INTRODUCTION:We aimed to clarify the prognostic impact of adjuvant chemotherapy intensity in patients with high-grade neuroendocrine carcinoma (HGNEC) of the lung using a post hoc analysis of the phase III JCOG1205/1206 trial comparing irinotecan plus cisplatin (IP) with etoposide plus cisplatin (EP). MATERIAL AND METHODS:We included 217 patients (109 and 108 received EP and IP, respectively) with p-stage I-IIIA HGNEC. Prognosis was assessed based on treatment completion (four cycles) and relative dose intensity (RDI) of adjuvant chemotherapy, calculated for each regimen and agent, using Cox proportional hazards models. RESULTS:Median regimen RDI was similar (87.2% vs. 89.6%), whereas treatment completion rate was higher in EP (89.0% vs. 74.1%; P = 0.0046). Five-year relapse-free survival (RFS) among patients who completed versus did not complete treatment was 66.0% versus 73.3% in EP arm (hazard ratio [HR], 1.944; 95% CI, 0.590-6.404) and 67.4% versus 64.1% in IP arm (HR, 0.874; 95% CI, 0.437-1.745). RDI ≥90% was associated with worse RFS in EP arm (HR, 2.024; 95% CI, 1.081-3.787) but not in IP arm (HR, 1.123; 95% CI, 0.608-2.072). In EP arm, cisplatin and etoposide RDI ≥90% were associated with worse RFS (HR, 1.926; 95% CI, 1.029-3.605 and HR, 2.024; 95% CI, 1.081-3.787, respectively), whereas no significant associations were observed for cisplatin or irinotecan in the IP arm. CONCLUSION:In completely resected HGNEC, high-intensity adjuvant chemotherapy was not clearly associated with improved prognosis. Higher RDI in the EP regimen was associated with poorer RFS, suggesting that the pursuit of high RDI may not be necessary in adjuvant HGNEC treatment.

INTRODUCTION:Segmentectomy has become a standard treatment for small-sized peripheral NSCLC. However, its advantages compared with lobectomy in NSCLC harboring pathologically invasive features remain unclear. METHODS:We conducted a post hoc supplementary analysis of randomized controlled phase 3 trial JCOG0802/WJOG4607L in patients with clinical stage IA NSCLC (≤2 cm) harboring one or more of the following pathologically invasive features: lymphatic, vascular, or pleural invasion and lymph node metastasis. The primary outcome was overall survival (OS), and secondary outcomes were relapse-free survival, cumulative incidence of locoregional relapse, lung cancer-specific death, and death from other causes. RESULTS:Of the 1106 participants randomly assigned to the lobectomy or segmentectomy arm, 298 (27%) were included in this analysis: 164 patients were in the lobectomy arm and 134 in the segmentectomy arm. At a median follow-up of 7.1 (interquartile range: 5.9-8.4) years, segmentectomy demonstrated a trend toward better OS than lobectomy, with hazard ratio (HR) of 0.657 (95% confidence interval [CI]: 0.401-1.077; p = 0.0936). The cumulative incidence of death from other causes was significantly reduced in the segmentectomy arm compared with the lobectomy arm (HR = 0.359 [95% CI: 0.143-0.900]). Relapse-free survival and cumulative incidence of lung cancer-specific death were not significantly different between the two arms, whereas the cumulative incidence of locoregional relapse was significantly higher in the segmentectomy than in the lobectomy arm (HR = 2.234 [95% CI: 1.334-3.741]). CONCLUSIONS:Segmentectomy demonstrated better OS compared with lobectomy even for NSCLC harboring pathologically invasive features. However, the risk of locoregional relapse after segmentectomy should be considered.

Background: This study employed artificial intelligence (AI) to analyze quantitative nuclear morphological features obtained from digital pathology images to predict postoperative recurrence in patients with lung squamous cell carcinoma (LSQCC). We aimed to develop a prediction model that contributes to the realization of 'personalized postoperative management' tailored to individual tumor biology by integrating AI-extracted morphological features with clinical information. Methods: A total of 185 of the 253 surgically resected LSQCC cases were included; 136 were randomly assigned to the training set and 49 to the test set. Nuclear features from manually selected regions of interest were extracted and used to build AI-based prediction models. Three recurrence models were developed: recurrence within 2 years, within 5 years, and a three-category model (≤2 years, 3-5 years, >5 years or no recurrence). Support vector machine (SVM) and random forest (RF) algorithms were applied to each, yielding six predictive models. An ensemble approach was used to calculate AI-based risk scores, and a "total risk score" was developed by integrating these with the pathologic stage. Results: All six AI models demonstrated stable predictive performance, with AUC values ranging from 0.76 to 0.91. Kaplan-Meier analysis showed that the total risk score provided the most precise risk stratification (p < 0.005), with clearer separation between risk groups than the AI-based risk score alone. Conclusions: The integration of AI-based nuclear morphology analysis and clinical data provides an objective and practical tool for personalized postoperative management in LSQCC. This approach enables tailored clinical decision-making by identifying patients at high risk for early recurrence and customizing postoperative treatment plans to meet the specific needs of each individual.

Introduction Accurate preoperative imaging is essential for improving the treatment of small lung cancers. Precise identification of non-invasive adenocarcinomas is critical for determining the suitability of sublobar resection. Conventional methodologies frequently demonstrate variability, particularly for small tumors or ground-glass nodules (GGNs). Artificial intelligence (AI) offers a consistent and objective alternative, enhancing non-invasive cancer diagnosis and facilitating more effective treatment decisions. Materials and methods A retrospective analysis was conducted on 324 patients who underwent surgical resection for small-sized lung adenocarcinomas at Tokyo Medical University. The Synapse Vincent system (Fujifilm Corporation, Japan) was employed to measure tumor size and classify the nodules as GGN (AI-GGN) or non-GGN (non-AI-GGN) based on confidence scores. The ability of AI to predict pathological non-invasive adenocarcinomas was evaluated. Results AI-measured tumor sizes were significantly more accurate than those measured by thoracic surgeons (p < 0.001) AI-GGN demonstrated a high specificity of 98.3% for predicting pathological non-invasive adenocarcinoma, closely aligned with the 98.3% specificity of the traditional consolidation tumor ratio (CTR) method. The positive predictive values of AI-GGN and CTR were similarly high, (98.5% and 98.2%, respectively), confirming the effectiveness of both methods in identifying non-invasive adenocarcinomas. Conclusion AI technology significantly enhances the precision of tumor size measurement and identification of non-invasive adenocarcinomas in small-sized lung tumors. By providing objective and automated evaluations, AI can refine surgical planning and decision-making. Further prospective multicenter studies are warranted to validate these findings and to fully integrate AI into clinical practice, ultimately improving patient outcomes.

8009 Background: JCOG0802/WJOG4607L confirmed the superiority of segmentectomy on overall survival (OS) over lobectomy for small-sized peripheral non-small cell lung cancer (NSCLC). However, it remains unclear whether technically demanding complex segmentectomy offers therapeutic efficacy compared to lobectomy, similar to simple segmentectomy. This study therefore aimed to evaluate the oncological outcomes of complex and simple segmentectomy compared to those of lobectomy using final analysis data from JCOG0802/WJOG4607L. Methods: Simple segmentectomy was defined as resection of the bilateral superior division (S 6 ), left lingular (S 4+5 ), or superior division (S 1-3 ); all other segmentectomies were defined as complex. The primary outcome was OS, and secondary outcomes were respiratory function, relapse-free survival (RFS), cumulative incidence of locoregional relapse, and lung cancer-specific death. To ensure comparability, a location-adjusted analysis was performed, separately comparing lobectomy to simple segmentectomy in patients with tumors in the bilateral S 6 , left S 1-3 , or S 4+5 , and to complex segmentectomy in patients with tumors in the right S 7-10 , S 1-3 , or left S 8-10 , S 1-3 . Results: 1106 patients were assigned to either lobectomy (n = 554) or segmentectomy (n = 552) including 318 complex and 234 simple segmentectomies. At a median follow-up of 10.5 years, the 10-year OS was 83.5% (95% CI: 78.8–87.3%), 83.5% (95% CI: 77.7–87.9%) and 79.8% (95% CI: 76.1–83.0%) for complex, simple segmentectomy, and lobectomy, respectively. In the location-adjusted analysis, the 10-year OS were 83.6% (95% CI: 78.9–87.3%) for complex segmentectomy and 79.2% (95% CI: 74.7–82.9%) for lobectomy (HR 0.839 [95% CI 0.608–1.158]). Similarly, 10-year OS were 82.9% (95% CI: 76.9–87.4%) for simple segmentectomy and 78.0% (95% CI: 72.5–82.6%) for lobectomy (HR 0.791 [95% CI 0.540–1.158]). The reduction of median forced expiratory volume in 1 second at 1 year was less after complex (−7.9%) and simple segmentectomy (−9.0%) than lobectomy (−12.0%; p < 0.001 and p < 0.001, respectively). RFS and lung cancer-specific death were not significantly different among the arms, while the cumulative incidence of locoregional relapse was higher after complex and simple segmentectomy than lobectomy (HR 2.124 [95% CI 1.327–3.339] and HR 1.817 [95% CI 1.071–3.083], respectively). Surgical margins were shorter in complex (median 2.2 cm, p < 0.001) and simple (2.5 cm, p < 0.001) segmentectomy than lobectomy (4.0 cm). Conclusions: Complex segmentectomy showed a trend toward improved OS compared to lobectomy in small-sized peripheral NSCLC similar to simple segmentectomy. However, due to a higher risk of locoregional relapse, complex segmentectomy should be performed with meticulous attention to securing adequate surgical margin. Clinical trial information: UMIN000002317.

BACKGROUND:Tumor maximum standardized uptake value (tumor-SUVmax) on ¹⁸F-fluorodeoxyglucose positron emission tomography/computed tomography (FDG PET/CT) is an established prognostic marker in lung cancer. However, metabolic activity of the background lung parenchyma has received little attention. Idiopathic pulmonary fibrosis (IPF) significantly worsens lung cancer prognosis; however, CT assessments have limitations in predicting outcomes. We investigated whether measuring SUVmax in noncancerous lung areas (NCA-SUVmax) could capture subclinical inflammatory activity and provide additional prognostic information. METHODS:We retrospectively analyzed 616 patients with pathological stage I lung cancer, who had undergone surgical resection between 2012 and 2019. Both tumor-SUVmax and NCA-SUVmax were measured using preoperative FDG PET/CT. Receiver operating characteristic analysis revealed optimal NCA-SUVmax cutoff values. Survival outcomes between high (≥1.34) and low (<1.34) NCA-SUVmax groups were compared using Kaplan-Meier analysis and Cox regression models. RESULTS:During a median follow-up of 60 months, 56 patients (9.1%) experienced recurrence and 89 (14.4%) died. Tumor-SUVmax and NCA-SUVmax showed weak correlations, independently predicting survival. Patients with high NCA-SUVmax (n = 162, 26.3%) had significantly worse 5-year disease-free (72.2% vs. 91.7%) and overall survival (77.2% vs. 93.1%). IPF prevalence was markedly higher in the high NCA-SUVmax group (29.6% vs. 2.9%). Multivariate analysis identified tumor-SUVmax and NCA-SUVmax as independent predictors (hazard ratios: 1.60 and 1.56). Patients with high NCA-SUVmax and IPF demonstrated particularly inferior outcomes (5-year survival: 52.0% disease-free, 52.4% overall). CONCLUSIONS:NCA-SUVmax provides independent prognostic information beyond conventional tumor-SUVmax for identifying high-risk patients with concurrent IPF. This parameter may improve risk stratification in patients with Stage I lung cancer.

INTRODUCTION:Acute kidney injury (AKI) following lung transplantation is associated with long-term outcomes. Although AKI is diagnosed based on absolute creatinine, this level may not reliably reflect kidney function due to reduced muscle mass in this population. Thus, this study investigated persistent kidney injury, defined by early creatinine trajectories, and its association with long-term outcomes regardless of AKI diagnosis. METHODS:In this retrospective study of adult lung-transplant recipients, we used linear mixed-effects models to compare first-week creatinine trajectories between patients based on the development of adverse long-term outcomes, specifically 2-year chronic kidney disease (CKD) and major adverse kidney events (MAKE). We also assessed the association between Day 7/Baseline Creatinine Ratio and these outcomes using multivariable logistic regression. RESULTS:Among 150 recipients, 26% developed postoperative AKI. Although none had preoperative CKD, 60% of AKI patients and 40% of non-AKI patients developed postoperative CKD. Those who developed CKD showed a significantly slower decline in creatinine over the first week compared to patients who did not (difference: 0.17 mg/dL/week, p < 0.001), consistent in patients with and without AKI. Day 7/Baseline Creatinine Ratio was significantly higher in patients with adverse outcomes and independently predicted both 2-year CKD (Adjusted Odds Ratio: 4.54, p = 0.017) and MAKE (Adjusted Odds Ratio: 3.84, p = 0.026). CONCLUSION:Early persistent kidney injury was associated with adverse long-term outcomes following lung transplantation, regardless of AKI diagnosis. Day 7/Baseline Creatinine Ratio may serve as an early prognostic marker for risk stratification at the bedside or in clinical research.

BACKGROUND:We aimed to investigate the clinicopathological characteristics and prognostic significance of programmed death ligand 1 (PD-L1) expression in patients with pathological stage I-II epidermal growth factor receptor (EGFR)-mutant lung adenocarcinoma (LUAD) undergoing surgical resection. PATIENTS AND METHODS:Patients with EGFR-mutant LUAD who underwent complete surgical resection between 2017 and 2019 at 2 institutions were retrospectively analyzed. PD-L1 expression was assessed using the tumor proportion score (TPS) with a cutoff of ≥ 1%. Clinical outcomes, including recurrence-free survival (RFS) and overall survival, were examined based on PD-L1 expression. Propensity score matching was used to reduce confounding, and multivariate analyses were performed to identify independent prognostic factors. Additionally, progression-free survival (PFS) was assessed based on PD-L1 expression to investigate the efficacy of EGFR-tyrosine kinase inhibitors (EGFR-TKIs) after postoperative recurrence. RESULTS:Among 243 patients identified, those classified as PD-L1-positive (TPS ≥ 1%) exhibited significantly shorter 5-year RFS than PD-L1-negative patients (81.3% vs. 95.3%, P < .001). Male sex, advanced pathological T factor, tumor differentiation, and visceral pleural invasion or lymphovascular invasion were identified as significant predictors of recurrence. Although the population was small, the PFS for PD-L1-positive patients who received EGFR-TKIs was 21.4 months, which was significantly longer than the 7.6 months for PD-L1-negative patients. CONCLUSIONS:PD-L1 expression is a useful biomarker for predicting postoperative recurrence in patients with EGFR-mutant LUAD, and the therapeutic effect of EGFR-TKIs is sufficient even in PD-L1-positive patients. These findings support the current treatment guidelines and highlight the need for further studies to explore the role of PD-L1 in postoperative management.

A 50-year-old woman with stage IVB lung adenocarcinoma tested negative for driver mutations using the Oncomine Dx Target Test Multi-CDx system (Thermo Fisher Scientific, Waltham, MA). After undergoing chemotherapy and immunotherapy, FoundationOne Liquid CDx (Foundation Medicine, Inc., Cambridge, MA) identified a rare EML4-ALK gene rearrangement. Treatment with alectinib led to rapid clinical improvement and sustained disease control for more than 7 months. This case highlights the value of next-generation sequencing-based profiling in detecting rare actionable alterations missed by standard tests. We also include a discussion on why the EML4-AKL fusion was not detected in the usual test.

Background: Visceral pleural invasion (VPI) has traditionally been regarded as a negative prognostic indicator in non-small-cell lung cancer (NSCLC). However, with the increasing adoption of sublobar resection for small-sized NSCLC, the clinical significance of VPI is being fundamentally reassessed. Specifically, it remains uncertain whether VPI is indicative of tumor size or represents distinct metastatic behavior. Methods: We conducted a retrospective comprehensive multicenter study involving 2464 patients with pathologically confirmed NSCLC ≤ 3 cm who underwent complete resection at three Japanese institutions. The prevalence, metastatic patterns, and prognostic impact of VPI were systematically evaluated, with particular focus on histological growth patterns. Results: VPI was identified in 370 patients (15%). Notably, VPI-positive tumors demonstrated a doubled incidence of lymph node metastasis (31% vs. 15%, p < 0.001) and a distinct metastatic profile characterized by preferential hilar spread (#12, 16.9%) and an increased risk of skip N2 metastasis (4.0% vs. 2.0%). Five-year recurrence-free survival was significantly reduced in the VPI group (33.7% vs. 50.6%, respectively). Conversely, adenocarcinomas with lepidic characteristics demonstrated a minimal risk of VPI or nodal metastasis, with incidences of 2% and 1%, respectively. This finding highlights the heterogeneity in the biological aggressiveness of small-sized NSCLC. Conclusions: Our findings suggest that VPI is not merely a histopathological descriptor but also acts as a clinically significant indicator of aggressive metastatic behavior, potentially enhancing surgical and staging approaches beyond just considering tumor size. With the increasing adoption of sublobar resection for small-sized NSCLC, recognizing that VPI appears to be associated with predominant hilar involvement and an elevated risk of skip N2 metastasis may help refine decisions on the extent of lung and lymph node resection.

OBJECTIVES:The advantages of preoperative three-dimensional (3D) image simulations, which require enhanced computed tomography (ECT), for anatomical lung resection are well documented. However, the necessity for contrast agent presents a significant barrier for some patients. This study thus aims to evaluate the accuracy of an artificial intelligence-based 3D simulation using unenhanced computed tomography (UECT) data in comparison to ECT data. METHODS:The study enrolled 18 lung cancer patients who underwent anatomical lung resections. Utilizing the artificial intelligence software Version6.7 within the Synapse Vincent system (Fujifilm Corporation, Tokyo, Japan), automatic construction of 3D images of the bronchovascular trees was achieved using both ECT and UECT. We further assessed the accuracy of pulmonary vessel identification on UECT, and compared the calculated lung segment volumes obtained from UECT with those obtained from ECT. RESULTS:The comparison of accuracy to operative findings showed that ECT identified 98.9% of artery branches (PAs) and 85.7% of vein branches (PVs), while UECT identified 96.6% of PAs and 82.1% of PVs. Out of 371 PAs and 319 PVs identified on ECT, UECT failed to detect 16 PAs (4.4%) and 32 PVs (10.1%), yielding a correlation coefficient for branch detection of 0.9783 (P < 0.001). There was a significant correlation between ECT and UECT in measuring artery-oriented volumes on both the right-side segments (R = 0.8330) and the left-side segments (R = 0.8082). CONCLUSIONS:This 3D image technique using UECT data may be comparable to that obtained with ECT data in terms of achieving lobar and partial segmental branch levels.

OBJECTIVE:Renal dysfunction, including acute kidney injury (AKI) and chronic kidney disease (CKD), is a major complication following lung transplantation (LT) and is associated with increased morbidity and mortality. This study aims to evaluate the clinical significance of AKI in relation to the development of post-LT CKD and poor prognosis. METHODS:Among 133 patients who underwent LT, 116 were included in the analysis. AKI was defined according to the Kidney Disease Improving Global Outcomes criteria. AKI was classified into early AKI (E-AKI), occurring within a few hours to one week postoperatively, and late AKI (L-AKI), occurring between one week and one month after LT. The Major Adverse Kidney Event within 30 days following LT (MAKE30)-a composite outcome that includes all-cause mortality, new renal replacement therapy, or persistent renal dysfunction-was also used in this study. Univariate and multivariate analyses were conducted to identify factors associated with the development of CKD. Overall survival (OS) was analyzed using the Kaplan-Meier method. RESULTS:The proportions of patients who developed E-AKI, L-AKI, MAKE30, and CKD were 73%, 31%, 15%, and 46%, respectively. Multivariate analysis identified older age and the occurrence of MAKE30 as independent predictors of post-LT CKD. Notably, all recipients aged 50 years or older who experienced either L-AKI or MAKE30 subsequently developed CKD. In addition, the incidence of MAKE30 was marginally correlated with reduced OS. CONCLUSION:The occurrence of L-AKI and MAKE30 following LT is associated with the development of CKD and MAKE30 also has a negative impact on OS.

Oligometastatic non-small cell lung cancer (omNSCLC) is increasingly recognized as a clinically actionable subset, characterized by a limited number of metastatic lesions and the potential to benefit from combined systemic and local treatments. Advances in systemic therapy, particularly immune checkpoint inhibitors (ICI) and molecular targeted agents, have led to prolonged disease control in selected patients. Prospective clinical trials have shown that incorporating local therapy into systemic treatment can improve progression-free and overall survival outcomes in carefully selected patients with metastatic disease. Radiotherapy has increasingly become the preferred modality for local consolidation, especially when surgical options are limited or impractical. Key factors influencing treatment selection include biomarker status, the number and distribution of metastases, and the response to the initial systemic therapy. The optimal timing and modality of local interventions remain under investigation. This review examines the evolving treatment strategies for omNSCLC, primarily from the perspective of systemic therapies. By contextualizing local treatment modalities within the framework of immunotherapy and targeted therapy, we reinterpret current evidence to clarify when and how local therapy contributes to long-term disease control.

Small extracellular vesicles (sEVs) mediate cell-to-cell communication by carrying RNAs and proteins. Ubiquitin-like 3 (UBL3) functions as a posttranslational modification factor, regulating protein sorting to sEVs. Programmed cell death ligand 1 (PD-L1) binds to programmed cell death 1 (PD-1) on immune cells, suppressing their function. Although immune checkpoint inhibitors, anti-PD-L1 and anti-PD-1 antibodies, have improved cancer treatment, efficacy remains limited ( 25