Citations

Abstract Background: Effective treatments (Tx) are needed for MTAP-del cancers (10-15% of all cancers). BMS-986504 (formerly MRTX1719) is a potential first-in-class MTA-cooperative protein arginine methyltransferase 5 (PRMT5) inhibitor that selectively binds to the PRMT5-MTA complex, a synthetic lethal target in MTAP-del but not MTAP-wild-type cells. In the first-in-human phase 1/2 CA240-0007 study, BMS-986504 was well tolerated and showed clinical activity in heavily pretreated pts across multiple advanced solid tumors with homozygous MTAP-del. Here, we report results of exploratory PD analyses of PRMT5 inhibition with BMS-986504 in CA240-0007. Methods: Pts with advanced, unresectable or metastatic solid tumors with homozygous MTAP-del received BMS-986504 (50 to 800 mg) in 3-wk cycles. Symmetric dimethylarginine (SDMA) and intron retention are known PD BMs of PRMT5 inhibition. Therefore, PD effects of BMS-986504 were assessed via changes in plasma and tumor SDMA levels (mass spec and IHC), intron retention, and gene expression (RNASeq) based on samples collected at baseline (BL) and cycle 2 day 1 (C2D1). Additional analyses correlating efficacy outcomes with PD results and select mutations at BL were performed in clinically evaluable pts as of 19-SEP-24. Results: Robust PD modulation of the PRMT5 pathway was observed with BMS-986504. Among pts with matched samples (n = 63), median plasma SDMA levels were reduced by 56% from BL (122.6 ng/mL) to C2D1 (53.8 ng/mL). There were dose-dependent reductions in median plasma SDMA with the greatest reductions at 400 mg QD (59.7% [n = 20]), 400 mg BID (61.9% [n = 9]) and 600 mg QD (59.1% [n = 14]). These PD effects were corroborated in the tumor. Median tumor SDMA levels decreased from an HScore of 285 at BL to 0 at C2D1. Consistent with the SDMA decreases, increased intron retention was observed in 9/11 pts with matched samples. BMS-986504 led to downregulation of several gene pathways including DNA repair and mitotic spindle formation, and MYC and E2F targets, as assessed by RNASeq. There was no significant change in expression of MAT2A, PRMT5, or other PRMT genes, suggesting a lack of compensation for PRMT5 inhibition through these genes. Responses were observed with BMS-986504 across EGFR, KRAS, and TP53 mutation subgroups. Additional correlative analyses among BMs and efficacy outcomes will be presented. Conclusions: BMS-986504 demonstrated robust PD effects across multiple doses and solid tumors which is consistent with the proposed mechanism of action. There was a trend of increasing plasma SDMA reduction across doses, with the greatest reductions observed at 400 mg QD and above. Together these results support further investigation of BMS-986504 at 400 mg QD and higher doses as a potential first-in-class synthetic lethal Tx option in pts with advanced solid tumors with MTAP-del. Citation Format: Jordi Rodón, Tyler Simpson, Ben George, Pasi A. Jänne, Kathryn C. Arbour, Konstantinos Leventakos, Kyriakos P. Papadopoulos, Melissa L. Johnson, Alexander I. Spira, Cesar A. Perez, Hani M. Babiker, Richard Zuniga, Candace L. Haddox, Tapsi Kumar, Yidi Qin, Wen-Chi Chou, Peter Olson, Kenna Anderes, Alice Wozniak, Curtis Chin, Ming Lei, Jason T. Henry. Pharmacodynamic (PD) and exploratory biomarker (BM) analysis of the PRMT5 inhibitor BMS-986504 in patients (pts) with advanced solid tumors with homozygous MTAP deletion (MTAP-del) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_2):Abstract nr CT079.

AbstractINTRODUCTIONHigher male prevalence in sporadic behavioral variant frontotemporal dementia (bvFTD) has been reported. We hypothesized differences in phenotypes between genetic and sporadic bvFTD females resulting in underdiagnosis of sporadic bvFTD females.METHODSWe included genetic and sporadic bvFTD patients from two multicenter cohorts. We compared behavioral and cognitive symptoms, and gray matter volumes, between genetic and sporadic cases in each sex.RESULTSFemales with sporadic bvFTD showed worse compulsive behavior (p = 0.026) and language impairments (p = 0.024) compared to females with genetic bvFTD (n = 152). Genetic bvFTD females had smaller gray matter volumes than sporadic bvFTD females, particularly in the parietal lobe.DISCUSSIONFemales with sporadic bvFTD exhibit a distinct clinical phenotype compared to females with genetic bvFTD. This difference may explain the discrepancy in prevalence between genetic and sporadic cases, as some females without genetic mutations may be misdiagnosed due to atypical bvFTD symptom presentation.Highlights Sex ratio is equal in genetic behavioral variant of frontotemporal dementia (bvFTD), whereas more males are present in sporadic bvFTD. Distinct neuropsychiatric phenotypes exist between sporadic and genetic bvFTD in females. Phenotype might explain the sex ratio difference between sporadic and genetic cases.

Abstract INTRODUCTION Sex differences are apparent in neurodegenerative diseases but have not been comprehensively characterized in frontotemporal dementia (FTD). METHODS Participants included 337 adults with autosomal dominant FTD enrolled in the ALLFTD Consortium. Clinical assessments and plasma were collected annually for up to 6 years. Linear mixed‐effects models investigated how sex and disease stage are associated with longitudinal trajectories of cognition, function, and neurofilament light chain (NfL). RESULTS While sex differences were not apparent at asymptomatic stages, females showed more rapid declines across all outcomes in symptomatic stages compared to males. In asymptomatic participants, the association between baseline NfL and clinical trajectories was weaker in females versus males, a difference that was not present in symptomatic participants. DISCUSSION In genetic FTD, females show cognitive resilience in early disease stages followed by steeper clinical declines later in the disease. Baseline NfL may be a less sensitive prognostic tool for clinical progression in females with FTD‐causing mutations. Highlights Females with genetic FTD exhibit overall steeper increases in plasma neurofilament light chain (NfL) than males. Females with genetic FTD outperform NfL levels in asymptomatic stages compared to males. Once symptomatic, females with genetic FTD decline more rapidly than males. Plasma NfL is a stronger prognostic marker in asymptomatic males than females.

ImportanceUnderstanding the global barriers to otolaryngology–head and neck surgery (OHNS) care is crucial in addressing disparities in access to care, particularly in low-income and middle-income countries (LMICs).ObjectiveTo characterize barriers to comprehensive otolaryngology care across World Bank income groups.Design, Setting, and ParticipantsUsing an online cross-sectional survey that was administered by the Global OHNS Initiative via international and national professional societies, personal contacts, and social media, this study captured the perceptions of otolaryngologists regarding barriers to OHNS care at the levels of the country, health sector, clinician, and patient. Participants included otolaryngologists from the 194 World Health Organization member states and Taiwan. Eligibility criteria included a medical degree and specialized training in managing conditions of the ear, nose, and throat. The nonresponse rate was not recorded. The data collection period spanned from October 2022 to June 2023.ExposuresExposures included World Bank income group classification.Main Outcomes and MeasuresThe primary outcomes were Likert scale responses regarding frequency of barriers to OHNS care. The a priori hypothesis was that LMICs would report more frequent barriers to OHNS care.ResultsThe study involved 146 otolaryngologists (47 female individuals [32%]), with 69 (47%) from high-income countries and 77 (53%) from LMICs. Male individuals represented 45 high-income country respondents (65%) and 54 LMIC respondents (70%). Barriers were reported across income groups at all levels of the health system, with a higher frequency in LMICs. Several barriers were reported to be more substantial in LMICs, such as the national volume and distribution of otolaryngologists, financial compensation for clinicians, and patient stigma, and others were common across income settings, such as the availability of operating rooms and inflexible working hours. Common concerns included national and health sector barriers: OHNS workforce, referral networks, government support; clinician barriers: excessive clinician workloads, understaffing, poor administration support; patient barriers: distance to health care facilities, financial burdens such as medical costs and foregone wages, stigma, and health literacy.Conclusions and RelevanceThe results of this cross-sectional study suggest that there are barriers to otolaryngology care globally that affected all levels of the health care system. This work may inform prioritization of otolaryngology within research and policy, and it emphasizes the need for effective strategies to expand access to otolaryngology care, particularly in lower-income settings.

PURPOSE Sertoli-Leydig cell tumors (SLCTs) are rare sex cord-stromal tumors, representing <0.5% of all ovarian tumors. We analyze the role of germline DICER1 status in outcomes of ovarian SLCT. METHODS Patients with SLCT were enrolled in the International Pleuropulmonary Blastoma/ DICER1 Registry and/or the International Ovarian and Testicular Stromal Tumor Registry. Medical records were systematically abstracted, and those with known germline DICER1 status were selected for analysis. RESULTS Of 162 patients with SLCT, 60% had a germline DICER1 pathogenic or likely pathogenic (P/LP) variant. The adjusted 3-year recurrence-free survival (RFS) was 87.2% (95% CI, 79.4 to 95.8) for patients with a germline DICER1 P/LP variant compared with 78.1% (95% CI, 66.4 to 91.9) for those without a germline DICER1 P/LP variant ( P = .043). The adjusted 3-year and 5-year overall survival (OS) was 93.9% (95% CI, 87.3 to 100.0) for those with a germline DICER1 P/LP variant compared with the 3-year OS of 91.3% (95% CI, 83.4 to 100.0) and the 5-year OS of 78.2% (95% CI, 63.8 to 95.9) for those without a germline DICER1 P/LP variant ( P = .021). Among patients with a germline DICER1 P/LP variant, the risk of a subsequent, nonrecurrent event was 36.2% (95% CI, 21.4 to 48.1) within 10 years. Previous/concurrent and subsequent neoplasms were rare among those without a germline DICER1 P/LP variant. CONCLUSION This cohort study of patients with SLCT demonstrated that those with germline DICER1 P/LP variants had superior RFS and OS even when adjusting for other prognostic factors. Beyond prognostic implications of a germline DICER1 P/LP variant, germline testing helps identify patients at risk of subsequent neoplasms, including metachronous SLCT.

AbstractBackgroundOvarian juvenile granulosa cell tumors (juvGCT) are rare sex cord‐stromal tumors that occur primarily in children and adolescents. This study summarizes the clinical presentation and outcomes of patients with juvGCT.MethodsPatients were enrolled in the International Ovarian and Testicular Stromal Tumor and/or International Pleuropulmonary Blastoma/DICER1 Registries. Available medical records were abstracted, and pathology was centrally reviewed. Surgical staging was classified using the 2014 International Federation of Gynecology and Obstetrics (FIGO) criteria.ResultsIn total, 70 patients with juvGCT enrolled and were diagnosed between 2001 and 2024; most patients (81%, 57 of 70) presented with FIGO stage I disease. Adjuvant chemotherapy was given in 30% (21 of 70); all regimens were platinum‐based. Three‐year event‐free survival among patients with stage IA tumors was 80.2% (95% confidence interval [CI], 62.4%–100.0%), IC1 was 87.4 (95% CI, 72.4%–100.0%), IC2‐IC3 was 63.6% (95% CI, 40.7%–99.5%), and II‐IV was 48% (95% CI, 24.6%–93.8%). Of the patients with recurrent juvGCT with known mitotic index (MI), all had MI greater than 19 mitoses per 10 high power fields (HPF) at diagnosis.ConclusionOutcomes were worse for patients with FIGO stage ≥IC2 disease and for tumors with >19 mitoses per 10 HPF. Given the prognostic significance of MI, the authors strongly recommend the assessment of MI for all juvGCTs. More information about tumor biology is critical to identify which patients may benefit from adjuvant chemotherapy and to facilitate the development of novel therapies.

The gracilis free functioning muscle transfer is an established procedure for reconstructing elbow, wrist, and hand function in adult traumatic brachial plexus injury patients. Elbow flexion or distal wrist or hand function can be compromised by gracilis bowstringing in up to 17.8% of patients. Two techniques for pulley reconstruction to correct bowstringing and improve the function of the gracilis transfer are described.

This review examines the applications and challenges of large language models (LLMs), like OpenAI’s ChatGPT, in radiology research. ChatGPT can assist radiology researchers in generating new ideas, finding and summarizing research papers, designing studies, analyzing data, and facilitating manuscript writing. LLMs are powerful tools with numerous applications in radiology research. However, users should be mindful of potential pitfalls, such as producing incorrect or biased outputs and inconsistent responses, along with ethical and privacy concerns. We discuss approaches to optimize models and address these issues, including prompting techniques like chain-of-thought prompting, retrieval-augmented generation, and fine-tuning. For researchers, prompt engineering can be particularly effective. This review seeks to demonstrate how researchers can utilize ChatGPT for radiology research while offering strategies to mitigate associated risks. We aim to help researchers harness these potent tools to safely boost their productivity.

Abstract Recent evidence has highlighted the critical requirement for “immune triads” of CD8+ T cells, CD4+ T cells and dendritic cells (DC) for tumor elimination in response to checkpoint inhibition (CPI) immunotherapy. However, the mechanistic underpinnings of this cross-talk are poorly understood. Immune triads are often located in peripherally-distributed DC-rich niches within the tumor stroma. We have hypothesized that stromal remodeling in response to tumor expansion generates homeostatic signals that trigger an adaptive immune response that may ultimately fail through effector exhaustion or apoptosis. In particular, stromal proteolysis of the large matrix proteoglycan versican (VCAN) has been associated with T-cell infiltration across multiple tumor types. The objective of this study was to interrogate a mechanistic link between stromal remodeling, immune triad formation and response to CPI. We used HALO image analysis to determine the spatial relationship of CD4+ and CD8+ T cells in a panel of 95 human non-small cell lung cancers. Each tumor was VCAN proteolysis-scored based on a binning system measuring staining intensity for a neoepitope exposed through site-specific VCAN proteolysis. Tumors displaying VCAN proteolysis intensity of zero (0) had an average of 0.122 CD8+ T cells located with 10um of a CD4+ T cell vs. 0.216 in tumors with any VCAN proteolysis (intensity 1, 2, 3 combined); p=0.04. Similar results were obtained when measuring proximity of CD4+ to CD8+ T cells (0.124 vs 0.223, p=0.02). These data demonstrate that remodeling stroma promotes CD4+:CD8+ crosstalk. Site-specific VCAN proteolysis releases a 441 N-terminal bioactive fragment, versikine. Versikine constitutes a classical “matrikine”, i.e., a bioactive matrix fragment possessing novel functions compared to its parent macromolecule. To determine the mechanisms by which versikine may promote immune triad niches, we generated several transplantable syngeneic tumor cell lines engineered to stably secrete versikine into the TME. One CPI-refractory tumor cell line (Lewis Lung Carcinoma, LLC) and two partially CPI-responsive transplantable tumor lines (CT26 and MC38 colorectal carcinoma) were extensively characterized through flow cytometry, spatial immunofluorescence and scRNAseq. Our results demonstrate that in all contexts, versikine results in expansion of Tfh-like CD4+ T cells expressing Cd40lg and Icos. This expansion is associated with specific patterns of CD8+ T cell exhaustion that will be discussed. Therapeutically, versikine reversed anti-PD-1 pathway refractoriness in the poorly-immunogenic LLC model and demonstrated superior synergy with CPI in the more immunogenic CT26 and MC38 models, leading to tumor eradication with resistance to tumor rechallenge. Our data bolster the mechanistic rationale for exploitation of stromal remodeling signals to promote CD4+T:CD8+T:DC cross-talk for enhanced CPI efficacy. Citation Format: Daniel Lagal, Duncan Hong, Athanasios Papadas, Alicia Gibbons, Yun Huang, Yaling Dou, Alexander Cicala, Elsa Molina, Kristina Matkowskyj, Dustin Deming, Fotis Asimakopoulos. Stromal remodeling promotes immune triad formation in the tumor microenvironment (TME) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 2588.

Objective: To explore the associations between social determinants of health (SDOH) and the access to, delivery of, and outcomes of cholesteatoma care. Study Design: Retrospective review. Setting: Multisite tertiary care institution. Methods: Seventy-five adults (aged 18–83) with cholesteatoma who completed SDOH questionnaires were included. Outcome measures included SDOH risk factor prevalence (stress, housing instability, financial resource strain, social connectedness, food insecurity, intimate partner violence), disease severity, hearing loss degree at presentation, mean time from symptom onset to diagnosis, postoperative improvements in air-bone gaps (ABG), complication rates, and two-stage surgery rates. Results: Stress (n = 45; 60%) was the most prevalent SDOH risk factor. Females (n = 23; 79.3%; P = 0.05; d = –0.24]), younger adults (mean age = 45; P = 0.01; d = –0.69), and individuals with lower education (n = 23; 82.1%; P = 0.04; d= –0.26) were more likely to have at least one SDOH risk factor. Patients with SDOH risk factors had better preoperative air pure tone averages (mean [SD] = 39.7 [16]; P = 0.01; d = –0.69) than patients without SDOH risk factors (mean [SD] = 50.1 [13.5]); but the ABG was similar between groups (P = 0.16; d = –0.38). No differences were identified in any measure of cholesteatoma care between patients with and without SDOH risk factors. Conclusion: Stress is a prevalent SDOH risk factor among patients with cholesteatoma, but it might not influence cholesteatoma care. Though female sex, younger age, and lower education levels were associated with having at least one SDOH risk factor, these also might not influence cholesteatoma care. Intentional study of larger, more heterogeneous populations is necessary to validate these observations.