Citations

Importance Left atrial appendage occlusion (LAAO) is used in patients with contraindications to oral anticoagulation, who are at increased risk for major bleeding (MB). Objective To evaluate the incidence, predictors, management, and clinical outcomes of MB after LAAO in the Amulet IDE trial. Design, Setting, and Participants The randomized clinical Amulet IDE trial enrolled patients from 2016 through 2019 with 5-year follow-up. Procedures were performed at specialized LAAO centers. Of 1878 randomized patients (1:1 Amulet vs Watchman), 1833 underwent attempted LAAO implantation. These data were analyzed from May 2025 through November 2025. Main Outcomes and Measures Pooled (Amulet and Watchman) patients with vs without MB (Bleeding Academic Research Consortium [BARC] score ≥3: overt bleeding with transfusion and ≥3 g/dL hemoglobin drop) were compared. Results This study included a total of 1833 patients (57.7% male and 42.3% female; mean [SD] age, 75.8 [7.5] years). MB occurred in 331 patients (18.1%) over 5 years (annualized rate 5.9% per year). Patients with MB were older (76.8 vs 74.7 years) and had higher CHA 2 DS 2 -VASc (4.8 vs 4.6) and HAS-BLED (3.4 vs 3.2) scores, as well as greater prevalence of diabetes (38.7% vs 34.1%), prior MB (45.3% vs 28.0%), and kidney disease (9.4% vs 4.5%). MB risk was highest in the first 6 months after LAAO (20.5% per year), then decreased to 3.9% per year through 5 years. Most MB events were nonprocedural (88.8%) with gastrointestinal bleeding accounting for 252 of 438 events. Independent predictors of MB included increasing age (hazard ratio [HR], 1.04; 95% CI, 1.02-1.06), female sex (HR, 1.25; 95% CI, 1.01-1.56), diabetes (HR, 1.26; 95% CI, 1.01-1.58), prior MB (HR, 1.93; 95% CI, 1.55-2.40), and kidney disease (HR, 2.15; 95% CI, 1.48, 3.12). At first MB event, 47.1% of patients were not receiving antithrombotic therapy and 92 patients had recurrent events. Patients with MB had significantly higher rates of the composite of stroke, systemic embolism, or cardiovascular death (32.5% vs 18.0%; P < .001), driven by higher stroke (14.7% vs 6.6%) and cardiovascular death (24.4% vs 12.9%) rates. All-cause mortality was also higher (49.2% vs 25.4%; P < .001). MB was fatal (BARC score of 5) in 25 patients (1.4%). Conclusions and Relevance In this study, MB was common in this high-risk population and largely related to underlying patient factors. Early MB risk was highest 6 months post-LAAO, then dropped considerably. Most events were gastrointestinal and occurred even in patients on minimal or no antithrombotic therapy. MB after LAAO was strongly associated with increased stroke and mortality. Trial Registration ClinicalTrials.gov Identifier: NCT02879448

Glioma-associated microglia/macrophages (GAMs) have traditionally been described as immunosuppressive. However, within their highly heterogeneous repertoire, pro-phagocytic and cytotoxic subsets with anti-tumoral properties exist. Although macrophages (MACs) can exhibit tumor-suppressive functions, their anti-glioma properties largely remain elusive. To identify anti-glioma myeloid cell effectors, we performed directionally concatenated ligand-receptor (L-R) interactome analyses from dendritic cells (DCs) and microglia (MG) to lymphoid (CD4 + T, Tregs, CD8 + T, NK, and NKT) cells identified by our recent single-cell transcriptomics interrogation of tumor-associated CD45 + leukocytes from tumor brains of eighteen isocitrate dehydrogenase (IDH)–stratified glioma patients. Within DC-specific and MG-specific interactomes, we identified LGALS9 , which encodes Galectin-9, as a key mediator of cell–cell interactions in IDH-wild type (IDH-wt) gliomas. Spectral cytometry, immunohistochemistry, and Western blotting analyses confirmed the abundant expression of Galectin-9 in glioma-associated MG, but not in tumor cells. Furthermore, differential gene enrichment analyses revealed transcripts associated with cellular adhesion (coronin 1A, integrin) and phagocytosis (FcγR, phospholipase D, Rab family proteins, etc.) pathways that were significantly upregulated in Galectin-9 + compared to Galectin-9 − MG and MACs. Using an ex-vivo primary human microglia (pMG) and patient-derived glioma stem cells (GSCs) co-culture system, we evaluated the functional role of Galectin-9. Confocal imaging analyses of co-cultured pMG with GSCs revealed that siRNA-mediated knockdown or antibody-based neutralization of Galectin-9 significantly impaired pMG–GSC adhesion. In addition to reduced adhesion, phagocytosis of GSCs was dramatically attenuated across all Galectin-9 silenced or neutralized pMG. Altogether, our study underscores the unappreciated non-canonical role of Galectin-9 in MG as a regulator of glioma cell adhesion and phagocytosis that can be harnessed for glioblastoma immunotherapy.

Summary Evidence for an association between insulin‐like growth factors (IGF) and multiple myeloma (MM) is inconsistent. We examined total IGF‐I concentrations and risk of MM by combining baseline serological data among UK Biobank participants ( n = 444 187; 732 incident MM) with a two‐sample Mendelian randomisation (MR) analysis using identified genetic variants associated with circulating total IGF‐I and IGF‐binding protein 3 (IGFBP‐3) in the InterLymph consortium (2434 MM and their 2567 controls). Finally, additional lymphoid neoplasm (LN) subtypes were included for comparison with the main hypothesis. Circulating IGF‐I level was positively associated with MM risk Hazard ratio‐HR‐per one standard deviation‐SD‐increase (HR 1‐SD = 1.11, 95% confidence interval [CI]: 1.01–1.22; p ‐value = 0.03), especially closer to diagnosis. Genetically inferred IGF‐I levels were associated with increased MM risk (odds ratio [OR] = 1.27, 95% CI: 1.05–1.54) but not with any other LNs. Genetically inferred IGFBP‐3 levels showed no associations with any LN evaluated. Corroborating previous findings, in a secondary analysis, IGF‐I levels were associated with the risk of chronic lymphocytic leukaemia/small lymphocytic lymphoma (CLL/SLL) in males with higher body mass index (HR 1‐SD in obese male = 1.36, 95% CI: 1.14–1.61). Our serological and MR analyses suggest a contributing role of IGF‐I in the susceptibility of MM; the CLL/SLL findings warrant further investigation considering sex‐specific adiposity.

Objective: To examine the benefit of cochlear implantation (CI) in pediatric patients with a history of temporal bone fracture resulting in single-sided deafness (SSD). Study design: Retrospective chart review. Setting: Two tertiary academic centers. Patients: Pediatric patients less than 18 years of age with SSD secondary to temporal bone fracture who underwent CI from 2012 to 2022. Intervention(s): CI. Main outcome measure(s): Postoperative audiometric testing. Results: Seven subjects were identified (median age: 10 years (y); Q1 to Q3: 5 to 16 y). Median time from temporal bone trauma to CI was 7 months (mo) (Q1 to Q3: 3 to 7 mo) and 85% had otic capsule involvement. Subjects were followed for a median length of 12 months (Q1 to Q3: 6 to 24 mo) after CI. All patients achieved full electrode insertion, though 2 required scala vestibuli insertion due to ossification of the scala tympani (one of whom had a history of meningitis after temporal bone fracture). Postoperative audiometric testing revealed variable speech perception outcomes with 4 of 7 obtaining open or closed set speech perception and 3 of 7 obtaining only sound awareness. No postoperative complications occurred. Conclusions: CI is a feasible intervention for SSD following pediatric temporal bone fractures, but outcomes are variable. Early evaluation and timely CI, ideally within 6 months of temporal bone fracture, may optimize outcomes. Cochlear ossification, either as a result of otic capsule fracture or subsequent meningitis, may lead to suboptimal outcomes.

Abstract Glioblastoma (GBM) remains the most common and lethal adult malignant primary brain cancer with few treatment options. A significant issue hindering GBM therapeutic development is intratumor heterogeneity and plasticity. GBM tumors contain neoplastic cells within a fluid spectrum of diverse transcriptional states. Identifying effective therapeutics requires a platform that predicts the differential sensitivity and resistance of these states to various treatments. Here, we develop scFOCAL (Single-Cell Framework for -Omics Connectivity and Analysis via L1000), to quantify the cellular drug sensitivity and resistance landscape. Using single-cell RNA sequencing of newly diagnosed and recurrent GBM tumors, we identify compounds from the LINCS L1000 database with transcriptional response signatures selectively discordant with distinct GBM cell states, and leverage this capability to predict combination synergy. We validate the significance of these findings in vitro, ex vivo, and in vivo, and use the Olig2 inhibitor CT-179 as a reference drug to identify additional small molecules that would maximize the cell-drug discordance across the GBM transcriptional landscape. Our analysis leads to the combination of Olig2 inhibition with treatment with Depatux-M, of with which we demonstrate synergy in vivo. Our studies suggest that scFOCAL identifies cell states that are sensitive and resistant to targeted therapies in GBM using a measure of cell and drug connectivity, which can be applied to identify new synergistic combinations. Citation Format: Robert K. Suter, Anna M. Jermakowicz, Rithvik Veeramachaneni, Matthew D'Antuono, Longwei Zhang, Rishika Chowdary, Simon Kaeppeli, Madison Sharp, Pravallika Palwai, Vasileios Stathias, Grace Baker, Luz Ruiz, Winston Walters, Maria Cepero, Danielle Burgenske, Edward B. Reilly, Anatol Oleksijew, Mark G. Anderson, Sion Ll. Williams, Michael E. Ivan, Ricardo J. Komotar, Macarena I. De La Fuente, Gregory Stein, Alexandre Wojcinski, Santosh Kesari, Jann N. Sarkaria, Stephan C. Schürer, Nagi G. Ayad. Drug and single-cell gene expression integration identifies heterogeneity-aware synergistic combinations for glioblastoma [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Brain Cancer; 2026 Mar 23-25; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2026;86(6_Suppl):Abstract nr B032.

Abstract Purpose: The Pancreatic Cancer Detection Consortium (PCDC) performed a blinded Early Detection Research Network–defined phase II biomarker bakeoff study of blood-based biomarker panels. The aims were to evaluate panel performance, to compare the panels’ performance with that of cancer antigen 19-9 (CA19-9) alone, and to evaluate the performance of new combinations of the individual biomarkers. Experimental Design: Ten biomarkers representing eight biomarker panels and CA19-9 were evaluated using plasma, serum, and germline DNA from 140 stage I to IV pancreatic ductal adenocarcinoma (PDAC) cases and 140 controls from three tertiary care institutions, with controls frequency matched to cases on age and sex. LASSO regression was employed to explore new biomarker combinations. The primary metric was area under the receiver operating characteristic curve (AUC). Results: The study population was 51% female, with median age 67.3 (minimum: 45, maximum: 90) years. Biomarker panel AUCs ranged from 89.9 to 96.3; the AUC for serum CA19-9 alone was 91.7 [95% confidence interval (CI), 87.8–95.6]. Two panels had significantly higher AUCs than serum CA19-9 alone, the CA19-9/FUT2/3 panel (AUC = 96.3, P = 0.002), and the tissue factor pathway inhibitor/tenascin C (TFPI/TNC-FNIII-C) panel (AUC = 95, P = 0.01). Exploratory models to recombine biomarkers retained all but two biomarkers [optimism-corrected AUC = 96.4 (94–98.9)]. Conclusions: The CA19-9/FUT2/3 panel was the best performing panel in this biomarker bakeoff. Its evaluation in larger studies is warranted. Biomarker bakeoffs are an effective strategy for comparing the performance of promising biomarkers for pancreatic cancer early detection, and the PCDC is well poised to conduct such studies. Recommendations for performing such studies are provided.

BACKGROUND: Social determinants of health (SDOH) are associated with adverse cancer outcomes, yet the prevalence and impact of SDOH screening across Commission on Cancer (CoC)-accredited programs are unknown. We evaluated national SDOH screening practices and their association with adherence to CoC quality measures. STUDY DESIGN: A cross-sectional survey of 1,445 CoC-accredited programs (October to December 2024) was linked to National Cancer Database data (2020 to 2022). Adult patients treated at 435 responding hospitals (30.1%) were included. Programs were categorized by routine outpatient SDOH screening status. Multivariable logistic regression assessed associations between screening and receipt of quality measure–concordant care, adjusting for screening duration, age, race, ethnicity, Charlson Comorbidity Index, insurance status, rurality, and program type or case count. RESULTS: Of 435 programs, 165 (37.9%) reported routine SDOH screening. Screening programs more frequently treated ≥10% Medicaid or uninsured patients (29.1% vs 19.6%, p = 0.023). Mean performance was higher at screening hospitals for breast radiation within 60 days (66.6% vs 64.6%, p = 0.046), colon adjuvant chemotherapy within 120 days (84.6% vs 81.9%, p = 0.018), and lung systemic therapy within 90 days (77.2% vs 75.4%, p = 0.043). On adjusted analysis, screening for more than 3 years was independently associated with timely colon adjuvant chemotherapy (odds ratio 1.05; 95% CI 1.01 to 1.07; p = 0.033). Findings persisted after excluding safety net hospitals. CONCLUSIONS: Only one-third of responding CoC programs routinely screen for SDOH. Sustained screening was independently associated with improved adherence to time-sensitive colon cancer chemotherapy, supporting integration of patient-level SDOH assessment into oncology care delivery.

Abstract Vertebral metastatic disease results from many types of cancer and can have a devastating impact on patient mobility, psychological health, quality of life, and ultimately overall patient survival. However, the development of radiotherapy and surgical techniques has rapidly surged in conjunction with ongoing advances in basic science and translational studies. In this review, we discuss the paradigm shift in our understanding of the epidemiology and treatment algorithms for spinal oncology, ranging from preoperative optimization strategies, radiation and surgical techniques, the utilization of molecular markers and targeted therapeutics in medical oncology, and prognostication tools that underscore a new multidisciplinary approach to spinal oncology care.