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 Rare Mendelian disorders affect 300-400 million people globally. Although genetic testing has become widely adopted, gene-specific evidence for tailored variant interpretation remains scattered across resources. We present Gene Portals, a framework for gene-centered multimodal knowledge bases that co-localize expert-harmonized clinical data, functional assays, population variation, structural annotations and gene-specific ACMG/AMP specifications within a single resource. A modular interface integrates this unified evidence with VCEP-refined ACMG specifications to enable automated gene-specific variant classification, infer molecular mechanisms, and support cross-gene analyses. We demonstrate the framework’s utility across five Gene portals spanning eleven neurodevelopmental disorder-associated genes, integrating data from 4,423 individuals with 2,838 unique variants, 36,149 ClinVar submissions, and 1,044 expert-curated molecular readouts. By organizing evidence that is otherwise dispersed across multiple sources into a unified, queryable framework, the SCN, GRIN, CACNA1A, SATB2 and SLC6A1 Gene Portals became widely used community resources and provide an extensible template for standardized rare-disease variant interpretation and mechanism-aware discovery.

Abstract Background: Currently, the gold standard in cancer diagnosis, prognosis, and treatment is assessing cancer cell mitosis in tumor tissue biopsies, which identifies patients with more aggressive cancer subtypes that may require more tailored treatment regimens. Circulating tumor cells (CTCs), cancer cells that detach from primary tumors, enter the bloodstream, and seed metastatic sites, are a well-known non-invasive blood biomarker which can also be used to aid in stratifying metastatic breast cancer (mBC) patients with highly aggressive subtypes. Initial pilot studies have identified a particular subtype of CTCs which are undergoing mitosis that appears to correlate with very poor survival outcomes compared to non-mitotic CTCs alone. In a multi-institutional prospective study, we isolated CTCs from the blood of n=167 mBC patients to categorize mitotic CTCs and evaluate their association with progression-free survival (PFS) and overall survival (OS) over a 3 year period. Methods: Peripheral blood samples (7.5ml) were collected from n=167 mBC patients progressing on systemic therapies and prior to new systemic therapy induction (i.e. chemotherapy n=102, hormone therapy n=13, immunotherapy n=63, targeted therapy n=62). Samples were processed using CellSieve microfilters to isolate CTCs via size exclusion and fluorescently stained for CD45, Cytokeratin, and DAPI. CTCs were imaged, enumerated, and subtyped based on the presence of ≥1 mitotic event, using previously established visual indicators. PFS and OS were assessed over 3 years by censored univariate and multivariate analyses. Results: CTCs were detected in ∼47% (n=79/167) of patients, while mitotic CTCs were identified in a subset of this group, ∼48% (n=38/79). The presence of any CTC was associated with poor outcomes (PFS HR=0.49, 95%CI=0.3-0.7, p=0.0002 and OS: HR=0.42, 95%CI=0.3-0.7, p=0.0002). However, the presence of mitotic CTCs correlated with significantly poorer outcomes compared to non-mitotic CTCs (PFS: HR=0.3, 95%CI=0.2-0.5, p<0.0001 and OS: HR=0.3, 95%CI=0.2-0.6, p=0.0002). Further, patients with no CTCs had a median PFS (mPFS) of 6 months and median OS (mOS) of 22 months, patients with non-mitotic CTCs had a mPFS of 4 months and mOS of 14.5 months; patients with mitotic CTCs had a mPFS of 2.4 months and mOS of 4.4 months. Notably, 95% of patients with a mitotic CTC progressed within 6 months, regardless of systemic therapy type. Interestingly, there were 5 patients who survived longer than 1 year with a mitotic CTC all of which were receiving specific targeted therapies. Conclusion: In this study, the detection of CTCs indicated poor outcomes in patients. Additional cytological analysis of CTCs further identified CTCs undergoing mitosis which correlated to highly aggressive disease with the poorest survival rates. These results indicate that while the presence of CTCs is a prognostic indicator for survival, subtyping CTCs and identifying mitosis may correlate to therapy response. This study highlights the need for larger, more comprehensive studies to expand upon and validate these findings. Citation Format: A. B. Duffy, M. Cristofanilli, C. Reduzzi, W. V. Williams, G. Del Priore, S. Chumsri, C. Tang, T. Iwase, N. T. Ueno, D. L. Adams. Mitotic Circulating Tumor Cells Correlates with Poor Clinical Outcomes in Metastatic Breast Cancer Patients over a 3 Year Period [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 PS4-01-05.

Abstract Background Management of metastatic breast cancer (MBC) continues to present obstacles, as many pts develop resistance to or cannot tolerate standard of care treatments. Bria-IMT combines two modalities to both overcome immune exhaustion and minimize the toxic safety profiles commonly observed in contemporary late stage therapies: an allogeneic whole-cell vaccine (SV-BR-1-GM) and checkpoint inhibition (CPI). The SV-BR-1-GM cell line originates from breast cancer cells and are engineered to secrete GM-CSF and irradiated before administration. These cells upregulate surface presentation of tumor associated antigens on both HLA class I and II, enhancing tumor recognition by T cells. Coadministration w/ an anti-PD-1 CPI, the vaccine response is reinforced, counteracting the immuno-suppressive tumor microenvironment. Methods This phase I/II study evaluated the Bria-IMT regimen: low-dose cyclophosphamide (Day –2) followed by SV-BR-1-GM and CPI (pembrolizumab or retifanlimab), then low-dose local peg- interferon α. Cycles q3w. In the phase II study, pts were randomized 1:1 to start CPI immediately at cycle 1 (C1) or delayed start at cycle 2 (C2). There were 2 formulations of SV-BR-1-GM w/ IFNγ stimulation (IFNγ) or unstimulated (PH3). Cancer-associated macrophage-like cells (CAMLs), circulating tumor cells (CTCs), and PD-L1 expression scores on these cells were monitored as biomarkers. Candida skin test assessed anergy status before cycle 1, and a delayed type hypersensitivity (DTH) skin test to SV-BR-1-GM was assessed at each cycle w/ a small SV-BR-1-GM dose before the full dose. Results Results of the randomized phase II study cohort are reported (n = 32). Retifanlimab was co-administered w/ SV-BR-1-GM at C1 or C2. Median age 61 (41-80) years; median number of prior regimens was 6 (2-13). 20(63%) pts were ER+/PR+/HER2-; 3(9%) HER2+, and 9 (28%) triple-negative (TNBC). The Bria-IMT regimen was well tolerated, w/ no drop-outs attributable to Bria-IMT. The majority of adverse events (93.8%) grade 1-2, w/ (40.6%) grades 3 and 4. Common AEs included injection site reactions (53%), nausea (43.8%), and fatigue (34%). The median progression free survival (PFS) was 3.5 (range: 1.8-24.5) and overall survival (OS) 9.5 (2.4-31.6) months. One patient remains on therapy, approaching 25 months of PFS. PFS and OS among pts who received immediate vs. delayed start of CPI (PFS 3.7 vs. 3.3 mo, HR: 0.59; 95% CI 0.3-1.2, p=0.16 | OS 13.3 vs. 7.4 months, HR: 0.78; 95% CI 0.34-1.8, p = 0.56). Pts who received the SV-BR-1-GM Ph3 formulation (n=21) had an increase in both PFS (4.1 vs 2.6 months, p = 0.005) and OS (16.6 vs. 9.1 months, HR: 0.6; 95% CI 0.2 - 1.4, p = 0.24); best objective response rate was 12% and the clinical benefit rate was 53%. In ER+/PR+/HER2-, overall OS was 11.7 (3.5-31.6) mo, 17.3 mo (3.5-27.9) in Ph3; HER2+ 7.2 (4.7-24.5) mo, all received Ph3; TNBC 9.9 (2.4-23.0) mo, 16.6 mo (2.4-23.0) in Ph3. In pts w/ available data, pts w/ post-dose CTC count < 5 significantly improved OS compared w/ a CTC count > 5 (16.6 vs. 5.5 months, p = 0.0003). Pts w/ positive DTH response had significantly improved PFS (3.6 vs. 2.4 months, p = 0.01) and OS (11.9 vs. 4.7 months, p < 0.0001). Conclusions In heavily pretreated MBC pts, the Bria-IMT regimen demonstrated promising results and a favorable safety profile across all subtypes of breast cancer. A clinically meaningful, though not statistically significant, difference in OS was observed between pts receiving CPI at C1 versus C2. Superior outcomes were observed in pts receiving SV-BR-1-GM w/o IFNγ incubation, guiding selection of Ph3 formulation for ongoing and subsequent clinical trials. Pts w/ post-dose CTC count < 5, and positive DTH response had significantly improved outcomes. On basis of these results, a randomized phase III trial comparing the Bria-IMT regimen to physician's choice is ongoing (NCT06072612). Trial information: NCT03328026. Citation Format: C. Nangia, S. Chumsri, K. Rowland, L. Negret, J. Knecth, B. Bayer, T. Aghajanian, W. Williams, G. Del Priore, C. Calfa. Survival Results of Phase II Bria-IMT Allogenic Whole Cell-Based Cancer Vaccine [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 PS1-13-23.

ABSTRACT Background Sex‐specific medicine (SSM) is increasingly recognized as vital for patient care yet remains underrepresented in graduate medical education curricula. Traditional didactics and workshops have limited reach at national conferences. Gamification has emerged as a strategy to increase engagement, though its use in professional networking and conference settings is not well described. Methods The Resident and Medical Student (RAMS) Hunt is a novel, gamified, team‐based event incorporating topics in SSM, health equity, and professional development. The Hunt was implemented at three consecutive Society for Academic Emergency Medicine (SAEM) Annual Meetings (2023–2025). At each conference, teams visited four city landmarks, completing content‐based challenges at each site. Post‐event surveys assessed enjoyment, perceived educational effectiveness, and design preferences. Quantitative data were summarized descriptively, and qualitative responses underwent thematic analysis. Future iterations will include pre‐ and post‐event knowledge and attitude assessments to enhance rigor. Results Across three Hunts, more than 66 teams registered, and there were 88 completed surveys (Austin 2023 n = 23; Phoenix 2024 n = 48; Philadelphia 2025 n = 17). Mean enjoyment ratings were 4.52, 4.44, and 3.47 (out of 5), respectively. Perceived educational effectiveness ratings were 4.09, 4.11, and 3.47. Participants reported that ideal numbers of challenge sites and participants per team were 3–4. Qualitative themes highlighted enhanced awareness of how biological sex and sociocultural attributes influence health outcomes, the value of interactive learning, and networking opportunities. Logistical barriers included registration, inclement weather including a downpour in Philadelphia, and course navigation. Conclusions The RAMS Hunt demonstrated feasibility and strong learner engagement in disseminating SSM content through a novel conference‐based gamification model. This innovation offers a replicable framework for integrating experiential, team‐based learning into professional society meetings. Opportunities remain to hone game logistics to enhance sustainability and broader adoption. Future evaluations will include objective measures of learning and knowledge retention.

Abstract Objective Recent studies suggest a unique disease profile in elderly patients with primary aldosteronism (PA), who have a high prevalence of comorbidities and low clinical cure rate post-adrenalectomy. This study aims to investigate histopathology and genetic characteristics of PA in late adulthood. Methods Formalin-fixed, paraffin-embedded adrenal tissue sections from 114 patients with PA who underwent unilateral adrenalectomy at age 60 or older were used. Aldosterone synthase (CYP11B2) immunohistochemistry (IHC) was performed for histopathologic analysis. Somatic DNA variants were identified in aldosterone-producing tissue following CYP11B2 IHC-guided sequencing. Results Histopathologic analysis revealed that 56 adrenals contained an aldosterone-producing nodule (APN) (49%), 44 contained an aldosterone-producing adenoma (APA) (39%), 7 contained multiple APN (6%), and 7 contained only non-functioning adenomas [NFA, of which 6 had at least one aldosterone-producing micronodule (APM) in the adjacent tissue] (6%). NFAs were also identified alongside APN/APA in 24 cases. An APN was the most common histologic subtype in men (51/88, 58%), while APA was predominant in women (18/26, 69%). Of 67 APNs with successful sequencing, the majority had variants in CACNA1D (40/67, 60%). KCNJ5 variants were the most common alteration in APA (14/44, 32%). Conclusions Older individuals with lateralized PA exhibit distinct genetic and histologic causes of disease with sex differences in mutation prevalence and adrenal histopathology. In APN, the most frequently altered gene is CACNA1D, while KCNJ5 variants are most common in APA. Unlike young patients with PA, the presence of NFA is a frequent observation in late adulthood individuals with PA.

Introduction Asthma is a multifactorial disease influenced by genetic and environmental factors, including diet. The gut microbiome contributes to airway inflammation via the gut-lung axis, partly through production of short chain fatty acids (SCFAs) from bacterial fermentation of dietary fiber. We hypothesized that dietary fiber supplementation could modulate the gut microbiome and increase SCFAs in children with asthma. Methods This is a double-blind, placebo-controlled trial of children who were randomized to consume 12 g of soluble corn fiber (SCF) as a supplement to their usual daily diet (50% the recommended daily fiber intake) or placebo for 4–6 weeks ( clinicaltrials.gov NCT03673618). Dietary surveys, asthma symptom questionnaires, fecal, blood and nasal samples were collected before and after the intervention period to quantify fiber intake, asthma control, nasal and gut microbiome, and serum short chain fatty acids (SCFAs). Results Of the 20 children enrolled, 15 completed the intervention with an average adherence rate of 83%. SCFA concentrations and gut microbiome changes varied by individual and treatment group. No significant differences in gut or nasal alpha or beta diversity were observed between groups post-intervention. However, differential abundance analysis showed a trend toward increased Bifidobacterium in the SCF group compared to placebo (ANCOM-BC p = 0.0004, FDR q = 0.073). Discussion Supplementation of 50% of recommended daily fiber intake had minimal impact on asthma symptoms, the microbiome, or SCFA levels. Future studies should consider higher fiber doses, different fiber types, or targeting individuals with low baseline fiber intake to account for observed variability in microbiome and SCFA responses. Clinical Trial Registration https://clinicaltrials.gov/study/NCT03673618 , identifier NCT03673618.

Abstract Objective To measure the relative levels of signal and noise in expert diagnosis of epilepsy. Methods Twenty multinational epileptologists independently reviewed 50 vignettes of adult and pediatric patients presenting with suspected seizure(s) on two separate occasions with a ≥30‐day washout period. Experts provided a diagnosis of epilepsy or non‐epilepsy based on clinical information and, if requested, routine EEG and neuroimaging data. Cases had an established clinical diagnosis of epilepsy or non‐epilepsy based on capture of habitual paroxysmal events on video‐EEG or long‐term clinical follow‐up. Experts' judgments were analyzed to decompose variability into different sources: signal (objective differences between cases), level noise (experts' bias toward over/under‐diagnosis), pattern noise (experts' idiosyncratic reactions to specific case features), and occasion noise (inconsistency across occasions). Results The probability of an expert making a different diagnosis for a given case on two different occasions was 16%. The probability of two different experts making a different diagnosis for the same case was 26%. Signal (case “difficulty”) accounted for 66–69% of total variation, with 31–34% attributable to noise. Level noise was the largest contributor in the absence of EEG/neuroimaging results (23%), while pattern noise dominated when test results were available (24%). Occasion noise contributed relatively little (1%) but was still sufficient to cause diagnostic reversals in 16–22% between occasions. Significance The degree of noise in expert diagnosis of epilepsy is substantial, stemming primarily from physicians' idiosyncratic interpretations of case features and variable dispositions toward over‐ or under‐diagnosis. Strategies to improve reliability are needed, including standardized data collection protocols and structured decision algorithms. For “difficult cases,” where expert reliability and accuracy are lowest, our findings support current clinical practice which favors early referral for video‐EEG monitoring over reliance on diagnostic anchoring. This diagnostic pathway may become more accessible with advances in EEG technology (e.g., wearable devices) and artificial intelligence.