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Abstract Background Talquetamab (talq) is a GPRC5D-directed bispecific antibody (BsAb) approved for the treatment of relapsed and refractory multiple myeloma (RRMM). The pivotal monumenTAL-1 clinical trial did not include patients with renal impairment (RI, creatinine clearance<40 mL/min) and therefore, data for the use of this agent in RI is lacking. Methods We examined the outcomes of patients with RRMM treated with standard of care (SOC) talq in a multicenter, retrospective cohort study. RI was defined as creatinine clearance (CrCl) <40 mL/min. For each patient we recorded demographics, disease characteristics, prior therapies, incidence and severity of adverse events of special interest, namely cytokine release syndrome (CRS) and immune-cell associated neurotoxicity syndrome (ICANS), along with response, progression-free (PFS) and overall survival (OS). We compared binary variables between different groups using Chi-squared test and assessed progression free survival (PFS) and overall survival (OS) using Kaplan Meier and Cox proportional hazards models. Patients who received talq as a bridge therapy prior to chimeric antigen receptor T-cells (CART cells) were censored for PFS analysis at the time of subsequent therapy. Results We included 417 patients who received SOC Talq and had complete datasets. 91 (22%) had RI, including 20 (5%) on dialysis. The median age was 68 and 65 years for patients with and without RI. Patients with RI were more likely to be female (64% vs. 51%), less likely to have prior CART cells (35% vs. 48%). There were no differences in performance status, race, presence of high-risk cytogenetic abnormalities [del17p, t(4;14), t(14;16), gain/amplification 1q], lines of prior therapy (median 6 vs. 6), prior ASCT (68% vs. 72%), presence of CNS disease (4% vs. 4%), prior plasma cell leukemia (8% vs 9%), prior BCMA therapy (54% vs. 61%) and triple class refractory disease (90% vs. 94%) among patients with and without RI. Rates of CRS (63% vs. 56%, P=0.21) were similar in the two groups, while severe CRS (grade ≥3: 6% vs 2%, P=0.02) was more common in patients with RI. Any grade (20% vs 14%, P=0.21) and high grade ICANS (grade ≥3: 4% vs 4%, P=0.97) were similar in patients with and without RI. There was no difference between groups on risk of infection (P=0.65) with cumulative risk at 6 months of 39% vs. 40%. With 11.1 months of median follow up, the overall response rate (60% vs 67%; P = 0.12), and progression-free survival (median 7.3 vs. 6.5 mo.; P = 0.9) were comparable between the two groups. There was no difference in outcomes according to RI in both patients previously treated with BCMA-directed therapy and BCMA-naïve. Conversely, among patients with RI, median PFS was 4.6 and 8.5 mo. for patients with and without prior BCMA therapy. Similarly, among patients without RI, median PFS was 6.5 and 6.2 mo, respectively. Among BCMA-naïve patients, there was no difference in OS between patients with and without RI (median not reached, 12 mo. OS rate 71% vs. 73%, P=0.53), while among patients with prior BCMA-directed therapy there was a trend towards better OS for patients without RI (median 8.9 vs. 13.8 mo; 12 mo. OS rate 43% vs 59%, P=0.06). Five patients (25%) became dialysis independent following talq therapy. On multivariable analysis, ECOG >1 (HR 1.62, 95% C.I. 1.25-2.10, P<0.001) and deletion of 17p (HR 1.55, 95% C.I. 1.17-2.06, P=0.003) but not RI or prior BCMA-directed therapy affected PFS. OS was affected by ECOG >1 (HR 2.37, 95% C.I 1.71-3.30, P<0.001), triple-class refractoriness (HR 3.03, 95% C.I. 1.12-8.21, P=0.03) and prior BCMA-directed therapy (HR 1.79, 95% C.I. 1.24-2.59, P=0.002) but not by RI. Conclusion Our findings support the feasibility of talq in patients with RI, including those on dialysis, with similar safety and efficacy profile to patients without RI. While neither prior BCMA-directed therapy nor RI affect PFS, refractoriness to conventional agents and prior exposure to BCMA-directed therapy adversely affects OS. This observation likely reflects better post progression survival following talq due to the availability of efficacious therapeutic options, including those directed at BCMA.

Abstract Follicular lymphoma (FL) is the most common indolent non-Hodgkin lymphoma. Although patients with FL have high response rates to therapy, most develop increasingly resistant disease. In addition, transformation into an aggressive lymphoma is associated with unfavorable outcomes. Many novel agents are under investigation, and early clinical data are encouraging. Aligning treatment with the underlying tumor biology and sequencing of therapies remain key clinical challenges. At the Lymphoma Research Foundation’s biannual 2024 Follicular Lymphoma Scientific Workshop, experts convened to discuss the role of chemotherapy in the context of new therapies, the impact of early progression on treatment sequencing, novel end points in clinical trials, disease biology and the tumor microenvironment, and new treatments on the horizon. This report focuses on updates in FL biology, first-line treatment, the role of progression of disease in 24 months, clinical trial design, and redefining cure in FL.

ABSTRACT Background Adolescents with youth‐onset type 2 diabetes (YO‐T2D) have an increased risk for cardiometabolic complications. The impact of vertical sleeve gastrectomy (VSG) on fat distribution and cardiac morphology/function in YO‐T2D is unknown. Objectives To evaluate changes in body composition, abdominal and cardiac fat depots, and cardiometabolic health in adolescents with YO‐T2D undergoing VSG. Methods Anthropometrics, labs and imaging were used to assess participants pre‐surgery and 3–12 months post‐surgery. MRI quantified pericardial (PAT), epicardial (EAT), subcutaneous (SAT) and visceral adipose tissue (VAT), hepatic fat fraction (HFF) and cardiac morphology/function. Mixed‐effects models assessed longitudinal changes. Results By 12 months, weight decreased from 134.3 ± 5.1 to 103.3 ± 5.2 kg, VAT 1943 ± 148 to 1248 ± 150 cm 3 , HFF 23.2% ± 2.3% to 5.3% ± 2.3% and PAT and EAT by 27% and 33% (all p < 0.01). Homeostatic model assessment of insulin resistance (HOMA‐IR) improved (7.8 ± 1.2 to 1.7 ± 1.2 [ p < 0.01]). BMI, SAT, resting heart rate (RHR), left ventricular (LV) mass and cardiac output (CO) also decreased (all p < 0.05). VAT decreases correlated with decreases in HFF ( r = 0.70, p = 0.01), HOMA‐IR ( r = 0.60, p = 0.04) and CO ( r = 0.70, p = 0.03). HFF decreases correlated with decreases in BMI ( r = 0.70, p = 0.03), HOMA‐IR ( r = 0.90, p < 0.001), RHR ( r = 0.90, p = 0.002), CO ( r = 0.80, p = 0.007) and LV mass ( r = 0.70, p = 0.02). Conclusions VSG reduces ectopic and regional fat and improves associated insulin sensitivity and cardiac health in adolescents with YO‐T2D.

Abstract Spontaneously arising canine high-grade gliomas (cHGG) offer a clinically relevant model for human glioblastoma, sharing conserved histopathological, genetic, and immunological traits. We established two cHGG cell lines and two canine adipose-derived mesenchymal stem cell (cAMSC) lines, and immune-competent 3D cHGG organoid models. Immunoblotting of cHGG cell lines showed that these models exhibit hallmark GBM features including SOX2, Nestin, GFAP, and activation of PI3K/AKT and p53 pathways. Given the established cytotoxic and differentiation-inducing effects of BMP4 in human GBM cell lines, we evaluated whether our canine glioma models recapitulate these responses to assess their translational relevance. BMP4 treatment of cHGG cells induced significant cytotoxicity and reduced migration, accompanied by downregulation of SOX2 and Nestin, upregulation of GFAP, and suppression of CDK6 and phospho-AKT—hallmarks of reduced stemness and astrocytic differentiation. In human-derived GBM cells, BMP4 enhanced radiosensitivity, likely via differentiation and depletion of therapy-resistant stem-like populations. Our cHGG models mirrored these molecular responses, suggesting a conserved BMP4 signaling axis in canine glioma. Quantitative phase imaging showed that BMP4 treatment was non-toxic to cAMSCs and did not impair their migration, supporting the feasibility of engineering cAMSC-BMP4 for therapeutic delivery. Observed molecular traits in canine and human gliomas—including mutually exclusive mutations in PDGFRA and PIK3CA, and shared expression of TP53, PTEN, p21, Rb1, mTOR, and MAPK—underscore the translational relevance of the cHGG model. High-content imaging further confirmed expression of p-AKT, p53, MDM2, and CD44 in cHGG lines, reinforcing activation of conserved gliomagenic pathways. To complement these findings, we developed a cHGG 3D organoids from freshly resected tumors, that recapitulate tumor heterogeneity with co-localized GFAP+/Nestin+ glioma cells, CD3+ infiltrating T cells, macrophages and cleaved caspase-3+ apoptotic cells, indicating active immune surveillance and ongoing programmed cell death. Our results support canine GBM model as a platform to assess glioma biology, cell therapy, and modeling immune engagement in a species-relevant, physiologically intact environment for streamlined translation of therapeutics to human clinical trials.

Abstract High-grade gliomas (HGGs) are aggressive, infiltrative brain tumors with poor survival outcomes and limited therapeutic options. Their spatial and molecular heterogeneity necessitates large, well-curated datasets integrating imaging, clinical, and genomic information to enable precision medicine and drive novel treatment development. Using the Medtronic StealthStation neuronavigation system, we collected over 1,000 spatially localized intraoperative biopsy samples from more than 250 patients undergoing resection for glioma at Mayo Clinic and partnering sites. Each biopsy site was recorded with 3D coordinates, labeled in real time, flash-frozen, and annotated with metadata including collection time, anatomical location, and surgical plan. Samples were processed and entered into a secure database along with the corresponding sampling coordinates, frozen pathology, whole-exome and RNA sequencing data, 5-ALA fluorescence status, patient demographics, and T1, T1Gd, T2, and T2-FLAIR MRI. This multimodal dataset supports radiogenomic research by enabling precise mapping of imaging features to molecular characteristics. A subset of this data, including 268 biopsies from 52 patients (25 male, 27 female) with reported intraoperative 5-ALA fluorescence, was used to develop a radiomics model predicting locoregional patterns of 5-ALA positivity based on preoperative MRI. Image features were extracted from the biopsy sample coordinates across multiple MRI sequences and paired with corresponding 5-ALA fluorescence status to train the model for regional fluorescence prediction. The final model achieved 83% accuracy on the training set and 86% on the validation set using a 70-15-15 data split; this included 208 samples for training and 42 for validation, stratified by patient to ensure no overlap of samples from the same individual across sets. These findings demonstrate the feasibility of predicting 5-ALA fluorescence using radiomic features from standard preoperative MRI, offering a promising noninvasive strategy for improving intraoperative decision-making and enabling more precise, personalized resections in patients with high-grade gliomas.

Introduction: Complex congenital heart disease (CHD) patients with atrial arrhythmias have higher rates of morbidity and mortality compared to less complex CHD patients. This study aims to identify echocardiographic predictors of thromboembolism (TE) and major bleeding in patients with Tetralogy of Fallot (ToF) or Pulmonary Atresia with Intact Ventricular Septum (PA-IVS) and atrial fibrillation or flutter (AF). Methods: This cohort study included patients with ToF or PA-IVS who had a diagnosis of AF who underwent a TTE across three sites. Outcomes were incidence rate of major bleeding or TE, calculated using univariable and multivariable cox regression with interaction for anticoagulant choice and fractional area change (FAC). The HAS-BLED score was augmented with major predictors of bleeding, and receiver operator curves compared. Results: We included 300 patients (287 ToF [95.7%], 13 PA-IVS [4.3%]), mean age 45.6 years. Most received warfarin (227 [79.4%]), 40 (13%) used DOACs, and 5 (1.6%) used enoxaparin. TTE predictors of TE included large LVOT diameter ≥3cm (HR 8.92, p=0.002), small LVOT VTI (p=0.014), FAC <30% (HR 7.08, p=0.026) and moderate RV dysfunction (HR 10.75, p=0.026). Predictors of major bleeding included moderate tricuspid regurgitation (HR 2.40, p=0.022), right atrial pressure (1.12, p<0.001), severe RA enlargement (HR 2.30, p=0.048), RV mid diameter (HR 1.06, p=0.005), RV end diastolic area (HR 1.04, p=0.021), RV end systolic area (HR 1.05, p=0.016) elevated RVSP and FAC ≤45% (HR 0.37, p=0.016). Among warfarin users, impaired RV function (FAC ≤45%) was linked to reduced major bleeding events (HR 0.27, p=0.025). There was a nonsignificant trend towards higher bleeding in DOAC users with FAC >45% (HR 3.87, p=0.284), but significantly higher bleeding in DOAC users with FAC ≤45% (HR 12.41, p=0.008) vs. warfarin users with normal RV function (table 1). We developed an augmented HAS-BLED score: the standard score plus one point for moderate-to-severe pulmonic or tricuspid regurgitation and one for FAC ≤45%. This outperformed the standard HAS-BLED in predicting major bleeding (AUC 0.67 augmented vs. 0.57 un-augmented, p=0.008) (figure 1). Conclusion: Echocardiographic evidence of right heart disease is a strong predictor of major bleeding in patients with ToF or PA-IVS. FAC is a useful tool to determine excess major bleeding risk, particularly in DOAC users. Augmenting HAS-BLED with right heart parameters improves diagnostic accuracy.

ABSTRACT Suicidality contributes substantially to global morbidity and mortality, yet despite its heritability, its biological etiology remains largely elusive. We conducted multi-ancestry genome-wide association study meta-analyses of suicidal ideation (259,747 cases), suicide attempt (64,993 cases), suicide death (9,197 cases), and suicidal behavior (suicide attempt/ death, 75,300 cases), across 54 cohorts (e.g., the Psychiatric Genomics Consortium, Million Veteran Program, UK Biobank). We identified 77 significant loci across meta-analyses, including 59 previously unreported for suicidality. SNP-based heritability ranged from 2.0-6.7% and there were strong, yet incomplete, genetic correlations between suicidality phenotypes (0.70-0.88). Fine-mapping prioritized putative causal SNPs and 20 credible genes. Enrichment analyses implicated synaptic pathways and neuronal populations predominantly in subcortical brain regions (e.g., amygdala excitatory, medium spiny, hippocampal CA1-3). Together, these findings establish suicidality as a polygenic set of traits with both shared and distinct genetic influences, providing a foundation for future studies of suicide biology and etiology.

Abstract eSource – particularly EHR-to-EDC – is an emerging paradigm in clinical research that enables automated transfer of electronic health record (EHR) data into electronic data capture (EDC) systems, with the potential to reduce site burden, improve data quality and accelerate oncology clinical trial workflows. However, widespread implementation remains limited due to technical, regulatory and operational barriers. To address these challenges, the European Institute for Innovation through Health Data (i~HD) launched the eSource Scale-Up Task Force in 2024. This multi-stakeholder initiative brings together leading oncology centres and pharmaceutical sponsors to establish a consensus-driven roadmap for eSource adoption. Central to this effort are three foundational resources: readiness criteria for early adopters, a performance indicator framework for monitoring success and an operational playbook to guide implementation. This article provides a structured overview of the Task Force’s objectives, collaborative model and outputs, with specific attention to its focus on interoperability, regulatory alignment and real-world validation. While initially developed for oncology, the Task Force’s framework is applicable across therapeutic areas characterized by data-intensive workflows.