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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.

Background: Evaluation of the performance of Cobas ® Pulse (Roche Diagnostics GmbH, Mannheim, Germany), a new blood glucose (BG) monitoring system (BGMS; referred to here as BGMSA) intended for point-of-care testing using samples from patients in diverse clinical settings by intended point-of-care test operators. Methods: Arterial, capillary, venous, or heel stick whole blood (WB) samples from patients in non-critical and critical care settings were collected and analyzed using BGMSA and the Nova StatStrip ® BGMS (Nova Biomedical, Waltham, MA; referred to here as BGMSB), and a hexokinase comparator (Cobas 6000 Analyzer Series; Roche Diagnostics GmbH). The blood glucose measurement accuracy was assessed by the Food and Drug Administration guidance criteria. Results: Two studies are presented. In the first, 2678 samples (622 arterial, 706 capillary, 1203 venous, 147 heel stick) were collected from 1577 patients in 14 US and three European sites. All accuracy criteria were met for arterial and venous samples considering all data combined. BGMSA showed better accuracy than BGMSB for arterial, venous, and heel stick, and similar results to BGMSB for capillary WB vs venous comparator. No endogenous interference from pO 2 , hematocrit, and sodium was identified. BGMSA was also accurate when analyzing contrived samples used to show accuracy over a wide range of glucose concentrations, alone and when combined with extreme hematocrit. In the second study, 117 capillary fingerstick samples collected at one US site were measured on both BGMSA and the comparator, and all accuracy criteria were met. No clinically significant medical risks were observed via Diabetes Technology Society Error Grids. Conclusions: BGMSA was effective for determining blood glucose in venous, arterial, neonatal arterial, neonatal heel stick, and capillary WB samples.

11506 Background: Catequentinib Hydrochloride (AL3818, Anlotinib, Catequentinib) is a novel, orally administered, small molecule tyrosine kinase inhibitor. There remains an unmet need for effective, well tolerated therapies for patients (pts) with advanced/ metastatic leiomyosarcoma (LMS). We performed a randomized, double blind trial of Catequentinib monotherapy versus placebo in advanced/metastatic LMS. Methods: Patients with a diagnosis of LMS requiring third or further line treatment were eligible. Catequentinib was administered in a 21-day cycle with 14 days on and 7 days off regimen. In this double blind phase 3 trial, patients were randomized 2:1 to Catequentinib or placebo, with the option of crossover to Catequentinib after confirmed Progression Disease (PD) on placebo. Progression-free survival (PFS) with Log Rank test was the primary endpoint and the trial was conducted at multiple sites in the US, UK and EU. Results: Total N = 111 patients were enrolled, and N = 110 were treated and evaluated, 74 randomized to Catequentinib (C), and 36 to placebo (P). In arms (C)/(P) median ages were 59.0/60.5 (range: 33-91) years respectively and 59/29 (79.7%/80.6%) were female. Median PFS by Blinded Independent Central Review (BICR) met the primary endpoint at 3.42 months (95% CI: 2.60, 6.83) for (C) and 1.41 months (95% CI: 1.35, 4.86) for (P) with a p-value of 0.0265 and a HR of 0.536 (95% CI: 0.307, 0.936). Median PFS for patients stratified at ≤ 3 prior lines was 4.86 months (95% CI: 2.04, 8.94) for (C) and 1.41 months (95% CI: 1.31, 4.86) for (P) with a p-value of 0.0046 and a HR of 0.386 (95% CI: 0.196, 0.760). The 6-month progression-free rate was 42.37% for (C) and 20.71% for (P). OS was 17.45 months (95% CI: 13.57, 19.32) for (C) and 16.33 months (95% CI: 11.27, NE) for crossover patients in the (P) arm. 30 (40.5%) of patients have experienced grade 3 treatment-related adverse events in the (C) arm compared to 3 (8.3%) of patients in the (P) arm. The most common TEAE for (C) vs (P) were diarrhea (50.0% vs 22.2%), stomatitis (31.1% vs 8.3%), fatigue (64.9% vs 41.7%), and hypertension (47.3% vs 19.4%). Conclusions: This phase 3 trial met the primary PFS endpoint and demonstrates superior PFS for Catequentinib vs placebo in metastatic/advanced LMS. This study confirms the acceptable benefit-risk profile of Catequentinib in LMS. Catequentinib is an effective and well tolerated treatment option for patients with LMS. Clinical trial information: NCT03016819 .

Background We hypothesized treatment with nivolumab and stereotactic radiosurgery (SRS) would be feasible, well tolerated, and may improve intracranial tumor control over SRS alone for breast cancer brain metastases (BCBM). Methods The study is a phase Ib trial of nivolumab and SRS for BCBM. Clinical trial information: NCT03807765 . Key eligibility criteria include BCBM of all subtypes, age ≥18, Eastern Cooperative Oncology Group Performace Status (ECOG-PS)≤2 with ≤10 brain metastases. Treatment was initiated with a dose of nivolumab (480 mg intravenously) that was repeated every 4 weeks. The initial dose of nivolumab was followed 1 week later by SRS. Blood was collected at baseline and every 4 weeks for flow cytometry and cell-free DNA (cfDNA) assessment. Results A total of 12 patients received SRS to 17 brain metastases. Breast cancer subtypes included triple negative (50%), hormone receptor (HR)+/HER2− (33%), and HR−/HER2+ (17%). Median follow-up from start of protocol therapy is 56 months. No cases of radionecrosis were noted. Two lesions were noted to undergo local failure, both pathologically confirmed, for a 12-month local control of 94%. Median distant intracranial control was 7.4 months with a 12-month control rate of 33%. Median systemic progression-free survival was 7.7 months with a 12-month rate of 42%. Median overall survival (OS) was 24.7 months with a 12-month OS of 75%. Most patients were noted to have an increase in cfDNA throughout study treatment, at week 5 compared with baseline (83%), week 25 compared with baseline (89%), and 100% at first follow-up. Intracranial control was associated with lower levels of CD4 regulatory T cells (Treg) (p=0.03) and higher levels of CD4 T effector memory (p=0.04). Conclusions Nivolumab and SRS is a safe and feasible treatment option in BCBM. Long-term follow-up revealed no cases of radiation necrosis. Trial registration number NCT03807765 .

AbstractCases of myelin oligodendrocyte glycoprotein (MOG) antibody‐associated disease (MOGAD) co‐occurring with neoplasms have been reported. In this international, retrospective cohort study in South Korea and the USA, 16 of 445 (3.6%) patients with MOGAD had concurrent neoplasm within 2 years of MOGAD onset, resulting in a standardized incidence ratio for neoplasm of 3.10 (95% confidence interval [CI], 1.77–4.81; P < 0.001) when compared to the age‐ and country‐adjusted incidence of neoplasm in the general population. However, none of the nine tumor tissues obtained demonstrated MOG immunostaining. The slightly increased frequency without immunohistopathological evidence suggest with true paraneoplastic MOGAD is extremely rare.

Abstract Background and Aims Artificial intelligence (AI) algorithms in 12-lead electrocardiogram (ECG) provides promising age prediction methods. This study investigated whether the discrepancy between ECG-derived AI-predicted age (AI-ECG age) and chronological age, termed electrocardiographic aging (ECG aging), is associated with atrial fibrillation (AF) risk. Methods An AI-ECG age prediction model was developed using a large-scale dataset (1 533 042 ECGs from 689 639 participants) and validated with six independent and multi-national datasets (737 133 ECGs from 330 794 participants). The AI-ECG age gap was calculated across two South Korean cohorts [mean (standard deviation) follow-up: 4.1 (4.3) years for 111 483 participants and 6.1 (3.8) years for 37 517 participants], one UK cohort [3.0 (1.6) years; 40 973 participants], and one US cohort [12.9 (8.6) years; 90 639 participants]. Participants were classified into two groups: normal group (age gap &lt; 7 years) and ECG-aged group (age gap ≥ 7 years). The predictive capability of ECG aging for new- and early-onset AF risk was assessed. Results The mean AI-ECG ages were 51.9 (16.2), 47.4 (12.5), 68.4 (7.8), and 56.7 (14.6) years with age gaps of .0 (6.8), −.1 (6.0), 4.7 (8.7), and −1.4 (8.9) years in the two South Korean, UK, and US cohorts, respectively. In the ECG-aged group, increased risks of new-onset AF were observed with hazard ratios (95% confidence intervals) of 2.50 (2.24–2.78), 1.89 (1.46–2.43), 1.90 (1.55–2.33), and 1.76 (1.67–1.86) in the two South Korean, UK, and US cohorts, respectively. For early-onset AF, odds ratios were 2.89 (2.47–3.37), 1.94 (1.39–2.70), 1.58 (1.06–2.35), and 1.79 (1.62–1.97) in these cohorts compared with the normal group. Conclusions The AI-derived ECG aging was associated with the risk of new- and early-onset AF, suggesting its potential utility to identify individuals for AF prevention across diverse populations.

Abstract BACKGROUND Patients with meningiomas that have progressed after surgery and/or radiation have limited treatments. Loss of NF2 and CDKN2A/B are common in higher-grade meningiomas and promote meningioma progression. We evaluated the efficacy of abemaciclib, a cyclin-dependent kinase (CDK) 4/6 inhibitor, as part of Alliance A071401, a genomically-driven phase II trial in recurrent or progressive meningiomas. METHODS Eligible patients (pts) with grade 2/3 tumors and NF2 mutations or CDK pathway alterations were treated with abemaciclib 200 mg orally twice daily. Two co-primary endpoints were used: progression-free survival at 6 months (PFS6) and response rate (RR); the trial would be declared positive if either endpoint was met. Twenty-four evaluable pts provided ≥85% power to detect a PFS6 ≥41.5% (vs. null 15%; alpha=0.02), and ≥89% power to detect RR ≥20% (vs. null 2.5%; alpha=0.021). RESULTS Of 83 pts screened while the abemaciclib arm was open between September 15, 2021 and October 3, 2022, 36 eligible pts received abemaciclib. The observed PFS6 rate in the first 24 evaluable pts was 54% (95% CI 33-75%), thus the study met PFS6 endpoint. Of all 35 evaluable pts, median PFS was 7.6 months (95% CI 3.6-17.1 months), estimated 6-month PFS was 55% (95% CI 40-75%) and estimated 6-month OS was 88% (95% CI 77-100%). No objective responses were observed. Of the 36 pts who started treatment, two had a grade 4 adverse event at least possibly related to treatment which included ALT elevation(1), AST elevation(1) and vomiting(1). Patients with NF2 alterations (n=24) had favorable PFS6 outcomes (58%, 95% CI 37-78%) compared to those with CDK (n=4, 25%, 95% CI 1-81%) and CDK+NF2 alterations (n=7, 29% 95% CI 4-71%), (Fisher’s Exact p=0.036). CONCLUSIONS Abemaciclib was well-tolerated and resulted in improved PFS6, meeting the trial’s co-primary endpoint. Abemaciclib warrants further investigation for the treatment of patients with progressive meningiomas.

Abstract Background Live cell-based assays (CBA) are considered the gold-standard methodology for detecting pathogenic antibodies targeting neural cell surface antigens. However, the adoption of these methods in clinical laboratories has been limited by their manual nature and low throughput. Here, we describe the development and validation of an automated system utilizing a live flow cytometry-based CBA to detect AQP4-IgG. Establishing AQP4-IgG serostatus is a critical component of the diagnostic criteria for Neuromyelitis optica spectrum disorders (NMOSD) as it enables the differentiation of NMOSD from Multiple Sclerosis where there may be significant clinical overlap. The accurate diagnosis of the correct disease state is vital, as the prognosis and treatment approach differ significantly for these two conditions. Two redundant systems were built that automatically receive reagents (live cells in suspension, buffers, diluents, secondary antibodies, and patients’ samples) and generate flow cytometer ready 96-well plates (each containing up to 45 serum or CSF samples tested in duplicate). Methods We assessed the analytical performance of an AQP4-IgG live flow cytometry-based CBA on these new automated systems. We measured intra- and inter-assay imprecision at three levels in 5x5 format and for end-point titer assessment, accuracy (20 positive and 20 negative sera; 5 positive and 5 negative CSF; established on the current manual assay), reference range (20 negative sera and 20 negative CSF from disease controls), analytical sensitivity (LOB and LOD) and specificity (high IgG containing serum specimens), within-plate draft (1 positive sample near the diagnostic cut-off [IgG-binding index of 2.0] that was tested across the entire plate), instrument to instrument correlation (42 positive samples/dilutions tested simultaneously on both systems), and total throughput for both CSF and Serum. Results Imprecision testing yielded the following results: Serum Intra/Inter precision level 1 (IBI = 2) CV% (current method:4.6%/20.7%), (system 1: 3.1%/18.4%), (system 2: 2.6%/22.5%), serum Intra/Inter precision level 2 (IBI=4) CV% (current method:4.9%/23.3%), (system 1: 3.2%/21.9%), (system 2: 2.6%/24.1%), and serum Intra/Inter precision level 3 (IBI =10) pos CV% (current method:6.0%/31.1%), (system 1: 3.8%/27.4%), (system 2: 4.2%/29.4%), and CSF Intra/Inter precision (IBI =2) CV% (System 1: 11.7%/16.8%), (system 2: 6.1%/10.7%). The median end-point titers for all four samples assessed matched within one end-point titer. For accuracy, 100% qualitative agreement between current and both automated systems, and titration accuracy (5 positive serums, 1 positive CSF) all matched within one titer between current and both automated systems. All reference range samples were negative. LOB/LOD in serum (Current: 0.85/1.11), (System 1: 0.82/0.95), (system 2: 0.82/0.96) and CSF (Current: 1.06/1.52), (System 1: 1.02/1.38), (system 2: 1.02/1.64) were comparable. All high IgG samples were negative. Plate drift analysis showed improved whole plate %CV: (Current:6.52%), (system 1: 4.51%), (system 2: 3.46%). Instrument to instrument comparison utilizing linear regression indicated strong agreement across the two systems (slope = 0.93 and R2= 0.95). Assessment of throughput based on real-time timings indicated a maximum output of approximately &gt;700 patient samples per 24hrs per system. Conclusions An automated system for performing live CBAs provides equivalent to superior analytical performance compared to pre-existing manual methods with improved testing capacity.

Abstract Background Myasthenia gravis (MG) is caused by disrupting the function of postsynaptic acetylcholine receptors (AChRs) at the neuromuscular junction. 85% of MG patients have autoantibodies targeting AChRs, while 6% of MG patients have autoantibodies targeting the muscle-specific receptor tyrosine kinase (MuSK). MuSK is located on the muscle membrane and is activated by the low-density lipoprotein receptor-related protein 4 (LRP4) upon the binding with ligand Agrin. Activated MuSK undergoes autophosphorylation and stimulates downstream signaling to cluster AChRs, which is important for the formation and maintenance of neuromuscular synapses. IgG4 antibodies that bind MuSK are thought to directly disrupt the ability of MuSK to cluster AChR. The gold standard methodology for MuSK antibody testing is radioimmunoprecipitation assay (RIA) using anti-human IgG secondary antibodies. Performing RIA methods in the clinical laboratory is a burden due to radioactive biohazard concerns and the analytical limitations of these assays. This study is to assess the analytical and clinical performance of a live cell-based flow cytometry assay as a potential replacement for the MuSK RIA. Methods HEK293T cells were transiently transfected with a vector co-expressing human MuSK protein and GFP. Patient sera were incubated with a mix of HEK293 cells (GFP-positive cells that express MuSK protein on the cell surface and GFP-negative cells that do no express MuSK) followed by incubation with anti-human IgG4 secondary antibody conjugated with alexa fluor 647 (AF647). An IgG binding index (IBI) was calculated for each sample as the ratio of the median AF647 fluorescence intensity (MFI) of the MuSK-expressing cells (GFP+) to the MFI of the non-MuSK expressing cells (GFP-). An arbitrary positive IBI cut-off of 2.0 was selected. A preliminary assessment of assay imprecision was performed for the flow cytometry assay, as well as a method comparison study to compare this assay to RIA utilizing a cohort of 130 (34 positive and 96 negative) residual samples previously tested by the gold-standard assay. 133 disease control samples were also tested to assess the clinical specificity of the flow cytometry-based assay. Results To assess the imprecision, eight samples with varying IBIs were tested with 5 replicates in each assay over five days. The coefficient of variation (CV) for intra-assay replicates ranged from 1% to 7% for all samples, while CV for inter-assay replicates ranged from 2% to 15%. Based on the 130 samples previously tested by RIA, the Positive Percentage Agreement (PPA) between these two assays was 76.5% and the negative Percentage Agreement (NPA) was 100%. Of the discordant samples (n=8), clinical information was available for only 1 sample (positive by RIA, negative by flow). This patient had a final non-MG diagnosis (ALS). All control samples were negative on the flow cytometry-based assay. Conclusions The live cell-based flow cytometry MuSK IgG4 assay demonstrated encouraging preliminary analytical performance that warrants further development and validation.

Abstract We conducted this systematic review and meta-analysis to clarify the trend of precocious puberty (PP) incidence after the COVID-19 outbreak and explore potential contributing factors, such as age at presentation and body mass index (BMI) SD score (SDS). Children visiting pediatric endocrinology clinics for the first time for suspected PP were included. We searched databases until February 28, 2023, for studies reporting various indicators of PP incidence before and during the pandemic. Total numbers of events and observations were recorded. A meta-analysis was performed to compare the odds of PP, BMI SDS, and age at presentation between the 2 periods. The dose-response relationships between time points (by number of years away from the pandemic) and PP risk were explored. In summary, a total of 32 studies including 24 200 participants were recruited. The COVID-19 pandemic was associated with the increasing odds of PP among children referred for a suspicious condition (odds ratio = 1.96; 95% CI, 1.56-2.47; I2 = 54%; P &lt; .001). Sensitivity analysis confirmed the robustness of the findings. The BMI SDS did not vary between the 2 periods, whereas age at presentation was lower after the pandemic. Precocious puberty incidence increased more rapidly during the pandemic period than during the prepandemic period. Trial registration: International Prospective Register of Systematic Reviews (PROSPERO; identifier: CRD42023402212)