Citations

Purpose: This study assesses intersurgeon variability in proptosis reduction after orbital decompression for thyroid eye disease. Methods: This multicenter retrospective study included patients with thyroid eye disease who underwent orbital decompression from 1 of 7 surgeons at 7 different institutions between January 2002 and December 2018. Data were included if a single decompression technique was performed on ≥10 patients by ≥2 surgeons. The primary outcome was postoperative change in proptosis with emphasis on comparison among surgeons utilizing similar surgical techniques. Statistical analysis was performed with χ 2 and ANOVA testing, and a multivariable logistic regression model was generated. Results: Six hundred thirty-three orbits that underwent orbital decompression were included. Five different decompression techniques were analyzed: medial wall (n = 29), fat + lateral wall (n = 113), medial wall + floor (n = 123), fat + lateral wall + medial wall (n = 140), and fat + lateral wall + medial wall + floor (n = 228), without significant difference in proptosis reduction among surgeons. Surgeons did not demonstrate significant differences in outcomes at different time points compared with each other or themselves. Outcomes when comparing endoscopic versus open medial wall decompression varied among surgery types. Multivariate modeling revealed a statistically significant association between postoperative change in proptosis with preoperative proptosis ( p < 0.001). Conclusions: Postoperative change in proptosis did not differ significantly between surgeons utilizing similar orbital decompression techniques for patients with thyroid eye disease. This study may strengthen the statistical validity of multicenter clinical trials assessing orbital decompression outcomes performed by surgeons employing uniform surgical techniques, thereby advancing our understanding of optimal surgical management strategies for thyroid eye disease.

98 Background: Prior authorization (PA) purports to control costs and ensure adherence to evidence-based guidelines but negatively impacts cancer care. Radiation oncology (RO) represents a minority of overall cancer spending yet bears a disproportionately high PA burden. Limited research exists on the effects of PA on patient outcomes and administrative workload within RO clinics. Methods: From 9/2024 to 10/2024, an online survey was open to U.S. members of the American Society for Radiation Oncology assessing experiences with PA including disposition (approval/denial/appeal including peer-to-peer [P2P] review) and perceived impact on patient care and administrative workload. Outcomes included treatment delays, changes from recommended treatment, and patient event including hospitalization, ED visits, permanent disability, or death. Descriptive statistics evaluated responses. Results: Of 736 responding radiation oncologists (16% response rate), 83% reported a rise in PA over the past three years, with 58% noting the burden has increased greatly. In the past year, 50% reported that more than half of their cases required PA, with a median approval rate of 75% and median overturn rate of 82% for denials. For more than half of their cases, nearly half of physicians (43%) noted that P2P was a futile effort to overturn PA denials due to insurance policies. Most (75%) reported that PA resulted in their practice needing to reallocate staff; 91% reported worsening burnout due to PA. P2P reviews were particularly burdensome, averaging 1.65 hours per week. A third (30%) reported that PA requirements had caused serious complications for their patients, including 7% who reported PA had contributed to patient death. Almost all (91%) reported PA-related treatment delays for some of their patients, with 58% indicating average delays of ≥5 days. Most (81%) reported that at times they had to use radiation techniques they considered less optimal due to PA, including 58% who were forced to deviate from national guidelines. The most common reasons for not appealing a PA denial were anticipated delays (73%), perceived futility based on prior PA experiences (62%), and administrative burden (45%). Conclusions: The administrative and clinical burdens associated with PA have significant implications for patient care, physician well-being, and healthcare resource allocation in RO. Treatment delays, compromised therapies, and adverse patient outcomes are commonly reported and underscore the need for PA reform to improve patient outcomes, reduce physician burnout, and improve efficiency.

Abstract Purpose: Isocitrate dehydrogenase (IDH) 1/2–isoform inhibitors have clinical efficacy in IDH1/IDH2-mutated neoplasms. However, primary resistance and secondary resistance limit their therapeutic potential. LY3410738, an oral, brain-penetrant, dual IDH1/IDH2-mutated isoform-selective inhibitor, was designed to overcome resistance. Patients and Methods: This global, multicenter, open-label, phase I study of patients with IDH-mutant solid tumors evaluated LY3410738 as monotherapy (dose escalation) for advanced solid tumors in combination with cisplatin–gemcitabine (CISGEM) for newly diagnosed cholangiocarcinoma or with durvalumab for relapsed/refractory cholangiocarcinoma (dose expansion; NCT04521686). Primary objectives were the maximum tolerated dose, recommended phase II dose, and preliminary antitumor activity. Safety, pharmacokinetics, inhibition of D-2-hydroxyglutarate, and ctDNA were assessed. Results: Overall, 119 patients received LY3410738 alone (N = 94) or in combination with CISGEM (N = 19) or durvalumab (N = 6). No dose-limiting toxicities were observed; the maximum tolerated dose was not determined. Common adverse events included nausea, vomiting, and decreased appetite. Overall response rates of 5.2% and 11.1% and disease control rates of 56.9% and 63.0% were observed for patients with relapsed/refractory IDH1- or IDH2-mutant cholangiocarcinoma or IDH1-mutant glioma, respectively. D-2-hydroxyglutarate normalization was rapid and durable. In dose-expansion cohorts, combination treatments were tolerable, with one dose-limiting toxicity in the durvalumab cohort. LY3410738 plus CISGEM demonstrated a response rate of 42.1%, a median duration of response of 8.1 months, and a median progression-free survival of 10.2 months for patients with newly diagnosed IDH-mutant cholangiocarcinoma. Conclusions: LY3410738 demonstrated largely cytostatic antitumor activity in IDH1- or IDH2-mutated cholangiocarcinoma and IDH1-mutated gliomas. LY3410738 plus CISGEM exhibited favorable antitumor activity in patients with treatment-naïve IDH-mutated cholangiocarcinoma, warranting further exploration as a treatment strategy.

Abstract Background Acupuncture, a key modality in traditional Chinese medicine, is gaining global recognition as a complementary therapy and a subject of increasing scientific interest. However, fragmented and unstructured acupuncture knowledge spread across diverse sources poses challenges for semantic retrieval, reasoning, and in-depth analysis. To address this gap, we developed AcuKG, a comprehensive knowledge graph that systematically organizes acupuncture-related knowledge to support sharing, discovery, and artificial intelligence–driven innovation in the field. Methods AcuKG integrates data from multiple sources, including online resources, guidelines, PubMed literature, ClinicalTrials.gov, and multiple ontologies (SNOMED CT, UBERON, and MeSH). We employed entity recognition, relation extraction, and ontology mapping to establish AcuKG, with human-in-the-loop to ensure data quality. Two cases evaluated AcuKG’s usability: (1) how AcuKG advances acupuncture research for obesity and (2) how AcuKG enhances large language model (LLM) application on acupuncture question-answering. Results AcuKG comprises 1839 entities and 11 527 relations, mapped to 1836 standard concepts in 3 ontologies. Two use cases demonstrated AcuKG’s effectiveness and potential in advancing acupuncture research and supporting LLM applications. In the obesity use case, AcuKG identified highly relevant acupoints (eg, ST25, ST36) and uncovered novel research insights based on evidence from clinical trials and literature. When applied to LLMs in answering acupuncture-related questions, integrating AcuKG with GPT-4o and LLaMA 3 significantly improved accuracy (GPT-4o: 46% → 54%, P = .03; LLaMA 3: 17% → 28%, P = .01). Conclusion AcuKG is an open dataset that provides a structured and computational framework for acupuncture applications, bridging traditional practices with acupuncture research and cutting-edge LLM technologies.

Abstract Diffuse large B-cell lymphoma (DLBCL) poses a challenge in hematology given its varied symptoms, and the complex interplay between disease and treatment effects on health-related quality of life (HRQoL). The phase 3 POLARIX study demonstrated superior progression-free survival and a similar safety profile with polatuzumab vedotin plus rituximab, cyclophosphamide, doxorubicin, and prednisone (Pola-R-CHP) vs R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) in patients with previously untreated DLBCL. Here, we evaluate HRQoL through patient-reported outcome (PRO) instruments to fully characterize the patient experience in the POLARIX study. Changes from baseline in HRQoL, lymphoma symptoms, and gastrointestinal (GI) symptoms were assessed, as well as incidence and severity of common symptoms by PROs vs clinician-reported adverse events (AEs). Baseline characteristics of PRO-evaluable patients (N = 874) were consistent. Comparison between PROs and clinician-reported AEs revealed a notable discordance; patients generally reported a higher incidence of symptoms than clinicians, emphasizing the need for patient-centric tools to accurately capture the patient experience. Both treatments exhibited rapid and sustained improvements in HRQoL and lymphoma symptoms, with the most substantial improvements seen in global health status/QoL, lymphoma symptoms, fatigue, role, emotional, and social functioning. GI symptoms (diarrhea, constipation, nausea, and vomiting) were generally similar between treatment arms and returned to baseline levels after treatment completion. These HRQoL data underscore the complementarity of PROs, as an adjunct to clinician-reported AEs, in evaluating the efficacy and tolerability of new treatments, including Pola-R-CHP, which may represent a new benchmark for patient-reported HRQoL in previously untreated DLBCL. This trial was registered at www.clinicaltrials.gov as NCT03274492.

Abstract BACKGROUND Tau‐derived cerebrospinal fluid (CSF) biomarkers correlate with amyloid‐beta (Aβ) plaques or tau tangles in Alzheimer's disease (AD). This study assessed the effects of long‐term anti‐Aβ antibodies on amyloid plaques, tau tangles, and CSF tau species to determine the relationships between them. METHODS A post‐hoc analysis of the DIAN‐TU‐001 trial (NCT01760005) examined 142 participants at risk for dominantly inherited AD randomized to solanezumab ( n = 50), gantenerumab ( n = 52), or placebo ( n = 40). High‐resolution mass spectrometry quantified CSF tau species over four years. RESULTS Phosphorylated tau (p‐tau) species (153, 181, 217, 231) increased early in preclinical AD but were reduced with gantenerumab‐mediated Aβ plaque reduction. Nearly a decade later, MTBR‐tau243 and p‐tau205 increased, showing no association with Aβ reduction, aligning with tau tangle pathology progression. DISCUSSION Initially changing soluble p‐tau species track Aβ plaque reduction, while ptau205 and MTBR‐243 reflect tau tangle pathology, informing different pathways of therapeutic strategies. Highlights p‐tau217 and p‐tau231 correlate with Aβ‐PET and respond to Aβ‐plaque lowering therapies. Aβ immunotherapy trials support a direct link between p‐tau changes and Aβ plaques Gantenerumab reduces Aβ plaques but does not affect tau NFT‐related biomarkers. Blood‐based p‐tau217 assays may provide a non‐invasive tool to monitor Aβ therapies. MTBR‐tau243 strongly correlates with tau PET and tracks NFT pathology progression. Further studies are needed to validate tau biomarkers for tracking NFT‐targeting therapies.

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.

Précis: Glaucoma patients with significant visual field defects show poorer driving performance, higher collision risks, and a greater likelihood of driving cessation. They face difficulties with lane maintenance, slower hazard responses, and self-regulation while driving. Purpose: Glaucoma is a chronic, progressive optic neuropathy associated with visual field (VF) defects, which in advanced disease has been shown to affect patients’ activities of daily living. This systematic review qualitatively analyzes existing literature that explores the impact of glaucomatous VF loss on the driving performance of glaucoma patients, the extent of driving limitation and cessation, as well as the risk of motor vehicle collisions (MVCs). Methods: A literature search of MEDLINE and Embase (via Ovid), PubMed, Cochrane Library, and Web of Science databases was performed for studies published from 2003 to 2023, with the terms “glaucoma,” “visual field defect/disorder,” and “driving,” followed by selective vetting based on inclusion criteria. Within studies, data pertaining to study design, subject demographics, VF defect characteristics, driving performance and related outcomes were extracted. Results: Initial search yielded 835 studies, with 20 studies selected. Three more studies were included through hand-searching, with a total of 23 studies included for final review. Moderate to severe VF defects resulted in poorer driving performance, with slower response times to road hazards, decreased ability for lane maintenance, and increased difficulty driving at night. Patients with more severe VF defects and with bilateral glaucoma were more likely to limit or cease driving compared with those with milder and unilateral glaucoma. A greater severity of VF loss was associated with a higher risk of MVCs. Conclusion: More severe glaucomatous VF and bilateral glaucoma is associated with worse driving performances and a higher risk of MVCs, in both simulator and real-world settings.

Background & aims Pregnancy can be a complex and risk filled event for women with inflammatory bowel disease (IBD). High-quality studies in this population are lacking, with limited data on medications approved to treat IBD during pregnancy. For patients, limited knowledge surrounding pregnancy impacts pregnancy rates, medication adherence, and outcomes. Limited provider knowledge leads to highly varied practices in care affected by local dogma, available resources, individual interpretation of the literature, and fear of harming the fetus. The variations in guidelines by different societies and countries reflect this and lead to confusion for physicians and patients alike. The Global Consensus Consortium is a group of 39 IBD and content experts and 7 patient advocates from 6 continents who convened to review and assess current data and come to an agreement on best practices based on these data. Methods The GRADE process was used when sufficient published data were available and the RAND process in those instances where expert opinion was needed to guide consistent practice. Recommendations were informed by the guiding principle that maternal health best supports infant health. Results The topics were divided into ten categories with 34 GRADE recommendations and 35 Consensus statements. Conclusions Overall, the goal of the group was to provide data-driven and practical guidance to improve the care of women with IBD around the globe based on the best available research.

Abstract Rationale Inflammation is central to chronic obstructive pulmonary disease (COPD) pathogenesis but incompletely represented in COPD prognostic models. The neutrophil-to-lymphocyte ratio (NLR) is a readily available inflammatory biomarker. Objectives To explore the associations of NLR with smoking status, clinical features of COPD, and future adverse outcomes. Methods We analyzed NLR calculated from the complete blood count of participants who currently or formerly smoked (n = 2,624) and tobacco-naive control subjects (n = 187) in the SPIROMICS multicenter observational cohort study. We assessed the stability of NLR at 6 weeks and 1 year, the association with select blood biomarkers, and the impact of smoking on NLR and cell counts. We stratified participants by NLR quartiles to compare cross-sectional clinical features at enrollment, prospectively observed exacerbations at 1 year, and mortality during longitudinal follow up. Results Higher NLR quartiles were broadly associated with more severe clinical features of COPD. NLR values were repeatable at 6 weeks (intraclass correlation coefficient, 0.74) and 1 year (intraclass correlation coefficient, 0.62). The impact of smoking on NLR varied with the severity of airflow limitation, mediated by an interaction between smoking, forced expiratory volume in 1 second percent predicted, and neutrophil counts but not lymphocyte counts. The highest NLR quartile (&gt;3.11) was associated with an increased risk of exacerbation over 1 year (adjusted odds ratio, 1.51; 95% confidence interval, 1.18, 1.92) and increased risk of mortality (adjusted hazard ratio, 1.41; 95% confidence interval, 1.20, 1.66) compared with quartiles 1–3. Conclusions Elevated NLR in stable COPD is a widely available biomarker associated with increased risk for exacerbation and death. The impact of cigarette smoking on NLR varies with disease severity.