Citations

e19554 Background: Adding daratumumab to standard multiple myeloma (MM) regimens improves response rates and clinical outcomes. Systematic reviews (meta-analyses) allow further evaluation of its effectiveness in MM patients with high-risk cytogenetic factors but are limited by model assumptions. his study addresses these limitations using a novel synthetic individual patient data (SynIPD) generation algorithm to enable a more robust analysis. Methods: Advances in AI have enabled the creation of synthetic data that mimics the statistical properties of real patient data, empowering aggregated analyses of clinical trials. This study focuses on newly diagnosed MM (NDMM) and relapsed/refractory MM (RRMM) patients with high-risk cytogenetic profiles. Six studies were included: ALCYONE, CASSIOPEIA, and MAIA for NDMM, and CANDOR, CASTOR, and POLLUX for RRMM. Large language models extracted clinical evidence, and SynIPD was generated, incorporating cytogenetic profiles. Random-effects meta-analyses were conducted, and results were compared with pooled analyses using synthetic data. Results: Synthetic data were generated for three studies for NDMM (ALCYONE, CASSIOPEIA, MAIA) and three studies for RRMM (CANDOR, CASTOR, POLLUX). The generated hazard ratios (HRs) for each study closely aligned with reported HRs for high-risk patients, with a maximum relative error of less than 2%. By pooling these datasets, we obtained synthetic datasets for NDMM and RRMM patients. Stratified Cox regression analyses yielded HRs (95% confidence interval) of 0.764 (0.529-1.104) for NDMM and 0.431 (0.294-0.613) for RRMM. Random-effects meta-analyses showed HRs (95% confidence interval) of 0.764 (0.529-1.104) for NDMM and 0.425 (0.287-0.621) for RRMM. Compared with traditional meta-analysis techniques, the synthetic data approach provides additional clinical insights that were not available in the original publications. For instance, the clinical results for the three NDMM studies are summarized as KM curves in Figure 1, which were not reported in the original studies. Conclusions: Our results suggest that the addition of daratumumab to standard regimens improves PFS for RRMM patients with high-risk cytogenetic factors, although its benefit for NDMM patients is not statistically significant. Pooling synthetic data enhances the robustness of conventional meta-analysis outcomes. The identification of HRs and corresponding confidence intervals through SynIPD improves the credibility of our proposed method, offering a reliable approach to evaluating the efficacy of daratumumab in high-risk patients. Since SynIPD includes individual covariate information, it provides deep clinical insights beyond merely enhancing meta-analysis. In other words, any statistical results derived from the original IPD can be effectively approximated using SynIPD.

7547 Background: Minimal residual disease (MRD) has been recently accepted by the Food and Drug Administration (FDA) as an endpoint for accelerated approval in Multiple Myeloma. However, emerging data from recent trials were not included in previous analyses. While literature-based meta-analyses on the correlation between MRD and approved clinical outcomes typically require extensive manual review, leveraging AI with expert-in-the-loop validation can efficiently generate reliable evidence from comprehensive clinical studies with up-to-date outcomes. Methods: An AI-assisted framework was developed to identify relevant studies and extract critical information via two independent objectives. The first objective examined trial-level associations, modeling treatment effects on MRD and clinical endpoints across patient populations using weighted least squares, with association strength measured by coefficients of determination (R²) and 95% confidence intervals (CIs). The second objective analyzed individual-level associations using synthetic individual patient data (SynthIPD) generated from the published Kaplan-Meier plots and summary statistics of patient subgroups. Results: AI-assisted screening identified eligible studies (>50 patients per treatment arm) reporting progression-free survival (PFS), overall survival (OS), and MRD-negative complete response rates (MRD-CR rate) using multi-parameter next-generation flow cytometry or sequencing methods (sensitivity threshold ≥10⁻⁵), expanding previous analyses from 15 to 20 two-arm studies. Trial-level analysis demonstrated an R² of 0.69 (95% CI 0.50–0.89) for PFS log hazard ratio versus MRD-CR rate log odds ratio. Analysis of synthetic individual data from Kaplan-Meier curves using a novel digitization method yielded a global odds ratio of 7.28 (95% CI 5.60–8.95) for individual-level correlation between MRD-CR rates and PFS outcomes. Conclusions: This study validates MRD-CR rate as an endpoint for accelerated approval in MM through rapid AI-assisted literature review and synthetic individual patient data. The findings demonstrate moderate correlation between MRD-CR rate and median PFS at both trial and individual levels, consistent with previous literature but incorporating additional eligible studies. The novel SynthIPD approach presents an efficient alternative to traditional data-sharing methods while maintaining analytical robustness. These results align with current Oncologic Drugs Advisory Committee (ODAC) surrogacy analysis methods and support the utility of MRD assessment in MM clinical trials.

Abstract Aims This study aimed to establish 2D and M-mode echocardiographic reference values for cardiac chambers, outflow tracts, and great vessels for school children living at high altitudes, differentiated between males and females. Methods and results This post hoc analysis included children with normal echocardiography from a cluster randomized cross-sectional survey of rheumatic heart disease among school children in Peru. The echocardiograms were acquired with a portable machine and the images were analysed centrally with a standardized methodology. Body surface area (BSA) was used as an independent variable to predict the mean values of echocardiographic measurements for both male and female groups. Reference values are presented on z-scores and nomograms based on sex. Propensity score matching was used to compare sexes. A total of 985 students aged 5–16 years were included. The Haycock formula provided the best fit and was used when presenting data as predicted values for a given BSA. The z-score and nomograms for all essential parameters of cardiac chambers, great vessels, and functional surrogates are presented based on sex. The majority of the parameters were significantly different per sex after propensity score matching. Conclusion Normal reference values and nomograms of cardiac chambers, outflow tracts, and great arteries in healthy school children living at high altitudes based on sex were reported. These data partly addressed the existing gaps in paediatric echocardiographic nomograms.

Pick’s disease (PiD) is a rare neurodegenerative disorder defined by dementia, frontotemporal lobe atrophy, and 3-repeat tau inclusions. To elucidate PiD pathobiology, we performed the first bulk transcriptomics study on PiD using short- and long-read sequencing on the parietal cortex of 28 PiD and 15 control samples. We identified several significantly differentially expressed genes, with CCL2 displaying the strongest association with 3-repeat tau pathology and increased burden in PiD compared to those in 4-repeat tau progressive supranuclear palsy (PSP) cases. Investigation of co-expressed genes and pathways suggested the involvement of mRNA processing, mitochondrial function, and immune processes in disease pathobiology. Long-read RNA sequencing on a subset of samples (eight PiD and four control) proposed novel, potentially disease-associated transcripts for AZGP1 , CD44 , HSD11B2 , and WIF1 , predicted to result in truncated proteins. In conclusion, we observed transcriptomic changes in the parietal cortex of patients with PiD that may inform into clinically relevant biomarkers and therapeutic strategies.

Background The Woven EndoBridge (WEB) device is a prevalent treatment for intracranial aneurysms. While many studies have assessed the obliteration rate post-WEB embolization, few have focused on long-term outcomes in partially thrombosed aneurysms. Objective To assess whether partially thrombosed aneurysms are at higher risk of recurrence or retreatment following WEB embolization compared with non-thrombosed aneurysms. Methods We evaluated data from 22 academic institutions, focusing on previously untreated cerebral aneurysms treated with the WEB device. Logistic regression was utilized to analyze factors predicting long-term aneurysm obliteration and retreatment necessity. Results Among 1303 patients, 26 presented with a partially thrombosed aneurysm. In the partially thrombosed group, the mean aneurysm maximal diameter was 10.7±4 mm with a neck ratio of 1.99±1.19 mm, larger than in the control group where the mean aneurysm maximal diameter was 6.81±2.37 mm with a neck ratio of 1.64±0.51 mm (P<0.001 for both maximal diameter and neck ratio). At the final follow-up, partially thrombosed aneurysms treated by the WEB device had a 38.5% retreatment rate, compared with 7.0% for non-thrombosed aneurysms (P<0.001). Among partially thrombosed aneurysms, the Raymond-Roy type IIIa/b occlusion rate was higher (38.5% vs 9.9%, P<0.001). On multivariate analysis, partially thrombosed aneurysms compared with non-thrombosed aneurysms had an increased rate of retreatment (OR 3.64, 95% CI 1.28 to 10.1). Conclusion Partially thrombosed aneurysms are associated with a poorer occlusion rate and a higher rate of retreatment following WEB embolization. For partially thrombosed aneurysms, the WEB device appears suboptimal as a first-line treatment, and therefore alternative techniques should be prioritized.

Abstract Approximately two-thirds of hypopharyngeal squamous cell carcinoma (HPSCC) are diagnosed in advanced stage, with the worst prognosis among head and neck squamous cell carcinomas (HNSCCs). Identifying biomarkers for high-risk patients who need aggressive treatment is crucial. We present mutational, transcriptomic and proteomic studies of 103 Chinese HPSCC patients, observing a higher prevalence and poorer prognosis in males comparing to females. Genes in estrogen response pathways are up-regulated and proteins phosphorylated by protein kinase C (PKC) and Cyclin-dependent kinases (CDKs) are aberrantly regulated. We identify aberrant copy number regions including SOX2 (3q26.33), FGFR (8p11.23), CCND1 (11q13.3), CDKN2A/2B (9p21.3), and MYC (8q24.21). HPV status combined with highly mutated genes as predictive markers was assessed, including SYNE1 in HPV(-), MUC4 in HPV(+) patients. We confirm the presence of four known gene expression (GE) subtypes of HNSCC in our HPSCC cohort and present the genomic alterations, patient characteristics and survival status of each subtype. A predictive model involving clinical factors and transcriptomic expression of six genes was established and cross-site validated. The findings open new opportunities for stratifying high-risk patients and molecular targets for novel therapeutic strategies. Citation Format: Yanxin Ren, Wei Xiong, Chun Feng, Dan Yu, Xiaoyan Wang, Qing Yang, Siting Yu, Hongjiang Zhang, Bangyun Huo, Honglu Jiang, Zuli Li, Junlin Wang, Yu-Xiong Su, Ping Yang, Yong Liao, Qi Zhong, Junwen Wang. Multi-omics insights into the molecular signature and prognosis of hypopharyngeal squamous cell carcinoma [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 4999.

Abstract INTRODUCTION Loss‐of‐function variants of the ABCA7 gene are associated with an increased risk of Alzheimer's disease (AD). How neuronal ABCA7 contributes to AD pathogenesis is unknown. METHODS Using neuron‐specific Abca7 KO mice (n Abca7 −/− ) with or without 5×FAD amyloid model background and post mortem AD brains, we investigated AD‐related phenotypes through comprehensive approaches including transcriptomics and lipidomics. RESULTS Lipidomics analysis detected altered lipid profiles in the brains and synaptosomes of 5×FAD; n Abca7 −/− mice compared to controls. Transcriptomics profiling revealed that neuronal ABCA7 deficiency altered the expression of genes and pathways related to mitochondrial homeostasis and apoptosis, particularly in excitatory neurons. Consistently, synaptosomes isolated from 5×FAD; n Abca7 −/− mice showed diminished mitochondria respiration and reduced synaptic protein levels, which is further supported by results from human AD brains. DISCUSSION Our findings reveal that neuronal ABCA7 plays a critical role in mitochondrial homeostasis important for neuronal function and survival in the presence of AD pathology. Highlights Neuronal ABCA7 deficiency exacerbates Aβ pathology and neuronal damage in 5×FAD mice. Neuronal ABCA7 deficiency alters brain transcriptomes and lipidomes of 5×FAD mice. Neuronal ABCA7 deficiency disturbs mitochondria functions in synaptosomes from 5×FAD mice. Neuronal ABCA7 expression associates with genes and pathways related to mitochondrial homeostasis in AD brains.

ABSTRACT Recent development of single-cell technology across multiple omics platforms has provided new ways to obtain holistic views of cells to study disease pathobiology. Alzheimer’s disease (AD) is the most common form of dementia worldwide, yet the detailed understanding of its cellular and molecular mechanisms remains limited. In this study, we analyzed paired single-cell transcriptomic (scRNA-seq) and chromatin accessibility (scATAC-seq) data from the Seattle Alzheimer’s Disease Brain Cell Atlas (SEA-AD) Consortium to investigate the molecular mechanisms of AD at a cell-subpopulation-specific resolution focusing on glial cells. We benchmarked various multi-omics integration methods using diverse metrics and built an analytic workflow that enabled effective batch correction and cross-modality alignment, creating a unified cell state space. Through integrative analysis of 26 human brain samples, we uncovered AD-associated gene expression and pathway changes in glial subpopulations and highlighted important transcriptomic and epigenomic signatures via functional inference and interpretable machine learning paradigms, discovering the profound involvement of the Solute Carrier proteins (SLC) family genes in multiple glial cell types. We also identified glial cell-specific regulatory programs mediated by key transcription factors such as JUN and FOSL2 in astrocytes, the Zinc Finger (ZNF) family genes in microglia, and the SOX family of transcription factors in oligodendrocytes. Our study provides a comprehensive workflow and a high-resolution view of how glial regulatory programs are disrupted in AD. Our findings offer novel insights into disease-related changes in gene regulation and suggest potential targets for further research and therapy.

OBJECTIVE Tobacco smoking is among the factors known to significantly augment the risk of untreated intracranial aneurysm (IA) growth and rupture. Smoking appears to have a variable effect on different endovascular treatment modalities. The impact of smoking on the safety, efficacy, and outcomes of Woven EndoBridge (WEB) device use for wide-neck IAs has not been evaluated. This study aimed to investigate the outcomes of WEB devices by smoking status. METHODS A retrospective multicenter analysis was conducted on the data of patients from 36 sites worldwide treated with the WEB device for intracranial saccular aneurysms. Patients were stratified based on smoking status (current, former, and never smokers). The Student t-test and chi-square test were performed for continuous and categorical variables, respectively. Multivariable logistic regression was used to adjust for confounders. RESULTS Of 1376 patients with available smoking status, 504 were current smokers, 358 were former smokers, and 514 were never smokers. Upon adjusting for significant confounders, no association was found between smoking and recurrence outcomes (OR 1.39, 95% CI 0.69–2.80; p = 0.36), thromboembolic and hemorrhagic complications, and mortality among IAs treated with the WEB device. There was no statistically significant difference in outcomes between former and never smokers (OR 1.23, 95% CI 0.70–2.18; p = 0.46). The location of aneurysms differed between smoking groups, with former smokers having more anterior circulation aneurysms compared with current and never smokers (99.0% vs 96.9% vs 95.3%; p = 0.01). In terms of clinical symptoms, headache and dizziness were more common in the never smokers compared with current and former smokers (13.9% vs 8.9% vs 7.7%, p = 0.01). CONCLUSIONS This large-scale study suggests no significant correlation between smoking and the recurrence of IAs treated with the WEB device. Biological studies are warranted to better understand the biological impact of smoking on the growth and rupture of treated IAs.