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The insulin-like growth factor 1 receptor (IGF1R) has been associated with growth and metastasis in various cancers. However, its role in postoperative recurrence and prognosis in lung cancer lacks clear consensus. Therefore, this study aimed to investigate the potential relationship between IGF1R and postoperative recurrence as well as long-term survival in a large cohort. Additionally, we assessed the relationship between IGF1R and programmed death ligand 1 (PD-L1) expression. Our study encompassed 782 patients with non-small cell lung cancer (NSCLC). Immunostaining of surgical specimens was performed to evaluate IGF1R and PD-L1 expression. Among the patients, 279 (35.8%) showed positive IGF1R expression, with significantly worse relapse-free survival (RFS) and overall survival (OS). Notably, no significant differences in RFS and OS were observed between IGF1R-positive and -negative groups in stages 2 and 3. However, in the early stages (0-1), the positive group displayed significantly worse RFS and OS. In addition, PD-L1 expression was detected in 100 (12.8%) patients, with a significant predominance in the IGF1R-positive. IGF1R may serve as a prognostic indicator and a guide for perioperative treatment strategies in early-stage lung cancer. In conclusion, our findings underscore an association between IGF1R expression and poor survival and PD-L1 expression in NSCLC., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Nagamine et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Objectives: Lorlatinib, a third-generation anaplastic lymphoma kinase (ALK) inhibitor, causes distinct adverse events (AEs), including hyperlipidemia and central nervous system (CNS) disorders. Although dose modifications are recommended to manage these AEs, whether dose modifications can achieve optimal blood lorlatinib concentrations and reduce the incidence of lorlatinib-induced AEs remains unclear. Therefore, we investigated the association between lorlatinib exposure and AEs in each patient., Materials and Methods: We retrospectively reviewed patients with advanced ALK-rearranged non-small cell lung cancer treated with lorlatinib between November 2018 and July 2022. Serum lorlatinib concentrations were assessed using high-performance liquid chromatography-tandem mass spectrometry. All AEs were evaluated using the Common Terminology Criteria for Adverse Events version 5.0., Results: The median age of the 55 eligible patients was 59 years (range: 23-79 years). All patients were administered lorlatinib after first line ALK-tyrosine kinase inhibitor failure. Grade ≥ 3 AEs occurred in 25 patients (25/55, 45 %), including hyperlipidemia in 17 (17/55, 31 %), CNS disorders in 7 (7/55, 13 %), and edema in 6 (6/55, 11 %). Dose modification was required in 23 patients (23/55, 42 %). Among the 36 patients with available data on serum lorlatinib levels at day 28 (±14) and no drug dose modifications, lorlatinib serum concentrations were significantly higher in patients with grade ≥ 3 AEs than in those without AEs (median: 462 ng/mL vs. 177 ng/mL, p < 0.01). In eight patients with data on serial lorlatinib serum concentrations following dose modifications, lorlatinib serum concentrations were effectively reduced, facilitating the ongoing administration of lorlatinib. Additionally, no significant difference was observed in the landmark analysis of progression-free survival between patients with dose modification within the first 16 weeks and those without (median: 24.8 months vs. 10.1 months, p = 0.46)., Conclusion: Dose modification of lorlatinib was associated with successful management of AEs and decreased serum concentration of lorlatinib., 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 © 2024 Elsevier B.V. All rights reserved.)

The usefulness of the derived neutrophil-to-lymphocyte ratio (dNLR) and its dynamics before/after durvalumab consolidation therapy to predict safety or efficacy remains unclear. We retrospectively reviewed patients with locally advanced non-small cell lung cancer treated with durvalumab consolidation therapy after chemoradiotherapy (D group) or chemoradiotherapy alone (non-D group) at multiple institutions. We investigated the association between dNLR, or its dynamics, and pneumonitis, checkpoint inhibitor-related pneumonitis (CIP), irAEs, and efficacy. Ninety-eight and fifty-six patients were enrolled in the D and non-D groups, respectively. The dNLR at baseline was significantly lower in patients who experienced irAEs or CIP than in those who did not. The low dNLR group, 28 days following durvalumab consolidation therapy (dNLR28 ≤ 3), demonstrated longer progression-free survival (PFS) and overall survival (OS) than the high dNLR group (dNLR28 > 3) (PFS, hazard ratio [HR] 0.44, 95% confidence interval [CI] 0.22-0.88, p = 0.020; OS, HR 0.39, 95% CI 0.16-0.94, p = 0.037). Among patients with high dNLR at baseline (dNLR > 3), the dNLR28 ≤ 3 group showed longer PFS than the dNLR28 > 3 group (p = 0.010). The dNLR is a predictive factor for irAEs and CIP in patients receiving durvalumab consolidation therapy. The dNLR at 28 days after durvalumab consolidation therapy and its dynamics predict favorable outcomes., (© 2024. The Author(s).)

Introduction: NECTINs are transmembrane proteins mediating cell-to-cell adhesion. NECTINs interact with integrins or other membrane receptors to trigger multiple cellular functions. Aberrant NECTIN expression is associated with cancer progression and poor outcomes. While NECTIN2 is overexpressed in various cancer types, its role in lung cancer is not well understood., Material and Methods: We investigated the function of NECTIN2 in lung adenocarcinoma (LUAD) using the Cancer Genome Atlas (TCGA) dataset and clinical samples of 105 LUAD patients who had undergone surgical resection. Cell proliferation, apoptosis, migration and invasion were investigated using human lung adenocarcinoma cell lines., Results: We found that high NECTIN2 expression correlated with reduced overall survival in LUAD in TCGA database. In clinical samples, high NECTIN2 expression was associated with lower recurrence-free survival in all patients (P < 0.001) and in stage I patients (P = 0.001). Functional analyses demonstrated that NECTIN2 knockout promoted cell apoptosis and diminished cell proliferation and migration capacity. NECTIN2 overexpression did not significantly affect cellular functions., Discussion: Our results suggest that NECTIN2 plays a significant role in cell apoptosis and cancer cell migration, leading to increased postoperative recurrence. Furthermore, NECTIN2 serves as a prognostic indicator and a potential therapeutic target in LUAD., Conclusions: High NECTIN2 expression in LUAD was found to be associated with postoperative recurrence, and was observed to play an important role in cell apoptosis and migration., Competing Interests: Declaration of competing interest The authors have no conflicts of interest., (Copyright © 2024 The Japanese Respiratory Society. Published by Elsevier B.V. All rights reserved.)

Introduction: Programmed cell death ligand-1 (PD-L1) expression is a predictive biomarker for the efficacy of anti-programmed cell death receptor-1/PD-L1 antibodies in advanced non-small cell lung cancer (NSCLC). Although several assays have been approved for evaluating PD-L1 expression status, inter-assay discordance has been observed between some assays. The clinical significance of these discrepancies is still unclear., Methods: We retrospectively reviewed treatment-naïve NSCLC patients whose PD-L1 expression was evaluated using both 22C3 and SP142 assays. Among those, efficacy analysis was performed for patients with PD-L1 tumor proportion score (TPS) ≥ 50 % (22C3), who had received first-line pembrolizumab monotherapy. Additionally, transcriptome analysis was conducted in the available tumors with TPS ≥ 50 % to investigate the distinct immune profiles that accompany inter-assay discordance., Results: In total, 611 patients were eligible. Among 198 patients with TPS ≥ 50 %, 91 (46 %) had tumor cell score ≤ 1 (SP142, i.e., inter-assay discrepancy). In the 52 patients who received first-line pembrolizumab monotherapy, treatment efficacy was significantly lower in patients with the discrepancy than that in those without (objective response rate: 18 % vs. 83 %, p < 0.001; median progression-free survival [months]: 3.2 vs. 8.3, p < 0.001). Transcriptome analysis revealed significantly more CD274 splice variants with aberrant 3'-terminal sequences in tumors with the inter-assay discrepancy than in those without., Conclusion: The inter-assay discrepancy in the PD-L1 status of tumor cells between the 22C3 and SP142 assays, reflecting an imbalance in the CD274 splice variants, could be a biomarker for primary resistance against pembrolizumab monotherapy in high PD-L1-expressing NSCLCs., 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 © 2024 Elsevier B.V. All rights reserved.)

Background and Objective: Endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) is a diagnostic procedure with adequate performance; however, its ability to provide specimens of sufficient quality and quantity for treatment decision-making in advanced-stage lung cancer may be limited, primarily due to blood contamination. The use of a 0.96-mm miniforceps biopsy (MFB) permits true histological sampling, but the resulting small specimens are unsuitable for the intended applications. Therefore, we introduced a 1.9-mm standard-sized forceps biopsy (SFB) and compared its utility to that of MFB., Methods: We prospectively enrolled patients from three institutions who presented with hilar/mediastinal lymphadenopathy and suspected advanced-stage lung cancer, or those who were already diagnosed but required additional tissue specimens for biomarker analysis. Each patient underwent MFB followed by SFB three or four times through the tract created by TBNA using a 22-gauge needle on the same lymph node (LN). Two pathologists assessed the quality and size of each specimen using a virtual slide system, and diagnostic performance was compared between the MFB and SFB groups., Results: Among the 60 enrolled patients, 70.0% were diagnosed with adenocarcinoma. The most frequently targeted sites were the lower paratracheal LNs, followed by the interlobar LNs. The diagnostic yields of TBNA, MFB and SFB were 91.7%, 93.3% and 96.7%, respectively. The sampling rate of high-quality specimens was significantly higher in the SFB group. Moreover, the mean specimen size for SFB was three times larger than for MFB., Conclusion: SFB is useful for obtaining sufficient qualitative and quantitative specimens., (© 2024 Asian Pacific Society of Respirology.)

Purpose: The gut microbiota is hypothesized as a prognostic biomarker for cancer immunotherapy. Antibiotic-induced dysbiosis negatively affects the clinical outcomes of immunotherapy. However, the effect of dysbiosis on the efficacy and safety of Chemoimmunotherapy (chemo-IOs), the frontline standard of care, in advanced non-small cell lung cancer (NSCLC) remains unknown. We aimed to compare the efficacy and safety of chemo-IOs in patients exposed to antibiotics before treatment with those of patients who were not exposed., Methods: We retrospectively reviewed patients with advanced NSCLC treated with first-line chemo-IOs between 2018 and 2020 at the National Cancer Center Hospital. The patients were divided into two groups: those exposed to antibiotics within 30 days before induction therapy (ABx group) and those did not antibiotics (Non-ABx group). Propensity score matching was used to control for potential confounding factors. Clinical outcomes including progression-free survival (PFS), overall survival (OS), and immune-related adverse events (irAEs) were compared., Results: Of 201 eligible patients, 21 were in the ABx group, and 42 were in the non-ABx group after propensity score matching. No differences in PFS or OS emerged between the two groups (ABx group vs. Non-ABx group) (PFS:7.0 months vs. 6.4 months, hazard ratio [HR] 0.89; 95% confidence interval [CI], 0.49-1.63, OS:20.4 months vs. 20.1 months, HR 0.87; 95% CI 0.44-1.71). The frequency of irAEs before propensity score matching was similar across any-grade irAEs (39.4% vs. 42.9%) or grade 3 or higher irAEs (9.1% vs. 11.3%)., Conclusion: Antibiotic-induced dysbiosis may not affect the efficacy of chemo-IOs in patients with advanced NSCLC., (© 2024. The Author(s).)

Background: Endobronchial ultrasound-guided transbronchial cryobiopsy (EBUS-cryobiopsy) is advantageous for collecting larger specimens with minimal crushing; however, it has not been widely used for mediastinal tumors., Case Presentation: A 73-year-old woman with a history of left breast cancer underwent surgery followed by radiotherapy. Computed tomography showed a mass in the anterior mediastinum that was in extensive contact with the sternum on the ventral side and partly with the trachea on the dorsal side. Two computed tomography-guided needle biopsies (CTNBs) were performed on the mass; however, a definitive diagnosis was not made because of severe crush artifacts. Subsequently, we performed EBUS-cryobiopsy and safely obtained sufficient specimen volume with minimal crushing. The histopathological diagnosis was adenocarcinoma, with immunobiological features distinct from those of previous breast cancers. Her overall diagnosis was a rare tumor originating in the anterior mediastinum., Conclusions: EBUS-cryobiopsy can be safely performed in narrow areas surrounded by major blood vessels, and the obtained specimens may be superior to CTNBs for histopathological diagnosis., (© 2024. The Author(s).)

Background: Leiomyosarcomas are among the most common histological types of soft tissue sarcoma (STS), with no effective treatment available for advanced patients. Lung metastasis, the most common site of distant metastasis, is the primary prognostic factor. We analysed the immune environment targeting lung metastasis of STS to explore new targets for immunotherapy., Methods: We analysed the immune environment of primary and lung metastases in 38 patients with STS using immunohistochemistry. Next, we performed gene expression analyses on primary and lung metastatic tissues from six patients with leiomyosarcoma. Using human leiomyosarcoma cell lines, the effects of the identified genes on immune cells were assessed in vitro., Results: Immunohistochemistry showed a significant decrease in CD8 + cells in the lung metastases of leiomyosarcoma. Among the genes upregulated in lung metastases, epithelial cellular adhesion molecule (EPCAM) showed the strongest negative correlation with the number of CD8 + cells. Transwell assay results showed that the migration of CD8 + T cells was significantly increased in the conditioned media obtained after inhibition or knock down of EPCAM., Conclusions: EPCAM was upregulated in lung metastases of leiomyosarcoma, suggesting inhibition of CD8 + T cell migration. Our findings suggest that EPCAM could serve as a potential novel therapeutic target for leiomyosarcoma., (© 2024. The Author(s).)

Background: The number of patients undergoing hemodialysis continues to increase globally, and the incidence of cancer is high among these patients. Immune checkpoint inhibitors are widely used in patients with advanced cancer, especially non-small cell lung cancer (NSCLC); however, their effectiveness in hemodialysis patients is poorly documented., Methods: This retrospective cohort study used data from a nationwide database. Patients diagnosed with NSCLC, undergoing hemodialysis, and who started chemotherapy between September 2008 and January 2023 were included. In the intention to treat (ITT) analysis, patients were divided into immune checkpoint inhibitor (ICI) and conventional chemotherapy group, and in the chronological analysis, patients were divided into 2 groups before and after ICI approval. Overall survival (OS) was analyzed using the Kaplan-Meier method with log-rank tests and Cox proportional hazards analyses. A propensity score approach was applied to address confounding factors, and analyses were performed by weighting each patient with the inverse of the estimated propensity score., Results: We identified 322 and 389 patients in the ITT and chronological analyses respectively. In both analyses, there were no notable difference of OS between 2 groups (P values by log-rank test 0.933 and 0.248, respectively). The hazard ratios for OS were 0.980 (95% confidence interval [CI]: 0.678-1.415) in the ITT analysis and 0.805 (95% CI: 0.531-1.219) in the chronological analysis., Conclusion: The ICI treatment and approval were not significantly associated with improvement of survival in patients with NSCLC undergoing hemodialysis., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Background: Delta-like ligand 3 (DLL3) is a therapeutic target in small-cell lung cancer (SCLC). However, how DLL3 expression status affects the tumor microenvironment (TME) and clinical outcomes in SCLC remains unclear., Methods: This retrospective study included patients with postoperative limited-stage (LS)-SCLC and extensive-stage (ES)-SCLC treated with platinum and etoposide (PE) plus anti-programmed cell death ligand 1 (PD-L1) antibody. We investigated the relationship of DLL3 expression with TME, mutation status, tumor neoantigens, and immunochemotherapy., Results: In the LS-SCLC cohort (n = 59), whole-exome sequencing revealed that DLL3 High cases had significantly more neoantigens (P = 0.004) and a significantly higher rate of the signature SBS4 associated with smoking (P = 0.02) than DLL3 Low cases. Transcriptome analysis in the LS-SCLC cohort revealed that DLL3 High cases had significantly suppressed immune-related pathways and dendritic cell (DC) function. SCLC with DLL3 High had significantly lower proportions of T cells, macrophages, and DCs than those with DLL3 Low . In the ES-SCLC cohort (n = 30), the progression-free survival associated with PE plus anti-PD-L1 antibody was significantly worse in DLL3 High cases than in DLL3 Low cases (4.7 vs. 7.4 months, P = 0.01)., Conclusions: Although SCLC with DLL3 High had a higher neoantigen load, these tumors were resistant to immunochemotherapy due to suppressed tumor immunity by inhibiting antigen-presenting functions., (© 2023. The Author(s), under exclusive licence to Springer Nature Limited.)

Background: It is essential to collect a sufficient amount of tumor tissue for successful next-generation sequencing (NGS) analysis. In this study, we investigated the clinical risk factors for avoiding re-biopsy for NGS analysis (re-genome biopsy) in cases where a sufficient amount of tumor tissue could not be collected by bronchoscopy., Methods: We investigated the association between clinical factors and the risk of re-genome biopsy in patients who underwent transbronchial biopsy (TBB) or endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) and required re-genome biopsy in cases enrolled in LC-SCRUM Asia, a prospective nationwide genome screening project in Japan. We also examined whether the frequency of re-genome biopsy decreased between the first and second halves of the enrolment period., Results: Of the 572 eligible patients, 236 underwent TBB, and 134 underwent EBUS-TBNA. Twenty-four TBBs required re-genome biopsy, and multivariate analysis showed that the risk of re-genome biopsy was significantly increased in lesions where the tumor lesion was centrally located. In these cases, EBUS-TBNA should be utilized even if the lesion is a pulmonary lesion. However, it should be noted that even with EBUS-TBNA, lung field lesions are at a higher risk of re-canalization than mediastinal lymph node lesions. It was also found that even when tumor cells were detected in rapid on-site evaluation, a sufficient amount of tumor tissue was not always collected., Conclusions: For centrally located pulmonary mass lesions, EBUS-TBNA, rather than TBB, can be used to obtain tumor tissues that can be analyzed by NGS., (© 2023. The Author(s).)

Background: Colorectal cancer is a disease of unmet medical need. Although extracellular vesicles (EVs) have been implicated in anti-tumor responses, discrepancies were observed among studies. We analyzed the role of tumor-derived EVs (TEVs) in tumor progression in vivo by focusing on regulatory T (Treg) cells, which play essential roles in tumor development and progression., Methods: A mouse model of colorectal cancer lung metastasis was generated using BALB/c mice by tail vein injection of the BALB/c colon adenocarcinoma cell line Colon-26. TEVs derived from Colon-26 and BALB/c lung squamous cell carcinoma ASB-XIV were retrieved from the culture media supernatants. A TEV equivalent to 10 µg protein was injected every other day for 2 weeks., Results: Histology and immunohistochemistry studies revealed that lung tumors reduced in the Colon-26-EV group when compared to the phosphate-buffered saline (PBS) group. The population of CD4 + FoxP3 + cells in the lung was upregulated in the PBS group mice when compared to the healthy mice (P < 0.001), but was significantly downregulated in the Colon-26-EV group mice when compared to the PBS group mice (P < 0.01). Programmed cell death protein 1, glucocorticoid-induced TNFR-related protein, and CD69 expression in lung Treg cells were markedly upregulated in the PBS group when compared to the healthy mice, but downregulated in the Colon-26-EV group when compared to the PBS group. The changes in expression were dose-dependent for Colon-26-EVs. ASB-EVs also led to significantly downregulated Treg cell expression, although non-cancer line 3T3-derived EVs did not., Conclusion: Our study suggests that TEVs possess components for tumor suppression., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Comprehensive genomic profiling (CGP) is implemented to detect actionable gene aberrations and design matched therapies. Although malignant thoracic tumors are commonly detected through respiratory endoscopy, it is questionable whether the small specimens obtained thereof are sufficient for CGP. Therefore, this study aimed to investigate the suitability of respiratory endoscopy for sampling primary and metastatic thoracic tumors for CGP. Patients whose specimens were collected through respiratory endoscopy and assessed by pathologists to determine their suitability for CGP at our institution between June 2019 and May 2022 were reviewed retrospectively. The suitability of each procedure as a sampling technique for CGP and, in the cases actually analyzed, the distribution of the detected gene aberration were assessed. In total, 122 patients were eligible for analysis; the median age was 61 (range, 29-86) years, and 71 (58.2%) patients were male. Primary intrathoracic tumors were found in 91 (74.6%) cases, including 84 (68.9%) primary lung cancers; the remaining thoracic metastases of extrathoracic origin included various types. The suitability rates of specimens obtained using conventional bronchoscopy with and without cryobiopsy, endobronchial ultrasound-guided transbronchial needle aspiration, and medical thoracoscopy were 82.8% (24/29), 70.4% (19/27), 72.9% (35/48), and 100% (18/18), respectively. Of the 96 cases judged suitable, 83 were subjected to CGP, and all but one were successfully analyzed. Finally, 47 (56.6%) patients had at least one actionable gene aberration and eight (9.6%) were treated with the corresponding targeted therapies. In conclusion, specimens obtained through respiratory endoscopy are suitable for CGP; medical thoracoscopy and cryobiopsy in conventional bronchoscopy are particularly useful., (© 2023 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.)

Background/aim: Immune checkpoint inhibitors (ICIs) are currently a standard treatment tool for non-small cell lung cancer (NSCLC). RNA-binding motif protein 17 (RBM17), a splicing factor, is frequently over-expressed in NSCLC, but little is known about the role of RBM17 in the efficacy of ICIs for NSCLC. Thus, we investigated the correlation between RBM17 expression and ICI efficacy in NSCLC., Patients and Methods: Biopsy or surgical specimens were collected from patients with advanced or recurrent NSCLC who received ICI monotherapy or chemo-immunotherapy in a first-line setting. RBM17 expression was examined using immunohistochemistry. The correlation between the efficacy of ICI monotherapy or chemo-immunotherapy and RBM17 expression was evaluated., Results: Among the 218 cases, 115 (52.8%) cases were positive for RBM17 expression. RBM17 expression was not associated with the objective response rate (ORR) or progression-free survival (PFS) in either of the ICI monotherapy or chemo-immunotherapy groups. However, among those with a low PD-L1 expression level (PD-L1 <50%; n=86), RBM17 expression was significantly associated with a better ORR (p=0.045) and a better PFS (p<0.001) in the ICI monotherapy group, and was significantly associated with a poor ORR in the chemo-immunotherapy group (p=0.041)., Conclusion: RBM17 might be a useful predictive marker for a higher efficacy of ICI monotherapy in NSCLC patients with a low PD-L1 expression level., (Copyright © 2023 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Background: Risk factors for predicting pneumonitis during durvalumab consolidation after chemoradiotherapy (CRT) in locally advanced non-small cell lung cancer (LA-NSCLC) are still lacking. Extracellular vesicles (EVs) play a crucial role in intercellular communication and are potential diagnostic tools for various diseases., Methods: We retrospectively collected predurvalumab treatment serum samples from patients treated with durvalumab for LA-NSCLC, isolated EVs using anti-CD9 and anti-CD63 antibodies, and performed proteomic analyses. We examined EV proteins that could predict the development of symptomatic pneumonitis (SP) during durvalumab treatment. Potential EV-protein biomarkers were validated in an independent cohort., Results: In the discovery cohort, 73 patients were included, 49 with asymptomatic pneumonitis (AP) and 24 with SP. Of the 5797 proteins detected in circulating EVs, 33 were significantly elevated (fold change [FC] > 1.5, p < 0.05) in the SP group, indicating enrichment of the nuclear factor kappa B (NF-κB) pathway. Patients with high levels of EV-RELA, an NF-κB subunit, had a higher incidence of SP than those with low levels of EV-RELA (53.8% vs. 13.4%, p = 0.0017). In the receiver operating characteristic analysis, EV-RELA demonstrated a higher area under the curve (AUC) than lung V20 (0.76 vs. 0.62) and was identified as an independent risk factor in the multivariate logistic regression analysis (p = 0.008, odds ratio 7.72). Moreover, high EV-RELA was also a predictor of SP in the validation cohort comprising 43 patients (AUC of 0.80)., Conclusions: Circulating EV-RELA may be a predictive marker for symptomatic pneumonitis in patients with LA-NSCLC treated with durvalumab., (© 2023 The Authors. Thoracic Cancer published by China Lung Oncology Group and John Wiley & Sons Australia, Ltd.)

Background: Sequential tyrosine kinase inhibitors (TKIs) following immune checkpoint inhibitors (ICIs) increases the incidence of serious adverse events (SAEs). However, the factors and the types of TKIs that affect the incidence of SAEs remain unknown., Methods: We retrospectively reviewed advanced non-small cell lung cancer (NSCLC) patients who received sequential TKIs following ICIs between November 2015 and April 2021. All AEs were evaluated using Common Terminology Criteria for Adverse Events (CTCAE) ver 5.0., Results: Among 1,638 NSCLC patients who received ICIs, 63 patients received sequential TKIs following ICIs. The types of TKIs included EGFR-TKIs in 48 patients, ALK-TKIs in 10 patients, and others in 5 patients. The median dosing interval was 57 days (range: 7-698). Eighteen (28.6%) patients developed SAEs (Grade 3/4 or hospitalized). The incidence of SAEs and withdrawal of TKIs due to AEs were significantly higher in patients (n = 40) who initiated TKI treatment within 3 months after ICIs than in patients (n = 23) who initiated TKI treatment 3 months after ICIs (SAEs, 40.0% vs. 4.3%, p < 0.01; withdrawal rate: 57.5% vs. 21.7%, p < 0.01). There was no significant difference in the incidence of SAEs and withdrawal rate due to AEs between EGFR-TKIs and other TKIs (SAE, 22.9% vs. 40.0%, p = 0.20; withdrawal rate: 41.7% vs. 53.3%, p = 0.55)., Conclusion: The dosing interval from last ICI to the initiation of TKI treatment can affects the incidence of SAEs and the withdrawal rate due to AEs regardless of the types of TKIs., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Background: Leptomeningeal metastases (LM) are devastating complications of epidermal growth factor receptor (EGFR)-mutated non-small-cell lung cancer (NSCLC). Although osimertinib, a third-generation EGFR-tyrosine kinase inhibitor (TKI), has better penetration into the central nervous system than first-generation EGFR-TKIs, data on the distinct activity of EGFR-TKIs in untreated advanced EGFR-mutated NSCLC with LM are lacking., Patients and Methods: We retrospectively reviewed patients treated with EGFR-TKIs for TKI-untreated common EGFR-mutated NSCLC with LM between July 2002 and July 2021 at the National Cancer Center Hospital. The patients were divided into two groups: patients treated with osimertinib (Osi group) and those treated with gefitinib or erlotinib [first-generation (1G)-TKI group]., Results: Of the 967 patients, 71 were eligible, including 29 in the Osi group and 42 in the 1G-TKI group. The median progression-free survival (PFS) and overall survival (OS) in the Osi group were better than those in the 1G-TKI group (PFS: 16.9 months versus 8.6 months, P = 0.007, and OS: 26.6 months versus 20.0 months, P = 0.158). The LM-overall response rate (ORR) and LM-PFS were significantly better in the Osi group than in the 1G-TKI group (LM-ORR: 62.5% versus 25.7%, P = 0.007; LM-PFS: 23.4 months versus 12.1 months, P = 0.021). In the subgroup analysis of EGFR mutation status, LM-PFS for patients with exon 19 deletion was significantly longer in the Osi group than in the 1G-TKI group (32.7 months versus 13.4 months, P = 0.013), whereas those with L858R mutation in exon 21 did not differ between the two groups. In the multivariate analysis, osimertinib and exon 19 deletion were significant factors for better LM-PFS and OS., Conclusion: Osimertinib can be more effective for untreated common EGFR-mutated NSCLC patients with LM, especially those with exon 19 deletion, compared to first-generation TKIs., Competing Interests: Disclosure The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: TY reports grants and personal fees from Amgen, grants and personal fees from AstraZeneca, grants from Takeda, grants from Daiichi Sankyo, grants and personal fees from Ono, grants and personal fees from MSD, grants from Abbvie, grants and personal fees from Novartis, grants and personal fees from Chugai, grants and personal fees from BMS, personal fees from Taiho, personal fees from Lilly, personal fees from Roche, personal fees from ArcherDX, outside the submitted work. KM reports personal fees from Ono, personal fees from AstraZeneca, personal fees from Chugai, personal fees from Bristol Myers Squibb, outside the submitted work. YM reports grants from the National Cancer Center Research and Development Fund, grants from Grant-in-Aid for Scientific Research on Innovative Areas, grants from Hitachi, Ltd. Grants, personal fees from Olympus, personal fees from AstraZeneca, personal fees from Novartis, personal fees from COOK, personal fees from AMCO Inc., personal fees from Thermo Fisher Scientific, personal fees from Erbe Elektromedizin GmbH, personal fees from Fujifilm, personal fees from Chugai, personal fees from Eli Lilly, outside the submitted work. YS reports personal fees from BMS, personal fees from Chugai, personal fees from AstraZeneca, personal fees from Eli Lilly, grants and personal fees from Ono, grants from Janssen, grants from Japan Clinical Research Operations K.K., outside the submitted work. YO reports grants from Roche, grants from ABBVIE K.K, personal fees from AstraZeneca, personal fees from EIi-Lilly K.K, personal fees from Bristol Myers Squibb, personal fees from Pfizer Taiho Pharma Co. Ltd., personal fees from AstraZeneca Nippon Boehringer Ingelheim, personal fees from Chugai Pharma Co. Ltd., personal fees from Ono Pharma Co. Ltd., personal fees from Taiho Pharma Co. Ltd., outside the submitted work. YG reports grants from AZK, grants and personal fees from Pfizer, grants from Abbvie, grants and personal fees from Eli Lilly, grants and personal fees from Bristol Myers Squibb, grants and personal fees from Ono, grants and personal fees from Novartis, grants from Kyorin, grants and personal fees from Daiichi Sankyo, grants from Preferred Networks, personal fees from Chugai, personal fees from Taiho, personal fees from Boehringer Ingelheim, personal fees from MSD, personal fees from Merck, personal fees from Thermo Fischer, personal fees from AstraZeneca, personal fees from Chugai, personal fees from Guardant Health Inc., personal fees from Illumina, outside the submitted work. HH reports grants and personal fees from MSD, grants from Abbvie, grants and personal fees from AstraZeneca, grants and personal fees from BMS, grants and personal fees from Ono, grants from Merck Biopharma, grants from Daiichi Sankyo, grants from Janssen, grants from Genomic Health, grants and personal fees from Chugai, grants and personal fees from Roche, grants and personal fees from Novartis, personal fees from Eli Lilly, personal fees from Kyowa-Kirin, outside the submitted work. NY reports grants and personal fees from Chugai, grants from Taiho, grants and personal fees from Eisai, grants and personal fees from Lilly, grants from Quintiles, grants from Astellas, grants and personal fees from BMS, grants from Novartis, grants from Daiichi Sankyo, grants and personal fees from Pfizer, grants and personal fees from Boehringer Ingelheim, grants from Kyowa-Hakko Kirin, grants from Bayer, grants and personal fees from Ono Pharmaceutical Co., Ltd., grants and personal fees from Takeda, grants from Janssen Pharma, grants from MSD, grants from Merck, personal fees from Sysmex, grants from GSK, grants from Sumitomo Dainippon, grants from Chiome Bioscience Inc., grants and personal fees from Otsuka, grants from Carna Biosciences, grants from Genmab, grants from Shionogi, personal fees from AstraZeneca, personal fees from Cimic, outside the submitted work. YO reports grants and personal fees from AstraZeneca, grants and personal fees from Chugai, grants and personal fees from Eli Lilly, grants and personal fees from Ono, grants and personal fees from BMS, grants and personal fees from Kyorin, grants from Dainippon-Sumitomo, grants and personal fees from Pfizer, grants and personal fees from Taiho, grants from Novartis, grants from Takeda, grants from Kissei, grants from Daiichi Sankyo, grants from Janssen, grants from LOXO, personal fees from Boehringer Ingelheim, personal fees from Bayer, personal fees from MSD, personal fees from Nippon Kayaku, personal fees from Kyowa-Hakko Kirin, personal fees from Celltrion, personal fees from Amgen, personal fees from AnHeeart Therapeutics Inc., outside the submitted work. KT has declared no conflicts of interest., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Purpose: Immune checkpoint blockade therapy is the standard treatment for metastatic or refractory non-small cell lung cancer (NSCLC). However, it is associated with immune-related adverse events (irAEs). irAEs are sometimes fatal; however, an efficient method for early irAEs detection has not been developed because their onset timing varies. We examined the significance of non-specific symptoms as a prodrome of irAEs in patients with NSCLC., Methods: We reviewed consecutive patients who received nivolumab at a dosage of 3 mg/kg every 2 weeks for metastatic NSCLC between December 2015 and August 2017. Patient demographics, irAEs and signal symptoms were recorded. Non-specific symptoms (fever and fatigue) occurred 7 days or earlier before the onset of irAEs were considered signal symptoms. For statistical analyses, the association between irAEs and clinical information, including signal symptoms, was evaluated using Fisher's exact test and logistic regression., Results: A total of 200 patients received nivolumab; 131 (65.5%) were male, their median age was 63 years (range 30-83), 174 (87.0%) had performance status of 0-1. Signal symptoms occurred in 38 (19.0%) of the 77 patients (38.5%) who experienced irAEs, and were positively associated with the occurrence of irAEs (P < 0.01). Multivariate analysis showed that the occurrence of irAEs was significantly higher in patients with PS 0-1 [odds ratio (OR) 7.01; 95% confidence intervals (CI), 1.69-29.13] and patients experienced signal symptoms (OR 17.30; 95% CI, 6.51-45.99)., Conclusion: The occurrence of signal symptoms could be used in the early detection and management of irAEs in patients during immune checkpoint blockade therapy., (© 2022. The Author(s).)

Background: It is still unclear whether patients with advanced non-small cell lung cancer (NSCLC), with disease progression after initial immune checkpoint inhibitor (ICI) therapy, would benefit from ICIs readministration., Patients and Methods: We retrospectively collected data from patients with advanced NSCLC who received ICI retreatment. Depending on the disease status at the discontinuation of the initial ICI therapy, the patients were divided into two groups: with disease progression (PD group) and without disease progression (Without PD group). Patients in the Without PD group were required to experience disease progression during the treatment-free period. Efficacy was assessed by measuring the objective response rate (ORR) and progression-free survival in retreatment (PFS-R), while safety was assessed using the incidence of immune-related adverse events (irAEs)., Results: 30 (46.7%) of 64 eligible patients were included in the PD group and 34 (53.1%) in the Without PD group. Patients in the Without PD group had better clinical outcomes than those in the PD group (ORR, 29.4% vs. 6.7%; p = 0.03, median PFS-R, 4.1 months vs. 2.2 months, hazard ratio [HR], 0.61; 95% confidence interval [CI], 0.36-1.04; p = 0.07). Multivariate Cox regression analysis showed that patients in the Without PD group had significantly longer PFS-R than those in the PD group (HR 0.42, 95% CI, 0.21-0.85; p = 0.015). In terms of safety, 28.1% of patients observed irAEs during ICI retreatment, and the incidence rate of grade 3 or higher irAEs was 7.8%. Specifically, of the 28 patients who discontinued their initial ICI treatment because of irAEs, 35.7% developed irAEs, and 28.6% experienced relapsed irAEs during ICI retreatment., Conclusion: Immune checkpoint inhibitor retreatment demonstrated efficacy in patients who discontinued initial ICI therapy for reasons other than disease progression. However, ICI retreatment was ineffective in patients with disease progression during the initial ICI treatment., (© 2023 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

Background: Platinum etoposide plus anti-programmed cell death ligand-1 (PD-L1) antibody therapy is the standard of care for extensive-stage small cell lung cancer (ES-SCLC). However, patient characteristics associated with the efficacy of the combination therapy in SCLC are unclear., Methods: We retrospectively reviewed post-surgical limited-stage (LS)-SCLC and ES-SCLC patients treated with atezolizumab plus carboplatin and etoposide (ACE). The association between SCLC subtypes based on transcriptomic data and pathological findings, including CD8-positive tumor-infiltrating lymphocyte (TIL) status, was investigated in the LS-SCLC cohort. The association between the efficacy of ACE therapy, pathological subtypes, and TIL status was evaluated in the ES-SCLC cohort., Results: The LS-SCLC cohort (N = 48) was classified into four SCLC subtypes (ASCL1 + NEUROD1 [SCLC-A + N, N = 17], POU2F3 [SCLC-P, N = 15], YAP1 [SCLC-Y, N = 10], and inflamed [SCLC-I, N = 6]) based on transcriptomic data. SCLC-I showed enriched immune-related pathways, the highest immune score (CD8A expression and T-cell-inflamed gene expression profiles), and epithelial-mesenchymal transition (EMT), in transcriptional subtypes. Immunohistochemical staining (IHC) showed that SCLC-I had the highest density of CD8-positive TILs in transcriptional subtypes. In the ES-SCLC cohort, the efficacy of ACE therapy did not differ according to pathological subtypes. The progression-free survival (PFS) of TIL High patients was significantly longer than that of TIL Low patients (PFS: 7.3 months vs. 4.0 months, p < 0.001)., Conclusion: Tumors with a high density of TILs, which represent the most immunogenic SCLC subtype (SCLC-I), based on transcriptomic data could benefit from ACE therapy., 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 © 2023 Elsevier B.V. All rights reserved.)

Objectives: Recently introduced cryobiopsy can provide quantitatively and qualitatively excellent specimens. However, few studies have directly compared the diagnostic yield of cryobiopsy for peripheral pulmonary lesions (PPLs) with that of conventional sampling methods., Material and Methods: We retrospectively reviewed data from consecutive patients who underwent diagnostic bronchoscopy using radial endobronchial ultrasound and virtual bronchoscopic navigation for PPLs (October 2015 to September 2020). Patients who underwent cryobiopsy were assigned to the cryo group, whereas those who did not undergo cryobiopsy were assigned to the conventional group. The diagnostic outcomes of both groups were compared using propensity score analyses., Results: A total of 2,724 cases were identified, including 492 and 2,232 cases in the cryo and conventional groups, respectively. Propensity scoring was performed to match baseline characteristics, and 481 pairs of cases were selected for each matched group (m-group). The diagnostic yield was significantly higher in the m-cryo group than in the m-conventional group (89.2% vs. 77.6%, odds ratio [OR] = 2.36 [95% confidence interval [CI] = 1.65-3.38], P < 0.001). Propensity score stratification (OR = 2.35 [95% CI = 1.71-3.23]) and regression adjustment (OR = 2.54 [95% CI = 1.83-3.52]) also demonstrated the diagnostic advantages of cryobiopsy. The subgroup analysis revealed that cryobiopsy was notably effective for lesions in the middle lobe/lingula, right/left lower lobe, lesions with ground-glass opacity, and lesions invisible on chest radiography. Although there were more cases of grade 2 and 3 bleeding in the m-cryo group than in the m-conventional group (38.0% vs. 10.2% and 1.5% vs. 0.8%, respectively; P < 0.001), no grade 4 bleeding was observed., Conclusion: The propensity score analyses revealed that cryobiopsy was associated with a higher diagnostic yield for PPLs than conventional sampling methods. However, increased bleeding risk should be noted as a potential complication., 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 © 2023 Elsevier B.V. All rights reserved.)

Background: The role of estrogen receptor (ER) status in the carcinogenesis of lung cancer and its impact on prognosis remain unclear., Materials and Methods: We previously reported a prospective, multicenter, molecular epidemiology study (Japan Molecular Epidemiology for Lung Cancer Study [JME]). We examined the relationship of ER status with reproductive and hormonal factors, mutational profile, and survival using JME study data. Patients were enrolled between July 2012 and December 2013, with follow-up until November, 2017., Results: Among 441 ever- and 435 never-smokers, ER expression was observed in 46.4% and 53.5%, respectively (P = .022). Hormone use and reproductive history of female patients were not associated with ER status. Mutations in EGFR (P = .003), TP53 (P = .007), and CTNNB1 (P = .027) were significantly associated with ER expression. Multivariate analysis showed that mutations in EGFR (P = .032) and CTNNB1 (P = .026) were significantly associated with ER expression, whereas TP53 mutations exhibited a trend toward significance (P = .059). Relapse-free survival (RFS) was longer in all the patients with ER-positive tumors than those with ER-negative tumors (P = .021). RFS and overall survival were longer (P = .024, P = .011, respectively) in the stage I patients with ER-positive tumors than those with ER-negative tumors., Conclusion: ERβ expression is positively associated with EGFR mutations and negatively with TP53 and CTNNB1 mutations. ER-positive tumors can be associated with better prognosis of the patients, suggesting that ER expression with coexisting EGFR mutations and wild-type TP53 contribute to the biology of non-small cell lung cancer., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Background: Renal cell carcinoma (RCC) and non-small cell lung cancer (NSCLC) are representative malignancies that respond well to immune checkpoint inhibitors (ICIs). Research has been conducted to identify biomarkers, such as programmed death ligand-1 (PD-L1), that would allow the response to ICI therapy to be predicted; however, the complex tumor immune system consisting of both host and tumor factors may also exert an influence., Case Presentation: Computed tomographic imaging (CT) incidentally revealed a left renal mass, and a left pulmonary nodule with multiple lymph node metastases (LNMs). Firstly, video-assisted thoracic surgery revealed a lung tumor invading the chest wall. Histologically, the findings of the tumor were consistent with squamous cell carcinoma (SCC), and immunohistochemistry (IHC) showed positive PD-L1 expression. The renal tumor was excised by robotic-assisted partial nephrectomy (RAPN). Histologically, the renal tumor showed the features of clear cell carcinoma (CCC). Four months after the RAPN, CT revealed left hydronephrosis caused by an enhancing ureteral tumor. Then, multiple right lung metastases appeared, and the left lung tumor increased. Following treatment including atezolizumab, the primary lung SCC and the multiple LNMs almost disappeared completely, while the ureteral and right lung metastases showed progression. The ureteral metastasis was resected by left open nephroureterectomy. Histology of the ureteral tumor revealed features consistent with CCC. Histological examination of the multiple right lung metastases that were resected by partial lobectomy via a small thoracic incision also revealed features consistent with CCC. Two months after nephroureterectomy, a solitary left lung metastasis was treated by nivolumab and ipilimumab. Six months after nephroureterectomy, the patient died of RCC. Further studies of specimens revealed that the tumor cells in the primary RCC and the ureteral and lung metastases showed negative results of IHC for PD-L1., Conclusions: The responses to ICI therapy of concomitant RCC and NSCLC were quite different. The PD-L1 expression status in individual tumors in cases of multiple primary malignancies (MPMs) may directly predict the response of each malignancy to ICI therapy, because the host immune system, which may affect the response to ICI therapy, could be the same in MPMs., (© 2023. The Author(s).)

Background: Integrins are transmembrane proteins that mediate cell adhesion to extracellular matrix. Whereas expression of integrin alpha 2 is associated with motility, invasiveness and cellular differentiation in various tumors, the role of integrin alpha 2 in lung cancer has not been studied in detail. The aim of this study was to determine whether and how aberrant integrin alpha 2 expression in non-small cell lung cancer leads to different outcomes., Methods: We measured expression of integrin alpha 2 by quantitative polymerase chain reaction in 100 samples collected from non-small cell lung cancer patients who had undergone surgical resection. We assigned patients to high and low expression groups and analyzed survival. Cellular morphology, adhesion, proliferation, migration and invasion were examined in human lung cancer cell lines., Results: Among 100 cases, 41 were female, with a median age of 71 years. High expression of integrin alpha 2 in non-small cell lung cancer was associated with lower recurrence-free survival (P = 0.004). Overexpression of integrin alpha 2 in cell lines had no effect on cell proliferation or invasion but resulted in increased cell size (1416 μm2 versus 470 μm2 in H522 cells, P < 0.001; 1822 μm2 versus 1029 μm2 in H661 cells, P = 0.02), adhesion (P < 0.001 in H522 and H661 cells) and migration (gap area filled was 71% versus 36% in H522 cells, P < 0.001; 57% versus 26% in H661 cells, P = 0.001). These changes were suppressed by E7820, an inhibitor of integrin alpha 2., Conclusions: Integrin alpha 2 may play a significant role in lung cancer adhesion and migration, and may lead to a higher risk of recurrence., (© The Author(s) 2022. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permission@oup.com.)

Background: Transbronchial cryobiopsy enables high-quality sample collection around the probe tip. Meanwhile, existing cryoprobes have less flexibility and a higher risk of bleeding. The ultrathin cryoprobe with a 1.1-mm diameter addresses these problems and allows specimens to be directly retrieved through the working channel of a thin bronchoscope., Objective: This study evaluated the diagnostic utility and safety of non-intubated cryobiopsy using an ultrathin cryoprobe added to conventional biopsy for diagnosing peripheral pulmonary lesions (PPLs)., Methods: The data of patients who underwent conventional biopsy followed by non-intubated cryobiopsy to retrieve specimens through the thin bronchoscope's working channel for diagnosing PPLs at Osaka Metropolitan University Hospital from July 2021 to June 2022 were retrospectively collected. They were analyzed to evaluate the diagnostic utility and safety of adding non-intubated cryobiopsy to conventional biopsy for PPLs. The characteristics of PPLs that obtain additional diagnostic benefits from cryobiopsy over conventional biopsy were also investigated., Results: The analysis included 113 patients. The diagnostic yields of conventional biopsy and non-intubated cryobiopsy were 70.8% and 82.3%, respectively (p = 0.009). The total diagnostic yield was 85.8%, higher than conventional biopsy alone (p &lt; 0.001). Although one moderate bleeding occurred, no severe complications developed. The additional diagnostic benefits of non-intubated cryobiopsy over conventional biopsy were demonstrated when the radial endobronchial ultrasound (R-EBUS) showed "adjacent to" (60.3% vs. 82.8%, p = 0.017)., Conclusions: Non-intubated cryobiopsy using an ultrathin cryoprobe has high diagnostic utility and safety for diagnosing PPLs, with additional diagnostic benefits over conventional biopsy depending on the R-EBUS image., (© 2023 S. Karger AG, Basel.)

Background: This study aimed to investigate whether the immunosenescence-related score is a critical prognostic predictor of anti-programmed cell death protein 1 (PD-1) axis inhibitors in elderly patients with advanced non-small cell lung cancer (NSCLC)., Methods: We reviewed 51 patients with advanced NSCLC aged ≥75 years, who were treated with nivolumab or pembrolizumab at the National Cancer Center Hospital between December 2015 and April 2019. Factors such as modified Glasgow prognostic score (mGPS), Neutrophil-to-lymphocyte ratio (NLR), and Charlson comorbidity index (CCI) were used to assess immunosenescence., Results: The objective response rate (ORR) and disease control rate (DCR) of all patients were 25.4% (95% confidence interval [CI]: 14.3-39.6) and 52.9% (95% CI: 38.5-67.1), respectively. High mGPS (score of 2) was associated with low DCR compared to low mGPS (score of 0-1) (26.0% vs. 54.0%, p = 0.03). However, none of these scores were significantly related to the ORR. High mGPS was significantly linked to shorter median progression-free survival (mPFS) (4.2 mos. vs. 12.7 mos, p < 0.01), and median overall survival (mOS) (4.8 mos. vs. 28.1 mos, p = 0.03). However, neither CCI nor NLR was associated with prognosis. Multivariate regression analysis identified high mGPS as a significant prognostic factor for mOS (hazard ratio, HR: 0.31 [95% CI: 0.13-0.71], p < 0.01)., Conclusions: High mGPS scores significantly impaired DCR, mPFS, and mOS in patients with advanced NSCLC treated with anti-PD-1 antibodies., Competing Interests: Conflict of Interest Yuichiro Ohe received honoraria (lecture fees) from AstraZeneca, Chugai pharmaceutical Co Ltd; Hidehito Horinouchi received honoraria (lecture fees) from AstraZeneca, Eli Lilly Japan K.K, ONO pharmaceutical Co Ltd, Bristol Myers Squibb; Yasushi Goto received honoraria (lecture fees) from AstraZeneca, Pfizer, Novartis, Eli Lilly Japan K·K; Tatshuya Yoshida received honoraria (lecture fees) from AstraZeneca, Chugai pharmaceutical Co Ltd, Eli Lilly Japan K·K, Takeda, ONO pharmaceutical Co Ltd; Yusuke Okuma received honoraria (lecture fees) from AstraZeneca, Eli Lilly Japan K·K, Chugai pharmaceutical Co Ltd; Tomohiro Tanaka, Yuki Takeyasu, Ken Masuda, Yuki Shinnno, Yuji Matsumoto and Noboru Yamamoto have no conflict of interest., (Copyright © 2022 The Japanese Respiratory Society. Published by Elsevier B.V. All rights reserved.)

Chemotherapy for peritoneal dissemination is poorly effective owing to limited drug transfer from the blood to the intraperitoneal (i.p.) compartment after intravenous (i.v.) administration. i.p. chemotherapy has been investigated to improve drug delivery to tumors; however, the efficacy continues to be debated. As anticancer drugs have low molecular weight and are rapidly excreted through the peritoneal blood vessels, maintaining the i.p. concentration as high as expected is a challenge. In this study, we examined whether i.p. administration is an efficient route of administration of high-molecular-weight immune checkpoint inhibitors (ICIs) for the treatment of peritoneal dissemination using a model of peritoneal disseminated carcinoma. After i.p. administration, the amount of anti-PD-L1 antibody transferred into i.p. tumors increased by approximately eight folds compared to that after i.v. administration. Intratumoral distribution analysis revealed that anti-PD-L1 antibodies were delivered directly from the i.p. space to the surface of tumor tissue, and that they deeply penetrated the tumor tissues after i.p. administration; in contrast, after i.v. administration, anti-PD-L1 antibodies were only distributed around blood vessels in tumor tissues via the enhanced permeability and retention (EPR) effect. Owing to the enhanced delivery, the therapeutic efficacy of anti-PD-L1 antibody in the peritoneal dissemination models was also improved after i.p. administration compared to that after i.v. administration. This is the first study to clearly demonstrate an EPR-independent delivery of ICIs to i.p. tumors by which ICIs were delivered in a massive amount to the tumor tissue via direct penetration after i.p. administration., Competing Interests: Declaration of Competing Interest Authors declare that they have no competing interests in this research., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Introduction: Administration of 400 mg pembrolizumab every 6 weeks (400 mg Q6W) has been approved on the basis of the results of simulated pharmacokinetic modeling and exposure-response analyses. Nevertheless, the safety of switching dosage from 200 mg every 3 weeks (Q3W) to 400 mg Q6W during treatment remains unclear., Methods: This study involved patients (N = 45) with advanced NSCLC, in whom the pembrolizumab dosage was switched from 200 mg Q3W to 400 mg Q6W between August 2020 and November 2021 in our institute., Results: At the time of switching, the median age of the patients was 71 (range: 32-84) years, and 32 patients (71.1 %) were males. The median number of cycles of 200 mg Q3W before switching was six (range: 1-31). After switching, new or worsening immune-related adverse events (irAEs) occurred in 17 of the 45 patients (37.8%) within three cycles. The irAEs were pneumonitis in 11 patients (24.4%), diarrhea in three patients (6.7%), renal dysfunction in two patients (4.4%), adrenal dysfunction in two patients (4.4%), a skin rash in one patient (2.2%), fulminant type 1 diabetes mellitus in one patient (2.2%)., Conclusions: The switching of pembrolizumab dosage from 200 mg Q3W to 400 mg Q6W resulted in the occurrence of new or worsening irAEs, in particular, pneumonitis, in the early cycles even in patients who had received stable treatment with 200 mg Q3W., (Copyright © 2022 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.)

Objectives: The effectiveness of PD-1 blockade therapy in advanced epidermal growth factor receptor (EGFR)-mutant non-small cell lung cancer (NSCLC) is limited. We investigated whether patient characteristics, PD-L1 expression, and immune cell (IC) status in the tumor microenvironment (TME) were associated with PD-1 blockade therapy outcomes., Materials and Methods: We retrospectively reviewed patients with advanced EGFR-mutant NSCLC treated with PD-1 blockade (nivolumab or pembrolizumab) between January 2016 and March 2018. The PD-L1 expression tumor proportion score (TPS) and types and distribution of ICs (CD8, PD-1, CD204, tumoral, and stromal) in the TME were analyzed., Results: Among 57 EGFR-mutant NSCLC patients treated with PD-1 blockade, 39 patients had sufficient tissues for analyzing the TME. The overall response rate (ORR) of PD-1 blockade was 12.3%. Only tumoral CD8 positive (CD8 + ) IC status was significantly associated with the response (median tumoral CD8 + ICs: 299/mm 2 vs. 115/mm 2 , P < .01). Among the 6 patients with concurrent high PD-L1 expression (TPS: ≥ 50%)/high tumoral CD8 + ICs (≥ 205/mm 2 ), 5 (83.3%) showed a response and a significantly longer progression-free survival (PFS) (PFS: 9.4M vs. 1.8M, P < .01). In contrast, none of the 7 patients with high PD-L1 expression/low tumoral CD8 + ICs (<205/mm 2 ) showed a response., Conclusion: Concurrent high PD-L1 expression and high tumoral CD8 + ICs could predict the response and longer PFS of PD-1 blockade therapy in EGFR-mutant patients., (Copyright © 2022. Published by Elsevier Inc.)

It is unclear whether tumor vascular endothelial growth factor receptor 2 expression affects the therapeutic efficacy of immune-checkpoint inhibitors and antiangiogenic agents. This retrospective, multicenter study included patients with advanced non-small cell lung cancer who were treated with immune-checkpoint inhibitors. We constructed tissue microarrays and performed immunohistochemistry with an anti-vascular endothelial growth factor receptor 2 antibody. We analyzed immune and tumor cell staining separately in order to determine their correlation with the objective response rate, progression-free survival, and overall survival in patients receiving immune-checkpoint inhibitors. Of 364 patients, 37 (10%) expressed vascular endothelial growth factor receptor 2 in immune cells and 165 (45%) in tumor cells. The objective response rate, progression-free survival, and overall survival were significantly worse in patients treated with immune checkpoint inhibitor monotherapy who expressed vascular endothelial growth factor receptor 2 in immune cells than those who did not (10% vs 30%, p = 0.028; median = 2.2 vs 3.6 months, p = 0.012; median = 7.9 vs 17.0 months, p = 0.049, respectively), while there was no significant difference based on tumor cell expression (24% vs 30%, p = 0.33; median = 3.1 vs 3.5 months, p = 0.55; median = 13.6 vs 16.8 months, p = 0.31). There was no significant difference in overall survival between patients treated with and without antiangiogenic agents in any treatment period based on vascular endothelial growth factor receptor 2 expression. Immune checkpoint inhibitor efficacy was limited in patients expressing vascular endothelial growth factor receptor 2 in immune cells., (© 2022 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.)

Background: We aimed to identify the relationship between thyroid transcription factor-1 (TTF-1) expression of lung adenocarcinoma and the efficacy of immune-checkpoint inhibitor (ICI) therapy., Methods: This retrospective multicenter study comprised patients with advanced lung adenocarcinoma treated with ICI monotherapy. We collected clinical medical records including data on TTF-1 expression and analyzed the relationship between TTF-1 expression and programmed death-ligand 1 tumor proportion score (PD-L1 TPS), objective response rate (ORR), progression-free survival (PFS), and overall survival (OS)., Results: In total, 108 patients with lung adenocarcinoma were analyzed. The rate of TPS ≥1% and ≥50% in patients with positive TTF-1 expression was significantly higher than that in patients with negative TTF-1 expression (88% vs. 60%, p < 0.001; 65% vs. 24%, p < 0.001). The ORR was significantly higher in TTF-1 positive patients than in TTF-1-negative patients (38% vs. 8%, p = 0.003). Among patients with TPS ≥50% and 1%-49%, the ORR in TTF-1 positive and negative patients was 48% (26/54) versus 17% (1/6) (p = 0.21), and 32% (6/19) versus 11% (1/9) (p = 0.37), respectively. The ORR for patients with TPS <1% was 0% in both the TTF-1 negative and positive cases. The median PFS and OS was significantly longer in TTF-1-positive patients than in TTF-1-negative patients (5.4 vs. 1.6 months, p < 0.001; 18.2 vs. 8.0 months, p = 0.041). Multivariate analysis revealed that TTF-1-negative status was an independent unfavorable prognostic factor for PFS., Conclusion: Patients with TTF-1-positive status receiving ICI monotherapy showed better outcomes than those with TTF-1-negative lung adenocarcinoma., (© 2022 The Authors. Thoracic Cancer published by China Lung Oncology Group and John Wiley & Sons Australia, Ltd.)

Background: Many previous studies have demonstrated that minor-frequency pretreatment T790M mutation (preT790M) could be detected by ultrasensitive methods in a considerable number of treatment-naïve, epidermal growth factor receptor (EGFR)-mutated, non-small cell lung cancer (NSCLC) cases. However, the impact of preT790M in resected cases on prognosis remains unclear., Methods: We previously reported that preT790M could be detected in 298 (79.9%) of 373 surgically resected, EGFR-mutated NSCLC patients. Therefore, we investigated the impact of preT790M on recurrence-free survival (RFS) and overall survival (OS) in this cohort by multivariate analysis. All patients were enrolled from July 2012 to December 2013, with follow-up until November 30, 2017., Results: The median follow-up time was 48.6 months. Using a cutoff value of the median preT790M allele frequency, the high-preT790M group (n = 151) had significantly shorter RFS (hazard ratio [HR] = 1.51, 95% confidence interval [CI]: 1.01-2.25, P = 0.045) and a tendency for a shorter OS (HR = 1.87, 95% CI: 0.99-3.55, P = 0.055) than the low-preT790M group (n = 222). On multivariate analysis, higher preT790M was independently associated with shorter RFS (high vs low, HR = 1.56, 95% CI: 1.03-2.36, P = 0.035), irrespective of advanced stage, older age, and male sex, and was also associated with shorter OS (high vs low, HR = 2.16, 95% CI: 1.11-4.20, P = 0.024) irrespective of advanced stage, older age, EGFR mutation subtype, and history of adjuvant chemotherapy., Conclusions: Minor-frequency, especially high-abundance of, preT790M was an independent factor associated with a poor prognosis in patients with surgically resected, EGFR-mutated NSCLC., (© 2022. The Author(s).)

Stereotactic body radiation therapy (SBRT) is a frequently used modality for the treatment of early stage non-small cell lung cancer and oligometastatic disease of the lung. The radiological changes observed in the lung after SBRT are likely to differ from those observed after conventional thoracic radiation therapy, primarily due to the small size of the target volume and highly conformal dose distributions with steep dose gradients from the target to surrounding normal lung tissues used in SBRT. Knowledge of the radiological changes that can occur after SBRT is required to correctly diagnose local failure. Herein, I report several radiological changes specific to SBRT that have been observed., (© 2022. The Author(s).)

Background: Malignant tumors occurring around both the spinal column and posterior chest wall are uncommon. Surgical resection of chest wall tumors adjacent to the spinal column is still challenging due to the surrounding anatomical structures. The purpose of the present study was to evaluate the long-term outcomes of surgical management in malignant tumors involving the spinal column and posterior chest wall., Methods: Between 1999 and 2007, 10 consecutive patients underwent en bloc resection combined with the posterior chest wall in the treatment of malignant tumors around the spinal column. There were 6 males and 4 females with a mean age at the surgery of 40.9 years old (range, 14-62 years old). The mean postoperative follow-up period was 159.7 months (range, 84-245 months). The clinical history, physical examination, laboratory data, radiological findings, and operative findings for each patient were retrospectively reviewed., Results: All surgeries were performed via a combined anterior and posterior approach. The mean numbers of partially resected vertebrae and ribs were 3.1 and 4.1, respectively. Lower or upper lobectomy was performed in four patients, and the diaphragm was partially resected in two patients. The surgical margin was wide in seven patients and marginal in two patients. Although five patients had postoperative respiratory problem, all patients improved immediately without life-threatening complications. There were no patients with respiratory insufficiency after surgery. One patient with osteosarcoma died of lung metastases 99 months after surgery. At the final follow-up, only one patient had local recurrence, five had been continuously disease-free, and three were alive with no evidence of disease., Conclusions: En bloc resection and reconstruction in selected patients with malignant tumors involving both the spinal column and posterior chest wall demonstrated good long-term results for local control and the respiratory function., Competing Interests: Declaration of competing interest None., (Copyright © 2021 The Japanese Orthopaedic Association. Published by Elsevier B.V. All rights reserved.)

Background: SMARCA4-deficient thoracic tumor is a novel disease entity characterized by mutations in SMARCA4 resulting in loss of its expression. They could be divided according to their phenotypes; carcinoma or sarcomatoid. It remains unclear how many patients with these SMARCA4-deficient tumors could benefit from inhibitors of programmed death 1 (PD-1) or programmed death ligand 1 (PD-L1)., Methods: SMARCA4-deficient thoracic tumor cases were retrospectively identified from pathology and gene expression databases at the National Cancer Center Hospital in Japan. Clinical outcomes of patients treated with PD-1/PD-L1 inhibitors were reviewed., Results: Eighteen patients with SMARCA4-deficient thoracic tumor [carcinoma (n = 10), sarcomatoid (n = 7), and ambiguous type (n = 1)] were identified. Of the twelve [carcinoma (n = 7), sarcomatoid (n = 5)] who had received immune checkpoint inhibitors (ICIs), 5 [carcinoma (n = 3), sarcomatoid (n = 2)] showed a partial response, all of whom had received an ICI as the first-line therapy. The overall response rate was The PD-L1 tumor proportion scores of the 5 responding patients were 100%, 80%, 5% (n = 2), and less than 1%. The median progression-free survival (PFS) of all the patients was 2.4 months [95% confidence interval (CI), 1.1 months-not achieved (NA)], while the median PFS of the 3 patients who received first-line ICIs was not reached (95% CI, 1.1 months-NA)., Conclusion: PD-1/PD-L1 inhibitors showed promising results in the treatment of SMARCA4-deficient tumor. Further studies, especially on patient selection and combination therapy, are needed., (Copyright © 2022. Published by Elsevier Inc.)

Background: Cryobiopsy is an established technique that yields larger and higher-quality samples than does a forceps biopsy. However, it remains underutilised in the diagnosis of peripheral pulmonary lesions (PPLs), mainly because of difficulties in handling conventional cryoprobes. A recently introduced single-use cryoprobe with a smaller diameter and more flexibility than conventional ones may improve its diagnostic ability for PPLs. We conducted this prospective study to evaluate the feasibility of transbronchial cryobiopsy in the diagnoses of PPLs, using a new 1.7-mm cryoprobe., Methods: The study included patients with PPLs less than 30 mm in diameter scheduled to undergo bronchoscopy. All the procedures were performed using a combination of virtual bronchoscopic navigation, radial endobronchial ultrasound (R-EBUS) and X-ray fluoroscopy, and all the samples were collected using the cryoprobe alone. Thereafter, we assessed the diagnostic outcomes and safety profiles., Results: A total of 50 patients were enrolled and underwent cryobiopsy. The median lesion size was 20.8 mm (range, 8.2-29.6 mm), and the negative bronchus sign was seen in 34% of lesions. The diagnostic yield was 94% (95% confidence interval, 83.5-98.8%). A positive bronchus sign had a significantly higher diagnostic yield than did a negative bronchus sign (100% vs. 82.4%; P = 0.035). The yield was achieved regardless of other variables, including lesion size, location, and R-EBUS findings. The major complications were mild and moderate bleeding in 28% and 62% of patients, respectively. Pneumothorax was identified in one patient., Conclusion: Transbronchial cryobiopsy using the new 1.7-mm cryoprobe is a feasible procedure that has the potential to increase the diagnostic accuracy for PPLs., Trial Registration: Japan Registry of Clinical Trials, jRCT1032200065. Registered July 8 2020, https://jrct.niph.go.jp/en-latest-detail/jRCT1032200065., (© 2022. The Author(s).)

Backgrounds/aim: Photodynamic therapy (PDT) with Talaporfin sodium (Talaporfin) is an effective and safe treatment for central-type early-stage lung cancer (CELC) that is associated with less skin photosensitivity. However, PDT is mostly performed in hospital for the purpose of light shading management in Japan. It is expected that it will be possible to perform PDT with Talaporfin (Talaporfin-PDT) as a day treatment with ≥14 days of shading management at home. This study aimed to confirm the safety of Talaporfin-PDT as day treatment., Methods: We retrospectively investigated the occurrence of adverse events among consecutive patients who received PDT for CELC in a day treatment setting in the Respiratory Endoscopy Division of our institution between January 2010 and February 2020., Results: A total of 12 patients (16 treatments) received day treatment of Talaporfin-PDT. Among the 12 patients, one patient (one treatment) was followed at another hospital. No severe adverse events after treatment were observed among the remaining 11 patients (15 treatments). Mild photosensitivity on a photosensitivity test was observed in 3 (3 treatments) of the 11 patients (15 treatments) but no major photosensitivity was observed. This photosensitivity was a temporary reaction., Conclusion: Talaporfin-PDT for CELC was safely performed as a day treatment., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Objective: Nivolumab and pembrolizumab have been the standard of care in patients with previously treated advanced non-small cell lung cancer (NSCLC). This study aimed to compare the efficacy and safety of nivolumab and pembrolizumab., Materials and Methods: We retrospectively reviewed data of advanced NSCLC patients with PD-L1 (Programmed death-ligand 1) [clone:22C3] positive tumors (Tumor proportion score [TPS] ≥ 1%) who had been treated with nivolumab or pembrolizumab as second- or subsequent line from 2015 to 2021.Propensity score matching was performed to reduce potential selection bias. We analyzed the clinical outcomes including objective response rate (ORR), progression-free survival (PFS), overall survival (OS), and immune-related adverse events (irAEs)., Results: Among a total of 202 eligible patients, 72 pairs of patients from each group were identified after propensity score matching. There were no significant differences in ORR, PFS, and OS between the two agents (nivolumab vs. pembrolizumab: ORR, 23.6% vs. 20.8%, median PFS, 3.7 months vs. 4.6 months, hazard ratio [HR] 1.02; 95% confidence interval [CI], 0.71 to 1.46; p = 0.92, and median OS, 27.4 months vs. 19.6 months, HR 0.78; 95% CI, 0.51 to 1.20; p = 0.24). Additionally, PFS was similar between the treatments in the PD-L1 TPS ≥ 50% subgroup (median PFS, 3.7 months vs. 4.6 months, HR 0.94; 95% CI, 0.56 to 1.59; p = 0.82) and PD-L1 TPS 1-49% subgroup (median PFS, 3.7 months vs.4.6 months, HR 1.13; 95% CI, 0.69 to 1.85; p = 0.61). There was also no significant difference in the frequency of grade ≥ 3 irAEs (9.7% vs. 11.1%; p = 1.0)., Conclusion: There is no significant difference in the efficacy and safety between nivolumab and pembrolizumab in advanced NSCLC patients with PD-L1-positive tumors in the subsequent line setting., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Background: Strategies to implement early specialized palliative care have not yet been established. The present study investigated the feasibility of a nurse-led, screening-triggered early specialized palliative care intervention programme and obtained data to design a randomized controlled trial., Methods: Patients with metastatic lung cancer undergoing first-line platinum-based chemotherapy were eligible. The intervention consisted of (1) a questionnaire-based screening programme and (2) advanced-level nurse counselling and care coordination with interdisciplinary team approach. The primary endpoint was the completion rate of the assessment questionnaire after the second course of first-line chemotherapy (T2). Secondary endpoints included changes in Functional Assessment of Cancer Therapy-Lung scores, depression and anxiety rates based on the Patient Health Questionnaire 9 and the Hospital Anxiety and Depression Scale, and the contents of specialized palliative care., Results: A total of 50 patients were enrolled between August 2012 and March 2014. Median age was 66 years (range, 40-78 year) and 84% were male. A total of 38 patients had stage IV non-small cell lung carcinoma and 12 had extensive disease small-cell lung carcinoma. The completion rate was 70% (95% confidence interval 56.0-81.0). The median duration between baseline and T2 was 53 days. Improvement from baseline were observed at T2 in Functional Assessment of Cancer Therapy-Lung scores (86.0 ± 18.1 vs 94.9 ± 18.2, P = 0.057), depression (16.0 vs 5.7%; P = 0.26) and anxiety (32.0 vs 22.9%; P = 0.65); however, these results were not statistically significant., Conclusions: This early specialized palliative care intervention is feasible and could be useful in improving patients' quality of life. The present results justify the initiation of a randomized control trial., (© The Author(s) 2022. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: Chemoradiotherapy (CRT) followed by durvalumab treatment improved prognosis in unresectable locally advanced non-small-cell lung cancer (LA-NSCLC). This study aimed to evaluate whether the status of the immune-related tumour microenvironment (TME) at baseline associates with the efficacy., Methods: This retrospective study evaluated immune-related TME factors, including programmed cell death ligand 1 (PD-L1) (clone: 22C3) expression on tumour cells and the density of CD8-positive tumour-infiltrating lymphocytes (TILs) at pre-CRT in patients with unresectable LA-NSCLC treated with CRT only (CRT alone group) and those treated with CRT followed by durvalumab (Durva group)., Results: A total of 551 patients were included (N = 113 in the Durva group). Progression-free survival (PFS) in the Durva group was significantly greater than that in the CRT alone group (not reached [NR] vs 12.9 months; p = 0.002). In the CRT alone group, neither PD-L1 expression nor TIL status affected PFS; in contrast, in the Durva group, high density of CD8-positive TILs (TIL High ≥100/mm 2 ) and PD-L1-positive expression (tumour proportion score ≥1%; PD-L1+) was significantly associated with longer PFS (TIL: NR vs 9.5 months; p = 0.002; and PD-L1: NR vs 7.7 months; p = 0.003). On the other hand, in patients with epidermal growth factor receptor mutations or anaplastic lymphoma kinase rearrangements, there was no significant difference in PFS between the groups (Durva vs CRT alone: 9.9 months vs 14.0 months; p = 0.77)., Conclusions: PD-L1+ and TIL High at baseline could be predictive markers of the efficacy of CRT followed by durvalumab., Competing Interests: Conflict of interest statement Shirasawa has nothing to disclose. Yoshida reports grants from ONO Pharmaceutical, during the conduct of the study; grants and personal fees from AstraZeneca, grants and personal fees from Bristol-Myers Squibb, grants from Takeda, personal fees from Chugai, personal fees from Novartis, grants from MSD, grants from Abbvie, outside the submitted work. Imabayashi reports grants from Hitachi High-Tech Corporation, personal fees from AstraZeneca, personal fees from COOK, personal fees from Chugai Pharma, personal fees from Eli Lilly Japan, personal fees from MSD, personal fees from Thermo Fisher Scientific K.K., personal fees from Johnson & Johnson Medical Devices Companies Personal fees for lectures, personal fees from Olympus Personal fees for lectures, outside the submitted work. K Okuma has nothing to disclose. Matsumoto reports grants from National Cancer Centre Research and Development Fund, grants from Grant-in-Aid for Scientific Research on Innovative Areas, grants from Hitachi, Ltd., grants from Hitachi High-Technologies, personal fees from Olympus, personal fees from AstraZeneca, personal fees from Novartis, personal fees from COOK, personal fees from AMCO INC. outside the submitted work. Masuda reports personal fees from Chugai, outside the submitted work. Shinno has nothing to disclose. Y Okuma reports grants from AbbVie, outside the submitted work. Goto reports grants and personal fees from Eli Lilly, personal fees from Chugai, grants and personal fees from Taiho Pharmaceutical, personal fees from Boehringer Ingelheim, grants and personal fees from Pfizer, grants and personal fees from Novartis, personal fees from AstraZeneca, grants and personal fees from MSD, grants and personal fees from Guardant Health, grants and personal fees from Ono Pharmaceutical, grants from Kyorin, grants and personal fees from Dai-ichi Sankyo, personal fees from Illumina, grants and personal fees from Bristol Myers Squibb, outside the submitted work. Horinouchi reports grants and personal fees from BMS, grants and personal fees from MSD, grants and personal fees from Chugai, grants and personal fees from Taiho, grants and personal fees from Astra Zeneca, grants from Astellas, grants from Merck Serono, grants from Genomic Health, grants and personal fees from Lilly, grants and personal fees from Ono, outside the submitted work. Tsuchida reports personal fees from Nippon Medical School Foundation, grants from Japan Agency for Medical Research and Development, grants from Foundation for Promotion Cancer Research, personal fees from Hamamatsu University School of Medicine, outside the submitted work;. Yamamoto reports grants from Chugai, grants from Taiho, grants from Eisai, grants from Lilly, grants from Quintiles, grants from Astellas, grants from BMS, grants from Novartis, grants from Daiichi-Sankyo, grants from Pfizer, grants from Boehringer Ingelheim, grants from Kyowa-Hakko Kirin, grants from Bayer, grants from Ono Pharmaceutical Co. Ltd., grants from Takeda, personal fees from Ono Pharmaceutical Co. Ltd., personal fees from Chugai, personal fees from AstraZeneca, personal fees from Pfizer, personal fees from Lilly, personal fees from BMS, personal fees from Eisai, personal fees from Otsuka, personal fees from Takeda, personal fees from Boehringer Ingelheim, personal fees from Cimic, grants from Janssen Pharma, grants from MSD, grants from Merck, personal fees from Sysmex, grants from GSK, grants from Sumitomo Dainippon, grants from Chiome Bioscience Inc., outside the submitted work. Nakayama has nothing to disclose. Watanabe has nothing to disclose. Motoi reports grants and personal fees from Ono, grants from NEC, personal fees from Miraca Life Sciences, personal fees from MSD, personal fees from Astra Zeneca, grants and personal fees from Roche Diagnostics, personal fees from Novartis, personal fees from Taiho, personal fees from Beckton Dickinson Japan, personal fees from Covidien Japan Inc, outside the submitted work. Ohe reports grants and personal fees from Bristol-Myers Squibb, grants and personal fees from ONO Pharmaceutical, grants and personal fees from MSD, during the conduct of the study; grants and personal fees from AstraZeneca, grants and personal fees from Amgen, personal fees from Boehringer Ingelheim, personal fees from Celltrion, grants and personal fees from Chugai, grants and personal fees from Eli Lilly, grants and personal fees from Janssen, grants and personal fees from Kyorin, grants from Kissei, grants and personal fees from Nippon Kayaku, grants and personal fees from Novartis, grants from Ignyta, grants and personal fees from Taiho, grants and personal fees from Takeda, personal fees from Pfizer, outside the submitted work., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Background: Cancer cachexia is a multifactorial syndrome characterized by weight loss leading to immune dysfunction that is commonly observed in patients with advanced non-small cell lung cancer (NSCLC). We examined the impact of cachexia on the prognosis of patients with advanced NSCLC receiving pembrolizumab and evaluated whether the pathogenesis of cancer cachexia affects the clinical outcome., Patients and Methods: Consecutive patients with advanced NSCLC treated with pembrolizumab were retrospectively enrolled in the study. Serum levels of pro-inflammatory cytokines and appetite-related hormones, which are related to the pathogenesis of cancer cachexia, were analyzed. Cancer cachexia was defined as (1) a body weight loss > 5% over the past 6 months, or (2) a body weight loss > 2% in patients with a body mass index < 20 kg/m 2 ., Results: A total of 133 patients were enrolled. Patients with cachexia accounted for 35.3%. No significant difference in the objective response rate was seen between the cachexia and non-cachexia group (29.8% vs. 34.9%, P = 0.550), but the median progression-free survival (PFS) and overall survival (OS) periods were significantly shorter in the cachexia group than in the non-cachexia group (PFS: 4.2 months vs. 7.1 months, P = 0.04, and OS: 10.0 months vs. 26.6 months, P = 0.03). The serum TNF-alpha, IL-1 alpha, IL-8, IL-10, and leptin levels were significantly associated with the presence of cachexia, but not with the PFS or OS., Conclusion: The presence of cachexia was significantly associated with poor prognosis in advanced NSCLC patients receiving pembrolizumab, not with the response to pembrolizumab., (© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Patient-derived xenografts (PDX) can adequately reflect clinical drug efficacy. However, the methods for evaluating drug efficacy are not fully established. We selected five non-small cell lung cancer (NSCLC) PDXs with genetic alterations from established PDXs and the corresponding molecular targeted therapy was administered orally for 21 consecutive days. Genetic analysis, measurement of drug concentrations in blood and tumors using LC/MS-MS, and analysis of drug distribution in tumors using matrix-assisted laser desorption/ionization mass spectrometry were performed. Fifteen (20%) PDXs were established using samples collected from 76 patients with NSCLC with genetic alterations. The genetic alterations observed in original patients were largely maintained in PDXs. We compared the drug efficacy in original patients and PDX models; the efficacies against certain PDXs correlated with the clinical effects, while those against the others did not. We determined blood and intratumor concentrations in the PDX model, but both concentrations were low, and no evident correlation with the drug efficacy could be observed. The intratumoral spatial distribution of the drugs was both homogeneous and heterogeneous for each drug, and the distribution was independent of the expression of the target protein. The evaluation of drug efficacy in PDXs enabled partial reproduction of the therapeutic effect in original patients. A more detailed analysis of systemic and intratumoral pharmacokinetics may help clarify the mode of action of drugs. Further development of evaluation methods and indices to improve the prediction accuracy of clinical efficacy is warranted., (©2021 American Association for Cancer Research.)

Introduction: The accelerated development of lung cancer treatments has resulted in a single global study that is sufficient for a new agent and indication to be approved. Not all new treatments predominate globally, and differences in standards of care may influence the efficacy of treatments in the real world., Methods: The results from Japanese domestic trials and global trials that included a subset population of Japanese patients were evaluated for 18 genomic targeted agents and immune therapies approved after 2000. The results were collected from drug applications that were reviewed for treatment approval in Japan., Results: Japan is one of the first countries to approve and fully reimburse new agents around the world. Alectinib and nivolumab, which were first developed by Japanese pharmaceutical companies, were evaluated in an independent domestic trial, which resulted in their early approval. For most other indications, 1.1-15.8% of the patients who participated in pivotal registration studies were Japanese, and their treatment results were comparable to those of the overall population. Overall survival was less likely to be improved by four agents for which the post-protocol therapy might have been different in Japan than in other countries., Conclusions: Overall, a positive result in a global trial was emulated in Japanese patients and led to the approval of a new standard treatment in Japan. Early approvals were attained by either participating in the global registrational study or conducting a domestic phase II study. The higher efficacy of new agents may be an issue in the future, as Japanese patients had early access to the new agent and may receive better treatment after the trial., (© The Author(s) 2021. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

A 68-year-old Japanese man was diagnosed with lung adenocarcinoma stage IVB. We introduced a first-line chemotherapy of four cycles of carboplatin and pemetrexed and pembrolizumab, followed by pemetrexed and pembrolizumab maintenance therapy. Approximately four months after anticancer therapy, a small nodule appeared in the right peripheral S3 lesion. After five months, the nodule was confirmed as a Mycobacterium tuberculosis (TB) nodule. We initiated anti-TB therapy without stopping pembrolizumab, and the right S3 nodule shrank immediately. This report supports the concurrent use of anti-TB treatment with an immune checkpoint inhibitor when the TB infection area is limited.

Background: Several factors have been reported to affect the diagnostic yield of bronchoscopy with radial endobronchial ultrasound (R-EBUS) for peripheral pulmonary lesions (PPLs). However, it is difficult to accurately predict the diagnostic potential of bronchoscopy for each PPL in advance., Objectives: Our objective was to establish a predictive model to evaluate the diagnostic yield before the procedure., Method: We retrospectively analysed consecutive patients who underwent diagnostic bronchoscopy with R-EBUS between April 2012 and October 2015. We assessed the factors that were predictive of successful bronchoscopic diagnosis of PPLs with R-EBUS using a multivariable logistic regression model. The accuracy of the predictive model was evaluated using the receiver operator characteristic area under the curve (ROC AUC). Internal validation was analysed using 10-fold stratified cross-validation., Results: We analysed a total of 1,634 lesions; the median lesion size was 25.0 mm. Of these, 1,138 lesions (69.6%) were successfully diagnosed. In the predictive logistic model, significant factors affecting the diagnostic yield were lesion size, lesion structure, bronchus sign, and visible on chest X-ray. The predictive model consisted of seven factors: lesion size, lesion lobe, lesion location from the hilum, lesion structure, bronchus sign, visibility on chest X-ray, and background lung. The ROC AUC of the predictive model was 0.742 (95% confidence interval: 0.715-0.769). Internal validation using 10-fold stratified cross-validation revealed a mean ROC AUC of 0.734., Conclusions: The predictive model using the seven factors revealed a good performance in estimating the diagnostic yield., (© 2022 S. Karger AG, Basel.)