INTRODUCTION: Antibiotics and proton pump inhibitors (PPIs) have been associated with the reduced efficacy of immune checkpoint inhibitor (ICI) in patients with advanced non-small cell lung cancer (NSCLC). This study assessed the clinical impact of these medications in the neoadjuvant setting. PATIENTS AND METHODS: This multicenter retrospective study was conducted in 29 Japanese institutions. Between March 2023 and July 2024, 131 patients with resectable clinical stage II-III NSCLC who received neoadjuvant chemoimmunotherapy with nivolumab were enrolled. In total, 113 patients who underwent definitive surgery were included in the surgical outcome analysis. We investigated the association between the use of antibiotics and PPIs within 30 days before treatment initiation and clinicopathological factors, including the pathological complete response (pCR) and major pathological response (MPR). RESULTS: Among 113 patients, 5 (4.4%) had received antibiotics and 23 (20.4%) PPIs. Antibiotic and PPI use showed no significant differences in any clinicopathological factors. Antibiotic and PPI use was not significantly associated with the objective response rate (ORR), pCR, or MPR; antibiotic (use/non-use): 80.0%/70.4% (p = 1.000), 40.0%/35.8% (p = 1.000), 60.0%/59.6% (p = 1.000) and PPI (use/non-use): 78.3%/68.9% (p = 0.532), 43.5%/33.3% (p = 0.507), 60.9%/58.9% (p = 1.000). CONCLUSION: Prior use of antibiotics and PPIs was not significantly associated with radiological or pathological response of neoadjuvant ICI in patients with resectable NSCLC. Further studies with larger sample size and longer survival follow-up are needed.

BACKGROUND: With the widespread adoption of immune checkpoint inhibitors (ICIs) for advanced non-small cell lung cancer (NSCLC), local recurrence after immunotherapy has become increasingly frequent. However, limited evidence is available regarding salvage surgery after ICI therapy. METHODS: A multi-institutional retrospective study (CReGYT-05 Immune Checkpoint Inhibitor-Salvage Study) was conducted across 14 centers in Japan, evaluating patients who underwent salvage surgery after ICI therapy between 2016 and 2023. Salvage surgery was classified as conversion surgery (downstaging from initially unresectable to resectable disease) or true salvage surgery (surgery for local recurrence or residual disease). The primary endpoints included perioperative outcomes, overall survival (OS), and recurrence-free survival (RFS). RESULTS: The study analyzed 32 patients. Radiologic response to ICI therapy showed complete response in 4 patients (12.5 %), partial response in 23 patients (71.9 %), and stable disease in 5 patients (15.6 %). Salvage procedures comprised true salvage surgery (n = 17, 53.1 %) and conversion surgery (n = 15, 46.9 %). Lobectomy was performed for 84.4 % of the patients. Perioperative complications occurred in eight (25.0 %) of the patients, with no perioperative mortality. Pathologic complete response was achieved for six (18.8 %) patients. The 3- and 5-year OS rates from the initial diagnosis were 86.9 % and 77.2 %, respectively. Conversion surgery demonstrated superior 3-year RFS compared with true salvage surgery (92.8 % vs 36.3 %; p = 0.010). Univariable analysis identified salvage type as a significant factor for RFS. CONCLUSIONS: Salvage surgery after ICI therapy can be safely performed and is associated with encouraging survival outcomes for carefully selected patients, particularly those undergoing conversion surgery.

Background: Recent trials, including JCOG0802/WJOG4607L and CALGB140503, have confirmed the oncological adequacy of segmentectomy for early-stage non-small-cell lung cancer (NSCLC). This shift emphasizes the preservation of pulmonary function and minimal invasiveness. Robot-assisted thoracic surgery (RATS) offers enhanced anatomical precision and potentially improves segmentectomy outcomes. Methods: We reviewed the current evidence comparing sublobar resection and lobectomy for early-stage NSCLC, focusing on RATS segmentectomy. Clinical trials, perioperative and long-term outcomes, technical innovations, and patient selection criteria were analyzed. Comparative data among RATS, video-assisted thoracoscopic surgery (VATS), and open approaches were synthesized, including the emerging roles of AI and 3D imaging. Results: Segmentectomy yields survival outcomes equivalent or superior to lobectomy for stage IA peripheral NSCLC ≤2 cm, with better pulmonary function despite higher locoregional recurrence. RATS enhances visualization, dexterity, and ergonomics, thereby enabling precise dissection and lymph node assessment. Compared to VATS and open surgery, RATS shows lower conversion rates, reduced pain, and comparable oncological control. Innovations, such as indocyanine green imaging, 3D modeling, and AI-guided navigation, support margin accuracy and personalized care. Conclusions: Segmentectomy has redefined the surgical standards for early-stage NSCLC. RATS maximizes the minimally invasive benefits by combining oncological safety and functional preservation. Its technical precision facilitates complex resections and integration with digital planning tools to advance personalized thoracic surgery. RATS represents the next evolution of minimally invasive thoracic surgery, redefining the balance between oncological safety and functional preservation in early-stage NSCLC.

Abstract While pathological stage I (pStage I) non-small cell lung cancer (NSCLC) has a good prognosis, some patients experience disease recurrence. Identification of prognostic markers for pStage I NSCLC may facilitate personalized perioperative treatment by expanding the candidates for adjuvant treatment. NSCLC patients with ground-glass opacity have excellent survival outcomes. Therefore, in this study, we explored prognostic biomarkers in pure solid non-squamous NSCLC. We focused on non-squamous NSCLC because the gene expression status is distinct from that of squamous cell carcinomas. RNA sequencing was performed on frozen tumor specimens from 33 non-squamous NSCLC patients with disease recurrence (recurrence group) and 33 counterparts (control group) extracted from patients without disease recurrence using propensity score matching (Cohort 1). The candidate genes were further refined using an independent real-world Cohort 2a (N = 125) and validated in The Cancer Genome Atlas cohort. Through the analysis of Cohort 1 and Cohort 2a, we found that low expression of six genes (BMP6, KCNK3, NFASC, OLFM1, PEG3, and TNXB) was associated with disease recurrence. The prognostic impact of the six genes was confirmed using The Cancer Genome Atlas lung adenocarcinoma database. Multivariable proportional hazard analysis using the Cohort 2a dataset revealed that the combination of BMP6 and OLFM1 status predicted recurrence-free survival. In conclusion, we found that low BMP6/OLFM1 gene status is a potential biomarker to identify high-risk pStage I pure solid non-squamous NSCLC patients after pulmonary resection.

BACKGROUND: This real-world study investigated the feasibility and profile of adverse events (AEs) associated with neoadjuvant chemoimmunotherapy in patients with resectable non-small cell lung cancer (NSCLC) in the real world. METHODS: We conducted a multicenter retrospective study using real-world data of patients with resectable stage II or III NSCLC treated with neoadjuvant chemoimmunotherapy with nivolumab between March 2023 and July 2024 at 29 Japanese institutions. The safety, AE profiles, and risk factors for grade ≥3 AEs were evaluated. RESULTS: A total of 126 patients were analyzed. In the neoadjuvant phase, grade ≥3 treatment-related AEs and immune-related AEs (irAEs) occurred in 36 (28.6%) and 12 (9.5%) patients, respectively. One patient (0.8%) died of a neoadjuvant treatment-related cytokine storm AE and subsequent multiorgan failure. Definitive surgery after neoadjuvant treatment was performed in 114 patients (90.5%), with only 1 death within 90 days of surgery. Half of endocrine-related irAEs occurred in the postoperative phase. Among the demographic characteristics, a history of coronary artery disease was a significant risk factor for grade ≥3 treatment-related AEs (odds ratio, 16.556; 95% CI, 1.698-161.479; P = .016) and irAEs (odds ratio, 10.196; 95% CI, 1.193-87.166;, P = .034). CONCLUSIONS: Real-world data from the era of neoadjuvant chemoimmunotherapy showed feasibility consistent with the results of randomized controlled trials. The incidence of grade ≥3 AEs was not particularly high but was clinically significant, and a history of coronary artery disease may be a predictor.

Afatinib and osimertinib are current treatment options for non-small cell lung cancer (NSCLC) patients with uncommon epidermal growth factor receptor (EGFR) mutations, although their efficacy is limited. To explore potentially effective drugs for these patients, we evaluated the efficacy of conventional EGFR tyrosine kinase inhibitors (TKIs) and novel third-generation (3G) TKIs using in vitro models. Ba/F3 cells transformed with each of the five most frequent uncommon EGFR mutations, Del18 (delE709_T710insD), E709K, G719A, S768I, and L861Q, were used. The growth inhibitory effects of five novel 3G-TKIs, almonertinib, lazertinib, furmonertinib, rezivertinib, and befotertinib, in addition to currently available TKIs, were evaluated. We also explored for secondary resistant mutations to afatinib or osimertinib and TKIs that can overcome these resistances. Afatinib was active against all uncommon EGFR mutations tested. The 3G-TKIs were all active against the L861Q mutation and were inactive against the S768I mutation. Furmonertinib and befotertinib showed efficacy against exon 18 mutations (Del18, E709K, and G719A). In the acquired resistance models to afatinib or osimertinib, we found T790M or a novel T725M secondary mutation, respectively, both of which could be overcome by lazertinib. However, some afatinib-resistant cells acquired V769L/M secondary mutations that were refractory to all EGFR-TKIs tested. In conclusion, afatinib exhibited broad activity and some 3G-TKIs showed promising efficacy in the front-line setting. Lazertinib is a potential second-line option after acquisition of resistance to afatinib or osimertinib.

This study aimed to clarify the risk factors for recurrence in epidermal growth factor receptor (EGFR) mutated and wild-type lung adenocarcinomas, with a focus on the newly proposed International Association for the Study of Lung Cancer (IASLC) grading system. We enrolled 2106 patients who underwent complete anatomical radical resection and had a known EGFR mutational status and IASLC grade. Patient characteristics and pathological features were analyzed to assess the cumulative incidence of recurrence (CIR). No significant differences were found in the CIR between the EGFR mutated (EGFRm) and wild-type groups. In the EGFRm group, multivariate analysis identified IASLC grade 2, grade 3 (reference: grade 1), pathological stage II/III, lymphatic invasion (ly), vessel invasion (v), and plural invasion as independent risk factors for recurrence. In the wild-type group, IASLC grades 2 and 3, pathological stage II/III, ly, and v were identified as independent risk factors for recurrence. Patients with any independent risk factor had a significantly poorer overall survival and a higher CIR compared with those without a risk factor in both the EGFRm and wild-type groups. The IASLC grading system is a valuable prognostic factor for recurrence in patients with lung adenocarcinoma harboring EGFRm.

INTRODUCTION: Neoadjuvant chemo-immunotherapy is one of the standard treatment options for resectable stage II to III NSCLC. Nevertheless, this treatment yielded insufficient local control in the CheckMate 816 trial. We hypothesized that adding radiotherapy could improve local control, thereby improving survival outcomes. METHODS: Eligible patients had clinical T1 to T3 or T4 (tumor size) N2 stage IIIA to B NSCLC (American Joint Committee on Cancer version 8), pathologically confirmed as N2 without extranodal invasion. Patients received concurrent chemoradiotherapy (carboplatin [area under the curve = 2] and paclitaxel [40 mg/m2] on days 1, 8, 15, 22, and 29, with 50 Gy radiation over 25 d) and durvalumab (1500 mg) on days 1 and 29, followed by surgical resection within two to six weeks. After surgery, durvalumab adjuvant therapy was administered for up to one year. The primary endpoint was major pathologic response (MPR: ≤10% viable tumor), with secondary endpoints being pathologic complete response, progression-free survival (PFS), overall survival (OS), and safety. RESULTS: From January 2020 through February 2022, 31 patients were enrolled from 10 Japanese institutions. The MPR rate was 63% (90% confidence interval: 47%-78%), which met the primary endpoint, and the pathologic complete response rate was 23%. At a median follow-up of 28 months, the two-year PFS and OS rates were 43% and 76%, respectively. Grade 3 or 4 adverse events occurred in 48% of cases, including one treatment-related death. CONCLUSIONS: Compared with recently published results of peri-operative chemo-immunotherapy trials, this treatment regimen had a higher MPR rate. Nevertheless, this benefit did not necessarily translate into improved PFS or OS.

BACKGROUND: The standard treatment for unresectable non-small cell lung cancer (NSCLC) is anti-PD-L1 therapy combined with chemoradiotherapy (anti-PD-L1-CRT). Although some patients achieve complete cancer eradication and cure, more than half of patients retain persistent cancer cells. Our research aimed to unravel the nuanced mechanisms involved in both immune attack and evasion induced by anti-PD-L1-CRT with single cell spatial transcriptome. METHODS: Xenium is a cutting-edge single-cell spatial analysis tool that enables pathology-based and single-cell analyses while preserving spatial information. In our study, we used Xenium to identify the tumour microenvironment (TME), immune dynamics, and residual cancer cells at the single-cell level following treatment with anti-PD-L1-CRT. RESULTS: Posttreatment alterations included a significant increase in CXCL9+ cells and CXCL13 + T cells, particularly around tumour cells. Additionally, we discovered that CXCL13 + T cells directly impact cancer cells in the posttreatment environment. Moreover, we identified clusters of immune-cold cancer cells posttreatment, revealing their activation of DNA repair pathways and high proliferative capacity. The novel spatial analysis tool Xenium enabled identification of the immune environment at the single-cell level following treatment with anti-PD-L1-CRT, elucidating its characteristics. CONCLUSIONS: These findings suggest potential advancements in developing new treatments to improve posttreatment immune responses and address resistance challenges.

OBJECTIVES: Reliable prognostic tools are essential for improving the management of stage I non-small cell lung cancer. Whereas fluorodeoxyglucose positron emission tomography has proven valuable, metrics such as maximum standardized uptake value are limited by interinstitutional variability. This study evaluates the Deauville score for its clinical utility in predicting pathological invasiveness and survival outcomes. METHODS: Data were retrospectively collected from 495 patients with stage I non-small cell lung cancer who underwent pulmonary resection across 4 institutions in Japan. Tumors were classified by a visual 5-point scale Deauville scores into groups: 1 and 2, 3, and 4 and 5. Associations between these scores, pathological invasiveness (defined as lymphatic invasion, vascular invasion, pleural invasion, and/or nodal involvement), and survival outcomes were analyzed. RESULTS: High Deauville scores (4 and 5) were significantly associated with pure solid tumors (85%; P < .0001) and pathological invasiveness (66%; P < .0001). Multivariable analysis showed the Deauville score to be an independent predictor of invasiveness (odds ratio, 10.145; P < .0001 for scores 4 and 5 vs 1 and 2). Survival analyses revealed poorer outcomes for patients with scores of 4 and 5, with a 5-year recurrence-free survival of approximately 60% (P < .0001). Even in part-solid tumors, scores of 4 and 5 were linked to significantly worse recurrence-free survival compared with scores of 1 and 2 or 3 (P < .0001). CONCLUSIONS: The Deauville score provides a straightforward and consistent method to predict pathological invasiveness and survival in stage I non-small cell lung cancer. Its reliability and reproducibility across institutions highlight its potential as a valuable tool for both clinical practice and large-scale research.

OBJECTIVES: Adjuvant osimertinib is currently the standard of care after pulmonary resection in patients with non-small cell lung cancer (NSCLC) harbouring an activating epidermal growth factor receptor (EGFR) mutation. Several guidelines recommended up to 4 cycles of adjuvant platinum-doublet before adjuvant osimertinib treatment. However, whether adjuvant platinum-doublet prolongs the overall survival (OS) of patients with EGFR-mutated NSCLC as it did in the unselected LACE meta-analysis cohort is unclear. METHODS: A multicentre retrospective observational study was conducted at 21 centres in Japan, enrolling 4181 patients with lung adenocarcinoma who received pulmonary resection between 2015 through 2018. In this study, we compared the efficacy of adjuvant platinum-doublet between EGFR mutated and EGFR wild-type cohort focusing on 706 patients with pathological stage II-III disease. Propensity score matching (1:1 ratio, caliper = 0.2) was used to balance patient characteristics (age, sex, smoking, preoperative performance status, pathological stage, and EGFR status) between patients who received adjuvant treatment and those who did not. RESULTS: Among the 706 patients, 391 (55%) received adjuvant platinum-doublet. After 1:1 propensity score matching, patient characteristics were well balanced in the 2 groups (201 patients each). In subgroup analysis of overall and recurrence-free survival, the hazard ratios of adjuvant treatment were similar in the EGFR-mutated and EGFR wild-type groups (eg, OS, 0.56 [95% CI, 0.29-1.10] and 0.52 [95% CI, 0.33-0.82] in EGFR-mutated and EGFR wild-type subgroup, respectively). CONCLUSIONS: Adjuvant platinum-doublet chemotherapy showed similar trends of benefit in the EGFR-mutated and EGFR wild-type subgroups.

INTRODUCTION: Molecular residual disease detected by circulating tumor DNA (ctDNA) has been reported to be predictive of patients' outcomes in various types of cancers after curative intent treatment. Nevertheless, additional detailed information regarding the association of longitudinal ctDNA detection with long-term follow-up in lung cancer is needed. Here, we report on a cohort of patients with NSCLC who underwent definitive surgery and ctDNA analysis in the pre-operative, adjuvant, and surveillance settings. METHOD: Plasma samples were collected from 46 patients with clinical stage II-III NSCLC before surgery (n = 46), after surgery (n = 45), and every six months until two years thereafter (n = 78). A clinically validated, personalized, tumor-informed 16-plex polymerase chain reaction-next-generation sequencing assay was used for the detection and quantification of ctDNA in retrospectively analyzed plasma samples. RESULTS: Circulating tumor DNA was detected in the first postoperative (within 51 days after surgery) plasma samples in 13% (6/45) of patients (landmark analysis). All of them had disease recurrence within a median of 9.1 months. These patients had shorter recurrence-free and overall survivals than those without detectable ctDNA at a landmark time point (p < 0.01) and in multivariate analyses (p < 0.03). Longitudinally (considering all postoperative follow-up time points), ctDNA was detected in 13 patients, all of whom experienced disease recurrence (positive predictive value = 100%). Three patients who had central nervous system-only metastases did not have detectable ctDNA. CONCLUSIONS: The presence of ctDNA post-surgery or during surveillance identifies patients with NSCLC at high risk of recurrence. Serial testing is important to detect disease recurrence earlier (lead-time: 3.2 months).

BACKGROUND: While Epidermal growth factor receptor (EGFR) mutation-positive lung adenocarcinoma (LUAD) has favorable outcomes with targeted therapy, early-stage prognosis remains influenced by pathological factors and central nervous system (CNS) recurrence. The study aimed to clarify prognostic factors in pathological stage (pStage) I EGFR mutation-positive LUAD. METHODS: Between 2015 and 2018, 2,191 pStage I LUAD cases with known EGFR status (excluding EGFR testing after recurrence) who received anatomical resection were included from multiple institutions in Japan. Univariate and multivariate analyses of disease-free survival (DFS) and overall survival (OS) were performed. RESULTS: 1,073 (49.0%) cases harbored EGFR mutations, including 419 (19.1%) with 19del and 529 (24.1%) with L858R. In cases with major EGFR mutation (n = 948), multivariate analysis showed that the absence of noninvasive area (NIA) (hazard ratio [HR]: 1.778, 95% confidence interval [CI]: 1.174-2.692, P = .0065), pStage (IA2 vs. IA1, HR: 2.079, 95% CI: 1.129-3.827, P = .0345; IA3 vs. IA1, HR: 4.009, 95% CI: 2.088-7.696, P = .0001; IB vs. IA1, HR: 5.280, 95% CI: 2.871-9.709, P < .0001), and presence of lymphatic invasion (HR: 1.855, 95% CI: 1.103-3.119, P = .0197) were independent predictors of shorter DFS, and only advanced pStage was an independent predictor of CNS recurrence (relative risk for pStage IA3 or more: 9.729, P < .0001). CONCLUSION: In EGFR mutation-positive pStage I LUAD, those without NIA, with higher pStage and lymphatic invasion were independent predictive factors for DFS, and pStage ≥ IA3 was an independent predictor of CNS recurrence.

The expression of programmed cell death-ligand 1 (PD-L1) and mutation in epidermal growth factor receptor (EGFR) are biomarkers used for perioperative treatment of lung adenocarcinoma. However, the clinical significance of PD-L1 expression in surgically resected EGFR-mutant lung adenocarcinoma remains unclear. We conducted a real-world database of patients with surgically resected lung adenocarcinoma from 2015 to 2018 was constructed across 21 centers in Japan. The association among PD-L1 expression, EGFR mutations, and prognosis was evaluated. Among 847 patients, PD-L1 expression was negative (tumor proportion score [TPS] < 1%) in 429 (51%), weakly positive (TPS = 1%-49%) in 275 (32%), and strongly positive (TPS ≥50%) in 143 (17%) patients. EGFR mutations were detected in 331 (39%) patients. PD-L1 expression was associated with poor recurrence-free survival (RFS) (p < .001) in both EGFR-mutant and wild-type patients. However, in EGFR-mutant patients, PD-L1 expression was not associated with overall survival (OS) (p = .506). Multivariable analysis confirmed an association between PD-L1 expression and RFS but not OS. Furthermore, in EGFR-mutant patients treated with EGFR-tyrosine kinase inhibitor (EGFR-TKI) treatment post-relapse, PD-L1 expression was not associated with overall response rate (p = .714), disease control rate (p = .554), or progression-free survival (p = .660). In conclusion, PD-L1 expression predicted poor RFS-independent EGFR status but did not show any association with OS in EGFR-mutant patients. The efficacy of post-relapse EGFR-TKI treatment was independent of PD-L1 expression. The significance of PD-L1 expression in perioperative EGFR-TKI therapy should be evaluated.

BACKGROUND: Superior outcomes have been obtained for neoadjuvant treatment with immune checkpoint inhibitors (ICI) plus chemotherapy over neoadjuvant chemotherapy alone, especially in patients with high programmed cell death ligand 1 (PD-L1) expression. However, it is not always possible to obtain sufficient tumor specimens for biomarker testing before surgery. In this study, we explored clinical factors that can predict high PD-L1 expression. METHODS: We retrospectively enrolled 340 lung cancer patients who received pulmonary resection between 2014 and 2023 and who had PD-L1 expression data. Chi-squared tests and logistic regression analyses were used to identify clinical factors associated with high PD-L1 status. RESULTS: Univariable and multivariable analyses revealed that smoking, high maximum standardized uptake value (SUVmax) of 18F-fluorodeoxyglucose positron emission computed tomography (18F-FDG PET/CT), and high plasma fibrinogen are independent predictors of high PD-L1 expression. A predictive score for high PD-L1 expression (ranging from 0 to 3) was developed based on these parameters. Notably, only 5% of patients with a score of 0 exhibited high PD-L1 expression, whereas this proportion increased to 53% for patients with a score of 3. CONCLUSION: These results showed that plasma fibrinogen, smoking history, and SUVmax are predictors of high PD-L1 expression, providing a basis for identifying patients expected to benefit from neoadjuvant ICI treatment.

The emergence of acquired resistance to EGFR-tyrosine kinase inhibitors (TKIs) is almost inevitable even after a remarkable clinical response. Secondary mutations such as T790M and C797S are responsible for the resistance to 1st/2nd-generation (1/2G) TKIs and 3G TKIs, respectively. To overcome both the T790M and C797S mutations, novel 4G EGFR-TKIs are now under early clinical development. In this study, we evaluated the efficacy of a 4G EGFR-TKI in the treatment of lung cancer with EGFR mutation as well as explored resistance mechanisms to a 4G TKI. First, we compared the efficacies of seven TKIs including a 4G TKI, BI4020, against Ba/F3 cell models that simulate resistant tumors after front-line osimertinib treatment failure because of a secondary mutation. We also established acquired resistant cells to BI4020 by chronic drug exposure. Ba/F3 cells with an osimertinib-resistant secondary mutation were refractory to all 3G TKIs tested (alflutinib, lazertinib, rezivertinib, almonertinib, and befotertinib). BI4020 inhibited the growth of C797S-positive cells; however, it was not effective against L718Q-positive cells. Erlotinib was active against all Ba/F3 cells tested. In the analysis of resistance mechanisms of BI4020-resistant (BIR) cells, none harbored secondary EGFR mutations. HCC827BIR cells had MET gene amplification and were sensitive to a combination of capmatinib (MET-TKI) and BI4020. HCC4006BIR and H1975BIR cells exhibited epithelial-to-mesenchymal transition. This study suggests that erlotinib may be more suitable than 4G TKIs to overcome secondary mutations after front-line osimertinib. We found that off-target mechanisms that cause resistance to earlier-generation TKIs will also cause resistance to 4G TKIs.

OBJECTIVES: To clarify the impact of central nervous system (CNS) metastasis on performance status (PS) at relapse, on subsequent treatment(s), and on survival of patients with lung adenocarcinoma harboring common epidermal growth factor receptor (EGFR) mutation. METHODS: We conducted the multicenter real-world database study for patients with radical resections for lung adenocarcinomas between 2015 and 2018 at 21 centers in Japan. EGFR mutational status was examined at each center. RESULTS: Of 4181 patients enrolled, 1431 underwent complete anatomical resection for lung adenocarcinoma harboring common EGFR mutations. Three-hundred-and-twenty patients experienced disease relapse, and 78 (24%) had CNS metastasis. CNS metastasis was significantly more frequent in patients with conventional adjuvant chemotherapy than those without (30% vs. 20%, P = 0.036). Adjuvant chemotherapy did not significantly improve relapse-free survival at any pathological stage (adjusted hazard ratio for stage IA2-3, IB, and II-III was 1.363, 1.287, and 1.004, respectively). CNS metastasis did not affect PS at relapse. Subsequent treatment, mainly consisting of EGFR-tyrosine kinase inhibitors (TKIs), could be equally given in patients with or without CNS metastasis (96% vs. 94%). Overall survival after relapse was equivalent between patients with and without CNS metastasis. CONCLUSION: The efficacy of conventional adjuvant chemotherapy may be limited in patients with lung adenocarcinoma harboring EGFR mutations. CNS metastasis is likely to be found in practice before deterioration in PS, and may have little negative impact on compliance with subsequent EGFR-TKIs and survival after relapse. In this era of adjuvant TKI therapy, further prospective observational studies are desirable to elucidate the optimal management of CNS metastasis.

INTRODUCTION: Although the standard treatment for patients with resectable early-stage non-small-cell lung cancer (NSCLC) is pulmonary lobectomy, recent clinical trials have demonstrated the efficacy of anatomical segmentectomy for small-sized early-stage NSCLC measuring ≤2 cm. Segmentectomy is gaining attention as an alternative procedure to lobectomy for early-stage NSCLC. PATIENTS AND METHODS: In January 2024, we have initiated a randomized phase III trial in Japan to confirm the noninferiority of anatomical segmentectomy to lobectomy in patients with peripheral clinical stage IA3 pure-solid NSCLC (tumor measuring >2 cm and ≤3 cm; consolidation-to-tumor ratio = 1.0). We plan to enroll 520 patients from 61 institutions over a period of 5 years. The primary endpoint is overall survival, and the secondary endpoints include relapse-free survival, postoperative respiratory function, proportion of patients with respiratory failure and cerebrovascular disease, cumulative incidence of death from other diseases, cumulative incidence of local recurrence, proportion of patients who undergo segmentectomy, number of resected segments, operative time, blood loss, and adverse events. This trial has been registered in the UMIN Clinical Trials Registry under the code UMIN000052064. CONCLUSIONS: This trial will help establish a novel treatment strategy for patients with peripheral clinical stage IA3 pure-solid NSCLC.

Several clinical trials have been revolutionizing the perioperative treatment of early-stage non-small cell lung cancer (NSCLC). Many of these clinical trials involve cancer immunotherapies with antibody drugs that block the inhibitory immune checkpoints programmed death 1 (PD-1) and its ligand PD-L1. While these new treatments are expected to improve the treatment outcome of NSCLC patients after pulmonary resection, several major clinical questions remain, including the appropriate timing of immunotherapy (neoadjuvant, adjuvant, or both) and the identification of patients who should be treated with neoadjuvant and/or adjuvant immunotherapies, because some early-stage NSCLC patients are cured by surgical resection alone. In addition, immunotherapy may induce immune-related adverse events that will require permanent treatment in some patients. Based on this fact as well, it is desirable to select appropriate patients for neoadjuvant/adjuvant immunotherapies. So far, data from several important trials have been published, with findings demonstrating the efficacy of adjuvant atezolizumab (IMpower010 trial), neoadjuvant nivolumab plus platinum-doublet chemotherapy (CheckMate816 trial), and several perioperative (neoadjuvant plus adjuvant) immunotherapies (AEGEAN, KEYNOTE-671, NADIM II, and Neotorch trials). In addition to these key trials, numerous clinical trials have reported a wealth of data, although most of the above clinical questions have not been completely answered yet. Because there are so many ongoing clinical trials in this field, a comprehensive understanding of the results and/or contents of these trials is necessary to explore answers to the clinical questions above as well as to plan a new clinical trial. In this review, we comprehensively summarize the recent data obtained from clinical trials addressing such questions.

INTRODUCTION: Approximately 10% of mutations in the epidermal growth factor receptor (EGFR) gene in non-small cell lung cancer (NSCLC) are in-frame insertions in exon 20 (X20ins). These tumors usually do not respond to conventional EGFR-tyrosine kinase inhibitors (TKIs). Several novel EGFR-TKIs active for X20ins are in clinical development, including mobocertinib, which was recently approved by the US FDA. However, acquired resistance during treatment with these TKIs still occurs as in the case of EGFR-TKIs of earlier generations. METHODS: We chronically exposed Ba/F3 cells transduced with five most common X20ins (A763_Y764insFQEA, V769_D770insASV, D770_N771insSVD, H773_V774insNPH and H773_V774insH) to mobocertinib in the presence of N-ethyl-N-nitrosourea and searched for secondary EGFR mutations. We evaluated the efficacies of several EGFR X20ins inhibitors, including zipalertinib and sunvozertinib, against cells with acquired resistant mutations. RESULTS: All secondary mutations resulting in acquired resistance to mobocertinib were exclusively C797S in insFQEA and insSVD. However, in the case of other X20ins (insASV, insNPH and insH), T790M or C797S secondary mutations contributed to acquired resistance to mobocertinib. The emergence of T790M was more frequent in cells treated with lower drug concentrations. Sunvozertinib showed good activity against resistant cells with T790M. Cells with C797S were refractory to all EGFR-TKIs, except for erlotinib, which was active for insFQEA with C797S. CONCLUSIONS: T790M or C797S, depending on the original X20ins mutations, conferred acquired resistance to mobocertinib. Sunvozertinib may be the treatment of choice for patients with tumors resistant to mobocertinib because of T790M.

INTRODUCTION: Lung tumor organoids (LTOs) have attracted attention as in vitro preclinical models; however, their clinical and experimental applications have not been fully established. METHODS: We attempted to establish LTOs from resected specimens of patients with lung cancer who underwent lung resection. Clinicopathologic characteristics related to the establishment of LTOs were evaluated. Histologic assessment and genetic analysis were conducted for both LTOs and their parental tumors. Organoid-derived xenografts were generated in immunocompetent mice. Drug sensitivity was assessed using cell proliferation assays. RESULTS: We established 53 LTOs from 79 lung cancer samples, including 10 long-term culture models. The establishment rate was significantly lower in squamous cell carcinomas than in other histologic types (48% versus 75%, p = 0.034). Histologic similarities were confirmed among LTOs, the parental tumors, and organoid-derived xenografts. Seven mutations, including two EGFR L858R and one EGFR exon 20 H773delinsYNPY mutations, were detected in both LTO and parental tumors; the other four mutations were detected in either LTO or parental tumors. The extensive culture ability of LTO (passaged >10 times) correlated with poor patient prognosis. LTO9 cells harboring EGFR H773delinsYNPY were sensitive to osimertinib. The parental patient, who had new metastatic lesions, was treated with osimertinib and exhibited a remarkable response. CONCLUSIONS: The establishment and growth rates of LTOs were associated with the histologic subtype and tumor size. LTOs derived from resected specimens have become preclinical models that can be used to predict drug responses and accelerate the development of treatment strategies for patients with rare mutations.

OBJECTIVES: Despite the prognostic impacts of preoperative fluorine-18 fluorodeoxyglucose-positron emission tomography/computed tomography examination, fluorine-18 fluorodeoxyglucose-positron emission tomography/computed tomography-based prognosis prediction has not been used clinically because of the disparity in data between institutions. By applying an image-based harmonized approach, we evaluated the prognostic roles of fluorine-18 fluorodeoxyglucose-positron emission tomography/computed tomography parameters in clinical stage I non-small cell lung cancer. METHODS: We retrospectively examined 495 patients with clinical stage I non-small cell lung cancer who underwent fluorine-18 fluorodeoxyglucose-positron emission tomography/computed tomography examinations before pulmonary resection between 2013 and 2014 at 4 institutions. Three different harmonization techniques were applied, and an image-based harmonization, which showed the best-fit results, was used in the further analyses to evaluate the prognostic roles of fluorine-18 fluorodeoxyglucose-positron emission tomography/computed tomography parameters. RESULTS: Cutoff values of image-based harmonized fluorine-18 fluorodeoxyglucose-positron emission tomography/computed tomography parameters, maximum standardized uptake, metabolic tumor volume, and total lesion glycolysis were determined using receiver operating characteristic curves that distinguish pathologic high invasiveness of tumors. Among these parameters, only the maximum standardized uptake was an independent prognostic factor in recurrence-free and overall survivals in univariate and multivariate analyses. High image-based maximum standardized uptake value was associated with squamous histology or lung adenocarcinomas with higher pathologic grades. In subgroup analyses defined by ground-glass opacity status and histology or by clinical stages, the prognostic impact of image-based maximum standardized uptake value was always the highest compared with other fluorine-18 fluorodeoxyglucose-positron emission tomography/computed tomography parameters. CONCLUSIONS: The image-based fluorine-18 fluorodeoxyglucose-positron emission tomography/computed tomography harmonization was the best fit, and the image-based maximum standardized uptake was the most important prognostic marker in all patients and in subgroups defined by ground-glass opacity status and histology in surgically resected clinical stage I non-small cell lung cancers.

For decades, lobectomy has been the recommended surgical procedure for non-small cell lung cancer (NSCLC), including for small-sized lesions. However, two recent pivotal clinical trials conducted by the Japanese Clinical Oncology Group/West Japan Oncology Group (JCOG0802/WJOG4607L) and the Cancer and Leukemia Group B (CALGB140503), which compared the survival outcomes between lobectomy and sublobar resection (the JCOG0802/WJOG4607L included only segmentectomy, not wedge resection), demonstrated the efficacy of sublobar resection in patients with early-stage peripheral lung cancer measuring ≤ 2 cm. The JCOG0802/WJOG4607L demonstrated the superiority of segmentectomy over lobectomy with respect to overall survival, implying the survival benefit conferred by preservation of the lung parenchyma. Subsequently, the JCOG1211 also demonstrated the efficacy of segmentectomy, even for NSCLC, measuring up to 3 cm with the predominant ground-glass opacity phenotype. Segmentectomy has become the standard of care for early-stage NSCLC and its indications are expected to be further expanded to include solid lung cancers > 2 cm. However, local control is still a major concern for segmentectomy for higher-grade malignant tumors. Thus, the indications of segmentectomy, especially for patients with radiologically pure-solid NSCLC, remain controversial due to the aggressive nature of the malignancy. In this study, we reviewed previous studies and discussed the efficacy of segmentectomy for patients with such tumors.

BACKGROUND: Capmatinib and tepotinib are guideline-recommended front-line treatments for non-small-cell lung cancer (NSCLC) patients with MET exon 14 skipping mutations (METex14). However, the emergence of acquired resistance to capmatinib/tepotinib is almost inevitable partially due to D1228X or Y1230X secondary mutations of the MET. In this study, we explored agents that are active against both D1228X and Y1230X MET to propose an ideal sequential treatment after capmatinib/tepotinib treatment failure in NSCLC patients with METex14. METHODS: The inhibitory effects of 300 drugs, including 33 MET-TKIs, were screened in Ba/F3 cells carrying METex14 plus MET D1228A/Y secondary mutations. The screen revealed four-candidate type II MET-TKIs (altiratinib, CEP-40783, foretinib and sitravatinib). Therefore, we performed further growth inhibitory assays using these four MET-TKIs plus cabozantinib and merestinib in Ba/F3 cells carrying MET D1228A/E/G/H/N/V/Y or Y1230C/D/H/N/S secondary mutations. We also performed analyses using Hs746t cell models carrying METex14 (with mutant allele amplification) with/without D1228X or Y1230X in vitro and in vivo to confirm the findings. Furthermore, molecular dynamics (MD) simulations were carried out to examine differences in binding between type II MET-TKIs. RESULTS: All 6 type II MET-TKIs were active against Y1230X secondary mutations. However, among these 6 agents, only foretinib showed potent activity against D1228X secondary mutations of the MET in the Ba/F3 cell and Hs746t in vitro model and Hs746t in vivo model, and CEP-40783 and altiratinib demonstrated some activity. MD analysis suggested that the long tail of foretinib plays an important role in binding D1228X MET through interaction with a residue at the solvent front (G1163). Tertiary G1163X mutations, together with L1195F/I and F1200I/L, occurred as acquired resistance mechanisms to the second-line treatment foretinib in Ba/F3 cell models. CONCLUSIONS: The type II MET-TKI foretinib may be an appropriate second-line treatment for NSCLCs carrying METex14 after campatinib/tepotinib treatment failure by secondary mutations at residue D1228 or Y1230.

Introduction: Recent studies have suggested that including presence or absence of ground-glass opacity (GGO) may improve the tumor descriptor (T descriptor) classification in clinical stage I NSCLC. In this study, we analyzed prognostic implications of presence or absence of GGO, size of the solid component, and predominant histology to identify the true prognostic determinant for early-stage NSCLC. Methods: We retrospectively examined 384 patients with clinical stage I NSCLC (solid: 242, part solid: 142) who underwent complete resection between 2009 and 2013. Results: Survival curves of the whole cohort revealed good separation using the current TNM classification. Nevertheless, the part-solid group had a favorable prognosis irrespective of solid component size. Conversely, patients in the solid tumor group with tumors between 3 and 4 cm had a worse prognosis than patients whose tumors were less than or equal to 3 cm. Thus, we propose the following novel T descriptor classification: IA, part-solid tumors; IB, solid tumors less than or equal to 3 cm; and IC, solid tumors between 3 and 4 cm. This novel classification system stratified patient prognosis better than the current classification. On pathologic evaluation, the part-solid group always had better prognoses than the solid group in each subgroup divided by pathologic grade. Conclusions: These results suggest that presence of GGO is the true prognostic determinant of stage I NSCLC, irrespective of the size of the solid component. Our novel T descriptor classification system could more accurately predict prognoses of clinical stage I NSCLC cases.

BACKGROUND: The differential diagnosis of a solitary solid-type lung nodule is diverse. 18F-fluorodeoxyglucose positron emission tomography (PET) has a high sensitivity in the diagnosis of solid-type lung cancers; however, PET-negative, solid-type lung cancers are rarely observed. In this study, we analyzed the clinical/genetic features and prognosis of PET-negative, solid-type lung cancers. PATIENTS AND METHODS: Between January 2007 and February 2020, 709 patients with solid-type lung cancers (tumor size ≥2.0 cm) underwent pulmonary resection. Clinical, genetic, and prognostic features were evaluated in 27 patients (3.8%) with tumors showing negative PET results defined as SUVmax <2.0. RESULTS: All 27 patients had lung adenocarcinoma; 23 had invasive adenocarcinomas and 4 had invasive mucinous adenocarcinomas. The PET-negative group showed high frequencies of females and never-smokers. Recurrence-free survival was significantly better in the PET-negative group compared with PET-positive counterparts extracted using propensity score matching from patients who underwent pulmonary resection during the same period (P = .0052). Furthermore, 83% of PET-negative, solid-type invasive lung adenocarcinoma patients harbored EGFR mutation, which was significantly higher than that of PET-positive, solid-type invasive lung adenocarcinoma patients (38%, n = 225) who received EGFR mutation testing in our cohort (P < .0001). PET-negative, solid-type lung adenocarcinoma patients with EGFR mutations had significantly better recurrence-free survival compared with PET-positive, solid-type lung adenocarcinoma patients with EGFR mutations extracted using propensity score matching (P = .0030). CONCLUSION: PET-negative, solid-type lung cancers are characterized with a high incidence of EGFR mutation and a better prognosis compared with PET-positive, solid-type lung cancer.

OBJECTIVES: The LUX-Lung 8 randomized trial (LL8) demonstrated a prolonged progression-free survival (PFS) in patients with metastatic squamous cell carcinoma (SCC) of the lung after treatment with afatinib compared with erlotinib. A secondary analysis of the LL8 reported that the presence of rare HER2/HER4 mutations may be partly responsible for this result. Patients with HER2 (hazard ratio [HR] 0.06/p-value 0.02) or HER4 (HR 0.21/p-value unreported) mutations had longer PFS after treatment with afatinib. However, the biological function of these mutations is unclear. MATERIALS AND METHODS: Ten HER2 and 13 HER4 point mutations that were detected in the secondary analysis were transduced into the mouse pro-B cell line (Ba/F3) to determine changes in interleukin-3 (IL-3) dependence and sensitivity to six EGFR or pan-HER tyrosine kinase inhibitors (TKIs), including afatinib and erlotinib. The efficacy of the six TKIs was compared using a sensitivity index, defined as the 50% inhibitory concentration divided by trough concentration of each drug at clinically recommended doses. RESULTS: Seven out of 10 Ba/F3 clones expressing HER2 mutations and all 13 Ba/F3 clones expressing HER4 mutations did not grow in the absence of IL-3, indicating these mutations were non-oncogenic. Three Ba/F3 clones expressing the HER2 mutations E395K, G815R, or R929W acquired IL-3-independent growth. The sensitivity indices for afatinib were ≤ one-fifth of those for erlotinib in all three lines. Other second/third-generation (2G/3G) TKIs showed high efficacy against clones expressing these HER2 mutations. CONCLUSIONS: The majority of HER2/4 mutations detected in lung SCC from LL8 were not oncogenic in the Ba/F3 models, suggesting that the presence of HER2/4 mutations were not responsible for the superior outcomes of afatinib in the LL8 study. However, SCC of the lung in some patients may be driven by rare HER2 mutations, and these patients may benefit from 2G/3G pan-HER-TKI treatment.

The emergence of immune checkpoint inhibitors (ICIs) has dramatically changed the treatment landscape for patients with metastatic non-small cell lung cancer (NSCLC). These achievements inspired investigators and pharmaceutical companies to conduct clinical trials in patients with early-stage NSCLC because both adjuvant and neoadjuvant platinum-based doublet chemotherapies (PT-DCs) showed only a 5% improvement in 5-year overall survival. IMpower010, a phase 3 trial (P3), showed that adjuvant PT-DC followed by maintenance atezolitumab significantly prolonged disease-free survival over adjuvant PT-DC alone (hazard ratio, 0.79; stage II to IIIA). Since conventional therapies, including chemotherapy and radiotherapy, can promote immunogenic cell death, releasing tumour antigens from dead tumour cells, ICI combination therapies with conventional therapies are widely proposed. The Checkmate 816 trial (P3) indicated a significantly higher pathological complete response rate of neoadjuvant nivolumab/PT-DC combination therapy than of neoadjuvant PT-DC alone (odds ratio, 13.9, for stage IB to IIIA). Detection of circulating tumour DNA is highly anticipated for the evaluation of minimal residual disease. Multimodal approaches and new ICI agents are being attempted to improve the efficacy of ICI treatment in phase 2 trials. This review presents the development of perioperative treatment using ICIs in patients with NSCLC while discussing problems and perspectives.

Background: HER2 (ERBB2) activating mutations are present in 2-3% of lung adenocarcinomas; however, no targeted therapy is approved for HER2-altered lung cancers. A novel pan-HER inhibitor, tarloxotinib, is designed to release the active form (tarloxotinib-E) under hypoxic conditions in tumor tissues after being administered as a prodrug. Following the evaluation of the in vitro activity of tarloxotinib-E in HER2-mutant cells, we explored the mechanisms of resistance to tarloxotinib-E in these cells. Methods: Growth inhibitory assays were performed with tarloxotinib-E and its prodrug using Ba/F3 cells expressing one of six HER2 mutations or wild-type (WT) HER2, in addition to H1781 cells with HER2 exon 20 insertions. Resistant clones were established from N-ethyl-N-nitrosourea (ENU)-treated HER2-mutant Ba/F3 cells and H1781 cells by chronic exposure to tarloxotinib-E. Results: Tarloxotinib-E showed potent activity against HER2-mutant Ba/F3 cells and H1781 cells. Furthermore, the half maximal inhibitory concentration (IC50) of tarloxotinib (inactive form) for WT HER2 was 180 times higher than that of tarloxotinib-E, indicating a wide therapeutic window of tarloxotinib. We established 30 resistant clones with secondary mutations of HER2 by ENU mutagenesis, all of which harbored C805S in exon 20. In the analysis of H1781 cells that acquired resistance to tarloxotinib-E, we found that increased HER3 expression was the molecular mechanism of tarloxotinib-E resistance. Conclusions: Tarloxotinib-E exhibited potent activity against cell line models with HER2 mutations. We identified a secondary C805S HER2 mutation and HER3 overexpression as the mechanisms of acquired resistance to tarloxotinib-E.

INTRODUCTION: KRAS mutations have been recognized as undruggable for many years. Recently, novel KRAS G12C inhibitors, such as sotorasib and adagrasib, are being developed in clinical trials and have revealed promising results in metastatic NSCLC. Nevertheless, it is strongly anticipated that acquired resistance will limit their clinical use. In this study, we developed in vitro models of the KRAS G12C cancer, derived from resistant clones against sotorasib and adagrasib, and searched for secondary KRAS mutations as on-target resistance mechanisms to develop possible strategies to overcome such resistance. METHODS: We chronically exposed Ba/F3 cells transduced with KRASG12C to sotorasib or adagrasib in the presence of N-ethyl-N-nitrosourea and searched for secondary KRAS mutations. Strategies to overcome resistance were also investigated. RESULTS: We generated 142 Ba/F3 clones resistant to either sotorasib or adagrasib, of which 124 (87%) harbored secondary KRAS mutations. There were 12 different secondary KRAS mutations. Y96D and Y96S were resistant to both inhibitors. A combination of novel SOS1 inhibitor, BI-3406, and trametinib had potent activity against this resistance. Although G13D, R68M, A59S and A59T, which were highly resistant to sotorasib, remained sensitive to adagrasib, Q99L was resistant to adagrasib but sensitive to sotorasib. CONCLUSIONS: We identified many secondary KRAS mutations causing resistance to sotorasib, adagrasib, or both, in vitro. The differential activities of these two inhibitors depending on the secondary mutations suggest sequential use in some cases. In addition, switching to BI-3406 plus trametinib might be a useful strategy to overcome acquired resistance owing to the secondary Y96D and Y96S mutations.

INTRODUCTION: We describe our ongoing multicenter, prospective, single-arm, phase II trial of neoadjuvant concurrent chemo-immuno-radiation therapy followed by surgical resection and adjuvant immunotherapy for resectable stage IIIA-B (discrete N2) non-small-cell lung cancer (NSCLC) (registered at the Japan Pharmaceutical Information Center, Clinical Trials Information-195069). PATIENTS AND METHODS: Key inclusion criteria include (1) clinical T1-3/T4 (tumor size) N2 stage IIIA-B NSCLC, and (2) pathologically confirmed N2 without extranodal invasion (based on diagnostic imaging). Patients will receive concurrent chemoradiotherapy (carboplatin [area under the curve = 2] and paclitaxel [40 mg/m2] on days 1, 8, 15, 22, and 29, with involved-field radiation therapy [RT] [dose 50 Gy] on days 1-25) and neoadjuvant immunotherapy (durvalumab [1500 mg] on days 1 and 29). Surgical resection with mediastinal lymph node dissection is performed within 2 to 6 weeks after RT. Consolidation therapy with durvalumab is administered for up to 1 year after surgery. The primary endpoint is major pathologic response (MPR) (≤10% residual viable tumor) according to the central pathological assessment. Secondary endpoints are progression-free survival, overall survival, and safety. The sample size is planned to be 31 patients based on the exact binomial distribution with a 1-sided significance level of 5% and a power of 80%, and assuming a threshold MPR rate of 40% and an expected MPR rate of 65%. CONCLUSION: This trial will help establish a novel treatment strategy for resectable N2-positive NSCLC.

BACKGROUND: Previous studies have reported the feasibility and efficacy of thoracoscopic anatomical sublobar resection under three-dimensional computed tomography (3DCT) simulation; however, its long-term outcomes have not been clearly established in primary lung cancer. This study aimed to evaluate the long-term outcomes of this technique. METHODS: We retrospectively reviewed data from 112 consecutive patients with selected clinical stage IA non-small cell lung cancer (NSCLC) who underwent thoracoscopic anatomical sublobar resection from 2004 to 2014. This procedure was planned using preoperative 3DCT simulation to ensure sufficient surgical margins and enabled tailor-made surgery for each patient. Patients who had predominantly ground glass opacity lung cancers underwent anatomical sublobar resection as a curative-intent resection. Other patients who were high-risk candidates for lobectomy underwent anatomical sublobar resection as a compromised limited resection. RESULTS: Of the 112 cases, 82 had a curative-intent resection, while 30 had a compromised limited resection. Recurrence occurred in only 2 cases (1.8%), both of which were in the compromised limited group. A second primary lung cancer was observed in 5 cases (4.5%). Of the 5 patients, 4 underwent surgery for a second cancer and had no recurrence. The 5-year overall survival, lung cancer-specific overall survival, and recurrence-free survival rates were 92.5%, 100%, and 98.2%, respectively, for all cases; 97.6%, 100%, and 100%, respectively, in the curative-intent group; and 75.8%, 100% and 92.6%, respectively, in the compromised limited group. CONCLUSIONS: Thoracoscopic anatomical sublobar resection under 3DCT simulation may be an acceptable alternative treatment in selected patients with NSCLC. TRIAL AND CLINICAL REGISTRY: Clinical registration number: IRB No. 2020-98 (Dated: 2020.6.30).

OBJECTIVE: Emergence of acquired resistance is almost inevitable during EGFR-tyrosine kinase inhibitor therapy for non-small-cell lung cancer (NSCLC) harboring EGFR mutations. Drug tolerance, a reversible state of drug insensitivity in the early phases of tyrosine kinase inhibitor therapy, is considered to serve as the basis of recurrent disease. Therefore, it is important to elucidate the molecular mechanisms of drug tolerance. MATERIALS AND METHODS: Five EGFR-mutated NSCLC cell lines were used in this study. We established drug-tolerant cells (DTCs) via 72 h treatment with osimertinib (600 nM) or afatinib (60 nM). Acquisition of drug tolerance was evaluated by growth inhibitory assay, and the molecular mechanisms of drug tolerance were analyzed by phospho-RTK array. RESULTS: DTCs were successfully induced in PC9, HCC4006, and H1975 cells against osimertinib and in PC9 cells against afatinib. We observed that a high drug concentration was required to induce DTCs, and HCC4006 cells become tolerant when a higher dose of afatinib (>180 nM) was used. In the analysis of HCC4006 DTCs against osimertinib, we observed increased receptor-like tyrosine kinase (RYK) expression, and siRNA-mediated RYK knockdown inhibited the proliferation of DTCs. CONCLUSIONS: These results suggest that induction of DTCs is dose-dependent, and increased RYK expression was the mechanism of drug tolerance in HCC4006 cells against osimertinib.

BACKGROUND: Several clinical and preclinical studies suggest that non-small cell lung cancers (NSCLCs) with EGFR compound mutations were associated with lower efficacies of first-generation EGFR inhibitors than tumors with single EGFR mutation. Some researchers hypothesize that EGFR mutation status is heterogeneous in such tumors and that second-generation EGFR inhibitors may eliminate cancer cells with uncommon EGFR mutations from tumors with EGFR compound mutations. However, this hypothesis is currently unproven; therefore, we performed the current study to determine if tumor cells with EGFR compound mutations are present in heterogeneous or homogeneous manners. PATIENTS AND METHODS: Multiregion analysis was performed for surgically resected primary NSCLC tumors with EGFR compound mutations to examine the intratumor heterogeneity of EGFR compound mutations. In addition, we evaluated the intertumor heterogeneity of EGFR compound mutations using 2 pleural disseminations obtained from a patient with NSCLC at exploratory thoracotomy and 9 primary or metastatic lesions obtained from 2 autopsied NSCLC patients. Digital polymerase chain reaction, target sequencing, or direct sequencing were used to detect EGFR mutations. RESULTS: This study included 5 NSCLC cases; their compound mutations were L858R+S768I, G719X+S768I, G719A+R776H, L858R+E709G, and L858R+I759M. Noncancerous pulmonary tissues from each patient did not harbor EGFR mutations, which revealed that all mutations were somatic. We did not detect any intra- or intertumor heterogeneity in these EGFR compound mutations. CONCLUSION: No intra- or intertumor heterogeneity was observed for EGFR compound mutations. Our results indicate that both EGFR mutations were truncal and selective elimination of cancer cells with uncommon EGFR mutations is unrealistic.

PURPOSE: Few studies have so far focused on the preoperative presence of venous thromboembolism (VTE) in lung cancer patients undergoing surgery. In this study, we investigated the prevalence and risk factors for preoperative deep venous thrombosis (DVT) in patients scheduled to undergo lung cancer surgery. METHODS: Between June 2013 and December 2018, 948 consecutive patients underwent lung cancer surgery in Kindai University Hospital. Four patients did not undergo screening for DVT; thus, 944 patients were enrolled in this study. Preoperatively, venous ultrasonography of the lower extremities was performed in patients deemed at risk for DVT, and the prevalence and risk factors for preoperative DVT were examined. RESULTS: Ninety-one patients (9.6%) were diagnosed with preoperative DVT, and postoperative symptomatic pulmonary thromboembolism occurred in one patient (0.11%). A multivariable logistic regression analysis demonstrated that female sex, age ≥ 72 years, history of VTE, a Wells score ≥ 2 points, chronic obstructive pulmonary disease (COPD), and lower hemoglobin levels were significantly associated with preoperative DVT. CONCLUSION: Female sex, age ≥ 72 years, history of VTE, Wells score ≥ 2 points, COPD, and lower hemoglobin levels were identified to be independent risk factors for preoperative DVT. Monitoring for these risk factors and management considering them should help improve the outcomes after lung cancer surgery.

Definitive chemoradiotherapy (CRT) has been a standard of care for patients with unresectable stage III non-small cell lung cancer (NSCLC). However, locoregional recurrence occurs in about 30% of patients after definitive CRT. Recently, the addition of durvalumab as maintenance therapy has shown to improve the outcome of these patients. However, locoregional recurrence will still remain. "Salvage surgery" has been performed to achieve local control in clinical practice, although its clinical significance is unclear. In this review, we define salvage surgery as lung resection for local control of the tumor which was not planned initially, after failure or insufficient treatment effect of the initial CRT for locally advanced cancer and evaluated nine studies to gain some insights on its role in the treatment of lung cancer. The time from radiotherapy (RT) to salvage surgery varied considerably (range, 3 to 282 weeks). Salvage surgery was performed for persistent disease (47%) and locoregional recurrence (52%). Lobectomy (63%) and mediastinal lymph node dissections (90%) were the most common procedures. However, the rate of pneumonectomy was higher in salvage surgery (28%) compared to that in lung resection in general. The median morbidity was 41% (range, 15% to 62%) and the mortality was 4% (range, 0 to 11%) which appeared acceptable. The median recurrence-free survival and overall survival (OS) after salvage surgery ranged from 10 to 22 months and 13 to 76 months, respectively. Favorable prognostic factors of salvage surgery were longer period from RT to salvage surgery and radiological downstaging. The pathological response was also prognostic, although this information cannot be obtained preoperatively. We conclude that salvage surgery can be considered especially for those with late local recurrence or those with the metabolic response. Given the condition where phase III trials are difficult, the accumulation of real-world evidence in a prospective fashion will be necessary.

PURPOSE: A high plasma level of either fibrinogen or D-dimer has been shown to correlate with a poor prognosis in patients with surgically resected non-small-cell lung cancer (NSCLC). The present study aimed to identify whether or not both markers combined had a superior prognostic value to either alone. METHODS: Of the 1344 patients who underwent surgical resection for NSCLC at our institution between January 2007 and December 2016, 1065 had preoperative plasma fibrinogen and D-dimer data available and were included in the analysis. RESULTS: The recurrence-free survival (RFS) and overall survival (OS) rates were similar for patients with high plasma levels of either or both fibrinogen (> 4.0 g/L) or D-dimer (> 1.0 μg/mL); therefore, these three groups were combined for a further analysis into a single group with high plasma levels of either or both proteins. The high-level group had significantly lower 5-year RFS (53% vs. 68%, p < 0.001) and 5-year OS (65% vs. 80%, p < 0.001) rates than patients with normal plasma levels of fibrinogen and D-dimer (control group). CONCLUSIONS: Our results suggest that preoperative tests for both plasma fibrinogen and D-dimer are necessary to identify patients with surgically resected NSCLC likely to have a poor RFS and OS.

BACKGROUND: Overcoming acquired resistance against targeted therapies to improve outcomes of lung cancer patients harboring driver mutations is a critical issue. While drug therapy oriented to a resistance mechanism appears attractive, spatial heterogeneity of resistance mechanisms in each patient will diminish treatment efficacy. However, the frequency, clinical backgrounds, clinical implications, and patterns of spatial heterogeneity in resistance mechanisms to EGFR tyrosine kinase inhibitors (TKIs) are largely unknown. PATIENTS AND METHODS: This study included 128 specimens from 24 autopsied patients with lung adenocarcinoma harboring EGFR mutation. Acquired resistance mechanisms reported as relatively frequent in lung cancer, e.g., T790 M and other secondary EGFR mutations, MET and ERBB2 gene amplification, and histological transformation, were retrospectively examined. All patients had received 1st/2nd generation EGFR-TKI and showed acquired resistance to the drug before death. No patient received osimertinib. RESULTS: No resistance mechanism was identified in two patients. T790M mutation was detected in 20 patients (83 %); however, nine of these patients also had lesions without T790M mutation. Among 22 patients whose resistance mechanisms were identified, ten had spatial heterogeneity of resistance mechanisms (45 %), and these patients had significantly shorter time-to-treatment failure compared with those without heterogeneity (median 4.7 months vs. 14.7 months, p = 0.0004). CONCLUSION: We observed significant spatial heterogeneity of acquired resistance mechanisms to EGFR-TKIs in lung adenocarcinoma. Our results also indicate that the incidence of resistance mechanisms may vary based on the biopsied tumor locations.

Background: Recent studies of advanced lung cancer patients have shown that circulating tumor DNA (ctDNA) analysis is useful for molecular profiling, monitoring tumor burden, and predicting therapeutic efficacies and disease progression. However, the usefulness of ctDNA analysis in surgically resected lung cancers is unclear. Methods: This study included 20 lung cancer patients with clinical stage IIA-IIIA disease. Preoperative and postoperative (3-12 days) plasma samples were collected for ctDNA analysis. Cancer personalized profiling by deep sequencing, which can detect mutations in 197 cancer-related genes, was used for ctDNA detection. The cohort consisted of 18 men and 2 women with a median age of 69 (range, 37-88) years. Sixteen patients (80%) had a history of smoking. Histologically, there were four squamous cell carcinomas, 13 adenocarcinomas, two adenosquamous cell carcinomas, and one small cell carcinoma. Results: At the time of data analysis, the 20 patients had been monitored for a median follow-up of 12 months. Eight patients (40%) were positive for preoperative ctDNA, and this was significantly correlated with tumor size (≥5 vs. <5 cm, P=0.018). Four patients (20%) were positive for postoperative ctDNA, and this was significantly correlated with histological grade (3 vs. 1 or 2, P=0.032). Postoperative positivity for ctDNA also predicted shorter recurrence-free survival (RFS) (P=0.015), while pre- and post-operative carcinoembryonic antigen levels (P=0.150 and P=0.533, respectively) and preoperative positivity for ctDNA (P=0.132) were not correlated with RFS. Conclusions: Detecting ctDNA postoperatively was a poor prognostic factor in surgically resected lung cancer patients that may suggest there is minimal residual disease (MRD).

Four-dimensional computed tomography (4DCT) is a relatively new technology. A review of the relevant medical literature reveals only very limited previous investigations of the utility of this technique. We report two cases of lung cancer located adjacent to the pleura in which 4DCT was used to assess parietal pleural invasion or adhesion based on the differential movements of tumors. We performed 4DCT to determine the surgical approach after obtaining appropriate informed consent from the patient. Based on 4DCT, Patient 1 showed there was no adhesion and we could perform thoracoscopic right lower lobectomy and the final pathological diagnosis was pT1bN0M0. Patient 2 Based on 4DCT, showed suspicious of invasion or adhesion. we performed chest wall resection because of tumor invasion in the eighth and ninth costal bones; a final pathological diagnosis of pT3N0M0 was made.

OBJECTIVES: In this study, we aimed to determine conditions associated with the development of air bubbles in the pulmonary veins during lung resection. METHODS: A total of 28 patients who underwent lung resection at our institution between October 2016 and March 2018 were included in the study. An intraoperative transesophageal echocardiography was conducted, and the influx of air bubbles in the orifice of the pulmonary vein leading to the left atrium was observed during lung resection. RESULTS: The median age of all patients was 75 years. The study included 13 men and 15 women. Moreover, seven, 14, and seven patients underwent wedge resection, segmentectomy, and lobectomy, respectively. The presence of air bubbles was observed in 15 patients and was detected when the lung parenchyma was cut (13 patients) or compressed (3 patients) using staplers and when an energy device was used (1 patient). No postoperative organ infarction occurred in any patients. CONCLUSIONS: Although the presence of air bubbles was noted in the pulmonary vein during lung resection via transesophageal echocardiography, the clinical condition of the patients in our study did not deteriorate. The clinical significance of air bubbles is not clear. Therefore, more data about such events must be collected in future.

Since 2004, over 300 patients have undergone thoracoscopic segmentectomy without mini-thoracotomy. Thoracoscopic segmentectomy is one of the most complicated surgeries. To perform the complex segmentectomies, pre-operative simulation and 3-dimensional multi-detector computed tomography( 3DCT) are both essential for safely performing operations and for securing adequate surgical margins. Comprehension of the intersegmental and intrasegmental veins to visualize the segmental border facilitates an easier parenchymal dissection. We describe our method and knack for creating an inflation-deflation line for lung segmentectomy that could especially be useful in thoracoscopic procedures for seg-mentectomy. The 5-year over overall survival, cancer specific survival and recurrence free survival rates were 91.8%( curative intent 98.1% versus compromised 74.6%), 100% and 98.1%( curative intent 100% versus compromised 93.3%). According to these technical aspects, our method of thoracoscopic segmentectomy is acceptable for selective patient.

BACKGROUND: A total of 75% of patients with Sjögren's syndrome are complicated with pulmonary lesions, of which 12% are lymphoma and 6% are amyloid nodules; the coexistence of both is considered to be rare. CASE PRESENTATION: A 67-year-old female with Sjögren's syndrome presented with multiple pulmonary nodules on chest computed tomography. Since a definitive diagnosis by transbronchial biopsy was not obtained, wedge resection of the nodules was performed. Pathologic diagnosis revealed eosinophilic deposition that stained positive with Congo red. In addition, lymphoepithelial lesions and lymphocytic infiltration were observed. Lymphocytes with monoclonal proliferation predominantly had κ chain. Based on these findings, the nodules were diagnosed as mucosa-associated lymphoid tissue (MALT) lymphoma with amyloid deposition. CONCLUSIONS: The combination of these diseases is very rare, and this is the sixth resected case to the best of our knowledge.

BACKGROUND: Although malignant tumor with heterotopic ossification have often been reported, it is very rare in lung cancer. We report a case of primary lung adenocarcinoma with heterotopic ossification. CASE: A 43-year-old woman undergoing a health check was found an abnormal nodular lesion on chest X-ray. Chest computed tomography (CT) showed a calcified tumor, which was diagnosed adenocarcinoma by transbronchial biopsy. Right lower lobectomy and ND2a-2 lymph node dissection was done. Postoperative pathological examination identified the tumor as a bronchioloalveolar adenocarcinoma with other mixed subtypes, associated with ossification containing bone marrow tissue in the tumor. An immunohistochemical examination showed that cancer cells around the ossification expressed bone morphogenetic protein-2 and osteopontin, which generally induce and stimulate bone formation. CONCLUSION: This finding may serve to elucidate a probable mechanism for the heterotopic ossification observed in cancer lesions.

OBJECTIVES: There have been few prospective randomized studies, but many retrospective studies strongly suggest the benefits of segmentectomy in properly selected patients. The indications for video-assisted thoracic surgery segmentectomy are growing because of the effectiveness and minimal invasiveness of the procedure. The aim of the present study was to analyze the learning curve for video-assisted thoracic surgery segmentectomy procedures in our institution. METHODS: We prospectively collected data from patients undergoing video-assisted thoracic surgery segmentectomy and retrospectively reviewed 252 patients from 2004 to 2015. Operative time, bleeding, and complications were analyzed. The learning curve was evaluated using operative time and the cumulative sum value of operative time in all cases with regard to the leading surgeon and nonleading surgeon at our institution. RESULTS: Once we applied the cumulative sum method to all cases, we obtained a graph for the cumulative sum value of operative time that showed 3 well-differentiated phases: phase 1 (n = 61), the initial learning phase; phase 2 (n = 23), the increased competence phase; and phase 3 (n = 168), the highest skill phase. As we compared phases 1 and 2 with phase 3, we observed significant differences in relation to operative time (P < .001) and bleeding (P < .001). Without level 3 segmentectomy, we observed a significant reduction in operative time after 32 cases for the leading surgeon and a significant reduction in operative time and bleeding after 38 cases for the nonleading surgeon. CONCLUSIONS: The data suggest that the inflection point for the learning curve was achieved after 84 cases in our institution. Therefore, increased aptitude with video-assisted thoracic surgery is achievable within a relatively short time.

Background: Hyperbaric oxygen therapy (HBOT) has been used successfully in the treatment of specific ischemic injuries, but has been a little evaluated specifically in postoperative ischemic bronchitis (POIB). The purpose of this study was to evaluate the effect of HBOT when used for POIB after resection of lung cancer. Methods: From January 1999 to December 2016, 1,100 patients underwent lymph node dissection (LND) and either anatomic pulmonary resection or lung resection with bronchoplasty for lung cancer. POIB was diagnosed by bronchoscopy. HBOT was administered after POIB was diagnosed. HBOT comprised one 60-minute session daily in the hyperbaric chamber at 2.0 absolute atmospheres with 100% oxygen. We retrospectively analyzed the clinical course, timing of onset of POIB, outcomes, and any adverse events. Results: Seven patients were identified to have had POIB treated with HBOT, all of whom were men with a smoking history and a median age of 65 years (range, 57-72 years). The operative procedures included three lung resections with bronchoplasty, three right lower lobectomies, and one right middle lobectomy performed owing to torsion of the middle lobe after right upper sleeve lobectomy. All 7 patients underwent subcarinal LND. POIB was diagnosed at a median of 11 days (range, 4-41 days) postoperatively. The median duration of an HBOT session was 7 days (range, 3-11 days). POIB resolved in 5 patients but worsened in 2, both of whom required further surgery. Conclusions: Prospective clinical trials are now needed to confirm the potential benefits of HBOT in POIB.

A 77-year-old man with chronic obstructive lung disease was referred to our hospital for further management of his lung nodule. Chest computed tomography (CT) showed a lung nodule that increased in size up to 1.9 cm in the S8a of his left lung. Primary lung cancer was suspected. Thoracoscopic anatomical left S6b-S8a-S9a multiplex subsegmentectomy was performed according to the CT simulation. The operative time was 142 min, and the blood loss was 13 mL. Air leakage was not observed and the chest tube was removed on postoperative day (POD) 1. The final diagnosis was a lepidic adenocarcinoma, and he lives well without recurrence in this 4-year period after the surgery.

BACKGROUND: One-stage closure and fenestration are the available surgical options for bronchopleural fistula (BPF). One-stage closure may be applicable in cases with favorable infection control. Closing the bronchopleural stump is difficult due to thick adhesion caused by inflammation and a high risk of pulmonary artery injury. We report the successful closure of a BPF using a gastric seromuscular patch with an omental pedicle flap. CASE PRESENTATION: A 73-year-old man underwent right lower lobectomy with ND2a-2 lymph node dissection for lung adenocarcinoma. He was admitted to a local hospital for pneumonia. Three days after admission, his thoracic cavity was drained and a BPF was suspected. During the primary operation, the latissimus dorsi muscle and anterior serratus muscle were dissected via posterolateral incision, and we decided to close the fistula using the gastric seromuscular layer and omental pedicle flap. The patient was discharged 20 days after surgery. After 2 years, he has not had cancer recurrence and currently leads an active life. CONCLUSIONS: This method provided immediate airtight closure and luminal opening of the middle bronchus in our patient with a large BPF and appeared superior to using the omentum alone. This procedure is useful for one-stage closure and does not require fenestration in cases with favorable infection control.

Cases of rescue after rupture of pyogenic liver abscess into the thorax are rare. Here, we report 2 cases of rescue in patients with acute empyema due to rupture of a suppurative abscess into the thorax. Case 1:A 61-year-old male had high fever of 39 °C and right abdominal pain. Thoracic computed tomography(CT) showed encapsulated pleural effusion in the right thorax and ring-like enhancement in the right liver. The diagnosis was acute empyema caused by rupture of liver abscess. The pathogenic bacteria were Streptococcus group. The drain was removed after 6 days and the patient was discharged 32 days after surgery without reefing the diaphragm. Case 2:A 74-year-old male had a high fever of 39 °C and right chest pain. CT showed encapsulated pleural effusion in the right thorax, but not in the lung, and a low density area in the posterior segment of the liver. The diagnosis was acute empyema caused by rupture of liver abscess. The pathogenic bacteria were Streptococcus group and Bacteroides. The drain was removed after 8 days and the patient was discharged 32 days after surgery without reefing the diaphragm. CONCLUSION: Pathogenic bacteria in a pyogenic liver abscess are usually Gram-negative rods, but recently have also been reported to be Streptococcus anginosus group( SAG). Coinfection with SAG and anaerobic bacteria occurs in elderly patients, compromised hosts, and patients with a severe malignant disease. Therefore, early drainage using surgical treatment regardless of reefing the diaphragm should be considered to control severe infection due to liver abscess rupture.

With the recent increase in the detection of small-sized lung nodules because of the widespread use of computed tomography (CT), limited resection and minimally invasive surgery are preferred by patients with these lesions. In particular, the detection of nodules that show ground-glass opacity during high-resolution CT has increased. Although lobectomy and lymph node dissection were the standard procedures used for treating lung cancer, limited wedge resection and segmentectomy have become acceptable for treating small-sized lung cancers with nodules showing ground-glass opacity. These limited procedures are widely performed, especially because they can be accomplished thoracoscopically. Furthermore, not only simple segmentectomy but also complex segmentectomy and subsegmentectomy can be performed using three-dimensional (3D)-CT to achieve sufficient resection based on tumor size. There are, however, technical difficulties in thoracoscopic wedge resection and segmentectomy. While it may be curative for small-sized lung nodules, it is sometimes difficult to correctly perform wedge resection when the tumor is not identified intraoperatively. In such cases, we usually perform tumor marking before operating. However, serious complications, such as cerebral air embolism, have been reported. Further, although it can sufficiently resect small-sized lung nodules, segmentectomy is more technically complex than wedge resection. Therefore, we have developed methods to overcome these technical difficulties. By using a hookwire method in a hybrid operating room and 3D-CT simulation for each wedge resection and segmentectomy, we have obtained good outcomes. Limited resection individualized for each patient will continue to evolve with applications such as CT.

BACKGROUND: Despite the increasing demand for thoracoscopic lung segmentectomy, the appropriate training method is not well established. Therefore, we developed a swine model for anatomical thoracoscopic lung segmentectomy training. METHODS: Three-month-old pigs, weighing 40 to 45 kg, were used in this model. Anterior segmentectomy of the left cranial lobe and segmentectomy of the most anterior left caudal lobe were performed under general anesthesia and differential ventilation. Participants from several institutions participated in this program, which included training lectures and surgical skill drills. RESULTS: From 2010 to 2015, 33 pigs were used for the lung segmentectomy training with 51 trainees. Eight pigs were operated on using the hybrid approach, and 25 pigs were operated on using the complete thoracoscopic approach. Among 25 pigs in which the complete thoracoscopic approach was used, conversion to thoracotomy was required in 3 pigs, owing to hemorrhage in two and failure of differential ventilation in one. The no-touch method in supine position provided sufficient intersegmental delineation of 20 (76%) planes among 26 left anterior segmentectomies in the cranial lobe. CONCLUSIONS: Our live swine model of anatomical thoracoscopic lung segmentectomy is considered a good choice for training surgeons on how to perform minimally invasive lung segmentectomy in humans.

Intersegmental demarcation line on the surface of the visceral pleura could not be found at thoracoscopic findings. The resected segments inflation (RSI) method has been reported as a useful technique for visualizing the intersegmental demarcation line during segmentectomy. Thoracoscopic anatomic segmentectomy is performed as follows: firstly, the pulmonary vein and artery of the segment planned for resection are dissected from the hilum in order to isolate the segmental bronchus located behind the pulmonary artery. Secondly, a monofilament non-absorbable suture is passed through the segmental bronchus, and a slip-knot is made outside the thorax. Thirdly, bilateral lung ventilation with pure oxygen is conducted. When the affected segment has inflated sufficiently, the slip knot suture is pulled and the segmental bronchus is ligated and collapse of the lung is made on reserved segments. Fourthly, as inflation of the affected segment and collapse of the reserved segments could be found, resection of intersegmental plane could be easily performed with the inflation-deflation line and the intersegmental pulmonary vein. If resected segmental bronchus could be identified, thoracoscopic segmentectomy with the slip-knot technique would be applicable. This slip-knot procedure is economical and is not need special instrument.

Segmentectomy has been widely performed as one of the types of limited resections that are performed for the resection of small-sized lung nodules. Video-assisted thoracoscopic surgery has also been in demand as a minimally invasive surgery. Subsegmentectomy is a much more limited resection than segmentectomy, but the technique is complex because it requires keen anatomical identification of small pulmonary structures. Therefore, there has been little reported about subsegmentectomy in medical literature. The recent development of computed tomography is remarkable, and some reports describe three-dimensional computed tomography as providing useful information because it assists surgeons in the performance of thoracoscopic anatomical subsegmentectomy. The creation of an intersubsegmental line is a key process in subsegmentectomy, therefore, some methods have been reported. We have safely and accurately performed some video-assisted thoracoscopic subsegmentectomies for small-sized lung tumors, using the three-dimensional computed tomography simulation and creating the intersubsegmental line with the inflation-deflation technique. In this article, we describe the recent techniques and roles of video-assisted thoracoscopic subsegmentectomy, and offer prospects for this procedure with our clinical data.

Introduction of spinal surgery into the operation of lung cancer has made extensive surgical treatment feasible with acceptable long-term survival. We report our experience on total en bloc total spondylectomy for lung cancer invading the spine. A 60-year-old man was diagnosed with lung adenocarcinoma of the apicodorsal segment of the left lobe with invasion of the 2nd and 3rd thoracic vertebral bodies. After induction chemoradiotherapy, we performed en bloc resection through a posterolateral thoracotomy in the right decubitus position and a posterior median approach in the prone position. The thoracic manipulation was done earlier, making it useful for the dissection of the prevertebral plane from the posterior mediastinum at the upper thoracic level in addition to confirmation of non-N2 disease. Vertebral stabilization was achieved with rod fixation and placement of a titanium mesh cage between the remaining vertebral bodies.

A 17-year-old man was admitted to our hospital for the abnormal chest shadow. Chest computed tomography(CT) demonstrated mediastinal tumor, measuring 13 cm in diameter with high serum level of alpha fetoprotein (AFP) and human chorionic gonadotropin (hCG). The lesions were diagnosed as mixed germ cell tumors including a non-seminomatous malignant component by CT guided needle biopsy. After 5 courses of chemotherapy, the serum AFP and hCG were decreased almost normal level but the tumor size was not changed. Because it seemed to be difficult to get sufficient operating field with standard median sternotomy and patient wanted to treat funnel chest, we selected tumor resection with plastron approach. The tumor was completely resected with a good operation field by this procedure.

Extensive chest wall resection carries the risk of difficult reconstruction and surgical complications. We report our experience on chest wall reconstruction using titanium plates for a wide thoracic defect after tumor resection. A 74-year-old man was diagnosed with chondrosarcoma of the 6th rib on the right. He needed extensive chest wall resection because of skip lesions on 4th rib noted on operative inspection, leaving a defect measuring 33 × 20 cm. Reconstruction using 5 transverse titanium plates sandwiched between an expanded polytetrafluoroethylene patch and a polypropylene mesh sheet stabilized the chest wall. This reconstruction allowed successful separation from ventilatory support after operation. The postoperative course was uneventful, and he was discharged on postoperative day 20. The advantages of this form of reconstruction over conventional prostheses are rigidity, and stability and usability.

We report a rare case of pulmonary lipomatous hamartoma. A 61-year-old male was referred to our hospital due to abnormal mass densities on a chest radiograph. Thoracic computed tomography (CT) revealed a tumor with a maximum diameter of 42 mm. Bronchoscopic examination indicated the presence of a tumor at the orifice of the lateral segmental bronchus which was obstructed by the tumor. Endobronchial lipoma, was suspected by transbronchial biopsy, and we carried out a left upper lobectomy to prevent obstructive pneumonia. The pathological diagnosis was lipomatous hamartoma.

A 26-year-old man was admitted because of an abnormal shadow on a chest roentgenogram. Computed tomography(CT) revealed a very large tumor in the anterior mediastinum and bilateral mediastinal lymphadenopathy. Examination of a CT-guided biopsy specimen revealed a yolk-sac tumor. The patient received 4 courses of bleomycin, etoposide, and cisplatin chemotherapy. After chemotherapy, the tumor was markedly reduced in size, but the lymphadenopathy remained. The patient underwent thoracoscopic biopsy of the mediastinal lymph nodes. Sarcoid nodules were found in all the biopsied nodes, and the lymphadenopathy was thought to be a sarcoid-like reaction associated with the germ cell tumor. Resection of the residual tumor was performed according to the treatment algorithm of the International Germ Cell Cancer Collaborative Group. There were no viable tumor cells in the resected tissue. The patient is free of recurrence and without any sign of generalized sarcoidosis 3 years after the surgery.

A 63-year-old man with a left rib tumor, which had been diagnosed as a giant cell tumor 2 years previously, had been followed up at another hospital after embolization of a feeding artery of the tumor. He was admitted to the emergency room of our hospital with complaints of breathing difficulties. A chest computed tomography (CT) revealed a left chest wall tumor, about 11 cm in size, originating from the 8th rib and a massive left hemothorax. Emergency operation was performed to releave hemorrhagic shock. Bleeding from the tumor was confirmed at thoracotomy. Tumor was removed with combined resection of the adjacent chest wall and diaphragm. His postoperative course was uneventful and he was discharged on the 8th postoperative day.

肺癌の進展における長鎖非コードRNA(long noncoding RNA,lncRNA)の果たす役割は明らかにされつつあるが、その成果を臨床応用するための橋渡し研究はまだ少ない。本研究は、我々が新規に同定した癌遺伝子型lncRNA S180122に着目して、薬剤耐性を獲得した肺腺癌患者由来の癌細胞塊を用いた培養法(cancer tissue-originated spheroid、CTOS法)により、lncRNAを標的とした核酸医薬の探索とバイオマーカーへの展開を目的とする。そのため、1)EGFR-TKIに耐性を獲得した肺腺癌患者の血液を用いて、S180122のバイオマーカーとしての可能性を明らかにすること、2)細胞株及び耐性を獲得した患者腫瘍組織に由来するスフェロイドを用いた薬剤応答の解析を通じて、S180122を標的としたlncRNA阻害剤の肺腺癌再発の抑制効果を評価することを計画した。 本年度では、患者から採取した肺癌組織のCTOSの調製方法を検討し、3D培養条件を最適化して培養皿の上で肺癌オルガノイドの樹立に成功した。中短期間に(2-3ヶ月)培養されたオルガノイドに、患者体内の腫瘍と類似した遺伝子発現パターンがあることを確認した。この結果によって、今後、患者肺癌組織に由来するオルガノイドを用いた薬剤応答の解析が可能になった。また、肺腺癌細胞株を用いてS180122を標的としたlncRNA阻害剤を検討したところ、2D培養細胞により最適阻害剤の選定に成功したが、阻害剤の3Dスフェロイドへのデリバリー効率の改善が本研究の次なる進展の鍵となることが示唆された。

本年度は、LUX-Lung 8 試験（Soriaら、Lancet Oncol 2015）で同定された臨床的意義の不明なHER2変異（VUS：Variants of Unknown Significance）について検討を行った。LUX-Lung 8 試験は、ⅢB/Ⅳ期の肺扁平上皮がん患者を対象とし、EGFR-TKIであるアファチニブとエルロチニブの効果を比較検証した第Ⅲ相試験であり、その二次解析では（Gossら、JAMA Oncol 2018）、10種類のHER2遺伝子のVUSが報告されている。この10種類のHER2遺伝子をIL-3依存性細胞株である、マウスpro-B細胞株（Ba/F3細胞）に導入し、人工的な腫瘍細胞モデルを作成した。これらのHER2遺伝子のVUSの腫瘍原性を、IL-3除去下での増殖能を検証することで評価し、E395K変異、G815R変異、R929W変異で腫瘍原性があることを確認した。これらの変異を有する人工的な腫瘍細胞モデルに対して、アファチニブとエルロチニブを含む種々のEGFRチロシンキナーゼ阻害剤（EGFR-TKI）の効果をMTTアッセイで評価し、すべての変異で、エルロチニブよりもアファチニブが有効であることを確認した。さらに、これらのMTTアッセイの結果を、Western Blottingでも確認した。

参加4施設の乳癌症例のPET画像を集め、PETの定量値（腫瘍の最大集積であるSUVmax、集積の体積であるMTV、SUVmeanとMTVの積であるTLG）にファントム実験で検証したガウシャンフィルターをかけてハーモナイゼーション（標準化）を行う事に成功した。 手術が施行された乳癌stageⅠ～Ⅲ期の乳癌患者546人において、estrogen receptor (ER)-positive/human epidermal growth factor receptor 2 (HER2)-negativeの344人とHER2-positiveの110人とtriple-negative caseの92人に分けて、ハーモナイゼーションしたPET定量値（最大SUVmax、MTVの合計、TLGの合計）が予後予測（再発や死亡の予測）に有用であることを明らかにし、Oncotarget. 2021 Jan 19;12(2):95-105. doi: 10.18632/oncotarget.27851に論文発表できた。 化学療法で治療されたstageⅣ期の乳癌患者65人において、estrogen receptor (ER)-positive/human epidermal growth factor receptor 2 (HER2)-negativeの29人, HER2-positiveの23人とtriple-negative caseの13人分けて、ハーモナイゼーションしたPET定量値（最大SUVmax、MTVの合計、TLGの合計）が予後予測（再発や死亡の予測）に有用であることを明らかにし、Hell J Nucl Med. 2020 Sep-Dec;23(3):272-289.に論文発表できた。