The integration of artificial intelligence (AI) with low-dose computed tomography (LDCT) has the potential to transform lung cancer screening into a comprehensive approach to early detection of multiple diseases. Building on over 3 decades of research and global implementation by the International Early Lung Cancer Action Program (I-ELCAP), this paper reviews the development and clinical integration of AI for interpreting LDCT scans. We describe the historical milestones in AI-assisted lung nodule detection, emphysema quantification, and cardiovascular risk assessment using visual and quantitative imaging features. We also discuss challenges related to image acquisition variability, ground truth curation, and clinical integration, with a particular focus on the design and implementation of the open-source IELCAP-AIRS system and the ScreeningPLUS infrastructure, which enable AI training, validation, and deployment in real-world screening environments. AI algorithms for rule-out decisions, nodule tracking, and disease quantification have the potential to reduce radiologist workload and advance precision screening. With the ability to evaluate multiple diseases from a single LDCT scan, AI-enabled screening offers a powerful, scalable tool for improving population health. Ongoing collaboration, standardized protocols, and large annotated datasets are critical to advancing the future of integrated, AI-driven preventive care.

Chest radiographic (CXR) screening is currently not recommended in the United States by any major guideline organization. Multiple randomized controlled trials done in the United States and also in Europe, with the largest being the Prostate, Lung, Colorectal and Ovarian (PLCO) trial, all failed to show a benefit and are used as evidence to support the current recommendation. Nevertheless, there is renewed interest in CXR screening, especially in low- and middle-resourced countries around the world. Reasons for this are multi-factorial, including the continued concern that those trials still may have missed a benefit, but perhaps more importantly, it is now established conclusively that finding smaller cancers is better than finding larger ones. This was the key finding in those large randomized controlled trials for CT screening. So, while CT finds cancers smaller than CXR, both clearly perform better than waiting for cancers to be larger and detected by symptom prompting. Without it being well understood that treating cancers found in the asymptomatic state by CXR, there would also be no basis for treating them when found incidentally. In addition, advances in artificial intelligence are allowing for nodules to be found earlier and more reliably with CXR than in those prior studies, and in many countries around the world, TB screening is already taking place on a large scale. This presents a major opportunity for integration with lung screening programs.

RATIONALE:Lung cancer screening has made early-stage non-small cell lung cancer (NSCLC) more common and highly curable. However, evidence on post-treatment surveillance, new radiological findings, and distinguishing recurrence from new primary cancers remains limited. OBJECTIVES:Our study evaluated outcomes in patients with pathologic stage 0/1A first primary NSCLC after surgery, including overall survival and the classification of new findings as either recurrence or second primary tumors. We also explored potential improvements to current classification criteria. METHODS:We analyzed 653 patients with pathologic stage 0/1A NSCLC from the IELCART cohort (2016-2023). Radiological findings were reviewed to classify lung cancer diagnoses as second primaries or recurrences using a five-step approach based on histopathology, genetics, timing, and multidisciplinary discussions. Survival was analyzed with Kaplan-Meier curves and log-rank tests. RESULTS:Among 653 patients (61.1% women, median age 69 yr), 74 (11.3%) later had radiological findings confirmed as lung cancer, which was more frequent in men (15.7% vs. 8.5%), those with higher pack-years, and chronic obstructive pulmonary disease. New malignant events were most common in current smokers (19.1%), followed by former smokers (15.2%) and never smokers (1.6%). Of these, 30 (5%) were second primaries, and 44 (7%) were recurrences. Nonsolid cancers showed no recurrences. Recurrences peaked at 12-18 months, whereas second primaries occurred steadily at 0.6% annually. Overall survival differed significantly between patient groups (P < 0.0001), with overall survival of 58.2% with recurrences, 77.9% with new primaries, and 94.3% with no new cancer after a median follow-up of 3.5 years. CONCLUSION:Among 653 patients, 7% had recurrences, whereas new primaries (5%) became more frequent after 3 years, occurring steadily at 0.6% per year, with distinct survival outcomes. New malignant events were more common in men, smokers, and those with chronic obstructive pulmonary disease. Notably, all malignancies in nonsolid cancers were new primaries. These findings emphasize the need for tailored surveillance strategies.

About one-third of adults in the US have some grade of hepatic steatosis. Coronary artery calcium (CAC) scans contain more information than currently reported. We previously reported new artificial intelligence (AI) algorithms applied to CAC scans for opportunistic measurement of bone mineral density, cardiac chamber volumes, left ventricular mass, and other imaging biomarkers collectively referred to as AI-CVD. In this study, we investigate a new AI-CVD algorithm for opportunistic measurement of liver steatosis. We applied AI-CVD to CAC scans from 5702 asymptomatic individuals (52% female, age 62±10 years) in the Multi-Ethnic Study of Atherosclerosis. Liver attenuation index (LAI) was measured using the percentage of voxels below 40 HU. We used Cox proportional hazards regression to examine the association of LAI with incident CVD and mortality over 15 years. These analyses were minimally adjusted by BMI and fully adjusted for known CVD risk factors. A total of 751 CVD and 1343 deaths accrued over 15 years. Mean±SD LAI in females and males was 38±15% and 43±13%, respectively. Participants in the highest vs. lowest quartile of LAI had greater incidence of CVD over 15 years: 19% (95% CI: 17%-22%) vs. 12% (10%-14%), respectively, p<0.0001). Individuals in the highest quartile of both LAI and CAC score (n = 386) experienced 37.3% (32.3%-42.7%) incidence of all CVD events over 15 years. Individuals in the highest quartile of LAI (Q4) compared to the lowest quartile (Q1) showed a higher risk of CVD (HR: 1.43, 95% CI: 1.08-1.89), stroke (HR: 1.77, 95% CI: 1.09-2.88), and all-cause mortality (HR: 1.36, 95% CI: 1.10-1.67) independently of CVD risk factors and Agatston CAC Score. AI-enabled CT attenuation analysis of the entire liver visible in CAC scans provides opportunistic and actionable information for early detection of patients at elevated risk of CVD events and all-cause mortality. The clinical utility of incorporating LAI along with other opportunistic findings in CAC scans as part of the AI-CVD initiative to improve CVD risk prediction warrants investigation in other cohorts.

INTRODUCTION:Lung cancer screening (LCS) using low-dose-computed tomography reduces lung cancer mortality in high-risk individuals. Evaluating and monitoring LCS programs are important to ensure and improve quality, efficiency, and participant outcomes. There is no agreement on LCS quality indicators (QIs). METHODS:Twenty multidisciplinary members of the International Association for the Study of Lung Cancer used a Delphi process to develop consensus QIs. They considered 50 QIs during information/discussion sessions and two anonymous voting rounds. In total, 80% or more voting agree or strongly agree on a five-point Likert scale determined consensus. RESULTS:Twenty essential and six desirable QIs were identified in 10 of 11 LCS pathway domain categories (ENTRY: Proportion eligible who got screened; SMOKING_CESSATION: Proportion of current-smoking individuals offered cessation interventions; IMAGING: Proportion screened requiring clinical diagnostic assessment, scan results distribution, proportion scans requiring early follow-up, proportion baseline or regular scans with actionable additional findings; ADHERENCE to: Annual or regular scans, early interim scans, clinical diagnostic assessment; DIAGNOSTIC: Proportion suspicious-for-lung-cancer scans receiving clinical investigation, undergoing invasive diagnostic procedures; OUTCOMES: Cancer detection rate, stage distribution, interval cancer rate; HARMS: Number and proportion of serious complications after invasive procedures, non-lung cancer diagnoses after invasive procedures or surgery, 30-day mortality after invasive procedure; TREATMENT: Proportion early-stage cancers receiving treatment with curative intent; WAIT_TIMES: Suspicious-for-lung-cancer scan to definitive diagnosis, to curative-intent treatment for individuals with early-stage disease, scan completion to reporting results to primary care provider and participant; EQUITY: Race, sex, and socioeconomic differences in adherence to regular screens, early-stage cancer treatment, offer of smoking cessation interventions, clinical investigation of suspicious-for-lung-cancer screens). CONCLUSIONS:A review among panel members provided recommended LCS QIs that should be considered in the development of LCS initiatives.

Background The prognostic value of baseline visual emphysema scoring at low-dose CT (LDCT) in lung cancer screening cohorts is unknown. Purpose To determine whether a single visual emphysema score at LDCT is predictive of 25-year mortality from all causes, chronic obstructive pulmonary disease (COPD), and cardiovascular disease (CVD). Materials and Methods In this prospective cohort study, asymptomatic adults aged 40-85 years with a history of smoking underwent baseline LDCT screening for lung cancer between June 2000 and December 2008. Follow-up continued until death, loss to follow-up, or December 31, 2024. Emphysema was assessed at baseline LDCT and scored from 0 (none) to 3 (severe) by one of four experienced chest radiologists. Baseline smoking history and comorbidities were self-reported. Causes of death (International Classification of Diseases, 10th Revision) were obtained from the U.S. National Death Index, physicians, and family. Associations between emphysema and mortality were evaluated using adjusted Cox proportional hazards and adjusted Fine-Gray competing risks models. Results Among 9047 participants (4614 female; median age, 65 years [IQR, 61-69 years]; median pack-years of smoking, 43 [IQR, 28-64]), 2637 (29.1%) had emphysema (mild in 1908 [21.1%], moderate in 512 [5.7%], and severe in 217 [2.4%]). Median follow-up was 23.3 years. Emphysema was independently predictive of all-cause mortality (hazard ratio [HR], 1.29; 95% CI: 1.21, 1.38; P < .001), COPD mortality (HR, 3.29; 95% CI: 2.59, 4.18; P < .001), and CVD mortality (HR, 1.14; 95% CI: 1.01, 1.29; P = .04). A dose-response relationship was observed between emphysema severity and both all-cause and COPD mortality, but not CVD mortality. In the adjusted competing risk analysis, emphysema remained associated with COPD mortality (HR, 3.06; 95% CI: 2.40, 3.90; P < .001), but not CVD mortality (HR, 1.04; 95% CI: 0.91, 1.18; P = .59). Conclusion Baseline emphysema at LDCT in a prospective lung cancer screening cohort of asymptomatic adults was predictive of all-cause, COPD, and CVD mortality up to 25 years later. © RSNA, 2025 Supplemental material is available for this article. See also the editorial by Mascalchi and Diciotti in this issue.

Background Angiolymphatic invasion (ALI) is an important prognostic indicator in non-small cell lung cancer (NSCLC). However, few studies focus on radiologic features for predicting ALI in patients with early-stage NSCLCs 30 mm or smaller. Purpose To identify radiologic features for predicting ALI in NSCLCs 30 mm or smaller in maximum diameter. Materials and Methods This study was a secondary review of pathologic and CT findings from an integrated health care system between January 2016 and November 2023 for participants in the prospective study Initiative for Early Lung Cancer Research on Treatment, or IELCART. Preoperative diagnostic radiologic features possibly related to ALI, volume doubling time (VDT), and PET maximum standardized uptake value were evaluated. Multivariable logistic regression analysis, adjusted for sex, age, nodule size, and smoking status, was used to determine predictors of ALI. Model performance was analyzed with the area under the receiver operating characteristic curve (AUC). Results Of 778 resected NSCLCs 30 mm or smaller (median patient age, 69 years [IQR, 63-76 years]; 458 female patients), 715 (92%) were solid, 41 (5%) were part-solid, and 22 (3%) were nonsolid. ALI was documented in 271 (35%) resected NSCLCs, all in solid NSCLCs, representing 37.9% (95% CI: 34.4, 41.5) of solid NSCLCs. None of the 63 subsolid NSCLCs had ALI (0% [95% CI: 0, 5.75]). For the 715 solid NSCLCs (median patient age, 69 years [IQR, 63-76 years]; 420 female patients), multivariable logistic regression analysis showed that lollipop sign (odds ratio [OR] = 4.12 [95% CI: 2.82, 6.04]; P < .001) and spiculation (OR = 2.05 [95% CI: 1.42, 2.97]; P < .001) were independent predictors of ALI (AUC = 0.77 [95% CI: 0.73, 0.80]). Considering only the 474 patients in whom VDT could be calculated based on CT scans, VDT was also an independent predictor for ALI (OR = 0.96 [95% CI: 0.94, 0.98]; P < .001). Incorporating VDT into the model improved ALI prediction (AUC = 0.82 [95% CI: 0.77, 0.86]; P < .001). Conclusion For patients with NSCLCs 30 mm or smaller, ALI was present in 37.9% of solid NSCLCs and none of the 63 subsolid NSCLCs. Among solid NSCLCs, lollipop sign, spiculation, and VDT were independent radiologic predictors of ALI. © RSNA, 2025 Supplemental material is available for this article. See also the editorial by Czum in this issue.

Introduction: There is a strong correlation between CT and mammographic assessment of breast density. The purpose of this study was to assess whether women enrolled in the low-dose CT (LDCT) scan lung cancer screening program and had dense breasts on their CT scan were aware of their breast density, to confirm the correlation of CT and mammographic breast density, and to determine the utilization rates of supplemental screening. Methods: Participants were English-speaking women with dense breasts identified on LDCT done through the International Early Lung Cancer Action Program (I-ELCAP). All signed consent. Participants completed the I-ELCAP Dense Breast Questionnaire addressing patients' awareness and knowledge of breast density. Mammogram reports in the electronic medical record were analyzed for breast density category. Discrepant cases, i.e., where mammogram and LDCT dense breast density categories differed, were reviewed by an expert radiologist. Results: Most patients, 78/88 (89%), knew they had dense breasts. More than half of the participants, 56/88 (64%), did not receive additional testing. The CT and mammogram reported density was concordant in 52/60 (87%) of cases. All the discordant cases differed by one category-the mammograms were reported as having "scattered fibroglandular elements." Re-review of mammograms confirmed they were not dense in 5/8, and images were not available for 3/8. Conclusion: The lack of additional testing in those with documented dense breasts suggests weak adherence to recommendations and the potential for enhanced education about the potential benefits of supplemental screening. Additional education concerning breast density determination on CT relative to mammography may be useful.

Introduction: Limited information exists on next-generation sequencing (NGS) success for lung tumors of 30 mm or less. We aimed to compare NGS success rates across biopsy techniques for these tumors, assess DNA sequencing quality, and verify reliability against surgical resection results. Methods: We used data from the Initiative for Early Lung Cancer Research on Treatment study, including patients with lung tumors measuring 30 mm or less who had surgery and NGS on biopsies since 2016. We collected data on biopsy type, nodule characteristics, complications, sequencing feasibility, clinical actionable variants, surgery type, and TNM classification. We compared NGS feasibility and quality between biopsy methods and, for those with NGS on surgical samples, compared feasibility, quality, and detection of actionable variants. Results: Among the 654 participants with lung tumors of 30 mm or less who underwent surgery, 70 had NGS on prior biopsies. The median age was 68.5; 51.4% were male individuals, and 75.7% were smokers. The mean diameter of biopsied nodules was 17.7 mm, with 67.1% fine-needle aspiration, 17.1% computed tomography-guided trans- thoracic core needle biopsies, and 17.1% endobronchial ultrasound-guided transbronchial needle aspiration. DNA sequencing was feasible in 97.1% of biopsy samples; 2.9% had low tumor cellularity. Coverage depth was achieved in 89.7% of biopsies. RNA sequencing was successful in 66.2% of biopsies, especially in core needle biopsies. Actionable alterations were found in 41.4% of patients. Among the participants, 30% had NGS on surgical samples. RNA sequencing was more feasible on surgical samples (95.2% versus 42.9% for biopsies). NGS on surgical samples matched biopsy results in 90% of patients, with 10% showing additional alterations. Conclusion: DNA sequencing succeeded in 97.1% of biopsies of nodules 30 mm or less, whereas RNA sequencing feasibility was lower. NGS on biopsy samples is generally reliable but requires careful review. (c) 2024 The Authors. Published by Elsevier Inc. on behalf of the International Association for the Study of Lung Cancer. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/ 4.0/).

Reduction in lung cancer mortality is achievable through low dose computed tomography (LDCT) screening in high-risk individuals. Many countries are progressing from local LDCT screening studies to national screening programs. Implementation of effective large-scale screening programs is complex and requires a multidisciplinary approach. A recent overview of the technical aspects of implementing high quality LDCT for screening resulted from the inaugural international expert meeting of the Alliance for Global Implementation of Lung and Cardiac Early Disease Detection and Treatment (AGILE). This covers the most important aspects of the CT imaging process: standardisation in CT image acquisition and interpretation, CT protocol management, technology developments and minimal requirements, integration of lung cancer biomarkers, and the role of AI in CT lung nodule detection, segmentation, and classification, and related data security issues.

To address Croatia’s high lung cancer mortality and late-stage diagnoses, the Ministry of Health initiated a multidisciplinary effort to design a national lung cancer screening program. Lung cancer remains one of the leading causes of cancer-related mortality both globally and in Croatia. In 2021 alone, Croatia recorded over 3300 new cases of lung cancer and more than 2800 associated deaths, indicating a high mortality burden. In response to this public health concern, the Ministry of Health has established a multidisciplinary Lung Cancer Screening Working Group, tasked with developing a national screening approach. The Program incorporates several innovative elements, including the application of modified International Early Lung Cancer Action Program (I-ELCAP) criteria for nodule management, volumetric analysis assessed by artificial intelligence, complete digitalization, smoking cessation, and nationwide deployment to ensure equitable access. From October 2020 to August 2025, over 50,000 participants were screened, resulting in more than 70,000 LDCT scans performed. The cohort includes 54

There have been enormous advances in the approach to assessing malignancy status of indeterminate pulmonary nodules including risk models, image based biomarkers and numerous types of biologic and molecular markers. All of these have the advantage of guiding further workup once the nodule is identified. The traditional method, especially for smaller nodules relies primarily on assessing whether a nodule changes in size over time and is a feature in virtually every management protocol for both screen detected as well as incidentally detected nodules. Here, the potential downside is that during the waiting period for obtaining a second scan to assess for growth prognosis changes. However, there must be enough of a time delay to overcome potential measurement error. These two features must be balanced for optimal use of this approach. The alternative approaches do not have this inherent delay, however, their usefulness is a balance between the improvement in prognosis by not having any delays versus their potential to produce false positive and false negative results. Currently nodule volumetric approaches, especially for small nodules remains the method of choice for evaluation.

Introduction: Lung cancer screening is underutilized, especially in rural areas where lung cancer mortality is high. Approximately 11.2% of the U.S. population over age 50 years meet the U.S. Preventive Services Task Force (USPSTF) 2021 lung cancer screening eligibility criteria; the proportion of eligible Veterans is unknown. This study evaluated the proportion of Veterans who are USPSTFeligible and tested the hypothesis that more USPSTF 2021-eligible Veterans reside in rural versus nonrural areas. Methods: Investigators cross-sectionally surveyed a national sample of Veterans aged 50 years and older January-November 2022. Oversampling ensured inclusion of minority groups and accounted for geographic variation in tobacco use. Analyses in 2023-2024 evaluated the proportion of USPSTF-eligible Veterans by year (2013 and 2021) and tested USPSTF-2021 eligibility by rural status (rural versus nonrural) using chi square tests. Weighting accounted for survey nonresponse and applied results to the whole Veteran population in a sensitivity analysis. Results: Of 2,000 surveyed, 754 responded (37.7% response rate); most respondents were White (74.4%), male (92.6%), and resided in nonrural areas (66.0%). Proportions meeting USPSTF criteria were 35.5% (95% CI=31.6%, 39.6%) in 2021 and 27.8% (95% CI=24.3%, 31.7%) in 2013. The proportion of USPSTF 2021-eligible rural Veterans (41.2%; 95% CI=34.8%, 48.0%) was higher compared with nonrural (32.5%; 95% CI=27.7%, 37.7%), p=0.037. A sensitivity analysis found the proportion of Veterans USPSTF 2021 eligible in the whole population was 33.0%. Conclusions: The proportion of Veterans USPSTF2021 eligible was nearly 3 times higher than the general U.S. population (11.2%), and a greater proportion of eligible Veterans resided in rural compared with nonrural areas. These findings are critical for policies aimed at fully implementing lung cancer screening at scale.

Lung cancer is the leading cause of cancer-related mortality worldwide, largely due to late-stage diagnosis. Low-dose computed tomography (LDCT) screening has emerged as a powerful tool for early detection, enabling diagnosis at curable stages and reducing lung cancer mortality. Despite strong evidence, LDCT screening uptake remains suboptimal globally. This review synthesizes current evidence supporting LDCT screening, highlights ongoing global implementation efforts, and discusses key insights from the 1st AGILE conference. Lung cancer screening is gaining global momentum, with many countries advancing plans for national LDCT programs. Expanding eligibility through risk-based models and targeting high-risk never- and light-smokers are emerging strategies to improve efficiency and equity. Technological advancements, including AI-assisted interpretation and image-based biomarkers, are addressing concerns around false positives, overdiagnosis, and workforce burden. Integrating cardiac and smoking-related disease assessment within LDCT screening offers added preventive health benefits. To maximize global impact, screening strategies must be tailored to local health systems and populations. Efforts should focus on increasing awareness, standardizing protocols, optimizing screening intervals, and strengthening multidisciplinary care pathways. International collaboration and shared infrastructure can accelerate progress and ensure sustainability. LDCT screening represents a cost-effective opportunity to reduce lung cancer mortality and premature deaths.

Lung cancer screening program navigators improve adherence and patient experience. However, little is known about how navigators improve program outcomes. The aim of this qualitative study was to explore factors influencing the lung cancer screening program navigator role. From December 2020 to September 2021, we conducted a cross-sectional qualitative study of in-depth interviews in the Veterans Health Administration. We interviewed a national sample of healthcare team members involved in lung cancer screening at 10 Veterans Affairs Medical Centers. We performed interviews to elicit data on lung cancer screening team and organizational characteristics, barriers to and facilitators of lung cancer screening, and factors influencing the navigator role. We utilized an iterative inductive-deductive approach for qualitative analysis based on the health systems science framework and relational coordination theory. We conducted 30 interviews (participation rate = 56

TPS2696 Background: For resectable stage II/III non-small cell lung cancer (NSCLC), neoadjuvant chemoimmunotherapy has become standard of care. Patients with Stage I disease (as per AJCC 8) were excluded from chemoimmunotherapy studies given prior data demonstrating no survival benefit from perioperative chemotherapy. However, even patients with Stage 1A (< 2cm) tumors have a 30% chance of recurrence (Altorki et al, NEJM 2023). Recent research has revealed that tumor-infiltrating myeloid cells express an IL-4 responsive transcriptional signature, and IL-4 signaling within monocyte-derived macrophages plays an essential role in NSCLC progression and tumor microenvironment remodeling. Dupilumab, a monoclonal antibody targeting IL-4 receptor alpha (IL-4Rα), is currently approved for treating asthma and allergic rhinitis, and preclinical studies have demonstrated that blocking IL-4 signaling can significantly reduce lung tumor burden by activating dendritic cells and effector T cells to generate a robust immune response against tumor antigens. These findings are supported by early clinical evidence from a phase 1/2 trial showing that dupilumab can work synergistically with PD-(L)1 inhibition to induce sustained tumor responses in some patients with metastatic NSCLC who had previously progressed on immunotherapy. Whether similar synergy would be seen in the pre-operative setting in patients with Stage 1 tumors, or patients not suitable for chemoimmunotherapy, is not known, though an immunotherapy-alone approach may enable much more brief pre-operative treatment given that T cell changes peak at one week in the metastatic setting, and prior studies show PD-1 blockade alone can cause robust responses in some patients within only a few weeks. Methods: This Phase 1b/2a single-arm trial will enroll patients with early-stage (> T1b), resectable NSCLC. Patients will receive one dose each of dupilumab (600mg SC) and cemiplimab (350mg IV) on day 1, followed by surgical resection within 15-21 days, with delays beyond 8 weeks considered a delay of surgery. The trial consists of a 3+3 safety run-in (Phase 1b, up to 6 patients) followed by a Simon's two-stage expansion (Phase 2a, up to 24 total patients). The primary endpoints are safety/feasibility (Phase 1b) and major pathological response rate, defined as ≤10% viable tumor at resection (Phase 2a). Secondary endpoints include time to surgery, pathological complete response rate, event-free survival, and overall survival. Comprehensive correlative studies will characterize the immune response through serial blood sampling (days 1, 4, 8, 15, surgery, and 30 days post-op), matched proteomic and transcriptomic tumor tissue analysis (pre-treatment and operative samples), and stool microbiome profiling to identify potential biomarkers of response. Clinical trial information: NCT06088771 .

The single ordinal Early Lung and Cardiac Action Program coronary artery calcium score is predictive of up to 25-year cardiovascular disease (CVD) and all-cause mortality, highlighting the potential of low-dose CT for artificial intelligence–driven early detection of both CVD and lung cancer.