出版者・発行元：Annals of Surgical Oncology  

DOI： 10.1245/s10434-025-16907-8

Web of Science

Scopus

PubMed

記述言語：英語   出版者・発行元：Annals of Surgical Oncology  

DOI： 10.1245/s10434-025-17211-1

Web of Science

Scopus

PubMed

記述言語：英語   出版者・発行元：Clinical Lung Cancer  

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.

DOI： 10.1016/j.cllc.2024.12.011

Scopus

PubMed

DOI： 10.1016/j.clc.2024.12.011

Web of Science

記述言語：英語   出版者・発行元：International Journal of Clinical Oncology  

Background: CD155 has been identified as a ligand for T-cell immunoreceptor with Ig and ITIM domains. Herein, we investigated the relationship between the expressions of CD155 and programmed cell death-ligand 1 (PD-L1) and clinical outcomes in patients with surgically resected lung adenocarcinoma. Methods: This study included 426 patients diagnosed with pathological stage (pStage) I–III lung adenocarcinoma who underwent surgery at Kyushu University Hospital. The number of tumor cells expressing CD155 and PD-L1 was assessed by immunohistochemistry, and the clinical significance of CD155 expression and CD155/PD-L1 co-expression in prognosis was investigated. Results: Among the enrolled cohort, 320 (75.1%), 60 (14.1%), and 46 (10.8%) patients were diagnosed with pStage I, II, and III, respectively. Tissues from 112 patients (26.3%) were classified as having high CD155 expression. Co-expression of CD155 and PD-L1 was observed in 44 patients (10.3%). The High CD155 and CD155/PD-L1 co-expression groups had significantly poorer prognosis in pStage I–III lung adenocarcinoma. However, subgroup analysis revealed that the clinical significance of both CD155 expression and CD155/PD-L1 co-expression differed widely between patients with pStage I and II–III. Multivariate Cox proportional hazards regression analyses showed that high CD155 expression and CD155/PD-L1 co-expression were not independent poor prognostic factors in pStage II-III lung adenocarcinoma. Conclusion: Our findings suggest that neither CD155 expression or CD155/PD-L1 co-expression are associated with poor prognosis in pStage II-III lung adenocarcinoma.

DOI： 10.1007/s10147-025-02771-9

Web of Science

Scopus

PubMed

DOI： 10.1245/s10434-025-17255-3

Web of Science

PubMed

記述言語：英語   出版者・発行元：International Journal of Cancer  

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.

DOI： 10.1002/ijc.35270

Web of Science

Scopus

PubMed

記述言語：英語   出版者・発行元：Annals of Surgical Oncology  

Background: Tumor microvasculature is an important component of the tumor microenvironment (TME), and it has been reported that tumor microvasculature induces TME to become immunosuppressive via vascular endothelial growth factor. However, the significance of this in adenocarcinoma with epidermal growth factor receptor (EGFR) common mutations has not been fully investigated. Methods: We analyzed 262 patients with adenocarcinoma harboring EGFR common mutations who underwent surgery at Kyushu University Hospital between 2006 and 2021. Microvessel density (MVD) was calculated by CD34 immunohistochemistry. Patients were categorized into high and low MVD status, which was compared with the clinicopathological characteristics. Results: A total of 136 (51.9%) patients had L858R mutation, and 126 (48.1%) had Exon 19 Del. Regarding MVD status; 133 patients (50.8%) were classified as high and 129 (49.2%) as low. Fisher’s exact test revealed a significant association of high MVD status with high CD8+ tumor infiltrating lymphocytes (TILs) (p = 0.0187), low GZMB+ TILs (p = 0.0019), and high Foxp3+ TILs (p = 0.0003). On multivariate analysis, MVD status was significantly associated with Foxp3+ TILs and GZMB+ TILs. Fisher’s exact test also revealed that tumors with L858R mutation had a high MVD status (p = 0.0136) compared with tumors with deletions of exon 19 (Exon 19 Del), and multivariate analysis revealed that L858R mutation was significantly associated with high MVD status. Conclusions: In adenocarcinomas harboring EGFR common mutations, abundant tumor microvasculature might induce the TME to be immunosuppressive. Tumors with L858R mutation compared with Exon 19 Del might be more likely to form an immunosuppressive TME owing to the abundance of tumor microvasculature.

DOI： 10.1245/s10434-024-16806-4

Web of Science

Scopus

PubMed

記述言語：英語  

DOI： 10.1016/j.atssr.2024.09.005

PubMed

記述言語：英語  

DOI： 10.1186/s44215-025-00187-5

Web of Science

PubMed

記述言語：英語   出版者・発行元：BioMed Central  

出版者・発行元：Therapeutic Advances in Medical Oncology  

Background: Skin disorders are major adverse events associated with necitumumab plus gemcitabine and cisplatin (Neci + GC) administration. However, the prognostic effect of skin disorders in patients with lung squamous cell carcinoma (LSCC) administered Neci + GC is unclear. Objectives: We examined this prognostic effect in patients with LSCC, and the usefulness of minocycline administration. Design: This was a sub-analysis of the retrospective multicenter NINJA study. Methods: We performed a landmark survival analysis according to the presence of skin disorders at Day 30 of treatment and examined the usefulness of minocycline for treating skin disorders. Results: Among the 93 patients, 62 (66.7%) had a skin disorder at Day 30. Nineteen, 30, and 13 patients experienced Grade 1, 2, and 3 skin disorders, respectively. The overall survival (OS) and progression-free survival (PFS) of patients with skin disorders at Day 30 were longer than those of patients without skin disorders (median OS: 434 vs 278 days, p = 0.0201; median PFS: 148 vs 82 days, p = 0.0835). Multivariable analysis showed that a skin disorder at Day 30 was an independent prognostic factor for both OS (p = 0.0044) and PFS (p = 0.0514). Of the 62 patients with skin disorders at Day 30, 38 (61.3%) were taking minocycline, and their time to treatment failure (TTF) was better than that in patients not taking minocycline (median TTF: 148 vs 101 days, p = 0.0495). Conclusion: A skin disorder within 30 days was a favorable prognostic factor for patients with LSCC administered Neci + GC. Additionally, minocycline administration may be beneficial in patients who develop skin disorders within 30 days.

DOI： 10.1177/17588359241312503

Scopus

記述言語：英語   出版者・発行元：シュプリンガー・ジャパン(株)  

出版者・発行元：Therapeutic Advances in Medical Oncology  

Background: The clinical impact of hypomagnesemia induced by necitumumab plus gemcitabine and cisplatin (GCN) as a second-line or later therapy is unclear. Objective: We aimed to evaluate the clinical characteristics and survival impact of hypomagnesemia induced by this therapy. Design: This was a sub-analysis of the retrospective multicenter NINJA study. Methods: Among the 93 patients enrolled in the NINJA study, this subanalysis included 75 patients with baseline serum magnesium concentrations. Results: The incidence of grade ⩾2 hypomagnesemia was 18.0% in the patients with normal baseline serum magnesium concentrations and 42.8% in those with low concentrations (p = 0.073). The discontinuation rates of GCN treatment owing to hypomagnesemia in each group were 0% and 7.1%, respectively (p = 0.187). The number of necitumumab doses and severity of hypomagnesemia were positively correlated (r = 0.389, p < 0.001). Patients who developed hypomagnesemia in fewer than 21 days after the first dose of GCN (n = 12) had significantly poorer progression-free survival (PFS) than those without the condition (n = 63; median: 4.1 vs 4.4 months, p = 0.048). A similar trend was observed for OS (median: 9.7 vs 15.7 months, p = 0.062). These results were maintained after multivariate analyses (PFS: hazard ratio (HR) 2.46, p = 0.014; OS: HR 2.78, p = 0.021). Conclusion: GCN as a second-line or later therapy may be tolerable regardless of the patient’s baseline serum magnesium concentration. On the other hand, early serum magnesium reduction with this therapy is associated with a poor prognosis. However, caution should be needed because our results lacked sufficient information for confounding variables other than those analyzed here that may influence the correlation between hypomagnesemia and survival.

DOI： 10.1177/17588359251318850

Scopus

記述言語：英語   出版者・発行元：Interdisciplinary Cardiovascular and Thoracic Surgery  

OBJECTIVES: Spread through air spaces (STAS) is considered a poor prognostic factor in patients with resected non-small lung cell cancer; however, the clinical significance of STAS extent remains unclear. We hypothesized that the further the tumour cells spread from the tumour edge, the worse the prognosis becomes. METHODS: This study retrospectively reviewed the data of 642 patients with completely resected pathological stage I-III non-small lung cell cancer between 2008 and 2018. The maximum spread distance (MSD) from the tumour edge to the farthest STAS was quantitatively evaluated, and STAS was categorized as limited (MSD ≤1000 μm) or extended (MSD >1000 μm), based on the median MSD. Recurrence-free survival (RFS) and overall survival (OS) were compared among patients stratified by STAS classification. RESULTS: Patients were classified into STAS-negative (n = 382, 59.6%), limited STAS (n = 130, 20.2%) and extended STAS (n = 130, 20.2%) groups. Extended STAS was associated with a high maximum standardized uptake value, advanced pathological stage and vascular invasion compared with limited STAS. The extended STAS group demonstrated significantly shorter RFS and OS than both the limited STAS and STAS-negative groups (both P < 0.001 for RFS; P = 0.007 and P < 0.001 for OS, respectively). Multivariable analysis showed that extended STAS was an independent prognostic factor for both RFS and OS (P < 0.001, P < 0.001, respectively). CONCLUSIONS: The distance from tumour edge to STAS affects prognosis in patients with completely resected non-small lung cell cancer.

DOI： 10.1093/icvts/ivae181

Web of Science

Scopus

PubMed

記述言語：英語   出版者・発行元：Transplant International  

Bronchiolitis obliterans syndrome (BOS) is a chronic complication following lung transplantation that limits the long-term survival. Although the enhancer of zeste homolog 2 (EZH2) is involved in post-transplantation rejection, its involvement in BOS pathogenesis remains unclear. We aimed to investigate the therapeutic potential of EZH2 inhibition in BOS. 3-deazaneplanocin A (DZNep) was administered intraperitoneally to heterotopic tracheal transplant recipient model mice. Tracheal allografts were obtained on days 7, 14, 21, and 28 after transplantation. The obstruction ratios of the DZNep and control groups on days 7, 14, 21, and 28 were 15.1% ± 0.8% vs. 20.4% ± 3.6% (p = 0.996), 16.9% ± 2.1% vs. 67.7% ± 11.5% (p < 0.001), 47.8% ± 7.8% vs. 92.2% ± 5.4% (p < 0.001), and 60.0% ± 9.6% vs. 95.0% ± 2.3% (p < 0.001), respectively. The levels of interleukin (IL)-6 and interferon-γ on day 7 and those of IL-2, tumor necrosis factor, and IL-17A on days 14, 21, and 28 were significantly reduced following DZNep treatment. DZNep significantly decreased the number of infiltrating T-cells on day 14. In conclusion, DZNep-mediated EZH2 inhibition suppressed the inflammatory reactions driven by pro-inflammatory cytokines and T cell infiltration, thereby alleviating BOS symptoms.

DOI： 10.3389/ti.2024.13227

Web of Science

Scopus

PubMed

記述言語：英語   出版者・発行元：International Journal of Clinical Oncology  

Background: Cluster of differentiation 155 (CD155) is expressed in many tumor types. CD155 is involved in the immune avoidance of tumor cells and contributes to tumor development and progression. Therefore, CD155 is a novel target for cancer immunotherapy. The clinical significance of CD155 expression in lung squamous cell carcinoma (LUSC) has not been fully elucidated. Materials and methods: We performed a retrospective analysis of 264 patients with surgically resected LUSC. Immunohistochemistry was used to evaluate CD155 expression. The association of CD155 expression with clinicopathological features and clinical outcomes was assessed. We also analyzed the relationship between CD155 expression and programmed cell death-ligand 1 (PD-L1) expression and tumor-infiltrating lymphocytes. Results: Among the 264 patients, 137 patients (51.9%) were classified in the high CD155 expression group. High CD155 expression was significantly associated with pleural invasion, vascular invasion, PD-L1 positivity, and high CD3, CD4, and CD8 expressions. In multivariate analysis, the presence of pleural invasion and PD-L1 positivity were independent predictors of high CD155 expression. Kaplan–Meier curve analysis showed that high CD155 expression was significantly associated with shorter disease-free survival and overall survival. In multivariate analysis, high CD155 expression was an independent poor prognostic factor for overall survival, but not for disease-free survival. Subgroup analyses revealed that the prognostic effect of CD155 expression was observed in the PD-L1 positive group but not the PD-L1 negative group. Conclusion: Our analysis revealed that high CD155 expression significantly predicted poor prognosis in patients with surgically resected LUSC, especially in patients with PD-L1-positive tumors.

DOI： 10.1007/s10147-024-02640-x

Web of Science

Scopus

PubMed

記述言語：英語   出版者・発行元：Learning Health Systems  

Introduction: The reliability of data-driven predictions in real-world scenarios remains uncertain. This study aimed to develop and validate a machine-learning-based model for predicting clinical outcomes using real-world data from an electronic clinical pathway (ePath) system. Methods: All available data were collected from patients with lung cancer who underwent video-assisted thoracoscopic surgery at two independent hospitals utilizing the ePath system. The primary clinical outcome of interest was prolonged air leak (PAL), defined as drainage removal more than 2 days post-surgery. Data-driven prediction models were developed in a cohort of 314 patients from a university hospital applying sparse linear regression models (least absolute shrinkage and selection operator, ridge, and elastic net) and decision tree ensemble models (random forest and extreme gradient boosting). Model performance was then validated in a cohort of 154 patients from a tertiary hospital using the area under the receiver operating characteristic curve (AUROC) and calibration plots. Results: To mitigate bias, variables with missing data related to PAL or those with high rates of missing data were excluded from the dataset. Fivefold cross-validation indicated improved AUROCs when utilizing key variables, even post-imputation of missing data. Dichotomizing continuous variables enhanced performance, particularly when fewer variables were employed in the decision tree ensemble models. Consequently, regression models incorporating seven key variables in complete case analysis demonstrated superior discriminatory ability for both internal (AUROCs: 0.77–0.84) and external cohorts (AUROCs: 0.75–0.84). These models exhibited satisfactory calibration in both cohorts. Conclusions: The data-driven prediction model implementing the ePath system exhibited adequate performance in predicting PAL post-video-assisted thoracoscopic surgery, optimizing variables and considering population characteristics in a real-world setting.

DOI： 10.1002/lrh2.10469

Web of Science

Scopus

PubMed

Web of Science

Web of Science

記述言語：英語  

DOI： 10.1186/s40792-024-02023-4

Web of Science

PubMed

記述言語：英語   出版者・発行元：European Journal of Surgical Oncology  

Introduction: High recurrence rate following curative surgery for non-small cell lung cancer (NSCLC) presents a major clinical challenge. Understanding the site and timing of recurrence and their impact on post-recurrence survival (PRS) is important for optimal postoperative surveillance and therapeutic intervention. In this study, we investigated the influence of the time to recurrence (TTR) and initial recurrence site on PRS. Materials and methods: This multicentre prospective cohort study included patients who experienced recurrence after NSCLC resection between 2010 and 2015. The relationship between TTR and initial recurrence site, and their impact on PRS, was further evaluated. The hazard ratio (HR) for PRS was analysed using the Cox proportional hazards model. Results: Among 495 patients, the median TTR was 14 (range, 1–158) months; the mode of recurrence was 11 months. Early recurrence within 6 months was observed in 17 % of patients, and 68 % of patients showed recurrence within 2 years post-surgery. The HR for PRS was the highest in patients with a TTR within 6 months, and a noticeable decline was observed after the first 6 months. The HRs of TTRs beyond 2 years were not significantly different. The liver was a significantly unfavourable prognostic site for metastases (HR 2.2; P = 0.01), and metastases frequently recurred within 6 months after surgery. The timing of brain metastasis did not significantly impact the PRS. Conclusion: Earlier recurrence after surgery was associated with shorter PRS. In contrast, recurrences occurring >2 years after surgery do not significantly affect PRS.

DOI： 10.1016/j.ejso.2024.108374

Web of Science

Scopus

PubMed

記述言語：英語   出版者・発行元：Annals of Surgical Oncology  

Background: Signal-regulatory protein alpha (SIRPα) is an immune checkpoint molecule expressed on macrophages that functions to inhibit phagocytosis by binding to CD47 expressed on tumor cells. SIRPα has attracted increasing attention as a novel target for cancer immunotherapy; however, the expression and immune function of SIRPα in lung squamous cell carcinoma (LUSC) remain unclear. Therefore, this study aimed to identify the clinical importance of SIRPα expression in LUSC and to explore the factors that elevate SIRPα expression. Patients and Methods: Primary LUSC specimens surgically resected from 172 patients underwent immunohistochemical evaluation of the association of SIRPα expression on tumor-associated macrophages with clinicopathological features and clinical outcomes. Furthermore, we analyzed the association of SIRPα expression with tumor-infiltrating lymphocytes and the expression of programmed cell death ligand 1 (PD-L1). In vitro, monocytes were treated with cytokines, and SIRPα protein expression was assessed by flow cytometry. Results: There were no differences in SIRPα expression and clinicopathological factors. High SIRPα expression was significantly associated with PD-L1-positive expression, and high CD8, PD-1, and CD163 expression. The high SIRPα expression group showed significantly shorter recurrence-free survival (RFS) and overall survival (OS). On multivariate analysis, high SIRPα expression was an independent poor prognostic factor for RFS and OS. The expression of SIRPα protein in monocytes was upregulated by treatment with IFNγ. Conclusion: Our analysis revealed that high SIRPα expression significantly predicts poor prognosis in patients with surgically resected LUSC.

DOI： 10.1245/s10434-024-15649-3

Web of Science

Scopus

PubMed

記述言語：英語   出版者・発行元：(一社)日本外科学会  

症例は29歳男性で、定期検診時の胸部X線検査で右肺野に異常陰影がみられた。腫瘍マーカーを含む血液検査は正常であったが、CTでは第2肋間内に30mm大の境界明瞭な腫瘤を認め、MRIでもT2強調画像で高信号、T1強調画像で中程度の信号がみられた。神経鞘腫または孤発性線維性腫瘍が疑われたため、診断と治療を目的に胸腔鏡下手術を行った。腫瘍は第2肋軟骨前方の胸壁に認められ、表面は滑らかで胸膜と内側肋間筋に覆われていた。胸膜壁を腫瘍境界に沿って切開し、腫瘍を外側肋間筋および肋骨から剥離した。術後の病理組織学的検査では、毛細血管構造に配列された紡錘形の内皮細胞の増殖が認められ、これに伴って平滑筋線維、脂肪組織、筋肉血管が取り込まれていた。最終的に、切除断端陰性の筋肉内血管腫と診断した。術後経過は良好で、5日後に退院し、術後12ヵ月時点で再発の徴候は認められていない。

DOI： 10.1245/s10434-024-15960-z

Web of Science

PubMed

DOI： 10.1245/s10434-024-15246-4

Web of Science

PubMed

記述言語：英語   出版者・発行元：Journal of Thoracic Disease  

Background: The preoperative serum creatine kinase (CK) concentration is a prognostic factor for malignant diseases. We investigated the significance of CK in surgically resected thymic epithelial tumors and the relationship between CK and clinicopathological factors. Methods: We retrospectively evaluated the relationship between preoperative CK levels and prognosis in 120 patients with thymic epithelial tumors who underwent surgical resection at two centers. The cutoff for CK was determined by the standard value in our institution (<62 IU/L for men and <45 IU/L for women). The paravertebral muscle at the Th12 level was used to assess skeletal muscle area to investigate sarcopenia. Results: Eighteen patients (15.0%) were categorized into the low CK group. The CK level was not associated with age, sex, performance status, myasthenia gravis, and pathological findings. Preoperative serum albumin and total cholesterol concentrations were significantly lower in the low CK group than in the normal CK group (both P<0.001). Moreover, the Th12 muscle index was lower in the low CK group (P=0.03), indicating that low CK was related to sarcopenia. Kaplan-Meier curve analysis illustrated that patients in the low CK group had significantly shorter disease-free survival (DFS) and overall survival (OS) than those in the normal CK group (P=0.03 and P=0.002, respectively). Multivariate analysis identified low CK as an independent prognostic factor for DFS (P=0.03) and OS (P=0.005). Conclusions: Preoperative serum CK might reflect the host nutritional status in patients with resected thymic epithelial tumors; therefore, CK could be a biomarker of postoperative prognosis.

DOI： 10.21037/jtd-23-1797

Web of Science

Scopus

PubMed

記述言語：英語   出版者・発行元：Annals of Surgical Oncology  

Background: Glutathione peroxidase 2 (GPX2) is an antioxidant enzyme with an important role in tumor progression in various cancers. However, the clinical significance of GPX2 in lung adenocarcinoma has not been clarified. Methods: Quantitative reverse transcription polymerase chain reaction (qRT-PCR) was used to analyze GPX2 mRNA expression. Then, we conducted immunohistochemistry (IHC) to assess GPX2 expression in specimens acquired from 351 patients with lung adenocarcinoma who underwent surgery at Kyushu University from 2003 to 2012. We investigated the association between GPX2 expression and clinicopathological characteristics and further analyzed the prognostic relevance. Results: qRT-PCR revealed that GPX2 mRNA expression was notably higher in tumor cells than in normal tissues. IHC revealed that high GPX2 expression (n = 175, 49.9%) was significantly correlated with male sex, smoking, advanced pathological stage, and the presence of pleural, lymphatic, and vascular invasion. Patients with high GPX2 expression exhibited significantly shorter recurrence-free survival (RFS) and overall survival. Multivariate analysis identified high GPX2 expression as an independent prognostic factor of RFS. Conclusions: GPX2 expression was significantly associated with pathological malignancy. It is conceivable that high GPX2 expression reflects tumor malignancy. Therefore, high GPX2 expression is a significant prognostic factor of poor prognosis for completely resected lung adenocarcinoma.

DOI： 10.1245/s10434-024-15116-z

Web of Science

Scopus

PubMed

記述言語：日本語   出版者・発行元：特定非営利活動法人 日本気管食道科学会  

DOI： 10.2468/jbes.75.118

CiNii Research

記述言語：英語   出版者・発行元：European Journal of Cancer  

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.

DOI： 10.1016/j.ejca.2024.113951

Web of Science

Scopus

PubMed

記述言語：英語   出版者・発行元：Annals of Thoracic Surgery  

Background: Cluster of differentiation (CD) 155 is a transmembrane protein that belongs to the nectin-like molecule family, which is widely overexpressed in several types of cancer. However, the clinical significance of CD155 in pathologic stage I lung adenocarcinoma remains poorly understood. Methods: We analyzed 320 patients diagnosed with pathologic stage I lung adenocarcinoma who underwent surgical treatment at Kyushu University Hospital between 2006 and 2015. The number of tumor cells expressing CD155 was assessed by immunohistochemistry, and patients were categorized into high and low CD155 expression groups. We compared the clinical and pathologic characteristics and clinical outcomes between these groups. Results: Mutation status of the epidermal growth factor receptor gene (EGFR) was determined in 237 patients. A total of 106 patients (33.1%) had EGFR wild-type, and 131 patients (40.9%) had EGFR mutant-type. CD155 expression was classified as high in 77 patients (24.1%) and as low in 243 (75.9%) as low. Multivariate analysis identified pleural invasion and EGFR wild-type as independent predictors of high CD155 expression. The Kaplan-Meier plot demonstrated significantly poorer recurrence-free survival and overall survival in the high CD155 group compared with the low CD155 group. Multivariate analysis showed high CD155 expression was an independent poor prognostic factor for recurrence-free and overall survival. Subgroup analyses revealed that a prognostic difference related to CD155 expression was observed only in patients with EGFR wild-type but not in those with EGFR mutant-type. Conclusions: Our findings suggest that high expression of CD155 is associated with EGFR wild-type and could serve as a valuable prognostic marker in pathologic stage I lung adenocarcinoma, particularly in cases without EGFR mutation.

DOI： 10.1016/j.athoracsur.2024.05.042

Web of Science

Scopus

PubMed

記述言語：日本語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1245/s10434-023-14295-5

Web of Science

PubMed

記述言語：英語   掲載種別：研究論文（学術雑誌）  

記述言語：英語   出版者・発行元：Anticancer Research  

Background/Aim: Recent advances in surgery, such as thoracoscopic surgery, have made it possible to treat patients with chronic obstructive pulmonary disease (COPD) more safely than before. This study evaluated the short- and long-term prognosis of lobectomy in non-small cell lung cancer (NSCLC) patients with COPD. Patients and Methods: This retrospective, propensity-matched, cohort analysis was conducted from January 2014 to December 2018. Among 441 patients who underwent lobectomy for NSCLC, 158 (35.8%) had a preoperative diagnosis of COPD. Propensity-matched analysis, incorporating preoperative variables, was used to compare postoperative hospital stay and complications, and long-term prognosis between the groups. Results: Propensity matching estimated 145 patients in each group. There was no difference between the two groups for length of postoperative hospital stay (12 vs. 11 days, p=0.306). Postoperative complications were more frequent in the COPD group (24.1%) than in the non-COPD group (16.6%), but the difference was not significant (p=0.108). The 5-year overall survival rate was 86.2% in the COPD group and 82.1% in the non-COPD group after matching (p=0.580). The corresponding 5-year recurrence-free survival rate was 72.8% in the COPD group and 67.2% in the non-COPD group after matching (p=0.601). Conclusion: In case of Global Initiative for Chronic Obstructive Lung Disease (GOLD) I/II classification, COPD did not significantly worsen the prognosis of patients with NSCLC after lobectomy.

DOI： 10.21873/anticanres.16723

Web of Science

Scopus

PubMed

記述言語：英語   出版者・発行元：Annals of Surgical Oncology  

Background: Granzyme B (GZMB) is a serine protease produced by cytotoxic lymphocytes that reflects the activity of anti-tumor immune responses in tumor-infiltrating lymphocytes (TILs); however, the prognostic significance of GZMB+ TILs in lung adenocarcinoma is poorly understood. Methods: We analyzed 273 patients with pathological stage (pStage) I–IIIA lung adenocarcinoma who underwent surgery at Kyushu University from 2003 to 2012. We evaluated GZMB+ TIL counts by immunohistochemistry. We set the cut-off values at 12 cells/0.04 mm2 for GZMB+ TILs and divided the patients into GZMB-High (n = 171) and GZMB-Low (n = 102) groups. Then, we compared the clinicopathological characteristics of the two groups and clinical outcomes. Programmed cell death ligand-1 (PD-L1) and indoleamine 2,3-dioxygenase 1 (IDO1) expression in tumor cells was also evaluated, and combined prognostic analyses of GZMB+ TILs with PD-L1 or IDO1 were performed. Results: GZMB-Low was significantly associated with pStage II–III, PD-L1 positivity, and IDO1 positivity. Disease-free survival (DFS) and overall survival (OS) in the GZMB-Low group were significantly worse than in the GZMB-High group. In multivariable analysis, GZMB-Low was an independent prognostic factor for both DFS and OS. Furthermore, combined prognostic analyses of GZMB+ TILs with PD-L1 or IDO1 showed that GZMB-Low with high expression of these immunosuppressive proteins had the worst prognosis. Conclusions: We analyzed GZMB+ TIL counts in lung adenocarcinoma and elucidated its prognostic significance and association with PD-L1 and IDO1. GZMB+ TIL counts might reflect the patient’s immunity against cancer cells and could be a useful prognostic marker of lung adenocarcinoma.

DOI： 10.1245/s10434-023-14085-z

Web of Science

Scopus

PubMed

記述言語：英語   出版者・発行元：Scientific Reports  

There are great expectations for artificial intelligence (AI) in medicine. We aimed to develop an AI prognostic model for surgically resected non-small cell lung cancer (NSCLC). This study enrolled 1049 patients with pathological stage I–IIIA surgically resected NSCLC at Kyushu University. We set 17 clinicopathological factors and 30 preoperative and 22 postoperative blood test results as explanatory variables. Disease-free survival (DFS), overall survival (OS), and cancer-specific survival (CSS) were set as objective variables. The eXtreme Gradient Boosting (XGBoost) was used as the machine learning algorithm. The median age was 69 (23–89) years, and 605 patients (57.7%) were male. The numbers of patients with pathological stage IA, IB, IIA, IIB, and IIIA were 553 (52.7%), 223 (21.4%), 100 (9.5%), 55 (5.3%), and 118 (11.2%), respectively. The 5-year DFS, OS, and CSS rates were 71.0%, 82.8%, and 88.7%, respectively. Our AI prognostic model showed that the areas under the curve of the receiver operating characteristic curves of DFS, OS, and CSS at 5 years were 0.890, 0.926, and 0.960, respectively. The AI prognostic model using XGBoost showed good prediction accuracy and provided accurate predictive probability of postoperative prognosis of NSCLC.

DOI： 10.1038/s41598-023-42964-8

Web of Science

Scopus

PubMed

記述言語：英語   出版者・発行元：Cancer Medicine  

Background: Immunotherapy has become a standard-of-care for patients with non-small-cell lung cancer (NSCLC). Although several biomarkers, such as programmed cell death-1, have been shown to be useful in selecting patients likely to benefit from immune checkpoint inhibitors (ICIs), more useful and reliable ones should be investigated. The prognostic nutritional index (PNI) is a marker of the immune and nutritional status of the host, and is derived from serum albumin level and peripheral lymphocyte count. Although several groups reported its prognostic role in patients with NSCLC receiving a single ICI, there exist no reports which have demonstrated its role in the first-line ICI combined with or without chemotherapy. Materials and Methods: Two-hundred and eighteen patients with NSCLC were included in the current study and received pembrolizumab alone or chemoimmunotherapy as the first-line therapy. Cutoff value of the pretreatment PNI was set as 42.17. Results: Among 218 patients, 123 (56.4%) had a high PNI (≥42.17), while 95 (43.6%) had a low PNI (<42.17). A significant association was observed between the PNI and both the progression-free survival (PFS; hazard ratio [HR] = 0.67, 95% confidence interval [CI]: 0.51–0.88, p = 0.0021) and overall survival (OS; HR = 0.46, 95% CI: 0.32–0.67, p < 0.0001) in the entire population, respectively. The multivariate analysis identified the pretreatment PNI as an independent prognosticator for the PFS (p = 0.0011) and OS (p < 0.0001), and in patients receiving either pembrolizumab alone or chemoimmunotherapy, the pretreatment PNI remained an independent prognostic factor for the OS (p = 0.0270 and 0.0006, respectively). Conclusion: The PNI might help clinicians appropriately identifying patients with better treatment outcomes when receiving first-line ICI therapy.

DOI： 10.1002/cam4.6110

Web of Science

Scopus

PubMed

記述言語：英語   出版者・発行元：Thoracic Cancer  

Main Problems: In non-small-cell lung cancer, ground-glass opacity on computed tomography imaging reflects pathological noninvasiveness and is a favorable prognostic factor. However, the significance of pathological noninvasive areas (NIAs) has not been fully revealed. In this study, we aimed to elucidate the prognostic impact of NIAs on lung adenocarcinoma. Methods: We analyzed 402 patients with pathological stage (p-Stage) IA lung adenocarcinoma who underwent surgery in 2013–2016 at two institutions and examined the association of the presence of NIAs with clinicopathological factors and prognosis. Furthermore, after using propensity-score matching to adjust for clinicopathological factors, such as age, sex, smoking history, pathological invasive area size, pathological T factor (p-T), p-Stage, and histological subtype (lepidic predominant adenocarcinoma [LPA] or non-LPA), the prognostic impact of NIAs was evaluated. Results: Patients were divided into NIA-present (N = 231) and NIA-absent (N = 171) groups. Multivariable analysis showed that NIA-present was strongly associated with earlier p-T, earlier p-Stage, LPA, and epidermal growth factor receptor mutation. Kaplan–Meier survival analysis showed that the NIA-present group displayed a better prognosis than the NIA-absent group in disease-free survival (DFS) and overall survival (OS) (5-year DFS 94.6% vs. 87.2%, 5-year OS 97.2% vs. 91.1%). However, after adjusting for clinicopathological factors by propensity score matching, no significant differences in prognosis were identified between the NIA-present and NIA-absent groups (5-year DFS 92.4% vs 89.6%, 5-year OS 95.6% vs 94.3%). Conclusions: Our current study suggests that the prognostic impact of the presence of NIAs on lung adenocarcinoma is due to differences in clinicopathological factors.

DOI： 10.1111/1759-7714.14910

Web of Science

Scopus

PubMed

DOI： 10.1245/s10434-023-13396-5

Web of Science

PubMed

記述言語：英語   出版者・発行元：Cancer Immunology, Immunotherapy  

Background: Ectopic lymphoid formations are called tertiary lymphoid structures (TLSs). TLSs in cancer have been reported to be associated with good prognosis and immunotherapy response. However, the relationship between TLSs and lymph node (LN) metastasis is unclear. Methods: We analyzed 218 patients with radically resected lung adenocarcinoma. TLSs were defined as the overlap of T cell zone and B cell zone. Granzyme B + cells were defined as cytotoxic lymphocytes. We evaluated phenotypes of lymphocytes in TLSs, tumor-infiltrating lymphocytes (TILs) and LNs by immunohistochemistry. We divided the patients into mature TLS (DC-Lamp high) and immature TLS (DC-Lamp low) groups. The relationship between TLS maturation and clinicopathological factors was analyzed. Results: The mature TLS group was associated with significantly lower frequency of LN metastasis (P < 0.0001) and early cancer stage (P = 0.0049). The mature TLS group had significantly more CD8 + (P = 0.0203) and Foxp3 + (P = 0.0141) cells in TILs than the immature TLS group had. Mature TLSs were independently associated with a favorable overall survival (hazard ratio [HR] = 0.17, P = 0.0220) and disease-free survival (HR = 0.54, P = 0.0436). Multivariate analysis showed that mature TLS was an independent low-risk factor for LN metastasis (odds ratio = 0.06, P = 0.0003). The number of cytotoxic lymphocytes in LNs was higher in the mature TLS group than in the immature group (20.0 vs. 15.1, P = 0.017). Conclusion: Mature TLSs were associated with an increased number of cytotoxic lymphocytes in draining LNs, a lower frequency of LN metastasis, and favorable outcomes. Mature TLSs may support antitumor immunity by lymphocyte activation.

DOI： 10.1007/s00262-022-03353-8

Web of Science

Scopus

PubMed

記述言語：英語   出版者・発行元：Annals of Surgical Oncology  

Background: Many inflammatory and nutritional markers have been used to predict prognosis in lung cancer. The C-reactive protein (CRP)-to-lymphocyte ratio (CLR) is a useful prognostic factor in various cancers. However, the prognostic value of preoperative CLR in patients with non-small cell lung cancer (NSCLC) remains to be established. We examined the significance of the CLR compared with known markers. Methods: A total of 1380 surgically resected NSCLC patients treated at two centers were recruited and divided into derivation and validation cohorts. After CLRs were calculated, patients were classified into high and low CLR groups based on the cutoff value determined by receiver operating characteristics curve analysis. Subsequently, we determined the statistical associations of the CLR with clinicopathological factors and prognosis and further analyzed its prognostic impact by propensity-score matching. Results: Of all the inflammatory markers examined, CLR yielded the highest area-under-the-curve value. The prognostic impact of CLR remained significant after propensity-score matching. Prognosis was significantly worse in the high-CLR group than in the low-CLR group (5-year, disease-free survival [DFS]: 58.1% vs. 81.9%, P < 0.001; 5-year overall survival [OS]: 72.1% vs. 91.2%, P < 0.001). The results were confirmed in the validation cohorts. Multivariable analysis also showed high CLR as an independent factor for both DFS and OS (DFS: hazard ratio [HR] 1.42, P = 0.027; OS: HR 1.95, P = 0.0037). Conclusions: Preoperative CLR is a useful marker for predicting the prognosis of NSCLC patients who have undergone surgery.

DOI： 10.1245/s10434-023-13250-8

Web of Science

Scopus

PubMed

記述言語：英語   掲載種別：研究論文（学術雑誌）  

記述言語：英語   出版者・発行元：Interdisciplinary cardiovascular and thoracic surgery  

OBJECTIVES: Sarcopenia correlates with poor prognosis in various malignancies. However, the prognostic significance of sarcopenia remains to be determined in patients with non-small-cell lung cancer who undergo surgery after receiving neoadjuvant chemoradiotherapy (NACRT). METHODS: We retrospectively reviewed the patients with stage II/III non-small-cell lung cancer who underwent surgery following NACRT. The paravertebral skeletal muscle area (SMA) (cm2) at the 12th thoracic vertebra level was measured. We calculated the SMA index (SMAI) as SMA/squared height (cm2/m2). Patients were divided into low and high SMAI groups, and the association of SMAI with clinicopathological factors and prognosis was assessed. RESULTS: The patients' [men, 86 (81.1%)] median age was 63 (21-76) years. There were 106 patients including 2 (1.9%), 10 (9.4%), 74 (69.8%), 19 (17.9%) and 1 (0.9%) patients with stage IIA, IIB, IIIA, IIIB and IIIC, respectively. Of the patients, 39 (36.8%) and 67 (63.2%) were classified in the low and the high SMAI groups, respectively. Kaplan-Meier analysis showed that the low group had a significantly shorter overall survival and disease-free survival than the high group. Multivariable analysis identified low SMAI as an independent poor prognostic factor for overall survival. CONCLUSIONS: Pre-NACRT SMAI correlates with poor prognosis; therefore, assessing sarcopenia based on pre-NACRT SMAI may help determine optimal treatment strategies and suitable nutritional and exercise interventions.

DOI： 10.1093/icvts/ivad020

Web of Science

Scopus

PubMed

記述言語：英語   掲載種別：研究論文（学術雑誌）  

記述言語：英語   出版者・発行元：Frontiers in Oncology  

Osimertinib is a standard therapy for the treatment of advanced non-small cell lung cancer (NSCLC) harboring epidermal growth factor receptor gene (EGFR) mutations, but most patients with EGFR-mutant NSCLC develop secondary resistance to osimertinib. Mesenchymal-epithelial transition gene (MET) alterations and oncogene fusions have been identified as the most common mechanisms of resistance to osimertinib. However, MET exon 14 skipping mutation (METex14del) as an acquired resistance to osimertinib has rarely been reported. A non-smoking 76-year-old woman was diagnosed with lung adenocarcinoma in the right lower lobe (cT2bN2M1c [pulmonary and bone metastases], cStage IVB). The primary tumor was submitted to cobas® EGFR Mutation Test v2 (Roche Diagnostics Ltd.), next generation sequencing (Oncomine Comprehensive Assay v3; Thermo Fisher Scientific), the AmoyDx® Essential NGS panel (Amoy Diagnostics, Xiamen, China), all of which were positive for EGFR L858R and de novo T790M. We administered daily osimertinib (80 mg/day), and achieved a partial response. However, after 14.0 months, computed tomography showed progression of the primary tumor and lung metastases. Re-biopsy of the primary tumor was conducted, and the specimen was submitted to Archer®MET companion diagnostic for detection of METex14del. Although the primary tumor was negative for METex14del, the re-biopsy specimen was positive for METex14del. We validated that the biopsy specimen of the primary tumor at diagnosis before osimertinib administration was negative for METex14del using local reverse transcription PCR. We administered daily tepotinib (500 mg/day) to the patient as a further-line treatment, and achieved a partial response (tumor shrinkage rate: 34.5%) after 2.0 months, who responded to tepotinib therapy for 8.0 months. We described a patient with lung adenocarcinoma harboring METex14del as a potential acquired resistance to osimertinib, who responded to subsequent tepotinib therapy. Re-biopsy and re-analysis of genetic profiles should be considered in NSCLC patients who develop osimertinib resistance.

DOI： 10.3389/fonc.2022.965741

Web of Science

Scopus

PubMed

記述言語：英語   出版者・発行元：Thoracic Cancer  

Background: Consolidation tumor ratio (CTR) is associated with cancer progression and histological invasiveness in lung adenocarcinoma (LAD). However, little is known about the association between CTR and immune-related factors, including tumor-infiltrating lymphocytes (TILs) density or tumor expression of programmed death ligand 1 (PD-L1) and indoleamine 2,3-dioxygenase 1 (IDO1) in small-sized LAD. Methods: This study included 258 patients with LAD (<3 cm) who underwent surgery. Patients were assigned to four groups: CTR = 0; 0 < CTR <0.5; 0.5 ≤ CTR <1 (ground-glass opacity [GGO] group); and CTR = 1 (pure-solid group). CD4+, CD8+, and FoxP3+ TIL density and PD-L1 and IDO1 tumor expression were assessed by immunohistochemistry. Results: Among the GGO group, CD8+ and FoxP3+ TIL density increased significantly with increasing CTR (p < 0.001 and p < 0.001, respectively). Moreover, PD-L1 and IDO1 expression was significantly higher in the pure-solid group than in the GGO group (p < 0.001 and p < 0.001, respectively). Conclusions: CTR was correlated with the abundance of CD8+ and FoxP3+ TILs in the GGO group. PD-L1 and IDO1 positivity rates were significantly higher in the pure-solid group than in the GGO group. Increased CTR may be correlated with immunosuppressive condition.

DOI： 10.1111/1759-7714.14524

Web of Science

Scopus

PubMed

Web of Science

記述言語：英語   出版者・発行元：BMJ Open  

Introduction Immunotherapy is the fourth leading therapy for lung cancer following surgery, chemotherapy and radiotherapy. Recently, several studies have reported about the potential association between the gut microbiome and therapeutic response to immunotherapy. Nevertheless, the specific composition of the gut microbiome or combination of gut microbes that truly predict the efficacy of immunotherapy is not definitive. Methods and analysis The present multicentre, prospective, observational study aims to discover the specific composition of the gut microbiome or combination of gut microbes predicting the therapeutic response to immunotherapy in lung cancer using artificial intelligence. The main inclusion criteria are as follows: (1) pathologically or cytologically confirmed metastatic or postoperative recurrent lung cancer including non-small cell lung cancer and small cell lung cancer; (2) age≥20 years at the time of informed consent; (3) planned treatment with immunotherapy including combination therapy and monotherapy, as the first-line immunotherapy; and (4) ability to provide faecal samples. In total, 400 patients will be enrolled prospectively. Enrolment will begin in 2021, and the final analyses will be completed by 2024. Ethics and dissemination The study protocol was approved by the institutional review board of each participating centre in 2021 (Kyushu Cancer Center, IRB approved No. 2021-13, 8 June 2021 and Kyushu Medical Center, IRB approved No. 21-076, 31 August 2021). Study results will be disseminated through peer-reviewed journals and national and international conferences. Trial registration number UMIN000046428.

DOI： 10.1136/bmjopen-2022-061674

Web of Science

Scopus

PubMed

DOI： 10.1016/j.annonc.2022.02.071

Web of Science

記述言語：英語   出版者・発行元：Anticancer Research  

Background/Aim: Sublobar resection is widely performed for early-stage non-small cell lung cancer in the clinical setting. This study evaluated the optimal surgical procedures of clinical stage 0 or IA adenocarcinoma from the perspective of recurrence. Patients and Methods: A total of 508 lung adenocarcinoma patients diagnosed as c-stage 0 or IA were retrospectively investigated. Results: The types of surgical procedures were lobectomy (n=328), segmentectomy (n=73), and wedge resection (n=107). Clinical T descriptors were cTis in 74, cT1mi in 68, cT1a in 94, cT1b in 181 and cT1c in 91 patients. Recurrence was observed in 46 cases (9%), including 3 (3.1%) with cT1a, 23 (12.7%) with cT1b and 20 (22.0%) with cT1c. The patients who received sublobar resection developed recurrence more often than the patients who received lobectomy among cT1b cases (10.1% vs. 21.4%) and cT1c cases (18.0% vs. 46.2%) (p=0.053 and p=0.023). Conclusion: The cT1b and cT1c cases should be considered for lobectomy to prevent recurrence.

DOI： 10.21873/anticanres.15577

Web of Science

Scopus

PubMed

記述言語：英語   掲載種別：研究論文（学術雑誌）  

記述言語：英語   掲載種別：研究論文（学術雑誌）  

記述言語：英語   掲載種別：研究論文（学術雑誌）  

記述言語：英語   掲載種別：研究論文（学術雑誌）  

開催年月日： 2024年4月

記述言語：日本語  

国名：日本国  

開催年月日： 2023年4月 - 2024年4月

記述言語：日本語  

開催地：グランドプリンスホテル新高輪   国名：日本国  

記述言語：日本語  

記述言語：日本語  

記述言語：日本語  

記述言語：日本語  

記述言語：日本語  

記述言語：日本語  

記述言語：日本語  

記述言語：日本語  

記述言語：日本語  

記述言語：日本語  

記述言語：日本語  

記述言語：日本語  

記述言語：日本語  

記述言語：日本語  

記述言語：日本語  

記述言語：日本語  

記述言語：日本語  

記述言語：日本語  

記述言語：日本語  

記述言語：英語  

記述言語：日本語  

記述言語：日本語  

記述言語：日本語  

記述言語：日本語  

記述言語：日本語  

記述言語：日本語  

記述言語：日本語  

記述言語：日本語  

記述言語：日本語  

記述言語：日本語  

記述言語：日本語  

記述言語：日本語  

記述言語：英語  

記述言語：日本語  

記述言語：日本語  

記述言語：英語  

記述言語：日本語  

記述言語：日本語  

記述言語：日本語  

記述言語：日本語  

記述言語：日本語  

記述言語：日本語  

記述言語：日本語  

記述言語：日本語  

記述言語：日本語  

記述言語：日本語  

記述言語：日本語  

記述言語：日本語  

記述言語：日本語  

記述言語：日本語  

記述言語：日本語  

記述言語：日本語  

記述言語：日本語  

記述言語：日本語  

記述言語：日本語  

記述言語：日本語  

記述言語：日本語  

記述言語：日本語  

記述言語：日本語  

記述言語：日本語  

記述言語：日本語  

記述言語：日本語  

記述言語：英語  

記述言語：日本語  

記述言語：日本語  

記述言語：日本語  

記述言語：日本語  

記述言語：日本語  

記述言語：日本語  

記述言語：日本語  

記述言語：日本語  

記述言語：日本語  

記述言語：日本語  

記述言語：日本語  

記述言語：日本語  

記述言語：英語  

記述言語：日本語  

記述言語：日本語  

記述言語：日本語  

記述言語：日本語  

記述言語：日本語  

記述言語：日本語  

記述言語：日本語  

記述言語：日本語  

記述言語：日本語  

記述言語：日本語  

記述言語：日本語  

記述言語：日本語  

記述言語：日本語  

記述言語：日本語  

記述言語：日本語  

記述言語：日本語  

記述言語：日本語  

記述言語：日本語  

記述言語：日本語  

記述言語：日本語  

記述言語：英語  

記述言語：日本語  

記述言語：日本語  

記述言語：日本語  

記述言語：日本語