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 Background Sunlight has profound impacts on physical and mental health, beyond vision, including effects on circadian rhythms, alertness, mood, and sleep. A family history of any mood disorders is strongly associated with psychiatric disorders including bipolar disorder. The purpose of this study was to evaluate the association between a family history of any mood disorder in patients with bipolar I disorder and solar insolation at varied international onset locations. Methods Data for this analysis were available from 5842 patients with a diagnosis of bipolar I disorder obtained at 83 collection sites in both hemispheres. This included 4752 patients from 71 collection sites in the northern hemisphere and 1090 patients from 12 collection sites in the southern hemisphere. Patient data variables were obtained from records or interviews. Solar insolation data were obtained from The National Aeronautics and Space Administration (NASA) Power database for each onset location, and the ratio of the mean monthly minimum/mean monthly maximum solar insolation was calculated. Typically, the ratio is largest near the equator (little yearly change in solar insolation) and smallest near the poles (large yearly change in solar insolation). Results A significant relationship was found between a family history of any mood disorder, the ratio of the mean monthly minimum/mean monthly maximum solar insolation, and gender. The odds of a family history of mood disorder increased as patient location nears the poles and decreased near the equator. Female gender also increased the odds of having a family history of a mood disorder. Conclusions This study highlighted the association between family history, solar insolation, and gender in international patients with bipolar I disorder. Given the profound effects of sunlight on human health, the family of patients with bipolar disorder who live in the same location with the same solar insolation, and especially females, may be at increased risk for a mood disorder.

ABSTRACT Background Acute heart failure (AHF) exhibits marked heterogeneity in diastolic hemodynamics, yet comprehensive echocardiographic assessment of diastolic function (DF) and filling pressure (FP) is often infeasible. We evaluated whether artificial intelligence–enabled electrocardiography (AI-ECG) could provide scalable DF grading and FP estimation in hospitalized AHF patients. Methods We retrospectively studied adults hospitalized for AHF across Mayo Clinic sites (2013–2023) who received ≥1 dose of intravenous loop diuretic and had paired 12-lead ECG and TTE. The previously validated AI-ECG DF model was applied without retraining to generate four DF grades and a continuous FP probability. Clinical outcomes were all-cause mortality and heart failure rehospitalization. Associations with clinical severity markers and echocardiographic indices were examined. Kaplan–Meier survival analysis and adjusted multivariable Cox proportional hazards models were performed. Exploratory analyses examine the kinetics of change in FP probability and impact on mortality. Results Among 11,513 patients (median age 75 years, 39% female), AI-ECG DF grading was feasible in 100%, whereas echocardiographic DF was indeterminate in 44% of clinically eligible patients. In 2,582 patients with determinate echocardiographic DF, AI-ECG FP probability discriminated TTE Grade 2–3 dysfunction with AUC 0.85 (95% CI 0.83 – 0.86). Higher AI-ECG DF grades were associated with higher comorbidity burden, worse NYHA class, elevated NT-proBNP, higher MAGGIC scores, elevated PCWP, and more advanced structural remodeling. After multivariable adjustment, AI-ECG DF remained independently associated with mortality (hazard ratio [HR] 1.25, 95% CI 1.16–1.35 for Grade 2; HR 1.44, 95% CI 1.33–1.56 for Grade 3 versus Normal/Grade 1). Combining AI-ECG DF with MAGGIC scores yielded ordered risk gradients, with highest mortality in patients with both high MAGGIC and Grade 2–3 DF. Among patients with serial ECGs, improvement in FP probability was independently associated with lower mortality (HR 0.85, 95% CI 0.79–0.91), whereas worsening did not show a consistent adverse gradient beyond baseline DF. Conclusions In a large, geographically diverse AHF cohort, AI-ECG DF grading was universally feasible, correlated with established hemodynamic severity markers, and provided independent prognostic information beyond established risk factors, supporting its role as a pragmatic, scalable diastolic biomarker in AHF. CLINICAL PERSPECTIVE What Is New? In 11,513 hospitalized acute heart failure (HF) patients, artificial intelligence-enabled electrocardiography provided diastolic function grading in 100% of patients from a single 12-lead ECG without requiring additional clinical variables, compared with 56% feasibility for guideline-based echocardiography grading. AI-ECG diastolic function grades correlated with established marker of severity (NYHA functional class, NT-proBNP, MAGGIC risk scores, and pulmonary capillary wedge pressure) and remained independently associated with both mortality and HF rehospitalization after multivariable adjustment. Serial AI-ECG measurements identified post-discharge filling pressure trajectories, with improvement independently associated with 15% lower mortality, a first demonstration that longitudinal ECG assessment can track post-discharge hemodynamic recovery. What Are the Clinical Implications? AI-ECG transforms the universally obtained 12-lead ECG into an actionable hemodynamic biomarker that addresses the critical gap when echocardiographic diastolic function assessment is indeterminate or unavailable in acute HF patients. Despite markedly different hemodynamic severity and long-term outcomes across AI-ECG diastolic function grades, hospitalization length of stay did not differ, suggesting advanced diastolic dysfunction represents occult risk not easily recognized during routine acute care and highlighting the need for improved post-discharge risk stratification. The continuous filling pressure probability metric enables longitudinal monitoring of post-discharge hemodynamic status using serial routine ECGs, potentially identifying patients requiring intensified follow-up or specialist referral.

TPS890 Background: Although first-line (1L) EV + pembrolizumab has improved outcomes for patients with la/mUC, most experience disease progression, highlighting an unmet need for novel therapies. TROP2 is a glycoprotein highly expressed in several epithelial tumors, including UC. Dato-DXd is a TROP2-directed antibody–drug conjugate comprising an anti-TROP2 monoclonal antibody, a tetrapeptide-based cleavable linker, and a topoisomerase I inhibitor payload (DXd), designed to induce selective tumor-cell death and reduce systemic exposure to the payload. Dato-DXd has demonstrated durable efficacy and a manageable safety profile in patients with la/mUC both as monotherapy (TROPION-PanTumor01 [NCT03401385]) and in combination with immunotherapy (TROPION-PanTumor03 [NCT05489211]). We describe a phase 2/3 trial comparing the efficacy and safety of Dato-DXd + platinum CT (carboplatin or cisplatin) vs gemcitabine + platinum CT in participants with la/mUC with disease progression on or after EV + pembrolizumab. Methods: TROPION-Urothelial03 (NCT07129993) is a global, multicenter, randomized, open-label, phase 2/3 trial. In part A (phase 2), ~60 participants will be randomized 1:1 to receive Dato-DXd 4 or 6 mg/kg + platinum CT. In part B (phase 3), ~570 participants will be randomized 1:1 to receive Dato-DXd at the recommended phase 3 dose (determined using part A data) + platinum CT vs gemcitabine + platinum CT. Randomization in part A is stratified by assignment of platinum CT (carboplatin vs cisplatin), and in part B, by assignment of platinum CT, presence vs absence of liver metastasis at screening, and time to progression on 1L EV + pembrolizumab ( < 6 vs ≥6 months). Study treatment continues until disease progression, unacceptable toxicity, withdrawal of consent, death, loss to follow-up, or other reasons per protocol. Radiographic tumor assessments occur every 6 weeks for 54 weeks, then every 12 weeks. The primary endpoint of part A is objective response rate (ORR) by investigator per Response Evaluation Criteria in Solid Tumours, version 1.1 (RECIST 1.1). The dual primary endpoints of part B are progression-free survival (PFS) by blinded independent central review (BICR) per RECIST 1.1 and overall survival (OS). Secondary endpoints include duration of response by investigator per RECIST 1.1 (part A), and PFS by investigator per RECIST 1.1 and ORR by BICR and investigator per RECIST 1.1 (part B). In part A, ORR will be summarized with 2-sided 95% exact confidence intervals using the Clopper–Pearson method by trial group. In part B, PFS and OS will be compared between trial groups using a log-rank test stratified by randomization stratification factors, with hazard ratios from the stratified Cox regression model. Clinical trial information: NCT07129993 .

Abstract Objective: Subjective cognitive complaints (SCC) can precede cognitive decline and are associated with demographic, exposure, lifestyle, and psychological factors. Prevalences of SCC and their correlates in individuals with repetitive head impacts (RHI) are poorly understood. This study characterized SCC in former elite American football players by frequency, mood and behavioral correlates, concordance with informant reports, and associations with neuropsychological test performance, cerebrospinal fluid (CSF), and magnetic resonance imaging (MRI) markers of neurodegeneration. Method: Former American football players ( n = 180) completed measures of global and domain-specific SCC, neuropsychiatric symptom questionnaires, neuropsychological testing, lumbar puncture, and MRI. Elastic net regression evaluated the relative importance of potential SCC correlates. Intraclass correlation coefficients measured concordance between self and informant reports. Multiple linear regressions tested associations between SCC and verbal memory and executive functioning scores. CSF Aβ 1-42 , p-tau 181 , t-tau, neurofilament light (NfL), hippocampal volume, and regional cortical thickness were examined for their potential associations with SCC. Results: Rates of SCC ranged from 43 to 77% depending on the domain. Symptoms of depression, impulsivity, and anxiety were strongly associated with SCC. Self- and informant-reported SCC showed moderate inter-rater agreement. Adjusting for age, race, education, APOE ϵ4 carrier status, and depressive symptoms, SCC were associated with lower objective verbal memory and executive functioning performance. SCC were associated with lower parahippocampal cortical thickness but not with hippocampal volume or any of the measured CSF tests. Conclusions: SCC are strongly associated with neuropsychiatric factors in former American football players. SCC may also be a marker of cognitive decline and neurodegeneration.

Abstract Recent therapeutic advances, including bispecific antibodies (bsAbs), have improved outcomes for patients with relapsed/refractory multiple myeloma (RRMM). However, early mortality (EM) remains a significant challenge, even in the era of novel immunotherapies. We conducted a multicenter, retrospective analysis of real-world patients with RRMM treated with commercial bsAbs to evaluate the incidence and causes of EM. Between May 2022 and June 2025, a total of 441 patients were treated across 7 countries. EM, defined as death within 12 months of therapy initiation, occurred in 148 patients (34%), with a median time from bsAb initiation to death of 2.87 months (interquartile range, 1.38-6.85). The leading cause of EM was progressive disease (72%), followed by infection (13%); regardless of the cause of death, 82% had active disease at the time of death. Our findings highlight that despite encouraging efficacy, EM remains high among real-world bsAb recipients, emphasizing the need for improved disease control strategies and supportive care interventions.

Abstract Background: Male breast cancer (MaBC) is a rare malignancy, accounting for approximately 1% of all breast cancer cases. Our previous studies suggest that MaBC is biologically distinct from female breast cancer (FeBC), exhibiting a unique mutational profile and immune-genomic microenvironment. While the impact of these molecular alterations on site-specific metastases has been explored in FeBC, it remains poorly understood in MaBC. This gap limits accurate risk stratification and prediction of disease trajectory in male patients. In this study, we investigated site-specific genomic and immune alterations across metastatic sites in MaBC. Methods: 238 MaBC samples were tested by NGS (592, NextSeq; WES, NovaSeq) and WTS (NovaSeq; Caris Life Sciences, Phoenix, AZ). We performed analysis in hormone receptor-positive (HR+) and HER2-negative (HER2-) subtypes which are most common in male. HR+HER2- was defined as estrogen receptor (ER) or progesterone receptor (PR) positive and HER2 IHC 1+ or 2+ with negative chromogenic in situ hybridization (CISH) assay. Immune cells were estimated using WTS deconvolution (Quantiseq). Gene expression profiles were analyzed for T-cell inflamed score, interferon-gamma (IFN-gamma) score and MAPK Activation Score. We classified patients by site of biopsy/specimen site. Statistical significance was assessed with chi-square and Mann-Whitney U tests, p&lt;0.05 is considered statistically significant. Results: Our cohort included 86 HR+HER2- MaBC samples biopsied from primary breast cancer (pBC) (n=39), bone (n=15), liver (n=8), lung (n=8), lymph nodes (n=7), and skin (n=9) mets. We report here only the data on statistically significant differences, but the overall landscape has been depicted across all defined-sites investigated. pBC showed a significantly lower prevalence of PIK3CA mutations (23.6% vs. 53.3%, p&lt;0.05) compared to bone mets. ESR1 mutations were absent in pBC but present in 25% of liver and 25% of lung mets (all comparisons p&lt;0.05). Immune profiling revealed reduced infiltration of M2 macrophages (4.3% vs. 6%, p&lt;0.05) and neutrophil (2.2% vs. 6.9%, p&lt;0.05) in pBC relative to bone Mets. Further, CD4+ T cells were lower in pBC compared to lymph nodes (0% vs. 2.4%, p&lt;0.05). pBC had lower expression of immune checkpoint genes (PDCD1LG2, HAVCR2 and CD47) compared to other mets. pBC exhibited lower MAPK pathway activation score (-1.6 vs. 0.17, p=0.03) and a trend toward lower T cell-inflamed gene expression scores (-65 vs. 8, p=0.06) compared to bone mets. Bone mets had higher infiltration of M2 macrophage compared to lung (6% vs. 4.4%, p&lt;0.05) and lymph node (6% vs. 4.5%, p&lt;0.05). Neutrophil infiltration was elevated in bone versus liver (6.9% vs. 2%, p&lt;0.05) but T regulatory cells were lower in bone compared to lymph nodes (1% vs. 2.4%, p&lt;0.05). Bone showed reduced expression of CD47 (median TPM 50.6 vs. 109.9, p&lt;0.05) compared to skin. Further bone had lower IFN-gamma scores (-0.41 vs. -0.17, p&lt;0.05) compared to lymph node. Data on prior number and types of cancer treatment to give a context to the findings will be presented at the meeting. Conclusions: Our study highlights that each MaBC metastatic site harbors a unique genomic and immune landscape that can influence tumor behavior and potentially impact patient prognosis. Better understanding of metastatic site-specific molecular features in larger cohorts can help in the future research efforts and guiding treatment decisions. Citation Format: D. Trapani, S. Deshmukh, S. Wu, J. Xiu, N. Lin, G. Curigliano, P. Spanheimer, P. Advani, P. Barreto Coelho, M. Lustberg, G. Sledge Jr, S. Tolaney, J. Leone. Site specific Genomic and Immune Landscapes Underpinning in metastatic Male Breast Cancer [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 PS2-08-04.