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Importance Obesity is a risk factor associated with multiple myeloma (MM) and its precursor, monoclonal gammopathy of unknown significance (MGUS). However, it is unclear how cumulative exposure to obesity affects the risk of MGUS progression to MM. Objective To determine the association of cumulative exposure to excess body mass index (EBMI), defined as BMI (calculated as weight in kilograms divided by height in meters squared) greater than 25, with risk of MGUS progression to MM. Design, Setting, and Participants This cohort study included patients with MGUS, including immunoglobin G, immunoglobin A, or light chain MGUS, from the nationwide US Veterans Health Administration database from October 1, 1999, to December 31, 2021. A published natural language processing–assisted model was used to confirm diagnoses of MGUS and progression to MM. Data were analyzed from February 12 to November 4, 2024. Exposures Cumulative EBMI was calculated by area under the curve of measured BMI subtracting the reference BMI at 25 during the first 3 years after MGUS diagnosis. Main Outcomes and Measures The main outcome was progression from MGUS to MM. Multivariable Fine-Gray time-to-competing-event analyses, with death as the competing event, were used to determine associations. Results The cohort included 22 429 patients with MGUS (median [IQR] age, 70.5 [63.5-77.9] years; 21 613 [96.4%] male), with 8329 Black patients (37.1%) and 14 100 White patients (62.9%). There were 4862 patients (21.7%) with reference range BMI (18.5 to <25), 7619 patients (34.0%) with BMI 25 to less than 30, and 8513 patients (38.0%) with BMI 30 or greater at the time of MGUS diagnosis. Compared with reference range BMI at MGUS diagnosis, patients with BMI 25 to less than 30 (adjusted hazard ratio [aHR], 1.17; 95% CI, 1.03-1.34) or 30 or greater (aHR, 1.27; 95% CI, 1.09-1.47) at MGUS diagnosis had higher risk of progression to MM. In patients with reference range BMI at MGUS diagnosis, each 1-unit increase of EBMI per year was associated with a 21% increase in progression risk (aHR, 1.21; 95% CI, 1.04-1.40). However, for patients with BMI 25 or greater at MGUS diagnosis, the incremental risk associated with cumulative EBMI exposure was not statistically significant. Conclusions and Relevance This cohort study found that, for patients with BMI 18.5 to less than 25 at the time of MGUS diagnosis, cumulative exposure to BMI 25 or greater was associated with an increased risk of progression. These findings suggest that for these patients, maintaining a healthy and stable weight following MGUS diagnosis may prevent progression to MM.

Abstract Background Prosthetic valves are considered a risk factor for endocarditis however diagnosing prosthetic valve endocarditis (PVE) is complicated by acoustic shadowing on echocardiography. In 2023, the ISCVID published an update to the Duke Criteria (Duke 2023) which intended to increase the sensitivity in diagnosing PVE. The purpose of this study was to examine how TAVR infective endocarditis (TAVR-IE) was diagnosed at our institution 90 Day Mortality Kaplan Meier Curve Methods HERON was utilized to match cases between ACC/STS databases and the EMR at The University of Kansas Health System (TUKHS). Patients with bacteremia occurring after a TAVR were reviewed. Each case was evaluated if they met rejected/possible/definitive endocarditis criteria in the Modified Duke Criteria (Duke 2005) and the Duke 2023 Criteria. To adjudicate the diagnosis, an expert panel reviewed all cases that met definitive endocarditis criteria in any edition of the Duke Criteria. Results A total of 2371 TAVRs were conducted at TUKHS from 2012 to 2023. We identified 146 cases of post procedure bacteremia. We excluded 53 cases leaving 93 in the cohort. Transeophageal echocardiography was utilized in about half of the cases (TTE 73, TEE 45). F-FDG positron emission tomography/CT was done in six patients and Cardiac CT in one patient. Cultures returning with Enterococcus spp (16). viridans group streptococci (15), and Staphylococcus spp. (15) had similar incidence. About half had either atypical organisms (40) on 2005 Duke criteria or polymicrobial growth (7). Definitive criteria were met in 18 and 21 patients for the Duke 2005 and Duke 2023 Criteria respectively. Two cases had minor microbiological criteria upgraded to major in Duke 2023. One case was promoted to definitive endocarditis based on Cardiac CT. Upon adjudication the panel agreed with Duke 2023 Criteria classification. Sensitivity was calculated 85%/100% for Duke 2005 and Duke 2023 Criteria respectively. Kaplan Meier curves calculated no significant difference of 3 month mortality between TAVR patients who had met definitive criteria and those who did not. (Figure #1) Conclusion The 2023 ISCVID Duke Criteria in this study appeared to have superior sensitivity for TAVR-IE when compared to the older Modified Duke Criteria published in 2005. Disclosures Larry M. Baddour, MD, UpToDate, Inc.: Royalty payments (authorship duties). Wissam El Atrouni, MD, ViiV Healthcare: Advisor/Consultant

Abstract Introduction We describe the safety of sotorasib monotherapy in patients with KRAS G12C-mutated advanced non-small cell lung cancer (NSCLC) and discuss practical recommendations for managing key risks. Methods Incidence rates of treatment-related adverse events (TRAEs) were pooled from 4 clinical trials: CodeBreaK 100 (NCT03600883), CodeBreaK 101 (NCT04185883), CodeBreaK 105 (NCT04380753), and CodeBreaK 200 (NCT04303780) and graded according to CTCAE v5.0. Adverse events were deemed sotorasib-related per investigator causality assessment. Results In the pooled population (n = 549), TRAEs were reported in 388 (70.7%) patients (grade 1: 124 [22.6%]; grade 2: 117 [21.3%]; grade ≥ 3: 147 [26.8%]). Gastrointestinal and hepatic TRAEs, including diarrhea (171 [31.1%]), nausea (80 [14.6%]), elevated alanine aminotransferase (ALT; 68 [12.4%]), and elevated aspartate aminotransferase (AST; 67 [12.2%]) were the most common (≥10%). Dose interruption and dose reduction of sotorasib resulted in the resolution of >90% of diarrhea events; median time to resolution were 18.0 days and 22.0 days, respectively. Similar trends were observed for elevated ALT and AST events. Patients who stopped immunotherapy <3 months before initiating sotorasib had a higher incidence of treatment-related hepatotoxicity (80/240 [33.3%]) than those who stopped immunotherapy ≥3 months before initiating sotorasib (26/188 [13.8%]). Treatment-related pneumonitis/interstitial lung disease (ILD) and corrected QT (QTc) prolongation were observed in 9 (1.6%) and 4 (0.7%) patients, respectively. Two (0.4%) patients died with TRAEs, 1 with ILD whose ultimate cause of death was disease progression, and the other with an unknown cause. Conclusions Sotorasib has a well-characterized safety profile in patients with KRAS G12C-mutated advanced NSCLC, and key risks are manageable with dose modification.

Abstract Background Tumor necrosis factor-like ligand 1A (TL1A) is upregulated in inflammatory bowel disease and believed to promote inflammation and intestinal fibrosis. RO7790121, an anti-TL1A antibody, showed promising results in the phase IIa TUSCANY trial.1 Here we report post-hoc analyses of patient-reported outcomes from the TUSCANY-2 trial. Methods This phase IIb, multicenter, randomized, double-blind, treat-through, dose-ranging study evaluated RO7790121 in patients (pts) aged 18–75 years with moderately to severely active ulcerative colitis (UC) (total Mayo score [MS] ≥6, endoscopic subscore ≥2). Pts were randomized to receive subcutaneous (SC) RO7790121 50mg, 150mg, 450mg or matched placebo (PBO) monthly during the 12-week induction period, and SC RO7790121 50mg, 150mg or 450mg monthly during the 40-week treat-through maintenance period. To assess efficacy of RO7790121 in supporting pts achieving early symptomatic improvement, rectal bleeding (RB), stool frequency (SF) and partial modified MS (RB+SF) were evaluated at baseline and Weeks 2, 4, 8, 12 and 14. The exploratory endpoint of symptomatic remission, defined as a RB subscore of 0 and a SF subscore of 0 or 1, was assessed throughout induction. Safety was assessed throughout the study. Results Overall, 245 pts received ≥1 dose of RO7790121 or PBO. At Week 2, pts receiving RO7790121 were more likely to report a RB subscore of 0 (34% RO7790121; 20% PBO) and less likely to report a RB subscore of 2 or 3 (25% RO7790121; 40% PBO) (Figure). Improvements in SF increased from Week 2 and throughout induction, with ~60% of pts receiving RO7790121 reporting a SF subscore of 0 or 1 at Weeks 12 and 14, vs ~40% for PBO. Greater rates of symptomatic remission were observed in pts receiving RO7790121 vs PBO throughout induction and from Week 2 (17.5% RO7790121; 8.9% PBO) (Table). Treatment-emergent adverse events (TEAEs) were reported during induction in 117/245 pts, the most common (reported in ≥5% of pts in any treatment group) were nausea, urinary tract infection and UC (highest in the 50mg arm), anemia (highest in the placebo arm) and fatigue, headache and pyrexia (highest in the 450mg arm). Serious TEAEs were reported in ten pts during induction (PBO=4; 50mg=3; 450mg=3); two were treatment related (PBO=1; 450mg=1). There were six treatment discontinuations due to TEAEs and a generally similar safety profile was observed during the maintenance period. Conclusion Greater and earlier improvements in RB and SF were observed in pts receiving RO7790121 vs PBO. These results indicate early symptom relief and a favorable safety profile for pts treated with RO7790121, supporting its further clinical development. RO7790121 is currently being evaluated in phase III studies (NCT06589986 and NCT06588855). References 1.Danese S, Klopocka M, Scherl EJ, et al. Anti-TL1A antibody PF-06480605 safety and efficacy for ulcerative colitis: A phase 2a single-arm study. Clin GastroenterolHepatol. 2021;19(11):2324-2332.e6. http://doi.org/10.1016/j.cgh.2021.06.011

The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Lung Cancer Screening provide criteria for selecting individuals for screening and offer recommendations for evaluating and managing lung nodules detected during initial and subsequent annual screening. These NCCN Guidelines Insights focus on recent updates to the NCCN Guidelines for Lung Cancer Screening.

Abstract Objective Data extraction from the published literature is the most laborious step in conducting living systematic reviews (LSRs). We aim to build a generalizable, automated data extraction workflow leveraging large language models (LLMs) that mimics the real-world 2-reviewer process. Materials and Methods A dataset of 10 trials (22 publications) from a published LSR was used, focusing on 23 variables related to trial, population, and outcomes data. The dataset was split into prompt development (n = 5) and held-out test sets (n = 17). GPT-4-turbo and Claude-3-Opus were used for data extraction. Responses from the 2 LLMs were considered concordant if they were the same for a given variable. The discordant responses from each LLM were provided to the other LLM for cross-critique. Accuracy, ie, the total number of correct responses divided by the total number of responses, was computed to assess performance. Results In the prompt development set, 110 (96%) responses were concordant, achieving an accuracy of 0.99 against the gold standard. In the test set, 342 (87%) responses were concordant. The accuracy of the concordant responses was 0.94. The accuracy of the discordant responses was 0.41 for GPT-4-turbo and 0.50 for Claude-3-Opus. Of the 49 discordant responses, 25 (51%) became concordant after cross-critique, increasing accuracy to 0.76. Discussion Concordant responses by the LLMs are likely to be accurate. In instances of discordant responses, cross-critique can further increase the accuracy. Conclusion Large language models, when simulated in a collaborative, 2-reviewer workflow, can extract data with reasonable performance, enabling truly “living” systematic reviews.

Importance Molecular techniques, including next-generation sequencing, genomic copy number profiling, fusion transcript detection, and genomic DNA methylation arrays, are now indispensable tools for the workup of central nervous system (CNS) tumors. Yet there remains a great deal of heterogeneity in using such biomarker testing across institutions and hospital systems. This is in large part because there is a persistent reluctance among third-party payers to cover molecular testing. The objective of this Review is to describe why comprehensive molecular biomarker testing is now required for the accurate diagnosis and grading and prognostication of CNS tumors and, in so doing, to justify more widespread use by clinicians and coverage by third-party payers. Observations The 5th edition of the World Health Organization (WHO) classification system for CNS tumors incorporates specific molecular signatures into the essential diagnostic criteria for most tumor entities. Many CNS tumor types cannot be reliably diagnosed according to current WHO guidelines without molecular testing. The National Comprehensive Cancer Network also incorporates molecular testing into their guidelines for CNS tumors. Both sets of guidelines are maximally effective if they are implemented routinely for all patients with CNS tumors. Moreover, the cost of these tests is less than 5% of the overall average cost of caring for patients with CNS tumors and consistently improves management. This includes more accurate diagnosis and prognostication, clinical trial eligibility, and prediction of response to specific treatments. Each major group of CNS tumors in the WHO classification is evaluated and how molecular diagnostics enhances patient care is described. Conclusions and Relevance Routine advanced multidimensional molecular profiling is now required to provide optimal standard of care for patients with CNS tumors.

Esophageal squamous cell carcinoma (ESCC) remains a significant global health challenge, being the sixth leading cause of cancer mortality with pronounced geographic variability. The incidence rates range from 125 per 100,000 in northern China to 1–1.5 per 100,000 in the United States, driven by environmental and lifestyle factors such as tobacco and alcohol use, dietary habits, and pollution. Major modifiable risk factors include tobacco and alcohol consumption, with a synergistic risk increase when combined. Nonmodifiable risk factors include previous diagnoses of head and neck squamous cell carcinoma (H&N SCC), achalasia, and prior radiotherapy. Prevention strategies must be tailored to specific regional burdens to efficiently allocate medical and financial resources. Gastrointestinal endoscopy is crucial in reducing ESCC burden through early detection and characterization of neoplastic changes, such as high‐grade dysplasia. Early diagnosis significantly improves survival rates, while endoscopic resection of noninvasive dysplasia can prevent ESCC onset, reducing treatment burden for advanced disease. Postresection surveillance can detect high‐risk metachronous lesions. Despite these benefits, endoscopic prevention faces challenges, including the lack of high‐level evidence supporting its efficacy, opportunity costs, the need for specialized training and techniques, and the requirement for advanced technology investments. This Position Statement from the World Endoscopy Organization (WEO) aims to address these challenges, supplying recommendations for the exploitation of endoscopic resources regarding the possible role of screening, quality, and training for the detection, characterization, resection, and surveillance of ESCC.