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Abstract Background Lung adenocarcinoma in never-smokers is a major public health burden, especially among East Asian women. Polygenic risk scores (PRSs) are promising for risk stratification but are primarily developed in European-ancestry populations. We aimed to develop and validate single- and multi-ancestry PRSs for East Asian never-smokers to improve lung adenocarcinoma risk prediction. Methods PRSs were developed using genome-wide association study summary statistics from East Asian (8002 cases; 20 782 controls) and European (2058 cases; 5575 controls) populations. Single-ancestry models included a PRS with 25 single nucleotide variants (PRS-25), PRS clumping and thresholding (CT), and LDpred2; multi-ancestry models included LDpred2 plus European PRS-128, PRS-CSx, and clumping and thresholding, super learning, empirical Bayes (CT-SLEB). Performance was evaluated in independent East Asian data from the Female Lung Cancer Consortium and externally validated in the Nanjing Lung Cancer Cohort. We assessed predictive accuracy via area under the curve operating procedure (AUC), with 10-year and (ages 30-80 years) absolute risks estimates. Results The best multi-ancestry PRS, using East Asian and European data via CT-SLEB, outperformed the best East Asian-only (LDpred2; AUC = 0.629, 95% confidence interval [CI] = 0.618 to 0.641), achieving an AUC of 0.640 (95% CI = 0.629 to 0.653) and odds ratio of 1.71 (95% CI = 1.61 to 1.82) per standard deviation increase. Nanjing Lung Cancer Cohort validation confirmed robust performance (AUC = 0.649, 95% CI = 0.623 to 0.676). The top 20% PRS group had a 3.92-fold higher lung adenocarcinoma risk than the bottom 20%. Further, the top 5% PRS group reached a 6.69% lifetime absolute risk. Notably, this group reached the average population 10-year lung adenocarcinoma risk at age 50 years (0.42%) by age 41 years, 9 years earlier. Conclusions Multi-ancestry PRS approaches enhance lung adenocarcinoma risk stratification in East Asian never-smokers, with consistent external validation, suggesting future clinical utility.

Abstract Background Recurrent Clostridioides difficile infection (rCDI) is common, with a prior CDI linked to a risk of up to 65% for subsequent recurrences. Fecal microbiota, live-jslm (RBL) is the first microbiota-based product approved in the US for the prevention of rCDI in adult patients following antibiotic treatment for rCDI. This study reports the characteristics and outcomes of patients with rCDI who were administered RBL in a real-world setting. Methods Adult patients with rCDI who received RBL either at home or a clinic from healthcare professionals affiliated with a home-care provider network were included. Patients were required to have at least 8 weeks of follow-up after RBL administration, with CDI recurrence status assessed at week 8. Patient demographics, clinical characteristics, administration setting, prior medication use, and prior healthcare resource utilization were collected. The primary outcome was CDI recurrence within 8 weeks post-RBL administration. All variables were summarized descriptively using median and interquartile range (IQR) for continuous outcomes and count and percentage for categorical variables. Results Between July 2023 and March 2024, 136 patients with rCDI received RBL, of whom 73 had at least 8-week follow up and reported CDI recurrence status at week 8. Patients had a median age of 63.0 years (IQR = 47.0, 76.0), 68.5% were female, most (74.0%) had ≥ 3 prior CDI recurrences, 5.5% had received fecal microbiota transplant, and 9.6% had received bezlotoxumab (Table). One third of patients (32.9%) had previously been hospitalized and 38.4% had prior emergency room visits due to CDI. Most patients were previously treated with antibiotics for rCDI: 39.7% with vancomycin only, 11.0% with fidaxomicin only, and 43.8% with both vancomycin and fidaxomicin. All patients, except for 4 with missing data, received RBL 24-72 hours post-antibiotics. Most patients (83.6%) received RBL at home. At week 8, the overall treatment success rate (no CDI recurrence) was 87.7% (87.3% [62/71] in RBL-naïve; 100% [2/2] in previously RBL-treated). Conclusion RBL was effective in preventing recurrence of CDI at 8 weeks in a real-world setting, where most patients received RBL at home. These results suggest that RBL is effective in managing rCDI, including in a home care setting. Disclosures Sahil Khanna, MBBS, MS, Ferring Pharmaceuticals, Inc.: Grant/Research Support|Finch: Grant/Research Support|Immuron: Advisor/Consultant|Niche: Advisor/Consultant|Pfizer: Grant/Research Support|Probio Tech, LLC: Advisor/Consultant|Seres Therapeutics: Grant/Research Support|Takeda: Advisor/Consultant|Vedanta: Grant/Research Support Sanghyuk Seo, PharmD, MS, Ferring Pharmaceuticals, Inc.: Employee Min Yang, MD, PhD, Analysis Group, Inc.: I am an employee of Analysis Group, Inc., which has received consulting fees from Ferring for the conduct of this study. Viviana García-Horton, PhD, Analysis Group, Inc.: I am an employee of Analysis Group, Inc., which has received consulting fees from Ferring for the conduct of this study. Yipeng Gao, PhD, Analysis Group, Inc.: I am an employee of Analysis Group, Inc., which has received consulting fees from Ferring for the conduct of this study. Hannah Kim, PhD, Analysis Group, Inc.: I am an employee of Analysis Group, Inc., which has received consulting fees from Ferring for the conduct of this study. Loren Ormenaj, n/a, Analysis Group, Inc.: I am an employee of Analysis Group, Inc., which has receivedconsulting fees from Ferring for the conduct of this study. Amy Guo, PhD, Ferring Pharmaceuticals, Inc.: Employee

Abstract Purpose To propose a clinically oriented quantitative metric, the HU coefficient, to evaluate contour quality, gauge the performance of auto contouring methods, and aid effective allocation of clinical resources. Materials and Methods Publicly available pelvic CT data from the Cancer Imaging Archive was used to demonstrate the clinical utility of the HU coefficient in contour evaluation. The bladder was selected as the organ of interest. It was contoured by a certified medical dosimetrist and reviewed by a certified medical physicist. This contour served as the ground truth contour. From this contour, we simulated two contour sets. The first set had the same Dice similarity coefficient (DSC) but different HU coefficients, whereas the second set kept a constant HU coefficient while exhibiting different DSCs. Four individuals were asked to adjust the simulated contours until they met clinical standards. The corresponding contour modification times were recorded and normalized by individual’s manual contouring times from scratch. The normalized contour modification time was correlated to the HU and DSC to evaluate their suitability as quantitative metrics assessing contour quality. Results The HU coefficient maintained a strong correlation with the normalized contour modification time when both sets of simulated contours were included in analysis. The correlation between the DSC and normalized contour modification time, however, was weak. Compared to DSC, HU is more suitable for evaluating contour quality. Conclusions We demonstrated that the HU coefficient correlated well with the average normalized contour modification time. Clinically, contour modification time is the most relevant factor in allocating clinical resources. Therefore, the HU coefficient is better suited than DSC to assess contour quality from a clinical perspective.

3525 Background: Recent clinical trials support regorafenib dose optimization (ReDO), a combination therapy with trifluridine/tipiracil and bevacizumab (TAS-BEV), and fruquintinib (FRUQ) for the treatment of refractory metastatic colorectal cancer (mCRC). This study evaluated relative cost-effectiveness of ReDO, TAS-BEV, and FRUQ for mCRC from a payer perspective in the United States. Methods: A Markov model was constructed to estimate total costs and quality-adjusted life years (QALY) for each treatment. In the base case, clinical parameters were obtained from the ReDOS study for ReDO, the SUNLIGHT study for TAS-BEV, and the FRESCO study for FRUQ. Economic parameters were obtained from IBM Micromedex RED BOOK for treatment costs and from the Centers for Medicare & Medicaid Services and the Agency for Healthcare Research and Quality for health care resource use. Incremental cost-effectiveness ratio (ICER) was used to evaluate relative cost-effectiveness of treatments. Model robustness was checked with deterministic (DSA) and probabilistic sensitivity analysis (PSA). A subgroup analysis was performed in patients with and without previous use of anti-VEGF therapy, but using the FRESCO-2 study for FRUQ because OS and PFS for this subgroup was unavailable in the FRESCO study. Results: In the base case, ReDO provided a higher QALY at a lower cost than TAS-BEV and FRUQ. During the first two months following treatment initiation, TAS-BEV had a higher total cost ($67,862) than ReDO ($44,695) and FRUQ ($48,688), partly due to the cost of managing neutropenia and using concomitant granulocyte colony stimulating factors (GCSF). The base case results were robust in DSA and PSA. Most influential parameters determining relative cost-effectiveness were related to treatment cost and effectiveness. In patients with previous anti-VEGF therapy, ReDO provided a higher QALY at a lower cost (0.571 QALY; $86,694) than TAS-BEV (0.490 QALY; $148,784) and FRUQ (0.411 QALY; $101,236). In patients without previous anti-VEGF therapy, TAS-BEV had a higher QALY (0.755 vs 0.571) and a higher cost ($232,701 vs $86,694) than ReDO, resulting in an ICER of $790,988 per QALY. Conclusions: ReDO was cost-effective compared with TAS-BEV and FRUQ, regardless of previous use of anti-VEGF therapy. In the base case, ReDO had a lower treatment cost than TAS-BEV and FRUQ, especially during the first month of dose optimization. TAS-BEV had the highest total cost, partly due to the cost of managing neutropenia and GCSF use. [Table: see text]

Introduction: Spontaneous coronary artery dissection (SCAD) is an understudied cause of acute myocardial infarction due to hematoma formation in coronary arteries primarily affecting women. It is not known to what extent SCAD is genetically distinct from other cardiovascular diseases, including atherosclerotic coronary artery disease (CAD). Methods and Results: Through a meta-analysis of 8 GWAS (1917 cases, 9292 controls of European ancestry), we identified 17 risk loci, including 12 new. Functional annotations pointed at enrichment in enhancer marks of arteries, specifically smooth muscle cells, and strong candidate genes, such as tissue factor gene ( F3 ) on Chr1 near rs1146473 (OR=1.32, P=5.8 х10 -9 ). F3 is novel for SCAD or any cardiovascular disease. The risk allele correlated with F3 lower expression in arteries, supporting a mechanism consistent with hematoma formation. Bayesian gene regulatory networks constructed from expression and genetics data indicated the extracellular matrix organization in arteries as the biological function where most prioritized genes clustered (e.g. COL4A1/A2, HTRA1, and TIMP3 ). Overall, we report substantial polygenicity for SCAD (LDSC: h 2 SNP = 0.71 ± 0.11) and shared genetics with several neurovascular diseases (e.g intracranial aneurysm). Intriguingly, for 6 loci, colocalization analyses showed that SCAD and CAD are likely to share the same causal variants but involve opposite risk alleles (e.g COL4A1/A2 ). In addition, a negative genetic correlation was found between SCAD and CAD (rg=-0.12; P=3.7х10 -3 ), including after conditioning on BP (mt-COJO: rg CAD/SBP =-0.19, P=4.6х10 -6 ). Mendelian randomization analyses indicated higher BP to associate with increased risk for SCAD (beta IVW-SBP =0.05, P=7.6х10 -6 , beta IVW-DBP =0.10, P=1.9х10 -6 ) and CAD (beta IVW-SBP =0.04, P=8.6х10 -49 ; DBP: beta IVW-DBP =0.06, P=1.6х10 -44 ) but not BMI, lipids, or type 2 diabetes, which we confirmed as genetic risk factors for CAD Conclusions: Our results set the stage for future investigation of novel biological pathways relevant to both SCAD and CAD and potential therapeutic and preventive strategies specifically targeting this ischemic disease predominantly affecting women.

Introduction: Fibromuscular dysplasia (FMD) is a non-atherosclerotic arteriopathy of unknown etiology, afflicting mostly middle-aged women. It is characterized by stenotic lesions of the vascular wall in middle-size arteries, sometimes associated with dissection, aneurysm or tortuosity. Renovascular hypertension is a major presentation of FMD and 50–85% of FMD patients are hypertensive. Methods & Results: We report results from the first genome-wide association meta-analysis of six studies including 1556 FMD cases and 7100 controls. We identified four robustly associated loci (PHACTR1, LRP1, ATP2B1, and LIMA1). Using colocalization and transcriptome-wide association analysis with arterial expression datasets, we found PHACTR1, LRP1 and ATP2B1 as target genes at FMD loci and identified one additional locus (SLC24A3). We analysed chromatin accessibility in artery-derived primary cells and found that FMD associated variants were located in arterial specific regulatory elements active in smooth muscle cells. Target genes were broadly involved in mechanisms related to actin cytoskeleton and intracellular calcium homeostasis, central to vascular contraction. All FMD loci were also associated to at least one blood pressure trait. Colocalization analysis supported the same genetic variants to cause association to FMD and systolic blood pressure at PHACTR1, ATP2B1 and LIMA1 loci, and for FMD and pulse pressure at PHACTR1, LRP1 and ATP2B1 loci. Using genome-wide genetic correlation, we found a significant association between FMD and blood pressure. Mendelian Randomization analysis supported genetically determined systolic blood pressure to significantly increase the risk of FMD. However, we confirmed using adjusted and stratified analyses that hypertension status alone was not driving the association with FMD at top loci. We also report an important genetic overlap of FMD with migraine, intracranial aneurysm, coronary artery disease and myocardial infarction. Conclusion: Our study confirms FMD as a polygenic disease following a complex genetic mode of inheritance. We find that FMD shares an important part of its genetic basis with blood pressure regulation, involving in particular several genes related to intracellular calcium homeostasis and vascular smooth muscle contraction. These results are consistent with previous studies showing systemic alterations in vascular contraction in FMD patients, even outside of affected arterial beds. While the mechanisms through which FMD may cause renovascular hypertension are well known, further studies will be required to determine how alterations in vascular contraction may lead to the arterial remodeling observed in FMD.

Abstract Objective: Fibromuscular dysplasia (FMD) is an arteriopathy that presents mainly by hypertension, stroke or dissection. Diagnosis is often made in middle-aged women with few cardiovascular risk factors. We aim at identifying common genetic variants associated to FMD. Design and method: We tested ∼6.5 million common genetic variants (MAF > 0.01) in 1962 cases and 7100 controls from 6 studies using variants and gene-based association analyses. Participants were of European ancestry, with similar characteristics (91% multifocal, 88% women), diagnosis methods and inclusion/exclusion criteria. Transcriptome-wide association (TWAS), eQTL, gene expression by sex and colocalization analyses used expression data in arteries from GTEx and/or FMD patients and matched controls. Open chromatin regions were defined using ATAC-Seq on primary human fibroblasts, smooth muscle and endothelial cells. Genetic correlations were assessed using summary statistics from UKBiobank and/or published studies by linkage disequilibrium score regression and multi-trait-based conditional and joint analyses (mtCOJO). Results: We confirmed the previously identified PHACTR1 locus and identified three new loci (LRP1, ATP2B1, and LIMA1) associated with FMD. TWAS in arteries identified one additional locus (SLC24A3). Through integration of annotation datasets, we provided prioritization of variants and genes. These are consistently and specifically expressed in fibroblasts, smooth muscle cells, and arterial tissues. PHACTR1 and SLC24A3 showed sex differences in gene expressions consistent with the direction of effects of FMD risk alleles. FMD genes are involved in regulatory mechanisms related to actin cytoskeleton and intracellular calcium homeostasis, two mechanisms central to vascular contraction. We found significant genetic overlaps between FMD and blood pressure traits, for the associated loci and globally at the genome level, but demonstrated that hypertension is not driving the genetic association with FMD. We also found positive genetic correlations with migraine and intracranial aneurysm, and an inverse correlation with coronary artery disease, independently from the genetics of blood pressure. Conclusions: We describe robustly associated loci and genes with FMD and provide several new leads toward understanding biological mechanisms of stenosis and dissection in young women in the absence of atherosclerosis, which shares part of its genetic basis with more common cardiovascular and neurovascular diseases.