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Interstitial pneumonia (IP) is a refractory disease that causes severe inflammation and fibrosis in the interstitium of the lungs, often resulting in the development of lung cancer (LC) during treatment. Previous studies have demonstrated that the prognosis of LC complicated by IP is inferior to that of LC without IP. It is therefore of the utmost importance to gain a deeper understanding of the heterogeneity of such tumors. In the present study, we conducted spatial transcriptome analysis of squamous cell carcinoma arising from IP. The results suggested involvement of the glucocorticoid receptor pathway in treatment resistance. Immunostaining of squamous cell carcinoma specimens from patients with IP demonstrated that the tumors expressed NR3C1 to varying degrees. Furthermore, higher NR3C1 expression levels were associated with a significantly increased risk of recurrence. Our results point to a novel subtype of lung squamous cell carcinoma. Further analysis of the molecular mechanisms associated with this subtype may facilitate the development of novel diagnostic criteria and therapeutic approaches., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2025 The Authors. Published by Elsevier GmbH.. All rights reserved.)

Micropapillary adenocarcinoma (MPC) is an aggressive histological subtype of lung adenocarcinoma (LUAD). MPC is composed of small clusters of cancer cells exhibiting inverted polarity. However, the mechanism underlying its formation is poorly understood. Here we show that hypoxia is involved in MPC formation. Hypoxia induced the formation of MPC-like structures (MLSs) in a three-dimensional culture system using A549 human LUAD cells, and HIF-1α was indispensable for MLS formation. RNA sequencing analysis demonstrated that A549 cells forming MLSs exhibited a gene expression signature similar to that of lung MPC. Moreover, MLS formation enhanced the resistance of A549 cells to natural killer cell cytotoxicity. Our findings suggest that hypoxia drives lung MPC formation through HIF-1α and that immune escape from natural killer cells might underlie the aggressiveness of MPC., Competing Interests: Declarations. Competing interests: The authors declare no competing interests. Ethical approval: All experimental protocols involving human specimens were approved by the Ethics Review Board of the Graduate School of Medicine, Osaka University (approval no. 15234) and carried out in accordance with the committee’s guidelines and regulations. The study was performed in accordance with the Declaration of Helsinki., (© 2024. The Author(s).)

Isolation of tumor-specific T cells and their antigen receptors (TCRs) from malignant pleural effusions (MPE) may facilitate the development of TCR-transduced adoptive cellular immunotherapy products for advanced lung cancer patients. However, the characteristics and markers of tumor-specific T-cells in MPE are largely undefined. To this end, to establish the phenotypes and antigen specificities of CD8 + T cells, we performed single-cell RNA and TCR sequencing of samples from three advanced lung cancer patients. Dimensionality reduction on a total of 4,983 CD8 + T cells revealed 10 clusters including naïve, memory, and exhausted phenotypes. We focused particularly on exhausted T cell clusters and tested their TCR reactivity against neoantigens predicted from autologous cancer cell lines. Four different TCRs specific for the same neoantigen and one orphan TCR specific for the autologous cell line were identified from one of the patients. Differential gene expression analysis in tumor-specific T cells relative to the other T cells identified CXCL13 , as a candidate gene expressed by tumor-specific T cells. In addition to expressing CXCL13 , tumor-specific T cells were present in a higher proportion of T cells co-expressing PDCD1 (PD-1)/ TNFRSF9 (4-1BB). Furthermore, flow cytometric analyses in advanced lung cancer patients with MPE documented that those with high PD-1/4-1BB expression have a better prognosis in the subset of 57 adenocarcinoma patients ( p  = .039). These data suggest that PD-1/4-1BB co-expression might identify tumor-specific CD8 + T cells in MPE, which are associated with patients' prognosis. (233 words)., Competing Interests: This study was partly funded by NEC Corporation., (© 2024 The Author(s). Published with license by Taylor & Francis Group, LLC.)

Objectives: While segmentectomy is considered a viable option for small peripheral non-small-cell lung cancer, its efficacy for central lesions remains uncertain. This study aimed to assess the oncological outcomes of segmentectomy for central lesions compared to peripheral ones., Methods: We retrospectively examined 338 clinical stage IA non-small-cell lung cancer patients who underwent thoracoscopic anatomical segmentectomy at our institution from January 2013 to December 2021. Patients were divided into 2 groups based on intrapulmonary tumour location: inner two-thirds (central group, n = 82) and outer one-third (peripheral group, n = 256)., Results: The gender, body mass index, performance score, smoking, comorbidities and preoperative pulmonary function were similar in both groups. On computed tomography images, tumour diameter and consolidation-to-tumour ratio were comparable between the groups. The central group had significantly greater tumour-to-pleura distances [mm, 23 (18-27) vs 11 (8-14); P < 0.001], shorter margin distances [mm, 20 (15-20) vs 20 (20-20); P < 0.001] and larger resected lung volumes based on subsegment count [4 (3-6) vs 3 (3-5); P = 0.004] than the peripheral group. Surgery duration, bleeding, hospitalization or drainage period, mortality, readmission and pathological stage were equivalent between the groups. The central group showed significantly more postoperative pleural effusions (5% vs 1%; P = 0.03) than the peripheral group, with no adverse impact on postoperative pulmonary functions. During the follow-up period, local-only recurrence rates were 0% and 8% in the respective groups (Gray test P = 0.07), and total recurrence rates were 6% and 11% (Gray test P = 0.70), with no significant differences. Moreover, no significant inter-group difference in overall survival rates was observed (82% vs 93%; P = 0.15)., Conclusions: Segmentectomy may be a promising therapeutic option for early-stage non-small-cell lung cancer located in the inner two-thirds of the parenchyma., (© The Author(s) 2024. Published by Oxford University Press on behalf of the European Association for Cardio-Thoracic Surgery. All rights reserved.)

Whether circulating levels of specific cytokines at baseline link with treatment efficacy of immune checkpoint blockade (ICB) therapy in patients with non-small cell lung cancer remains unknown. In this study, serum samples were collected in two independent, prospective, multicenter cohorts before the initiation of ICB. Twenty cytokines were quantified, and cutoff values were determined by receiver operating characteristic analyses to predict non-durable benefit. The associations of each dichotomized cytokine status with survival outcomes were assessed. In the discovery cohort (atezolizumab cohort; N = 81), there were significant differences in progression-free survival (PFS) in accordance with the levels of IL-6 (log-rank test, P = 0.0014), IL-15 (P = 0.00011), MCP-1 (P = 0.013), MIP-1β (P = 0.0035), and PDGF-AB/BB (P = 0.016). Of these, levels of IL-6 and IL-15 were also significantly prognostic in the validation cohort (nivolumab cohort, N = 139) for PFS (log-rank test, P = 0.011 for IL-6 and P = 0.00065 for IL-15) and overall survival (OS; P = 3.3E-6 for IL-6 and P = 0.0022 for IL-15). In the merged cohort, IL-6 high and IL-15 high were identified as independent unfavorable prognostic factors for PFS and OS. The combined IL-6 and IL-15 status stratified patient survival outcomes into three distinct groups for both PFS and OS. In conclusion, combined assessment of circulating IL-6 and IL-15 levels at baseline provides valuable information to stratify the clinical outcome of patients with non-small cell lung cancer treated with ICB. Further studies are required to decipher the mechanistic basis of this finding., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Background: CD8 + tumor infiltrating lymphocytes (TILs) are often observed in non-small cell lung cancers (NSCLC). However, the characteristics of CD8 + TILs, especially T-cell populations specific for tumor antigens, remain poorly understood., Methods: High throughput single-cell RNA sequencing and single-cell T-cell receptor (TCR) sequencing were performed on CD8 + TILs from three surgically-resected lung cancer specimens. Dimensional reduction for clustering was performed using Uniform Manifold Approximation and Projection. CD8 + TIL TCR specific for the cancer/testis antigen KK-LC-1 and for predicted neoantigens were investigated. Differentially-expressed gene analysis, Gene Set Enrichment Analysis (GSEA) and single sample GSEA was performed to characterize antigen-specific T cells., Results: A total of 6998 CD8 + T cells was analyzed, divided into 10 clusters according to their gene expression profile. An exhausted T-cell (exhausted T (Tex)) cluster characterized by the expression of ENTPD1 (CD39), TOX , PDCD1 (PD1), HAVCR2 (TIM3) and other genes, and by T-cell oligoclonality, was identified. The Tex TCR repertoire (Tex-TCRs) contained nine different TCR clonotypes recognizing five tumor antigens including a KK-LC-1 antigen and four neoantigens. By re-clustering the tumor antigen-specific T cells (n=140), it could be seen that the individual T-cell clonotypes were present on cells at different stages of differentiation and functional states even within the same Tex cluster. Stimulating these T cells with predicted cognate peptide indicated that TCR signal strength and subsequent T-cell proliferation and cytokine production was variable but always higher for neoantigens than KK-LC-1., Conclusions: Our approach focusing on T cells with an exhausted phenotype among CD8 + TILs may facilitate the identification of tumor antigens and clarify the nature of the antigen-specific T cells to specify the promising immunotherapeutic targets in patients with NSCLC., Competing Interests: Competing interests: This study was partly funded by NEC Corporation., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Among anatomical sublobar resection techniques for non-small cell lung cancer (NSCLC), the clinical benefit of subsegmentectomy remains unclear. We investigated whether anatomical sublobar resection including subsegmentectomy-segmental resection with subsegmental additional resection or subsegmental resection alone-is an effective and feasible surgical procedure for NSCLC., Methods: We retrospectively reviewed data of 285 patients with clinical stage I NSCLC who underwent anatomical sublobar resection at our institution from January 2013 to March 2021 and compared surgical outcomes between patients who underwent anatomical sublobar resection including (IS; n = 50) and excluding (ES; n = 235) subsegmentectomy., Results: No significant intergroup differences were noted in terms of age, sex, smoking, comorbidities, tumor size or location, consolidation tumor ratio, and preoperative pulmonary function. The IS group had more preoperative computed tomography-guided markings (34 vs. 15%; p = .004) and smaller resected lung volumes converted to the total subsegment number [3 (2-4) vs. 3 (3-6); p = .02] than the ES group. No significant differences in margin distance [mm, 20 (15-20) vs. 20 (20-20); p = .93], readmission rate (2% vs. 3%; p > .99), and intraoperative (8% vs. 7%; p = .77) or postoperative (8% vs. 10%; p = .80) complication rates were observed, and the 5-year local recurrence-free survival (91% vs. 90%; p = .92) or postoperative pulmonary function change were comparable between both groups., Conclusions: Although further investigations are required, anatomical sublobar resection including subsegmentectomy for clinical stage I NSCLC could be an acceptable therapeutic option., (© 2023. The Author(s) under exclusive licence to Société Internationale de Chirurgie.)

Purpose: Identifying patients at high risk of immune-related adverse events (irAEs) that impede the achievement of durable efficacy of programmed cell death 1 (PD-1)/programmed death ligand 1 (PD-L1) blockade therapy is important in improving their management. Identification of a novel predictive factor of therapeutic benefit is also important in improving patient selection for treatment with PD-1/PD-L1 inhibitors. Further determinants driving response and linking with irAEs are urgently required., Methods: To address these unmet needs in the field, we explored whether 27 soluble checkpoint proteins and immunomodulatory proteins in serum at the therapy baseline and after week 3 were associated with irAE onset and therapeutic efficacy using MILLIPLEX Human Immuno-Oncology Checkpoint Protein Panel assays in a prospective, multicenter cohort of 81 patients with non-small cell lung cancer (NSCLC) receiving atezolizumab monotherapy., Results: By competing-risks regression analysis, we identified that high levels of B cell-activating factor (BAFF) at baseline were a significant and strong risk factor of irAEs (hazard ratio, 5.61; 95% confidence interval, 2.43-12.96; P < 0.0001). We also identified that increased inducible T cell co-stimulator (ICOS) during the first therapeutic cycle was an independent factor associated with prolonged progression-free survival and overall survival., Conclusion: These findings are in keeping with the reported mechanistic basis of these molecules and may provide potential guidance for clinical decision-making to improve patient care. Further validation studies are warranted. Trial registration UMIN000035616 (January 28, 2019)., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Alveolar macrophages (AMs) are crucial for maintaining normal lung function. They are abundant in lung cancer tissues, but their pathophysiological significance remains unknown. Here we show, using an orthotopic murine lung cancer model and human carcinoma samples, that AMs support cancer cell proliferation and thus contribute to unfavourable outcome. Inhibin beta A (INHBA) expression is upregulated in AMs under tumor-bearing conditions, leading to the secretion of activin A, a homodimer of INHBA. Accordingly, follistatin, an antagonist of activin A is able to inhibit lung cancer cell proliferation. Single-cell RNA sequence analysis identifies a characteristic subset of AMs specifically induced in the tumor environment that are abundant in INHBA, and distinct from INHBA-expressing AMs in normal lungs. Moreover, postnatal deletion of INHBA/activin A could limit tumor growth in experimental models. Collectively, our findings demonstrate the critical pathological role of activin A-producing AMs in tumorigenesis, and provides means to clearly distinguish them from their healthy counterparts., (© 2023. The Author(s).)

Aim: This study aims to evaluate Japanese patients' preferences in first-line therapy choice for advanced non-small cell lung cancer(NSCLC)with epidermal growth factor receptor(EGFR)mutations., Methods: A cross-sectional discrete-choice experiment was conducted on advanced NSCLC patients in Japan. Participants completed the online questionnaire that included different levels of 5 treatment attributes: time to disease progression, chance of rash, next therapy option, frequency of health care visits and administration route. The primary analysis estimated the relative attribute importance. The preferences of EGFR mutation-positive patients were compared with those of EGFR mutation-negative/unknown patients to observe whether preference differs by mutation status., Results: A total of 158 participants completed the survey. The analysis on the overall study population revealed next therapy option(mean relative attribute importance[SD]: 39.30 [17.07])as the most important attribute, followed by time to disease progression(25.52[10.51]), chance of rash(21.58 [11.74]), with administration route(7.63[6.99])and frequency of health care visits(5.96[3.40])the least preferred. The results in the subgroups by EGFR mutation status were similar., Conclusion: Next therapy option is the major influencing factor for treatment choice of molecular targeting therapy among advanced NSCLC patients in Japan, emphasizing the importance of communicating the next treatment options to patients at the time of their first treatment.

Objectives: For successful nodule localization and appropriate surgical margin distances in pulmonary segmentectomy for patients with lung malignancies, the effectiveness and feasibility of preoperative marking using an indigo carmine and lipiodol mixture remain unclear., Methods: Patients who underwent thoracoscopic pulmonary segmentectomy with (marking group, n = 69) and without (non-marking group, n = 265) preoperative marking at our institution from January 2013 to March 2020 were retrospectively reviewed and compared in terms of surgical outcomes. All markings were performed using a fine needle to percutaneously inject an indigo carmine and lipiodol mixture under the guidance of computed tomography fluoroscopy., Results: Successful localization was achieved in 66 (96%) patients, of whom 62 (94%) underwent dye pigmentation and 4 (6%) underwent intraoperative fluoroscopy. On images, the marking group showed a significantly longer distance between the lung surface and tumour [mm, 9 (1-17) vs 0 (0-10); P < 0.01] and smaller maximum tumour size [mm, 16 (11-21) vs 17 (13-23); P = 0.03] and consolidation tumour ratio [0.4 (0.3-1) vs 0.8 (0.4-1); P < 0.01] than the non-marking group. Both groups had comparable operative outcomes, perioperative complications, pulmonary function changes and surgical margin distances [mm, 20 (15-21) vs 20 (15-20); P = 0.96] without any local recurrence on the surgical margin. Propensity score-matching analysis also showed similar findings for both groups., Conclusions: Thoracoscopic pulmonary segmentectomy with preoperative marking using an indigo carmine and lipiodol mixture may be an acceptable therapeutic option for small malignancies located in deep lung parenchyma., (© The Author(s) 2022. Published by Oxford University Press on behalf of the European Association for Cardio-Thoracic Surgery. All rights reserved.)

Background: A better understanding of the tumor immune microenvironment (TIME) will facilitate the development of prognostic biomarkers and more effective therapeutic strategies in patients with lung cancer. However, little has been reported on the comprehensive evaluation of complex interactions among cancer cells, immune cells, and local immunosuppressive elements in the TIME., Methods: Whole-exome sequencing and RNA sequencing were carried out on 113 lung cancers. We performed single sample gene set enrichment analysis on TIME-related gene sets to develop a new scoring system (TIME score), consisting of T-score ( t umor proliferation), I-score (antitumor i mmunity) and S-score (immuno s uppression). Lung cancers were classified according to a combination of high or low T-score, I-score, and S-scores (eight groups; G1-8). Clinical and genomic features, and immune landscape were investigated among eight groups. The external data sets of 990 lung cancers from The Cancer Genome Atlas and 76 melanomas treated with immune checkpoint inhibitors (ICI) were utilized to evaluate TIME scoring and explore prognostic and predictive accuracy., Results: The representative histological type including adenocarcinoma and squamous cell carcinoma, and driver mutations such as epidermal growth factor receptor and TP53 mutations were different according to the T-score. The numbers of somatic mutations and predicted neoantigens were higher in T hi (G5-8) than T lo (G1-4) tumors. Immune selection pressure against neoantigen expression occurred only in T hi and was dampened in T hi /I lo (G5-6), possibly due to a reduced number of T cells with a high proportion of tumor specific but exhausted cells. T hi /I lo /S hi (G5) displayed the lowest immune responses by additional immune suppressive mechanisms. The T-score, I-score and S-scores were independent prognostic factors, with survival curves well separated into eight groups with G5 displaying the worst overall survival, while the opposite group T lo /I hi /S lo (G4) had the best prognosis. Several oncogenic signaling pathways influenced on T-score and I-scores but not S-score, and PI3K pathway alteration correlated with poor prognosis in accordance with higher T-score and lower I-score. Moreover, the TIME score predicted the efficacy of ICI in patients with melanoma., Conclusion: The TIME score capturing complex interactions among tumor proliferation, antitumor immunity and immunosuppression could be useful for prognostic predictions or selection of treatment strategies in patients with lung cancer., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Lipids have immunomodulatory functions and the potential to affect cancer immunity., Methods: The associations of pretreatment serum cholesterol and long-chain fatty acids with the objective response rate (ORR), progression-free survival (PFS), and overall survival (OS) were evaluated in 148 patients with non-small cell lung cancer who received nivolumab., Results: When each lipid was separately evaluated, increased low-density lipoprotein (LDL)-cholesterol (P < 0.001), high-density lipoprotein (HDL)-cholesterol (P = 0.014), total cholesterol (P = 0.007), lauric acid (P = 0.015), myristic acid (P = 0.022), myristoleic acid (P = 0.035), stearic acid (P = 0.028), linoleic acid (P = 0.005), arachidic acid (P = 0.027), eicosadienoic acid (P = 0.017), dihomo-γ-linolenic acid (P = 0.036), and behenic acid levels (P = 0.032) were associated with longer PFS independent of programmed death ligand 1 (PD-L1) expression. Meanwhile, increased LDL-cholesterol (P < 0.001), HDL-cholesterol (P = 0.009), total cholesterol (P = 0.036), linoleic acid (P = 0.014), and lignoceric acid levels (P = 0.028) were associated with longer OS independent of PD-L1 expression. When multiple lipids were evaluated simultaneously, LDL-cholesterol (P = 0.003), HDL-cholesterol (P = 0.036), and lauric acid (P = 0.036) were independently predictive of PFS, and LDL-cholesterol (P = 0.008) and HDL-cholesterol (P = 0.031) were predictive of OS. ORR was not associated with any serum lipid., Conclusions: Based on the association of prolonged survival in patients with increased serum cholesterol and long-chain fatty acid levels, serum lipid levels may be useful for predicting the efficacy of immune checkpoint inhibitor therapy., (© 2021. The Author(s).)

Epidermal growth factor receptor(EGFR)is a transmembrane receptor tyrosine kinase that plays an important role in regulating the growth and progression of cancer via signalling pathways. This review summarizes the differences in EGFR kinase structural changes, stability of active forms, and phosphorylation inhibitory effects of EGFR tyrosine kinase inhibitors between the exon 19 deletion mutation and the exon 21 L858R point mutation, which are frequently detected EGFR mutations in patients with non-small cell lung cancer.

Background: Human epidermal growth factor receptor 2 (HER2) is tyrosine kinase receptor that belongs to the ErbB family and is overexpressed on the membrane surface of various cancer cells, including small cell lung cancer (SCLC); however, no HER2 targeted therapy for SCLC have yet been established. Near-infrared photoimmunotherapy (NIR-PIT) is a novel cancer therapy based on photo-absorber, IRDye-700DX (IR700), -antibody conjugates, and near-infrared (NIR) light., Methods: We used HER2-positive SCLC parental cell lines (SBC-3) and its chemoresistant cell lines, and examined therapeutic efficacy of HER2 targeting NIR-PIT using anti HER2 antibody trastuzumab., Results: We found that HER2 expression was upregulated on chemoresistant cell lines, especially cisplatin-resistance (SBC-3/CDDP). In vitro, the rate of cell death increased with the amount of NIR-light irradiation, and it was significantly higher in SBC-3/CDDP than in SBC-3. In vivo, tumor growth was more suppressed in SBC-3/CDDP group than in SBC-3 group, and survival period tended to be prolonged., Conclusion: In this study, we demonstrated that HER2 targeting NIR-PIT using trastuzumab is promising therapy for HER2-positive SCLC, and is more effective when HER2 expression is upregulated due to CDDP resistance, suggesting that the HER2 expression level positively corelated with the efficacy of NIR-PIT., (© 2021 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

Background: Clinical efficacy of immune checkpoint inhibitors (ICIs) for non-small cell lung cancer (NSCLC) with uncommon histology (uNSCLC) is unknown., Methods: Patients with NSCLC treated with ICI monotherapy between January 2014 and December 2018 in 10 Japanese hospitals were retrospectively evaluated. The patients were divided into: (1) NSCLC with common histology (cNSCLC), defined as adenocarcinoma and squamous cell carcinoma; and (2) uNSCLC, defined as incompatibility with morphological and immunohistochemical criteria for adenocarcinoma or squamous cell carcinoma. Propensity score matching was performed to balance the two groups., Results: Among a total of 175 patients included, 44 with uNSCLC (10 pleomorphic carcinomas, 9 large cell neuroendocrine carcinomas, 2 large cell carcinomas, and 23 not otherwise specified) and 44 with matched cNSCLC (32 adenocarcinomas and 12 squamous cell carcinomas) were selected for analyses. Median progression-free survival (PFS) (4.4 months, 95% confidence interval [CI] 1.8-7.7 months) and overall survival (OS) (11.4 months, 95% CI 7.4-27.4 months) in the uNSCLC patients were not significantly different from those in matched cNSCLC patients (5.4 months, 95% CI 3.1-7.6 months, p = 0.761; and 14.1 months, 95% CI 10.6-29.6 months, p = 0.381). In multivariate analysis, Eastern Cooperative Oncology Group performance status (ECOG-PS) of 0-1 and programmed death ligand-1 (PD-L1) expression were predictive for PFS and OS in uNSCLC., Conclusions: ICIs had similar clinical efficacy for treatment of uNSCLC and cNSCLC. Good ECOG-PS and PD-L1 expression were predictive for efficacy of ICIs in uNSCLC., (© 2021. The Author(s).)

Background: Invasive mucinous adenocarcinoma (IMA) is a rare subtype of invasive lung adenocarcinoma. However, the clinical course and prognostic outcomes following IMA resection, particularly postoperative recurrence, remain unclear., Methods: We pathologically reevaluated 1362 lung adenocarcinoma resections performed at our institution, categorizing cases into the IMA group (72 cases) and non-IMA group (1290 cases). The IMA group was further classified into pneumonia and nodular types based on preoperative computed tomography., Results: Overall, the IMA group had lower carcinoembryonic antigen levels (3 vs 8 ng/mL; P < .01), fewer lymph node metastasis (4% vs 24%; P < .01), and more KRAS mutations (56% vs 7%; P < .01) than the non-IMA group. Although postoperative recurrence rates did not differ between both groups (32% vs 27%; P = 0.35), lung recurrence occurred more frequently in the IMA group (83% vs 17%; P < .01). Propensity score-matched pair analysis showed that the IMA group had fewer lymph node metastasis (3% vs 35%; P < .01), more KRAS mutations (56% vs 9%; P < .01), and higher intrapulmonary recurrence rate (84% vs 31%; P < .01) than the non-IMA group. The 5-year overall survival rates did not differ between both groups (74% vs 81%; P = 0.26). However, among patients with intrapulmonary recurrence, those in the IMA group had significantly worse prognosis than those in the non-IMA group (35% vs 77%; P < .01)., Conclusions: Intrapulmonary recurrence, which induced significantly worse prognosis, was more likely to occur in the IMA than non-IMA group., (Copyright © 2021 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.)

A 79-year-old woman was referred to our facility because of an abnormal chest shadow. Chest computed tomography (CT) showed a solitary right middle lung nodule with a maximum diameter of 3 mm and anterior mediastinal nodule with a maximum diameter of 21 mm. The lung nodule was suspected of being a primary lung cancer rather than a metastatic tumor because there were no primary malignant tumors, apart from an anterior mediastinal tumor visible on diagnostic imaging, including F 18 fluorodeoxyglucose-positron emission tomography, and a solitary lung nodule. Partial lung resection by video-assisted thoracoscopic surgery (VATS) was performed, and the intraoperative frozen section of the tumor tissue resulted in a diagnosis of carcinoid tumor. As a result, right middle lobectomy by VATS was performed. The final histological diagnosis of the permanent specimen was intrapulmonary type A thymoma. VATS thymectomy was performed three months later. The histological diagnosis was type A thymoma with intrapulmonary metastasis (Masaoka stage IVb). Additional therapy was not performed because complete resection was achieved. Follow-up CT was performed once every six months after the operation. The patient has been followed up for one year without any further recurrence., (© 2021 The Authors. Thoracic Cancer published by China Lung Oncology Group and John Wiley & Sons Australia, Ltd.)

Epidermal growth factor receptor(EGFR)is a transmembrane receptor tyrosine kinase the signaling of which is important for growth and progression of cancer. An exon 19 deletion mutation and an exon 21 L858R point mutation are frequently detected as EGFR mutations in patients with non‒small cell lung cancer. This review summarizes the differences in epidemiological, nonclinical, and clinical characteristics between the exon 19 deletion mutation and the exon 21 L858R point mutation.

Objectives: Despite the ubiquitous utilization of anatomical sublobar resection for malignant lung tumors, the effectiveness and feasibility of subsegmentectomy remains unclear. This study therefore compared the perioperative outcomes between anatomical sublobar resection including (IS) and excluding (ES) subsegmentectomy., Methods: Patients who had undergone anatomical sublobar resection at our institution from January 2013 to March 2019 were retrospectively reviewed. Clinicopathologic characteristics and perioperative outcomes of the IS group (n = 58) were then analyzed the compared to those of the ES group (n = 203)., Results: No statistically significant differences in age, sex, comorbidities, tumor location, preoperative pulmonary function, or tumor size on imaging were found between both groups. The IS group had significantly higher preoperative computed tomography-guided marking rates (40% vs. 18%; p < 0.01) and used significantly more staplers for intersegmental dissection than the ES group [4, interquartile range (IQR): 3-4 vs. 3, IQR: 3-4; p = 0.03]. Both groups had comparable 30-day mortality (0% vs. 0%; p > 0.99), intraoperative complications (7% vs. 10%; p = 0.61), and postoperative complications (5% vs. 8%; p = 0.58). After propensity score matching, the IS group experienced significantly lesser blood loss than the ES group (5 mL, IQR: 1-10 vs. 5 mL, IQR: 5-20; p = 0.03). Both groups experienced no local recurrence and demonstrated similar postoperative pulmonary functions after surgery., Conclusions: IS may be a feasible and acceptable therapeutic option for malignant lung tumors. Nonetheless, future investigations are required to further validate the current findings.

Background: We previously reported useful methods that can be implemented to identify intersegmental boundary lines (IBLs) by using an intravenous indocyanine green (ICG) fluorescence imaging system (ICG-FS) during a thoracoscopic anatomical segmentectomy (TAS). The aim of this study was to evaluate the recently released third-generation ICG-FS that features an emphasizing xenon-light source for IBL identification., Methods: We prospectively studied cases involving 106 consecutive patients who underwent TAS. Intraoperatively, we used the third-generation ICG-FS, the conventional ICG methods (CIM) emphasizing xenon-light (CIM-X), and the spectra-A method (SAM) emphasizing xenon-light (SAM-X), for IBL identification. Furthermore, 16 of the 106 patients (15%) could be simultaneously evaluated using old-generation ICG-FSs, CIM, and SAM. All images were completely quantified for illuminance and for three colors, red, green, and blue., Results: IBLs were successfully identified in all the patients (100%) with no adverse events. The SAM-X significantly increased the illuminance, especially in the resecting segments, compared to the CIM (39.0 versus 22.2, P < 0.01) and SAM (39.0 versus 29.3, P < 0.01), with enhanced red color compared to the CIM (33.1 versus 21.9, P < 0.01) and SAM (33.1 versus 14.0, P < 0.01). Furthermore, the SAM-X significantly increased the illuminance contrast compared to the CIM-X (34.1 versus 15.3, P < 0.01)., Conclusions: The present study suggests that the SAM-X potentially provided images with the highest visibility and colorfulness compared to the older generation ICG-FSs or CIM-X. Secure IBL identification can be more easily and safely performed using the SAM-X., (Copyright © 2020 Elsevier Inc. All rights reserved.)

The efficacy and safety of combination therapy with erlotinib and bevacizumab in elderly patients with non-small-cell lung cancer (NSCLC) harboring epidermal growth factor receptor (EGFR) gene mutations are unknown. Elderly patients aged ≥75 years old with advanced or recurrent NSCLC and EGFR mutations (exon 19 deletion or L858R mutation in exon 21) received erlotinib (150 mg, daily) and bevacizumab (15 mg/kg on day 1 of a 21-day cycle) until disease progression or the occurrence of unacceptable toxicities. The primary endpoint was progression-free survival from enrollment. Twenty-five patients were enrolled in this study, and the median age was 80 years. Fifteen (60.0%) and 10 patients (40.0%) had exon 21 L858R mutations and exon 19 deletions, respectively. The median progression-free survival from enrollment was 12.6 months [95% confidence interval (CI): 8.0-33.7 months]. The objective response rate was 88.0% [95% CI: 74.0%-99.0%], and the disease control rate was 100% [95% CI: 88.7%-100%]. Grade 3 or higher adverse events occurred in 12 patients (48.0%), and rash and nausea were the most common. Grade 3 or higher bevacizumab-related toxicities occurred in 4 (16.0%) patients, including proteinuria (n = 2), gastrointestinal perforation (n = 1) and pneumothorax (n = 1). A dose reduction of erlotinib and cessation of bevacizumab was required in 16 (64.0%) and 18 patients (72.0%), respectively. Erlotinib and bevacizumab combination therapy showed a minimal survival benefit with frequent dose reductions and/or treatment discontinuations in elderly patients with EGFR-positive NSCLC.

Importance: Robust predictors for response to anti-programmed death 1 and its ligand (PD-1/PD-L1) immunotherapy in non-small cell lung cancer (NSCLC) are not fully characterized., Objective: To evaluate whether PD-L1 (CD274) copy number gains (CNGs), comprising amplification and polysomy, in pretreatment specimens assessed by fluorescence in situ hybridization are associated with response to nivolumab monotherapy in NSCLC., Design, Setting, and Participants: This multicenter cohort study enrolled 200 patients, of whom 194 had assessable tumors, with advanced or recurrent NSCLC who were treated with nivolumab after progression following prior treatment at 14 institutions in Japan between July 2016 and December 2018. Median (interquartile range) duration of follow-up was 12.6 (5.6-20.4) months. Data were analyzed from December 2019 to February 2020., Exposures: Sequential nivolumab was given on day 1 of a 14-day cycle. Response was assessed every 4 cycles using Response Evaluation Criteria in Solid Tumors version 1.1., Main Outcomes and Measures: Overall response rate (ORR) according to the PD-L1 copy number status. Additional end points were progression-free survival, overall survival, and PD-L1 tumor proportion score (TPS) assessed by immunohistochemistry based on PD-L1 copy number status., Results: A total of 6 of the 200 patients were excluded because of poor-quality tumor specimens for the biomarker study, resulting in 194 assessable patients. Of these, 155 (79.9%) were men, with a median (range) age of 69 (43-83) years. PD-L1 CNGs were identified in 32 patients (16.5%), including 5 (2.6%) with amplification and 27 (13.9%) with polysomy. The ORR among patients with and without PD-L1 CNGs was 28.1% (95% CI, 13.7%-46.7%) and 17.9% (95% CI, 12.3%-24.7%), respectively. Although patients with PD-L1 polysomy did not demonstrate improved ORR (18.5% [95% CI, 6.3%-38.1%]) compared with those without PD-L1 CNGs, 4 of 5 patients (80.0% [95% CI, 28.4%-99.5%]) with PD-L1 amplification showed response, among whom median duration of response was not reached. Patients with PD-L1 amplification showed excellent survival outcomes for progression-free and overall survival. Overall, 3 PD-L1-amplified tumors (60.0%) showed PD-L1 TPS of at least 80%, but 2 (40.0%) had PD-L1 TPS of 15% or less., Conclusions and Relevance: In this study, tumor PD-L1 amplification but not polysomy was associated with response to nivolumab monotherapy among patients with NSCLC. External validation with a larger sample size is warranted.

Introduction: Programmed cell death protein 1 immune checkpoint inhibitors (ICIs) have been reported to improve the survival of patients with NSCLC. On the expansion of clinical administration for a variety of cancers, immune-related adverse events have been typically recognized to be associated with ICIs, therefore, necessitating the monitoring and management of these patients. Among immune-related adverse events, immune-related interstitial lung disease (ir-ILD) is a serious complication that interrupts treatment and can occasionally be fatal. However, no prospective studies have investigated the incidence of ir-ILD and associated risk factors for its development in the clinical setting., Methods: This is a prospective cohort study consisting of patients with NSCLC treated with ICIs. Baseline characteristics, including laboratory data, pulmonary function tests, daily symptoms of dyspnea defined by the modified Medical Research Council, and antitumor response were assessed., Results: Among the 138 patients with NSCLC who received anti-programmed cell death protein 1 monotherapy, 20 patients (14.5%) had ir-ILD within median 51.5 days (interquartile range: 29-147). This was approximately three times higher than those in clinical trials. A total of 11 patients (55.0%), including all eight patients with high-grade ir-ILD (≥grade 3), developed ir-ILD within 60 days. Impaired spirometry, decreased forced vital capacity and forced expiratory volume in 1 second, and daily symptoms of dyspnea measured using the modified Medical Research Council scale were identified as risk factors for ir-ILD development. In addition, combination assessment of forced vital capacity and forced expiratory volume in 1 second successfully classified patients at risk for ir-ILD development., Conclusions: The incidence of ir-ILD was substantially higher in the clinical setting. Assessment of spirometry and daily dyspneic symptoms before ICI treatment may be useful in monitoring and managing patients with NSCLC., (Copyright © 2020 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.)

A woman in her late 50s visited our department because an abnormal shadow of her right lung was seen on her chest radiographs. She was diagnosed with Stage ⅠA primary lung adenocarcinoma with EGFR exon 19 deletion mutation by performing thoracoscopic middle lobe resection and lymph node dissection. After 1 and a half years, the lung metastasis recurred and she received gefitinib(GEF)monotherapy for 9 months and withdrew because of the sustained complete response(CR). Three years and 7 months after the first visit, she was diagnosed as having complication of revised international staging system(R-ISS)Ⅱ multiple myeloma with anemia, retinal vein occlusion, and M proteinemia. It was decided that treatment for myeloma should be given priority and hence, Bd, high dose chemotherapy with auto-peripheral blood stem cell transplantation(aPBSCT), Ld, ELd and Pd therapy were performed sequentially until progressive disease(PD)and survival benefit were evident. As lung metastasis of adenocarcinoma also progressed, myeloma treatment was terminated, GEF was administered intermittently and consequently, shrinkage of the lung metastasis was confirmed. Depending on sequential alternating chemotherapy for both malignancies, a relatively long survival time of 5.4 years from the initiation of treatment for myeloma and 7.5 years from the recurrence of lung adenocarcinoma was achieved.

Background/aim: Pulmonary pleomorphic carcinoma (PPC) is rare, and few studies have reported its features. We assessed the clinicopathological features, surgical outcomes, oncogenic status and programmed death-ligand 1 (PD-L1) expression of PPC., Patients and Methods: We retrospectively reviewed data from 22 consecutive patients who underwent resection of PPC between 2007 and 2017., Results: The predominant tissue type of the epithelial component was adenocarcinoma in 15 patients (68%) and the others in 7 patients (32%), and the 3-year disease-free survival rate tended to be better in patients with an adenocarcinoma component compared to patients with another component (40.0% vs. 17.1%, p=0.059). PD-L1 expression was observed in all eight tumors whose PD-L1 status could be examined and high PD-L1 expression (≥50%) was frequent (5/8, 63%)., Conclusion: A predominant adenocarcinoma epithelial component in PPC might be associated with better survival outcomes and high PD-L1 expression might be frequent in PPC., (Copyright© 2019, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Esophageal schwannomas are extremely rare esophageal submucosal tumors. Herein, we report a case of simultaneous resection of left lung cancer and an esophageal schwannoma with video-assisted thoracoscopic surgery. An asymptomatic 74-year-old woman received a diagnosis of an esophageal submucosal tumor during the preoperative assessment of a left lung cancer. The esophageal submucosal tumor arose in the left wall of the lower esophagus, and the patient was diagnosed as having a schwannoma by endoscopic ultrasound-guided fine needle aspiration. She underwent video-assisted thoracoscopic surgery for the simultaneous removal of both tumors. Her postoperative course was uneventful. Thoracoscopic surgery is less invasive than thoracotomy, and this allowed the patient to undergo simultaneous operations for two tumors., (© 2018 Japan Society for Endoscopic Surgery, Asia Endosurgery Task Force and John Wiley & Sons Australia, Ltd.)

Background Optimal maintenance therapy for lung squamous cell carcinoma (SCC) has not been established. The aim of this study was to evaluate the efficacy and safety of switch maintenance therapy with S-1, an oral fluoropyrimidine, after induction therapy with carboplatin and nanoparticle albumin-bound paclitaxel (nab-paclitaxel) in chemotherapy-naïve patients with advanced SCC. Methods Chemotherapy-naïve patients with advanced SCC received induction therapy with four cycles of carboplatin (at an area under the curve of 6, day 1 of a 28-day cycle) and nab-paclitaxel (100 mg/kg, days 1, 8, and 15). Patients who achieved disease control after induction therapy received maintenance therapy with S-1 (80 mg/m 2 , days 1-14 of a 21-day cycle) until disease progression or unacceptable toxicity. The primary endpoint was progression-free survival (PFS) from the start of maintenance therapy. Results Seventy-two patients with SCC were enrolled to the study. After four cycles of induction therapy, 35 (48.6%) patients achieved disease control, and 31 (43.1%) of these patients received maintenance therapy. Median PFS from the start of maintenance therapy was 3.0 months (95% confidence interval: 2.1-3.8 months). The most common toxicities of grade 3 or higher during maintenance therapy were nausea (13.3%), neutropenia (10.0%), and diarrhea (6.7%). Conclusions Switch maintenance therapy with S-1 after induction therapy with carboplatin and nab-paclitaxel was associated with moderate efficacy and acceptable safety and may represent a feasible treatment option for patients with advanced SCC.

Early elevation of inflammatory cytokines, such as IL-6 or TNF-α, or CRP, which is a surrogate marker for IL-6, following commencement of PD-1/L1 inhibitors (PD1-I) may represent early activation of immune-cells. Serum IL-6 and TNF-α were measured in 10 non-small cell lung cancer patients who were evaluable within the 7 days before and after commencement of PD1-I. For CRP, medical records were reviewed and 34 patients with measured CRP within the 7 days before and after the treatment were evaluated. In the 10 patients analyzed for IL-6/TNF-α, the serum levels of IL-6/TNF-α were not significantly different between pre- and post-initial PD1-I [IL-6 20.3 (2.6-49.9) and 22.9 (3.6-96.1) pg/mL, p = 0.453; TNF-α 1.6 (0.7-6.3) and 3.3 (0.7-9.6) pg/mL, p = 0.329]; however, all four responses were observed among the 7 IL-6-elevated cases, resulting in a response rate of 57%. In the 34 patients analyzed for CRP, CRP was significantly increased after initial PD1-I [1.8 (0.1-17.8) mg/dL, 2.4 (0.0-27.8), p = 0.001]. Notably, in the 31 evaluable cases, all responses were again observed in either the IL-6 or CRP elevated groups and the response rate was 46% (11 of 24). The median overall survival time was not reached in the elevated group and was 112 days in the non-elevated group (p = 0.069). The early increase in inflammatory cytokines with PD1-I was indicated to be predictive for the efficacy in patients with non-small cell lung cancer.

Spontaneous regression (SR) of cancer implies the partial or complete disappearance of malignant disease without or with adequate medical treatment. Typically, SR of cancer is a sporadic event, especially in non-small cell lung cancer (NSCLC). Although the underlying mechanism of SR remains unknown, stimulation of an immunological response has been proposed. Herein, we report the case of a 56-year-old woman exhibiting SR of NSCLC with a mediastinal disease. Despite regression of the primary site after a lung biopsy, simultaneous progression of mediastinal lymph node metastasis occurred. Specimens obtained by surgical resection pathologically confirmed both primary and metastatic sites. Reportedly, primary and metastatic tumors shrink synchronously in SR of metastatic NSCLCs. Thus, the fact that the SR of NSCLC can present inconsistent development in primary and metastatic sites should be considered, and direct intervention is recommended if physicians diagnose this phenomenon., (© 2018 The Authors. Thoracic Cancer published by China Lung Oncology Group and John Wiley & Sons Australia, Ltd.)

Situs inversus totalis (SIT) is a rare anomaly. A limited number of reports document surgery for lung cancer in patients with SIT. We report the case of a 68-year-old man with SIT who underwent video-assisted thoracoscopic bisegmentectomies for synchronous double primary lung cancers. Preoperative evaluation of the pulmonary vessels and bronchus by three-dimensional computed tomography (CT) was unavailable owing to the patient's renal function disorder. However, the procedure was safely completed by adequate anatomic identification and careful operative manipulation based on plain CT study. His postoperative course was uneventful, and no recurrence has been observed 3 years after surgery.

Background: The adaptation criteria for administration of stereotactic body radiotherapy (SBRT) to patients with lung cancer who previously underwent surgery and subsequently developed a second primary lung cancer (SPLC) or intra-parenchymal lung metastasis (IPLM) are controversial, unlike the criteria for repeat surgery. We aimed to evaluate the feasibility of SBRT for these patients. Factors associated with decreased respiratory function were also evaluated., Material and Methods: Sixty-nine patients with 89 lesions who underwent SBRT between 2008 and 2017 were analyzed. Of these, 29 were diagnosed with SPLC while the remaining 40 had IPLM. The distribution of histological types was as follows: squamous cell carcinoma (n = 13 lesions); adenocarcinoma (n = 25); non-small cell carcinoma (n = 1); unknown histological type (n = 49). The prescribed doses to the planning target volume (PTV) were 50 Gy in five fractions for 85 lesions and 60 Gy in 10 fractions for four lesions at PTV mean., Results: Over a median follow-up period of 55 months, the 4-year overall survival and local control rates were 50.3% and 87.6%, respectively. Six patients experienced grade 2 radiation pneumonitis and one experienced grade 3. Two patients experienced grade 5 pulmonary fibrosis. Decreased respiratory function was observed in 10 patients (15.1%). On multivariate analysis, the presence of pulmonary disease before SBRT was the only statistically significant factor associated with decreased respiratory function., Conclusions: SBRT is safe and feasible in patients with SPLC or IPLM previously treated surgically. Pre-existing pulmonary disease was a predictive factor for decreased respiratory function.

Objectives: To assess the impact of a history of liver metastases on survival in patients undergoing surgery for lung metastases from colorectal carcinoma., Methods: We reviewed recent studies identified by searching MEDLINE and EMBASE using the Ovid interface, with the following search terms: lung metastasectomy, pulmonary metastasectomy, lung metastases and lung metastasis, supplemented by manual searching. Inclusion criteria were that the research concerned patients with lung metastases from colorectal cancer undergoing surgery with curative intent, and had been published between 2007 and 2014. Exclusion criteria were that the paper was a review, concerned surgical techniques themselves (without follow-up), and included patients treated non-surgically. Using Stata 14, we performed aggregate data and individual data meta-analysis using random-effect and Cox multilevel models respectively., Results: We collected data on 3501 patients from 17 studies. The overall median survival was 43 months. In aggregate data meta-analysis, the hazard ratio for patients with previous liver metastases was 1.19 (95% CI 0.90-1.47), with low heterogeneity (I 2 4.3%). In individual data meta-analysis, the hazard ratio for these patients was 1.37 (95% CI 1.14-1.64; p < 0.001). Multivariate analysis identified the following factors significantly affecting survival: tumour-infiltrated pulmonary lymph nodes (p < 0.001), type of resection (p = 0.005), margins (p < 0.001), carcinoembryonic antigen levels (p < 0.001), and number and size of lung metastases (both p < 0.001)., Conclusions: A history of liver metastases is a negative prognostic factor for survival in patients with lung metastases from colorectal cancer. We registered the meta-analysis protocol in PROSPERO (CRD42015017838)., (Copyright © 2018 Elsevier Ltd, BASO ~ The Association for Cancer Surgery, and the European Society of Surgical Oncology. All rights reserved.)

Switch maintenance therapy, using alternative agents that were not administered during induction chemotherapy, is a treatment option for advanced non-squamous non-small cell lung cancer (NSCLC). Bevacizumab is known to increase the efficacy of other chemotherapeutic agents; however, switch maintenance therapy with docetaxel and bevacizumab has not been adequately studied. The goal of this study was to evaluate the efficacy and safety of switch maintenance therapy with docetaxel and bevacizumab following induction therapy with cisplatin, pemetrexed, and bevacizumab. Chemotherapy-naïve non-squamous NSCLC patients received induction therapy of four cycles of cisplatin (75 mg/m 2 ), pemetrexed (500 mg/m 2 ), and bevacizumab (15 mg/kg). Patients who achieved disease control after induction therapy then received maintenance therapy with docetaxel (50 mg/m 2 ) and bevacizumab (15 mg/kg) until disease progression or unacceptable toxicity. The primary endpoint was progression-free survival from enrollment. This study enrolled 49 NSCLC patients, among which 38 (77.6%) completed the four cycles of induction therapy and received maintenance therapy. The median progression-free survival from enrollment was 7.8 months (95% confidence interval: 4.7-11.0 months). The most common toxicities of grade 3 or higher were neutropenia (68.4%), leukopenia (50.0%), febrile neutropenia (31.8%), and hypertension. Switch maintenance therapy with docetaxel and bevacizumab following induction therapy with cisplatin, pemetrexed, and bevacizumab demonstrated modest efficacy and frequent hematologic toxicity in non-squamous NSCLC patients.

Background: The management of skin toxicity is crucial for efficient afatinib treatment, but the role of tetracycline class antibiotics (TCs) in managing these rashes is relatively unknown., Methods: We reviewed the clinical records of patients who were administered afatinib for the treatment of non-small cell lung cancer harboring epidermal growth factor receptor mutations between October 2014 and November 2016. Twenty-five patients, who received TCs for the management of afatinib-related skin disorders, were enrolled., Results: Minocycline was administered orally to participants. Afatinib-related toxic effects, such as rash, diarrhea, and paronychia, were observed in 92%, 92%, and 40% of cases, respectively. Although 24% of diarrhea and 4% of paronychia cases were rated grade 3 or higher, no severe cases of rash were observed during afatinib treatment. Of the 18 afatinib dose reductions, 14 (78%), three (17%), and one (6%) resulted from diarrhea, paronychia, and stomatitis, respectively; no patients required a dose reduction because of rash. When minocycline treatment started, 21 patients (84%) had a rash of grade 1 or less, and three patients had a grade 2 rash. A response to afatinib was observed in 18 patients (72%) and the median duration of afatinib administration was 501 days. An adverse event related to minocycline (grade 1 nausea) was observed in one patient., Conclusions: A large proportion of the study patients started minocycline before grade 2 rash development and the severity of afatinib-related rash was lower than that previously reported. Oral TCs may be beneficial, especially if started early., (Copyright © 2017 The Japanese Respiratory Society. Published by Elsevier B.V. All rights reserved.)

The International Association for the Study of Lung Cancer, the American Thoracic Society, and the European Respiratory Society (IASLC/ATS/ERS) proposed a new histologic classification of lung adenocarcinoma in 2011. While several studies have already validated the prognostic value of this new classification of lung adenocarcinoma, we conducted own investigation in the present study. This study included 197 patients with invasive lung adenocarcinoma who underwent complete resection. Pathologic diagnoses were made in accordance with the new IASLC/ATS/ERS classification for lung adenocarcinoma. The lepidic/acinar/papillary group had a significantly better prognosis than the micropapillary/solid/invasive mucinous adenocarcinoma group (5-year recurrence-free survival [RFS] 73 vs. 21%: p < 0.01, 5-year overall survival 85 vs. 52%: p < 0.01). Age (hazard ratio [HR], 1.898; p = 0.03), CEA (HR, 1.873; p = 0.03), pStage (HR, 6.149; p < 0.01), and histologic subtype (HR, 2.342; p = 0.01) were independent prognostic factors for the RFS. Furthermore, age (HR, 3.242; p = 0.04), CEA (HR, 3.405; p = 0.03) and histologic subtype (HR, 11.108; p < 0.01) were independent prognostic factors for the progression-free survival in pStage I. The histologic subtype correlated with the prognosis of pStage I of lung adenocarcinoma. Patients in the high-grade group of lung adenocarcinoma, which included solid, micropapillary and invasive mucinous adenocarcinoma with pStage I, should be considered candidates for postoperative adjuvant therapy.

Aim: This phase II study assessed the efficacy and toxicity of an intermittent weekly capecitabine regimen in combination with oxaliplatin (XELOX) plus bevacizumab as a first-line treatment of metastatic colorectal cancer (mCRC)., Patients and Methods: Patients with measurable mCRC who were to receive first-line chemotherapy were enrolled onto this disease-oriented multicenter phase II trial. Patients with mCRC were required to have Eastern Cooperative Oncology Group performance status of 0 to 1, to be aged >20 years, and to have adequate organ function. Localization of tumor, toxicities, response rate, progression-free survival (PFS) and time to progression (TTP) were studied. Capecitabine dose was 2,500 mg/m(2)/day on days 1-7 (n=47) and was increased to 3,000 mg/m(2)/day (n=5) in combination with oxaliplatin (85 mg/m(2)) and bevacizumab (5 mg/kg), repeated every 2 weeks., Results: A total of 51 patients were enrolled from 14 institutions from December 2011 to July 2012. The median age was 66 (range=38-85) years, 29 (56.9%) had colonic cancer and 22 (43.1%) had rectal cancer in this study. Pertinent grade 3/4 toxicities were neutropenia (13.7%), peripheral neuropathy (13.7%), hypertension (13.7%), gastrointestinal perforation (3.9%), and hand-foot syndrome (5.9%). The response rate was 51% (one complete and 25 partial responses). Median PFS and TTP were 344 days and 196 days, respectively. Median overall survival has not been reached yet., Conclusion: The first-line treatment of mCRC using a biweekly combination of XELOX plus bevacizumab can also be administered safely and effectively in Japan. It is suggested that this regimen is an appropriate option for the treatment of mCRC., (Copyright© 2016 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved.)

Purpose: Pre-existing interstitial lung disease (pre-ILD) increases the risk of chemotherapy-related lung injury (CRLI). However, whether the risk varies by type of anti-cancer cytotoxic agent in patients with pre-ILD is unknown. In this study, we hypothesized that S-1, an oral fluoropyrimidine agent, is associated with a smaller CRLI risk than docetaxel (DTX) and investigated these agents together with radiological evaluations of pre-ILD via pre-treatment chest computed tomography (CT)., Methods: After reviewing 234 and 352 patients who underwent evaluable chest CT within 6 months prior to the administration of S-1 or DTX, respectively, from January 2006 to October 2014, 60 and 89, respectively, of these patients with pre-ILD were retrospectively analysed., Results: In total, 2 persons administered S-1 (3 %) and 16 treated with DTX (18 %) developed CRLI (p = 0.007) after the initial treatment (mean, 61 days), of whom 1 and 7, respectively, died because of respiratory failure. Pre-treatment CT revealed that 9 S-1-treated patients (16 %) and 15 DTX-treated patients (17 %) had pre-ILD occupying more than 25 % of the lung field. Multivariate analysis demonstrated that DTX administration increased the risk of CRLI by 6.47-fold versus S-1 therapy (p = 0.016). Of note, the area occupied by pre-ILD was also associated with the risk of CRLI (<25 %; odds ratio 0.309, p = 0.045)., Conclusions: Our results indicated that S-1 is associated with a smaller risk of CRLI than DTX. The area occupied by pre-ILD should also be noted when administrating anti-cancer agents.

Spindle cell carcinoma (SpCC) an aggressive squamous cell carcinoma, variant, frequently metastasizes to regional lymph nodes and distant organs. Unfortunately, an effective treatment method for oral SpCC distant metastasis has not yet been established. Here we present 2 of oral SpCC cases that showed distant metastases after initial treatment, and 2 that showed distant metastases following during surgery. We calculated the tumor doubling time (TDT) and onset of the pulmonary metastatic and examined the TDT of the pulmonary metastatic tumor in patients with or without chemotherapy to determine the effect of anticancer drugs on oral SpCC. Tumor growth curves revealed that pulmonary metastasis likely grew to 1mm, 122 days before the initial examination, indicating that most oral SpCC patients should be treated for metastases. Three patients underwent chemotherapy for pulmonary metastatic tumor, complete response (CR) in one patient and no change (NC) in two. Thus, SpCC patients may have pulmonary micro-metastases even at the initial examination. We recommend wide resection for oral SpCC patients, followed by chemotherapy to prevent metastases.

Introduction: This study investigated the clinical characteristics and predictive factors for developing acute extended radiation pneumonitis with a focus on the presence and radiological characteristics of preexisting interstitial lung disease., Methods: Of 1429 irradiations for lung cancer from May 2006 to August 2013, we reviewed 651 irradiations involving the lung field. The presence, compatibility with usual interstitial pneumonia, and occupying area of preexisting interstitial lung disease were retrospectively evaluated by pretreatment computed tomography. Cases of non-infectious, non-cardiogenic, acute respiratory failure with an extended bilateral shadow developing within 30 days after the last irradiation were defined as acute extended radiation pneumonitis., Results: Nine (1.4%) patients developed acute extended radiation pneumonitis a mean of 6.7 days after the last irradiation. Although preexisting interstitial lung disease was found in 13% of patients (84 patients), 78% of patients (7 patients) with acute extended radiation pneumonitis cases had preexisting interstitial lung disease, which resulted in incidences of acute extended radiation pneumonitis of 0.35 and 8.3% in patients without and with preexisting interstitial lung disease, respectively. Multivariate logistic analysis indicated that the presence of preexisting interstitial lung disease (odds ratio = 22.6; 95% confidence interval = 5.29-155; p < 0.001) and performance status (≥2; odds ratio = 4.22; 95% confidence interval = 1.06-20.8; p = 0.049) were significant predictive factors. Further analysis of the 84 patients with preexisting interstitial lung disease revealed that involvement of more than 10% of the lung field was the only independent predictive factor associated with the risk of acute extended radiation pneumonitis (odds ratio = 6.14; 95% confidence interval = 1.0-37.4); p = 0.038)., Conclusions: Pretreatment computed tomography evaluations of the presence of and area size occupied by preexisting interstitial lung disease should be assessed for safer irradiation of areas involving the lung field.

Background: Magnetic resonance imaging (MRI) enables a more sensitive detection of brain metastasis and stereotactic irradiation (SRI) efficiently controls brain metastasis. In limited-stage small cell lung cancer (LS-SCLC), prophylactic cranial irradiation (PCI) in patients with good responses to initial treatment is recommended based on the survival benefit shown in previous clinical trials. However, none of these trials evaluated PCI effects using the management of brain metastasis with MRI or SRI. This study aimed to determine the effects of MRI and SRI on the benefits of PCI in patients with LS-SCLC., Methods: The clinical records of pathologically proven SCLC from January 2006 to June 2013 in facilities equipped with or had access to SRI in Japan were retrospectively reviewed. Patients with LS-SCLC and complete or good partial responses after initial treatment were included in the study and analyzed by the Kaplan-Meier method., Results: Of 418 patients with SCLC, 124 met criteria and were divided into patients receiving PCI (PCI group; n = 29) and those without PCI (non-PCI groups; n = 95). At baseline, ratios of patients with stage III were significantly advantageous for the non-PCI group, although younger age and high ratios of complete response and MRI confirmed absence of brain metastasis were advantageous for the PCI group. Neither median survival times (25 vs. 34 months; p = 0.256) nor cumulative incidence of brain metastasis during 2 years (45.5 vs. 30.8%; p = 0.313) significantly differed between the two groups. Moreover, these factors did not significantly differ among patients with stage III disease (25 vs. 26 months; p = 0.680, 42.3 vs. 52.3%; p = 0.458, respectively)., Conclusion: PCI may be less beneficial in patients with LS-SCLC if the management with MRI and SRI is available.

Background: Solitary lung metastasis from prostate cancer is rare. There are few reports of such cases with neuroendocrine differentiation., Case Presentation: A 50-year-old man presented to our hospital with a chief complaint of dysuria. Histological examination revealed prostate cancer, which was classified as cT4 N0 M0, stage IV adenocarcinoma. Since the patient was at high risk, endocrine and radiation therapies were started. One year after starting radiation therapy, the patient developed bloody sputum. Chest radiography revealed a nodular shadow in his left lung (S5). Although 18-fluoro-2-deoxyglucose positron emission tomography revealed abnormal accumulation in the lesion, the cytological diagnosis was class IIIa, which did not yield a definitive diagnosis. Given that prostate specific antigen (PSA) was not elevated, a primary lung tumor was suspected, and thoracoscopic segmental resection of the lung was performed with lymph node dissection. The final pathological diagnosis was solitary lung metastasis from prostate cancer with neuroendocrine differentiation and mediastinal lymph node metastasis. The specimen showed a mixed pattern of conventional prostatic and neuroendocrine carcinomas., Conclusion: We herein report a case with neuroendocrine differentiation (NED), along with a review of the relevant literature, including histopathological findings. According to previous case reports, some patients with solitary lung metastasis from prostate cancer achieved relatively good long-term survival. We consider establishing the correct diagnosis and implementing an appropriate treatment plan to be essential in prostate cancer patients with oligometastases that have the potential to be neuroendocrine (NE) tumors.

Purpose: Hepatic or pulmonary resections for colorectal metastases are regarded as standard treatment worldwide; however, the clinical significance of both hepatic and pulmonary resections for colorectal metastases remains undefined. We reviewed our clinical experience to evaluate the benefit of this treatment., Methods: Between 1986 and 2010, 186 patients underwent potentially curative hepatic and/or pulmonary resections for colorectal metastases. Of these patients, 25 underwent both treatments (Group C), 100 underwent hepatic resections alone (Group H), and 61 underwent pulmonary resections alone (Group L). Univariate and multivariate analyses of the clinical and pathological variables in Group C and comparative survival analyses between Group C and Groups H-L were performed., Results: In Group C, the median survival after primary tumor resection, initial metastasectomy, and last metastasectomy were 97, 60, and 35 months, respectively, and the 5-year overall survival rates were 63, 54, and 38%, respectively. Multivariate analyses after initial metastasectomy revealed rectal tumors, multiple hepatic tumors, and simultaneous metastases as poor prognostic factors. Comparative survival analyses revealed no significant difference in overall survival between Group C and Groups H-L., Conclusion: Hepatic and pulmonary resections for colorectal metastases improve survival and may even offer the potential for cure in selected patients.

We report the case of a 52-year-old woman with lung adenocarcinoma treated with EGFR tyrosine kinase inhibitor (TKI) therapy. After disease progression, histological examination of a secondary biopsy specimen revealed small-cell lung cancer (SCLC) that was sensitive to standard SCLC treatment. Tumor markers, including ProGRP and NSE, were elevated. Transformation to SCLC is a mechanism for acquired resistance to EGFR-TKI therapy. Secondary biopsy is important for evaluation of genetic and histological changes and selection of appropriate treatment. Furthermore, ProGRP and NSE may be useful for early detection of SCLC transformation in cases resistant to EGFR-TKI therapy., (Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.)

We report a case of a 64-year-old man with multiple lung metastases after gastric cancer surgery. This patient was initially treated with S-1. However, he experienced adverse effects, and subsequently, he was effectively treated with cisplatin (CDDP) and irinotecan (CPT-11). In July 2010, the patient experienced a decrease in appetite and underwent a detailed examination. He also underwent distal gastrectomy in the same month. The postoperative diagnosis was T4a( SE), N2, M0, Stage IIIB. In November 2010, adjuvant chemotherapy with S-1 was initiated. In February 2011, the patient developed a skin disorder( grade 3) and generalized edema along with walking difficulty, which were identified as adverse effects of S-1. Evidently, S-1 was contraindicated for this patient, and adjuvant therapy was discontinued. In September 2011, contrast -enhanced thoracoabdominal computed tomography( CT) was performed and para-aortic lymph node metastasis and multiple lung metastases were detected. CDDP+CPT-11 therapy was initiated. By June 2012, 8 courses had been administered, and the patient had a good partial response. With regard to chemotherapy for advanced or recurrent gastric cancer, there is no consensus on a treatment policy for cases in which S-1 cannot be used owing to adverse effects. CDDP+CPT-11 therapy is considered a safe and effective choice.

In palliative chemotherapy, a focus on palliative treatment is recommended in cases that are unresponsive to multiple drugs. Careful judgment is needed, however, because when treatment is inadequate, cases that are considered to be unresponsive may include some in which chemotherapy would be effective. We treated a patient with metastatic colon cancer who was judged to be unresponsive to multiple drugs at another hospital, yet repetition of standard therapy proved effective. We report this case as an instructive example of the importance of maintaining dose intensity. The patient was a 60-year-old man. Lung metastasis appeared after he had undergone proctectomy and received adjuvant chemotherapy by his previous doctor. Low-dose intensity IFL therapy, FOLFOX4 therapy (once a month), and FOLFIRI therapy (once only) had been performed, but the patient's condition worsened and he was referred to our hospital. This case could not be considered unresponsive to multiple drugs because the treatment had been insufficient, and so we restarted FOLFIRI treatment with the international standard dose and obtained control of the disease. Treatment was then continued, and the patient died 2 years and 11 months after he was first examined at our hospital. Simple palliative treatment alone should not be given unthinkingly when patients are referred for outpatient palliative care. Full consideration of the dosing and schedule is needed.

A 70-year-old man was admitted to our hospital because of multiple ground-glass opacities on his chest CT scan. A transbronchial lung biopsy specimen revealed signet-ring cell carcinoma infiltrating into the alveolar septa. The histological findings of the carcinoma obtained from the lung were very similar to those of his gastric carcinoma which had been resected at age 66. Immunohistochemical staining of the cancer cells were positive for keratin 7 and keratin 20, therefore a metastatic lung tumor from gastric cancer was diagnosed. Although multiple, well-defined nodules are typically considered to be the presentation of pulmonary metastases, clinicians should also be aware that multiple, ill-defined ground-glass opacities can also be recognized as pulmonary metastasis.

Clinically obtainable concentrations of zoledronic acid (ZOL) inhibited the production of vascular endothelial growth factor and reduced the migration, adhesion, and invasiveness of osteosarcoma (OS) cells in vitro. The in vivo effects of ZOL were investigated by using a murine model of spontaneous lung metastasis. The higher dose of ZOL (80 microg/kg three times/week) inhibited the growth of OS at the primary site, accompanied by inhibition of neovascularization in the tumor. Interestingly, while the lower dose of ZOL (80 microg/kg once a week) could not inhibit the growth of OS at the primary site, it significantly prevented lung metastasis.

A 67-year-old woman was admitted to our hospital for weakness in her right hand. MRI showed multiple cerebral infarctions and ultrasonic cardiography revealed vegetation on her aortic valve, so embolic stroke was diagnosed. Though she was afebrile and her vital signs were normal, chest CT revealed several enlarged mediastinal lymph nodes and a small nodule in the left lower lobe of the lung. Stage III adenocarcinoma of the lung was diagnosed, and the cause of her cerebral infarctions was found to be nonbacterial thrombotic endocarditis (NBTE). NBTE is known as the cause of embolic stroke among patients with advanced cancer, particularly adenocarcinoma. Prompt initiation of continuous heparin administration is required to interrupt the progress of cerebral thromboembolism in NBTE. In cases of coexisting cancer and embolic stroke, we should consider the possibility of NBTE.