Background Extranodal extension (ENE) is a recognized adverse prognostic factor in several malignancies, but its pathological basis and clinical significance in lung adenocarcinoma (LUAD) remain poorly understood. Methods We retrospectively analyzed 105 patients with N1/N2 LUAD who underwent anatomical resection between 2016 and 2020. AI-assisted image analysis quantified tumor-infiltrating lymphocytes (CD8 + , FoxP3 + ), tumor-associated macrophages (CD204 + ), and cancer-associated fibroblasts (CAFs; podoplanin + ) and measured areas of cancer cells and fibrous stroma. In vitro, the effect of CAF quantity on A549 cell invasion was evaluated. Prognostic relevance of ENE was assessed using multivariate and cumulative incidence analyses. Results While primary tumors showed no significant differences in immune or stromal composition, ENE-positive metastatic nodes exhibited a markedly larger fibrous stroma area than ENE-negative nodes (14.2 vs. 4.0 mm(2), p < 0.001). In vitro, the invasion distance of A549 cells increased when cocultured with higher numbers of CAFs. Clinically, ENE independently predicted poorer overall survival (p = 0.04) and was associated with a higher incidence of distant metastasis in both multivariate (p = 0.03) and cumulative incidence analyses (p = 0.02). Conclusions ENE represents a pathological prognostic factor characterized by abundant fibrous stroma. It independently predicts distant metastasis and may warrant consideration as a qualitative parameter in N classification for lung adenocarcinoma.

Background: The cross-sectional area (CSA) of the iliopsoas muscle on computed tomography is associated with sarcopenia, but its perioperative changes and prognostic significance in lung cancer remain unclear. This study aimed to clarify postoperative changes in the iliopsoas CSA and their prognostic correlation in the perioperative period of lung cancer. Methods: We analyzed 270 patients with lung cancer age ≥70 years who underwent lobectomy between January 2016 and December 2020. Iliopsoas CSA at the L3 vertebral level was measured preoperatively and at 6 and 12 months postoperatively and analyzed with ImageJ software. Patients were grouped based on whether their CSA decreased or increased between 6 months and 12 months postoperatively. Recurrence-free survival (RFS) and overall survival (OS) were compared between groups. Results: Compared with preoperatively, the iliopsoas CSA was decreased significantly at 6 months (23.2 mm2; P < .01) and 12 months (15.5 mm2; P = .03). Patients in the decreasing CSA were older (P = .02), more often male (P = .02), and had poorer lung function (P = .04). Decreased CSA was linked to poorer 5-year RFS (P = .07) and significantly worse OS (P = .04). The multivariate analysis revealed that a decrease in iliopsoas muscle CSA between 6 months and 12 months postoperatively was an independent poor prognostic factor for RFS (P < .01) and OS (P = .05). Conclusions: In elderly patients with primary lung cancer, decreased iliopsoas CSA from 6 months to 12 months postoperatively was at least an independent poor prognostic factor for OS.

Sarcopenia was correlated with increased postoperative complications and poor outcomes in patients with lung cancer. The cross-sectional area of the iliopsoas muscle on computed tomography is a relevant indicator of sarcopenia. This study aimed to investigate whether the preoperative cross-sectional area of the iliopsoas muscle is associated with the incidence of postoperative complications after lobectomy. This retrospective study included 584 consecutive patients aged 70 years or older who underwent curative resection for non-small cell lung cancer between 2016 and 2020. The cross-sectional area of the iliopsoas muscle was measured at the level of the third lumbar vertebra, and the cumulative area of both sides was evaluated. Univariable and multivariable analyses were performed to identify the predictors of early postoperative complications (≥ grade II by the Clavien-Dindo classification) along with the preoperative iliopsoas muscle cross-sectional area. The patients were divided into two groups according to the Clavien-Dindo grade: 125 patients (21

Lung cancer remains a leading cause of cancer-related mortality worldwide, underscoring the critical need for early detection to improve patient outcomes. This study aimed to develop and validate a plasma microRNA biomarker panel for the early detection of non-small cell lung cancer in a Japanese cohort. We enrolled 525 participants, comprising 261 LC cases and 264 non-LC controls, divided into optimization and validation cohorts. A 12-miRNA panel was optimized and further combined with CEA to enhance diagnostic performance. The miRNA-alone model demonstrated robust performance in both the optimization (AUC = 77.0%) and validation cohorts (AUC = 77.9%). Integration with CEA significantly improved accuracy, achieving AUCs of 86.2% in optimization and 84.9% in validation, with particularly high performance in late-stage cancers (AUC = 94.4%) and squamous cell carcinoma (AUC = 90.7%). Sensitivity and specificity thresholds were evaluated, enabling model customization for diverse clinical scenarios. These findings highlight the potential of the miRNA-CEA panel as a minimally invasive tool for early LC detection, especially in non-smoking populations.

OBJECTIVES:Visceral pleural invasion (VPI) is a key upstaging T-factor in non-small cell lung cancer (NSCLC). This study aimed to investigate the prognostic significance of VPI patterns. MATERIAL AND METHODS:We retrospectively analyzed 107 participants pathologically diagnosed NSCLC (T2aN0M0) with VPI. Five VPI patterns were quantitatively evaluated and analyzed for their survival impact: (1) total tumor cell area beyond the elastic layer (TCA), (2) whole tumor area beyond the elastic layer (WTA), (3) minimum distance from the pleural surface to the tumor cell invading the pleura (min-DST), (4) maximum distance from the pleural surface to the deepest point of the invaginated elastic layer (max-DSI), and (5) density of tumor cells (DTC). RESULTS:Median values for TCA, WTA, min-DST, max-DSI, and DTC were 353,471 μm2, 2,370,436 μm2, 114 μm, 1,248 μm, and 19.2 %. Five-year recurrence-free survival (RFS) was significantly lower in participants with larger TCA and WTA (log-rank test). In univariable Cox regression analysis, smoking status, Eastern Cooperative Oncology Group performance status (ECOG PS), invasive component size, TCA, and WTA were significant predictors of RFS. In multivariable analysis, ECOG PS [HR = 2.475; 95 % CI, 1.049-5.838], invasive component size [HR = 2.347; 95 % CI, 1.137-4.845], and TCA [HR = 3.574; 95 % CI, 1.318-9.695] remained independent significant prognostic factors for RFS. CONCLUSION:TCA may serve as a novel prognostic factor in NSCLC with VPI.

Surgery is the standard treatment for early-stage pulmonary neuroendocrine tumors (NETs); however, long-term prognostic data are limited. This study aimed to establish the long-term outcomes of surgically resected pulmonary NETs. This study included 263 patients who underwent pulmonary resection between January, 1997 and December, 2019: 89 with small cell lung carcinoma (SCLC), 120 with large cell neuroendocrine carcinoma (LCNEC), 14 with atypical carcinoid (AC), and 40 with typical carcinoid (TC). We analyzed clinicopathological characteristics and long-term prognosis. The 5-year relapse-free survival (RFS) rates were 38.7

Extranodal extension (ENE) is a recognized adverse prognostic factor in several malignancies, but its pathological basis and clinical significance in lung adenocarcinoma (LUAD) remain poorly understood. We retrospectively analyzed 105 patients with N1/N2 LUAD who underwent anatomical resection between 2016 and 2020. AI-assisted image analysis quantified tumor-infiltrating lymphocytes (CD8 + , FoxP3 + ), tumor-associated macrophages (CD204 + ), and cancer-associated fibroblasts (CAFs; podoplanin + ) and measured areas of cancer cells and fibrous stroma. In vitro, the effect of CAF quantity on A549 cell invasion was evaluated. Prognostic relevance of ENE was assessed using multivariate and cumulative incidence analyses. While primary tumors showed no significant differences in immune or stromal composition, ENE-positive metastatic nodes exhibited a markedly larger fibrous stroma area than ENE-negative nodes (14.2 vs. 4.0 mm², p < 0.001). In vitro, the invasion distance of A549 cells increased when cocultured with higher numbers of CAFs. Clinically, ENE independently predicted poorer overall survival (p = 0.04) and was associated with a higher incidence of distant metastasis in both multivariate (p = 0.03) and cumulative incidence analyses (p = 0.02). ENE represents a pathological prognostic factor characterized by abundant fibrous stroma. It independently predicts distant metastasis and may warrant consideration as a qualitative parameter in N classification for lung adenocarcinoma.

INTRODUCTION:Nuclear receptor-binding SET domain 3 (NSD3) has been implicated as a driver of lung squamous cell carcinoma (LUSC) in preclinical studies. However, its clinicopathologic characteristics and prognostic significance remain unclear. To address this, we performed a histopathologic analysis of patient tissues. METHODS:The NSD3 gene copy number was evaluated using fluorescence in situ hybridization in multiple cohorts of surgically resected LUSC cases, categorized into the amplification (Amp) or diploidy (Diploidy) groups. Clinicopathologic characteristics were compared, and artificial intelligence-based histopathologic image analysis evaluated the associations between NSD3 amplification, its protein expression, and cancer cell proliferation activity. RESULTS:In the original cohort, NSD3 amplification was detected in 106 patients (39.6%). NSD3 protein expression was positively correlated with the NSD3 gene copy number (r = 0.528, p < 0.001). The Amp group exhibited higher mitotic counts (18 versus 13, p = 0.004) and Ki-67 index (18.5% versus 13.6%, p = 0.009) than the Diploidy group. The Amp group had shorter overall survival than the Diploidy group (110.6 versus 125.3 mo, p = 0.030), and multivariable analysis identified NSD3 amplification as an independent poor prognostic factor (hazard ratio = 1.59, p = 0.049). Furthermore, validation cohort analyses demonstrated consistent associations of NSD3 gene amplification with protein expression and cell proliferation, with comparable hazard ratios in prognostic evaluation. CONCLUSIONS:Our study highlights the clinical relevance of NSD3 amplification in LUSC through analyses of patient tissues. These findings emphasize the potential of NSD3 as a prognostic biomarker and therapeutic target, bridging the gap between preclinical research and clinical application.

This is a preliminary analysis of one of the secondary endpoints in the prospective study cohort. The aim of this study is to assess the image quality and diagnostic confidence for lung cancer of CT images generated by using cadmium–zinc–telluride (CZT)-based photon-counting-detector-CT (PCD-CT) and comparing these super-high-resolution (SHR) images with conventional normal-resolution (NR) CT images. Twenty-five patients (median age 75 years, interquartile range 66–78 years, 18 men and 7 women) with 29 lung nodules overall (including two patients with 4 and 2 nodules, respectively) were enrolled to undergo PCD-CT. Three types of images were reconstructed: a 512 × 512 matrix with adaptive iterative dose reduction 3D (AIDR 3D) as the NRAIDR3D image, a 1024 × 1024 matrix with AIDR 3D as the SHRAIDR3D image, and a 1024 × 1024 matrix with deep-learning reconstruction (DLR) as the SHRDLR image. For qualitative analysis, two radiologists evaluated the matched reconstructed series twice (NRAIDR3D vs. SHRAIDR3D and SHRAIDR3D vs. SHRDLR) and scored the presence of imaging findings, such as spiculation, lobulation, appearance of ground-glass opacity or air bronchiologram, image quality, and diagnostic confidence, using a 5-point Likert scale. For quantitative analysis, contrast-to-noise ratios (CNRs) of the three images were compared. In the qualitative analysis, compared to NRAIDR3D, SHRAIDR3D yielded higher image quality and diagnostic confidence, except for image noise (all P < 0.01). In comparison with SHRAIDR3D, SHRDLR yielded higher image quality and diagnostic confidence (all P < 0.01). In the quantitative analysis, CNRs in the modified NRAIDR3D and SHRDLR groups were higher than those in the SHRAIDR3D group (P = 0.003, <0.001, respectively). In PCD-CT, SHRDLR images provided the highest image quality and diagnostic confidence for lung tumor evaluation, followed by SHRAIDR3D and NRAIDR3D images. DLR demonstrated superior noise reduction compared to other reconstruction methods.

Accurate prediction of lymph node metastasis is the key to selecting the best surgical approach for clinical stage N0 small-sized invasive pulmonary adenocarcinoma, especially when sublobar resection is considered. This study aimed to explore the potential use of the International Association for the Study of Lung Cancer (IASLC)-graded intraoperative frozen section analysis in guiding thoracic surgeons toward optimal surgical decisions, particularly for lymph node procedures. In this retrospective study, we analyzed 190 invasive pulmonary adenocarcinomas staged clinically as N0, with tumors ≤2 cm and a consolidation-tumor ratio >0.5 on computed tomography, resected with intraoperative frozen section analysis between January 2015 and December 2022. The IASLC grade of frozen sections was evaluated by 3 independent pathologists. Interobserver agreement, concordance with corresponding permanent sections, and the association between the grade and lymph node metastasis were then assessed. Interobserver agreement of the IASLC grading on frozen sections among 3 pathologists was substantial (κ = 0.68). The overall concordance rate between the frozen and permanent sections for IASLC grade was 75.8%, with grade 3 tumors showing particularly high concordance (95.8%). While the sensitivity for detecting grade 3 tumors in frozen sections was 69.8% (60/86), as confirmed by permanent section diagnosis, the specificity was high at 97.1% (101/104), emphasizing the potential diagnostic value of frozen sections for accurately identifying grade 3 tumors. Moreover, multivariate analysis using preoperative and intraoperative characteristics identified IASLC grading of frozen sections as the only independent factor statistically associated with lymph node metastasis, characterized by an odds ratio of 4.34 (95% CI, 1.54-12.2; P = .006). Therefore, histological grading of frozen sections could serve as a predictor of lymph node metastasis and provide valuable information for thoracic surgeons when considering the surgical approach in small-sized lung adenocarcinomas (≤2 cm and consolidation-tumor ratio >0.5).

8065 Background: The LC-SCRUM-Advantage is a screening trial to evaluate oncogenic drivers in patients with surgically resected early-stage non-small cell lung cancer (NSCLC). Recent clinical trials, such as the ADAURA and ALINA trials, have demonstrated the efficacy of molecular targeted therapy as adjuvant therapy following surgery for patients with early-stage NSCLC harboring oncogenic drivers. Our study aims to determine the proportion of early-stage NSCLC with any actionable oncogenic drivers that are candidates for adjuvant targeted therapy. This abstract presents the initial data collected until Dec 2024. Methods: Patients with operable clinical stage I to III NSCLC were eligible for this study. Surgical tumor samples were collected post-surgery, and genomic analysis of oncogenic drivers was centrally evaluated using a next-generation sequencing system, the Oncomine Precision Assay, which targets 50 gene alterations. PD-L1 immunohistochemistry using the 22C3 antibody was also performed on the submitted tumor samples. If possible, preoperative biopsy tumor samples were also collected and evaluated using the AmoyDx Pan Lung Cancer PCR Panel. An actionable oncogene was defined as EGFR, ALK, ROS1, KRAS, BRAF, HER2, RET, MET, NRG1, or NTRK genes. Results: Between August 2022 and December 2024, 646 patients were enrolled in the LC-SCRUM-Advantage. Among them, 57% had stage I, 27% had stage II, 16% had stage III, and 71% had adenocarcinoma histology. Of the 591 evaluable patients in this analysis, an actionable oncogenic driver was found in 46% of cases (274/591). Identified oncogenic drivers included 190 (24%) EGFR mutations (89 L858R, 77 ex19del, 10 ex20ins, 14 uncommon), 26 (4%) MET ex14 skipping, 20 (3%) KRAS G12C, 18 (3%) HER2 mutations (including ex20ins), 7 (1%) ALK fusion, 5 (1%) NRG1 fusion, 4 (1%) BRAFV600E, 2 (<1%) RET fusions, 1 (<1%) ROS1 fusion, and 1 (<1%) NTRK fusion. PD-L1 expression was observed in 19% for >50%, 40% for 1-49%, and 41% for <1%. Among patients with paired tumor samples from surgery and preoperative biopsy, the concordance rate of detected actionable oncogenic drivers was 95%. Conclusions: Our study found actionable oncogenic drivers in 46% of Japanese patients with surgically resected early-stage NSCLC. Based on historical control, the proportion of any oncogenic drivers in early-stage NSCLC is similar to that in advanced NSCLC. Comprehensive genomic screening of patients with early-stage NSCLC will accelerate the development of clinical trials for adjuvant-targeted therapy.

INTRODUCTION:The developments of perioperative treatments for patients with high-risk early-stage lung cancer are ongoing, however, real-world data and evidence of clinical significance of genetic aberration are lacking in this population. This study aimed to identify patients with early-stage lung adenocarcinoma at high risk for recurrence based on pathological indicators of poor prognosis, including the International Association for the Study of Lung Cancer (IASLC) grade, and elucidate the prognostic impact of epidermal growth factor receptor mutation (EGFRm) status.METHODS:This retrospective study included 494 consecutive patients who underwent complete resection for pathological stage I lung adenocarcinoma between 2011 and 2016. The patients were evaluated for EGFRm and IASLC grade. Multivariable analysis was used to identify pathological factors for poor prognosis associated with recurrence-free survival (RFS) and overall survival (OS). Patients with any one of these factors were classified into the high-risk group. The prognostic impact of EGFRm was evaluated using RFS, OS, and cumulative recurrence proportion.RESULTS:Multivariable analysis for RFS and OS revealed that IASLC grade 3, pathological invasion size>2 cm, and presence of lymphovascular invasion were indicators of poor prognosis. EGFRm-positive patients had a higher incidence of all types of recurrence, including central nervous system (CNS) metastasis and distant metastasis in high-risk group, but not in low-risk group.CONCLUSIONS:This study provides evidence that patients with EGFRm-positive stage I lung adenocarcinoma in the high-risk group have an increased risk of recurrence, including CNS metastasis. These findings highlight the need for development of adjuvant treatment in this population.

Tumor budding in the cancer stroma has been reported to be a prognostic factor in non-small cell lung cancer. Micronest in cancer stroma (MICS) is often observed as a formation that is larger and more conspicuous than budding, but its clinicopathologic significance is unclear. In this study, we aimed to examine the clinicopathological significance of MICS in lung squamous cell carcinoma (LSqCC). A total of 198 consecutive patients with pathologically diagnosed LSqCC (anyT N0-1M0) were enrolled in this study. MICS were defined as those that met the following criteria: (1) consisting of 5-200 tumor cells or less than 200 μm in diameter and (2) more than 200 μm away from the adjacent main lesion. The prognostic impact of the presence or absence of MICS and the characteristics of MICS-forming cancer cells were evaluated by immunohistochemistry (IHC). MICS was observed in 57 patients (28.8%), and overall survival (OS) and recurrence-free survival (RFS) were significantly shorter in the MICS-positive group (OS: 44.4% vs. 84.4%, p < 0.001; RFS: 30.0% vs. 82.6%, p < 0.001). Univariate and multivariate analyses revealed that the presence of MICS was an independent poor prognostic factor for OS (hazard ratio [HR] 3.54, p < 0.001) and RFS (HR 4.99, p < 0.001). Immunohistochemistry showed that the expression levels of the cell-cell adhesion molecule E-cadherin and hypoxia-induced protein GLUT-1 were significantly decreased in cancer cells forming MICS lesions compared to the tumor component excluding MICS within the same tumor (non-MICS lesions). Our data show that MICS is a distinct morphological feature with important biological and prognostic significance.

Supplementary Table S3: Site of first recurrence in recurrent patients.

PURPOSE:We elucidated the effects of planned resection volume on postoperative pulmonary function and changes in residual lung volume during segmentectomy. METHODS:This study included patients who underwent thoracoscopic segmentectomy between January 2017 and December 2022 and met eligibility criteria. Pre- and post-resection spirometry and computed tomography were performed. Three-dimensional reconstructions were performed by using computed tomography images to calculate the volumes of the resected, remaining, and nonoperative side regions. Based on the resected region volume, patients were divided into the higher and lower volume segmentectomy groups. Changes in lung volume and pulmonary function before and after the surgery were comparatively analyzed. RESULTS:The median percentage of resected lung volume was 10.9%, forming the basis for categorizing patients into the two groups. Postoperative forced expiratory volume in 1 s (FEV1) and forced vital capacity (FVC) ratios to preoperative measurements in both groups did not differ significantly (FEV1, p = 0.254; FVC, p = 0.777). Postoperative FEV1 and FVC ratios to their predicted postoperative values were significantly higher in the higher volume segmentectomy group than in the lower volume segmentectomy group (FEV1, p = 0003; FVC, p < 0.001). The higher volume segmentectomy group showed significantly greater post-to-preoperative lung volume ratio in overall, contralateral, ipsilateral, residual lobe and residual segment than the lower volume segmentectomy group. CONCLUSIONS:Postoperative respiratory function did not differ significantly between the higher- and lower-volume segmentectomy groups, indicating improved respiratory function because of substantial postoperative residual lung expansion. Our findings would aid in determining the extent of resection during segmentectomy.

Background Most metastatic lung tumors present as solid nodules on chest computed tomography (CT). In contrast, ground-glass opacity on chest computed tomography usually suggests low-grade malignant lesions such as adenocarcinoma in situ or atypical adenomatous hyperplasia of the lung.Case presentation A 75-year-old woman with a history of gastric cancer surgery approximately 5 years prior was referred to the Department of Thoracic Surgery at our hospital because of two newly appearing pulmonary ground-glass opacity-dominant nodules on chest computed tomography. She had two ground-glass opacities in the right lower lobe, one in the S6 segment was 12 mm and the other in the S10 segment was 8 mm. On chest computed tomography 15 months prior to referral, the lesion in the S6 segment was 8 mm, and the lesion in the S10 segment was 2 mm. She was suspected to have primary lung cancer and underwent wide-wedge resection of the nodule in the S6 segment. In the resected specimen, polygonal tumor cells infiltrated the alveolar septa, with some tumor cells exhibiting signet ring cell morphology. Based on morphological similarities to the tumor cells of previous gastric cancers and the results of immunostaining, the patient was diagnosed with lung metastases of gastric cancer.Conclusions Pulmonary nodules in patients with a history of cancer in other organs, even if ground-glass opacity is predominant, should also be considered for the possibility of metastatic pulmonary tumors if they are growing rapidly.

Among non-small cell lung cancers (NSCLC), 5 years is a benchmark in cancer control and treatment, but a certain percentage of cases recur after 5 years. The long-term post-recurrence outcomes remain controversial. To examine the accurate prognostic factors associated with survival and cancer recurrence among 5-year survivors, a landmark analysis that considered competing risks was performed. Complete resection of NSCLC was performed in 2482 patients between January 2003 and December 2015. A total of 1431 patients were 5-year survivors without recurrence. A landmark time analysis was applied to the overall survival (OS) and recurrence-free survival (RFS) from 5 years after surgery, and the findings were calculated using the Kaplan–Meier method. The cumulative incidence of cause-specific death and recurrence was estimated using the cumulative incidence function, while carefully considering the competing risks. Postoperative recurrence was detected in 732 patients, of whom 68 (9.3

Supplementary Table S1: Patient characteristics of the FAS Population.

INTRODUCTION:The International Association for the Study of Lung Cancer (IASLC) grading system predicts early lung adenocarcinoma outcomes. METHODS:The purpose of this study is to examine prognostic value of the IASLC grading system and its association with the tumor microenvironment (TME) in Stage I EGFR-muted lung adenocarcinoma. Based on the IASLC grading system, we compared the clinicopathological characteristics of EGFR-mutated lung adenocarcinoma (n = 296). In addition, we examined the expression level of E-cadherin in tumor cells and counted the number of tumor-infiltrating lymphocytes (TILs; CD8, CD20, CD138, and Foxp3), tumor-associated macrophages (TAMs; CD204), and cancer-associated fibroblasts (CAFs; podoplanin) using semi-automatic digital pathology image analysis. RESULTS:Recurrence-free survival (RFS) curve showed that survival of grade 3 was significantly shorter than that of grade 1 (P < 0.01) and grade 2 (P = 0.03). Multivariate analysis of RFS revealed the invasive size, lymphatic permeation, and grade 3 (P < 0.01) as independent poor prognostic factors. The number of CD204 +TAMs and PDPN+CAFs was significantly higher in grade 3 than in grade 1 or 2 (all P < 0.01). Among the intermediate grade by the predominant subtype based classification, cases classified as grade 3 by the new classification had higher number of CD204 +TAMs (P < 0.01) and PDPN+CAFs (P = 0.02) than those classified as grade 2. CONCLUSION:The IASLC grading system correlated with the outcomes of EGFR-mutated lung adenocarcinoma. Grade 3 was found to have the TME that most contributes to tumor progression, which probably explained their poor prognosis.

Supplementary Appendix S2: EAST_ENERGY_Protocol_amendment.