8) predicted palbociclib benefit. These results are hypothesis-generating. Citation Format: O. Metzger, P. O'Brien, K. Ballman, M. Gnant, M. Watson, E. Chen, K. Tran, D. Hlauschek, M. Martin, J. Balko, Z. Nowecki, O. Hahn, C. Denkert, C. Curtis, F. Liu, A. Dueck, C. Fesl, E. Mayer, A. De Michele, W. Symmans. Exploratory analysis of palbociclib benefit in the PALLAS trial by SETERPR index and prior chemotherapy regimens (ABCSG-42/AFT-05/BIG-14-13) [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2025; 2025 Dec 9-12; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2026;32(4 Suppl):Abstract nr PS3-08-13.