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Family history of lung cancer (FHLC) has been widely studied but most prospective cohort studies have primarily been conducted in non-Asian countries. We assessed the association between FHLC with risk of lung cancer (LC) incidence and mortality in a population of East Asian individuals. A total of 478,354 participants from 11 population-based cohorts in the Asia Cohort Consortium were included. A Cox proportional hazards regression model was used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs). A total of 7,785 LC incident cases were identified. FHLC (any LC subtype) was associated with an increased risk of LC incidence (HR = 1.45, 95% CI = 1.30-1.63). The positive association was observed in men and women (HR = 1.44, 95% CI = 1.26-1.66 in men; HR = 1.47, 95% CI = 1.22-1.79 in women), and in both never-smokers and ever-smokers (HR = 1.43, 95% CI = 1.18-1.73 in never-smokers; HR = 1.46, 95% CI =1.27-1.67 in ever-smokers). FHLC was associated with an increased risk of lung adenocarcinoma (HR = 1.63, 95% CI: 1.36-1. 94), squamous cell carcinoma (HR = 1.88, 95% CI: 1.46-2.44), and other non-small cell LC (HR = 1.94, 95% CI: 1.02-3.68). However, we found no evidence of significant effect modification by sex, smoking status, and ethnic groups. In conclusion, FHLC was associated with increased risk of LC incidence and mortality, and the associations remained consistent regardless of sex, smoking status and ethnic groups among the East Asian population., (© 2024 The Author(s). International Journal of Cancer published by John Wiley & Sons Ltd on behalf of UICC.)

Objective: Surgical care has been significantly affected by the COVID-19 pandemic. This study was conducted to evaluate the effects of the pandemic on lung cancer and mediastinal tumor surgery., Methods: Changes in the number of surgical procedures for lung cancer and mediastinal tumors were analyzed using the National Clinical Database of Japan. Patient characteristics, including disease stage and histological type, from 2019 to 2022 were evaluated using annual datasets., Results: Comparisons with 2019 showed that the number of patients who underwent surgery for primary lung cancer or a mediastinal tumor decreased in 2020 and then remained stable. There were no clinically significant changes in the trend over the four-year period regarding the number of patients for each clinical and pathological stage of lung cancer. Regarding mediastinal tumors, there was no significant difference in tumor size between years. There was a slight change in the selection of surgical indication during the second quarter of 2020, although its impact on annual trends in the stage distribution for lung cancer and primary disease for mediastinal tumors was minimal., Conclusions: Analyses of lung cancer and mediastinal tumor surgery cases in Japan during the COVID-19 pandemic showed no significant disease profile changes related to treatment delay., Competing Interests: Declarations. Conflicts of interest: Hiroyuki Yamamoto is affiliated with the Department of Healthcare Quality Assessment of the University of Tokyo. This department is focused on social collaboration and is supported by grants from the National Clinical Database, Intuitive Surgical Sarl, Johnson & Johnson K.K., and Nipro Co. The other authors have no conflicts of interest to declare regarding this study., (© 2024. The Author(s).)

Background: Lung cancer surgery is associated with a high incidence of chronic postsurgical pain (CPSP), which necessitates long-term analgesic prescriptions. However, while essential for managing pain, these have shown various adverse effects. Current guidelines recommend using peripheral nerve blocks over epidural anaesthesia for perioperative analgesia in minimally invasive thoracic surgery (MITS). However, the impact of perioperative analgesia on chronic analgesic prescriptions remains unclear. Therefore, this study investigated chronic analgesic prescription patterns following MITS in patients with lung cancer who received either perioperative epidural anaesthesia or nerve block., Methods: We conducted a retrospective cohort study using data from the Japanese Diagnosis Procedure Combination database. Data were extracted from patients with primary lung cancer who underwent MITS between April 2018 and March 2022. Patients were divided into two groups based on the perioperative analgesia they received: the epidural anaesthesia group and the nerve block group. We compared the proportion of analgesic prescriptions 3-6 months postoperatively between both groups using multivariable logistic regression analysis. Inverse probability of treatment weighting was used to balance the covariates between the two groups., Results: Among the 38,719 eligible patients, 4513 (11.6%) were prescribed postoperative analgesics. We found no significant difference in the proportion of analgesic prescriptions between the epidural anaesthesia and nerve block groups (odds ratio, 1.00; 95% confidence interval, 0.99-1.01)., Conclusions: This nationwide retrospective study suggests that the choice between perioperative epidural anaesthesia or nerve block in patients with lung cancer undergoing MITS does not influence the proportion of postoperative chronic analgesic prescriptions., (© 2024 The Author(s). European Journal of Pain published by John Wiley & Sons Ltd on behalf of European Pain Federation ‐ EFIC ®.)

Purpose: Stereotactic body radiation therapy (SBRT) for patients with operable stage I non-small cell lung cancer (NSCLC) is less invasive than surgery. However, differences in lifetime costs and patient outcomes remain unclear. In this study, a cost-utility analysis of SBRT compared with surgery for Japanese patients with operable stage I NSCLC was conducted., Methods and Materials: A partitioned survival model was constructed using each treatment arm's overall survival (OS) and progression-free survival (PFS) data. The data for the SBRT arm were extracted from the Japanese multicenter cohort study, which enrolled 678 medically operable patients with stage I NSCLC, and patient registry data were used for the surgery arm. The 5-year OS rate was 78.2% for SBRT and 74.8% for surgery from both studies. The 5-year PFS rate was 57.0% for SBRT and 63.4% for surgery. The quality of life values of PFS and progressive disease were obtained from domestic and overseas literature (PFS: 0.74, progressive disease: 0.65). The time horizon was set to 10 years. The expected costs and quality-adjusted life years for each treatment group were calculated. All costs are expressed in Japanese yen converted to US dollars (USD)., Results: SBRT was the dominant strategy, reducing treatment costs by 4,443.8 USD and increasing quality-adjusted life years by 0.131 compared with surgery. According to probabilistic sensitivity analysis, the probability of SBRT being dominant and cost-effective was 50.6% and 72.4%, respectively. Under the budget impact analysis, the total savings for the patients with stage I NSCLC in Japan was 6,252,870.0 USD (n = 1,407)., Conclusions: SBRT is a more cost-effective option than surgery in patients with medically operable stage I NSCLC in Japan. Large-scale epidemiologic studies that reflect the latest clinical realities, such as OS/PFS, will be needed to validate this study's robustness., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

An enlarging ground-glass nodule (GGN) in the lungs closely resembles the characteristic appearance of a well differentiated lung adenocarcinoma or adenocarcinoma in situ (AIS). Herein, we present an unusual case characterized by clinical features suggestive of AIS but pathologically confirmed as exhibiting pulmonary alveolar proteinosis (PAP)-like changes. Patients with enlarging pure GGNs warrant consideration for diagnostic and curative surgery. While a considerable proportion of such cases receives a pathological diagnosis of lung malignancy, it is imperative to consider alternative benign conditions in the differential diagnosis, such as PAP-like changes.

Purpose: Nutritional scores have been reported to be useful prognostic factors for various cancers. This study evaluated the usefulness of the preoperative controlling nutritional status (CONUT) score as a predictor of recurrence of non-small cell lung cancer (NSCLC)., Methods: The present study included 422 patients with stage I-IIIA NSCLC who underwent complete resection at Tohoku University Hospital between January 2010 and December 2016. The patients were divided into the low-CONUT and high-CONUT groups based on their CONUT scores. Overall survival (OS), recurrence-free survival (RFS), and cumulative recurrence rates in the low- and high-CONUT groups were evaluated retrospectively., Results: One hundred forty-seven patients (34.8%) were assigned to the high-CONUT group. The high-CONUT group had a significantly worse performance status, pleural invasion, vascular invasion, and lung metastasis. In the whole cohort, the low-CONUT group showed better overall survival, recurrence-free survival, and a low cumulative recurrence rate in comparison to the high-CONUT group. There was no significant difference in prognosis or recurrence between the low- and high-CONUT groups after propensity score matching., Conclusion: Patients with a high CONUT score may be at high risk of recurrence because of the high frequency of pleural invasion, vascular invasion, and lung metastasis., Competing Interests: Declarations. Conflict of interest: The authors declare no conflicts of interest in association with the present study., (© 2024. The Author(s).)

Background: Cancer cachexia complicates advanced non-small cell lung cancer (NSCLC); however, it remains unclear how often cachexia occurs and how it affects the course of chemotherapy in patients receiving first-line systemic therapy., Methods: We conducted a multicentre, prospective observational study and enrolled previously untreated NSCLC patients with Eastern Cooperative Oncology Group Performance Status (ECOG PS) of 0-2 and cachexia between September 2020 and September 2021. The primary outcome measure was the trends in the Functional Assessment of Anorexia/Cachexia Treatment and Anorexia/Cachexia Subscale [FAACT (A/CS)] scores by cohort. Secondary outcome measures included the incidence of cachexia before the initiation of first-line systemic therapy, quality of life (QOL) measures, body weight (BW) changes, and efficacy and safety of first-line systemic therapy., Results: A total of 887 consecutive patients with previously untreated advanced NSCLC and ECOG PS of 0-2 who were initiated on first-line systemic therapy were evaluated. A total of 281 patients (31.7%) experienced BW loss consistent with the criteria of cachexia, and 186 were evaluated for QOL, BW and outcome measurements. Overall, 180/186 patients received first-line systemic therapy. Cohort 1 (targeted therapy), cohort 2 [cytotoxic chemotherapy (CTx) ± immune checkpoint inhibitors (ICIs)] and cohort 3 (ICIs) included 42, 98 and 40 patients, respectively. There were significant variations in QOL trends by cohort, with chemotherapy-associated emesis affecting early appetite-related QOL. The change in the FAACT (A/CS) score at 1 week from baseline was worse in cohort 2 (the least square mean change ± standard error: -3.0 ± 0.9) than in cohorts 1 (1.6 ± 1.2, p = 0.003) and 3 (1.8 ± 1.0, p = 0.002); meanwhile, the change at 6 weeks was worse in cohort 1 (-1.5 ± 1.2) than in cohorts 2 (3.6 ± 0.9, p = 0.001) and 3 (3.5 ± 1.1, p = 0.004). BW reduction was observed in all cohorts within 6 weeks of therapy initiation. The targeted therapy cohort demonstrated superior progression-free survival (PFS) and overall survival (OS) to CTx ± ICIs cohort or ICIs cohort (median PFS was 9.7 months, 6.3 months, 3.1 months, in cohort 1, 2, 3, respectively (cohort 1 vs. cohort 2: HR, 0.58, p = 0.018; cohort 1 vs. cohort 3: HR, 0.41, p = 0.001); median OS was not reached, 15.8 months, 9.9 months, respectively (cohort 1 vs. cohort 2: HR, 0.52, p = 0.033; cohort 1 vs. cohort 3: HR, 0.37, p = 0.003)., Conclusions: Approximately 1/3 patients with previously untreated advanced NSCLC have cachexia. Appetite-related QOL trends vary based on the type of first-line systemic therapy in cachectic NSCLC patients, and the PFS and OS of these patients seemed to be shorter., (© 2024 The Author(s). Journal of Cachexia, Sarcopenia and Muscle published by Wiley Periodicals LLC.)

Objectives: Programmed cell death ligand 1 (PD-L1) expression is widely used to predict the effectiveness of PD-(L)1 inhibitors despite its imperfection. Previous studies suggested the utilization of various serum biomarkers; nonetheless, findings are inconclusive because of limited sample sizes or the focus on a single biomarker in many of these studies. This study analyzed multiplex serum biomarkers to explore their predictive ability in a large cohort of patients with advanced non-small-cell lung cancer (NSCLC) treated with a PD-L1 inhibitor in a real-world setting., Materials and Methods: This was a sub-study of J-TAIL, a prospective observational study of atezolizumab monotherapy in pre-treated patients with advanced NSCLC. From April to October 2019, 262 patients were enrolled from 73 sites in Japan. Serum samples were collected at baseline and at the second dose of atezolizumab. Quantification of the 51 serum cytokines, chemokines, growth factors, and vascular endothelial growth factors was performed using the Luminex platform. Baseline values and fold changes of the time of the second dose to the baseline were examined in association with the effectiveness of atezolizumab., Results: Among the 51 proteins assessed, a higher baseline interleukin (IL)-12 level, a higher soluble CD40 ligand fold change, a lower IL-8 fold change were associated with higher objective response rate (ORR). Of these, only the lower IL-8 fold change was associated with better progression-free survival (PFS) (adjusted hazard ratio, 1.98; 95 % confidence interval, 1.45-2.70; P < 0.01). Multivariate analysis demonstrated that the lower IL-8 fold change was an independent factor for both the ORR and PFS. The IL-8 fold change was independent of the neutrophil/lymphocyte ratio, and durable PFS was observed in patients with both low., Conclusion: Comprehensive serum biomarker analysis revealed that a lower fold change in serum IL-8 was associated with better outcomes in pre-treated patients with advanced NSCLC receiving atezolizumab., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Hiroaki Akamatsu has received grants or contracts from Amgen, Eli Lilly, and Chugai; payment or honoraria for lectures, presentations, speaker’s bureau, manuscript writing, or educational events from Amgen, Ono, AstraZeneca, Pfizer, Boehringer Ingelheim, Takeda, Bristol Myers Squibb, Taiho, Chugai, Eli Lilly, MSD, Nippon Kayaku, and Novartis; and has participated in Data Safety Monitoring Boards or Advisory Boards for Amgen and Janssen. Yasuhiro Koh has received grants or contracts from Daiichi Sankyo, AstraZeneca, Boehringer Ingelheim, Takeda, Zeon, and Chugai; payment or honoraria for lectures, presentations, speaker’s bureau, manuscript writing, or educational events from Amgen, Takeda, Chugai, Guardant Health, CytoGen, Tosoh, and Novartis; and has participated in Data Safety Monitoring Boards or Advisory Boards for Tosoh. Makoto Nishio has received payment or honoraria for lectures from Ono, Chugai, Taiho, Bristol Myers Squibb, Daiichi Sankyo, Eli Lilly, AstraZeneca, MSD, AbbVie, Takeda, Pfizer, Boehringer Ingelheim, Novartis, Nippon Kayaku, Merck, and Janssen. Yasushi Goto has received grants or contracts from AstraZeneca, and Pfizer; grants for the institution from AbbVie, Eli Lilly, Bristol Myers Squibb, Ono, Novartis, Kyorin, Daiichi Sankyo, Novartis, and Preferred Network; payment or honoraria for lectures, presentations, speaker’s bureau, manuscript writing, or educational events from Eli Lilly, Chugai, Taiho, Boehringer Ingelheim, Ono, Bristol Myers Squibb, Pfizer, MSD, Novartis, Merck, and Thermo Fisher; has participated in Data Safety Monitoring Boards or Advisory Boards for AstraZeneca, Chugai, Boehringer Ingelheim, Eli Lilly, Taiho, Pfizer, Novartis, Guardant Health, Illumina, Daiichi Sankyo, Ono, Bristol Myers Squibb, and MSD; and had a leadership or fiduciary role in Cancer Net Japan and JAMT. Hidetoshi Hayashi has received grants or contracts from IQVIA Services, Syneos Health, EPS Corporation, Nippon Kayaku, Takeda, MSD, Amgen, Taiho, Bristol Myers Squibb, Janssen, CMIC, Pfizer, Labcorp Drug Development, Kobayashi, Eisai, EP-CRSU, Shionogi, Otsuka, GlaxoSmithKline, Sanofi, Chugai, Nippon Boehringer Ingelheim, SRL Medisearch, PRA Health Sciences, Astellas Pharma, Ascent Development Services, Bayer Yakuhin, Parexel, Kissei, EPS Corporation, Daiichi Sankyo, Ono, PPD-SNBL, SymBio, Mebix, AstraZeneca, Mochida, Japan Clinical Research Operations, Eli Lilly, Novartis, Otsuka, and SRL; payment or honoraria for lectures, presentations, speaker’s bureau, manuscript writing, or educational events from Ono, Daiichi Sankyo, AstraZeneca, Eli Lilly, Chugai Pharmaceutical, MSD, Pfizer, Nippon Boehringer Ingelheim, Merck, 3H Clinical Trial, Novartis, Bristol Myers Squibb, Amgen, Sysmex Corporation, Takeda, and Guardant Health. Satoru Miura has received payment or honoraria for lectures from Chugai, Taiho, Ono, AstraZeneca, Bristol Myers Squibb, Eli Lilly, Boehringer Ingelheim, and Takeda. Hiroshi Kagamu has received payment or honoraria for lectures from Chugai, Ono, AstraZeneca, and Bristol Myers Squibb. Ichiro Yoshino has received grants or contracts from AstraZeneca, Chugai, Daiichi Sankyo, and Taiho; consulting fees from AstraZeneca, Chugai, Covidien, and Johnson & Johnson; and payment or honoraria for lectures from AstraZeneca, Chugai, Daiichi Sankyo, Eli Lilly, Covidien, Johnson & Johnson, Taiho, Amgen, MSD, CSL Behring, KM Biologics, Intuitive Surgical, Shionogi, Tsumura, and Takeda. Toshihiro Misumi has received honoraria for lectures, presentations, speaker’s bureau, manuscript writing, or educational events from Chugai, AstraZeneca, and Miyarisan. Atsuto Mouri has received payment or honoraria for lectures from Chugai. Noriko Yanagitani has received consulting fee from Chugai and payment or honoraria for lectures from AstraZeneca, Eli Lilly, Pfizer, Chugai, Takeda, Bayer Yakuhin, Ono, and Bristol Myers Squibb. Hiroshi Nokihara has received payment or honoraria for lectures from MSD, Ono, AstraZeneca, and Chugai. Masahiro Seike has received payment or honoraria for lectures from Chugai, AstraZeneca, Bristol Myers Squibb, Pfizer, Takeda, Nippon Kayaku, Merck Biopharma, MSD, Taiho, Ono, Nippon Boehringer Ingelheim, Novartis, Kyowa-Kirin, and Daiichi-Sankyo. Masahide Mori has received research funding from Chugai, Ono, MSD, and Delta-fly; and payment or honoraria for lectures from AstraZeneca, Boehringer Ingelheim, MSD, Eli Lilly, Novartis, Chugai, Taiho, Kyowa-Kirin, Ono, Otsuka, Nihon-Kayaku, Pfizer, Daiichi Sankyo, Takeda, and Shionogi. Tetsuya Mitsudomi has received grants or contracts from MSD, Ono, AstraZeneca, and Chugai; payment or honoraria for speaker’s bureau from MSD, Ono, Bristol Myers Squibb, AstraZeneca, and Chugai; has participated in Advisory Boards for MSD, Ono, Bristol Myers Squibb, AstraZeneca, and Chugai; and has been a President at IASLC. The remaining authors have no conflict of interest to declare., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

Introduction: Immune checkpoint inhibitors (ICIs) plus chemotherapy is now a standard treatment for non-small cell lung cancer (NSCLC). Whether ICI plus chemotherapy (ICI-chemo) or ipilimumab plus nivolumab (I-N)-based therapy is superior for patients with NSCLC with a programmed death-ligand 1 (PD-L1) tumor proportion score (TPS) of 1-49 % has not been evaluated., Methods: This multicenter retrospective study included NSCLC patients with a TPS score of 1-49 %, who began first-line chemotherapy. Propensity score matching analysis was used to adjust for various confounders and evaluate treatment efficacy., Results: A total of 401 patients were enrolled, of whom 308 received ICI-chemo and 93 received I-N-based therapy. The median OS was 21.0 months in the ICI-chemo group and 20.0 months in the I-N-based therapy group. After propensity score matching, there was no difference in OS or PFS between the ICI-chemo group and the I-N-based therapy group (OS: hazard ratios (HR), 0.83; 95 % confidence interval [CI], 0.54-1.26, PFS: HR, 0.72; 95 % CI, 0.52-1.00). Among PD-L1 TPS 25-49 %, there was a tendency for OS to be favorable for the ICI-chemo group (OS: HR, 0.30; 95 % CI, 0.09-0.85). Treatment discontinuation occurred for 26.2 % of the patients in the ICI-chemo group and 41.9 % in the I-N-based therapy group., Conclusions: Among PD-L1 TPS 1-49 %, there was no significant difference in survival outcomes between the ICI-chemo group and the I-N-based therapy group. Based on the results of a subgroup analysis, ICI-chemo may be superior for treating NSCLC with a TPS of 25-49 %., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Dr. Tanaka reported receiving lecture fees from AstraZeneca K.K, Chugai Pharmaceutical Co., Boehringer-Ingelheim Japan Inc., Ono Pharmaceutical Co., Pfizer Japan Inc., and Bristol-Meyers Squibb. Dr. Makiguchi reported receiving honoraria from Asahi KASEI, Boehringer-Ingelheim Japan, Inc., AstraZeneca K.K, Eli Lilly, GlaxoSmithKline, Ono Pharmaceutical Co., Teijin Pharma, Taiho Pharmaceutical, Chugai Pharmaceutical Co., and LTD. Dr. Tozuka reported receiving honoraria from AstraZeneca and Chugai Pharmaceutical Co. Dr. Kawashima reported receiving honoraria from AstraZeneca K.K, Chugai Pharmaceutical Co, Taiho Pharmaceutical, Eli Lilly, Kyowa Hakko-Kirin, and Life Technologies Japan Ltd. Dr. Koyama reported receiving honoraria from AstraZeneca K.K. and Chugai Pharmaceutical Co. Dr. Tambo reported receiving honoraria from Chugai Pharmaceutical Co, Taiho Pharmaceutical, MSD K.K, and the Daiichi Sankyo Company. Dr. Ogusu reported receiving speakers’ bureau from MSD K.K, Bristol-Meyers Squibb, and Chugai Pharmaceutical Co. Dr. Hasegawa reported receiving honoraria from AstraZeneca K.K, Chugai Pharmaceutical Co., Eli Lilly, and Merck. Dr. Miyauchi reported receiving honoraria from AstraZeneca, Eli Lilly, Chugai Pharmaceutical Co, Boehringer-Ingelheim Japan, Inc., Taiho Pharmaceutical, Kyowa Hakko-Kirin, Daiichi-Sankyo, MSD, Bristol Myers Squibb, Merck, Amgen, Ono Pharmaceutical Co., Thermo Fisher Scientific, Nippon Kayaku, Takeda Pharmaceutical Co., and Sysmex. He received advisory roles from Boehringer-Ingelheim Japan Inc., Ono Pharmaceutical Co, Daiichi-Sankyo, and Merck outside of the submitted work. Dr. Sakatani reported receiving speakers’ bureau from AstraZeneca, Eli Lilly, MSD K.K, Boehringer-Ingelheim Japan, Inc., Takeda Pharmaceutical Co., Taiho Pharmaceutical, and Bristol Myers Squibb. Dr. Tsuchiya-Kawano reported receiving speakers’ bureau from Bristol Myers Squibb, AstraZeneca, Taiho Pharmaceutical, Chugai Pharmaceutical Co., MSD K.K, Ono Pharmaceutical Co., and Kyowa Hakko-Kirin. Dr. Nishio reported receiving honoraria from Pfizer Japan Inc, Bristol Myers Squibb, Ono Pharmaceutical Co., Chugai Pharmaceutical Co., Taiho Pharmaceutical, AstraZeneca, Boehringer-Ingelheim Japan, Inc., MSD K.K, Novartis, Eli Lilly, Nippon Kayaku, Takeda Pharmaceutical Co., Merck, Janssen, Amgen, Eisai, and Daiichi-Sankyo. He received research funding from Pfizer Japan Inc, Bristol Myers Squibb, Taiho Pharmaceutical, AstraZeneca, MSD K.K, Takeda Pharmaceutical Co, Merck, Janssen, and Amgen, outside of the submitted work. All remaining authors have declared no conflicts of interest., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Locoregional recurrence of non-small-cell lung cancer (NSCLC) after complete resection lacks standard treatment. Durvalumab after chemoradiotherapy (CRT) or CRT alone is often selected in daily clinical practice for patients with locoregional recurrence; however, the therapeutic efficacy of these treatments remains unclear, and we aimed to assess this. This retrospective observational study used data from patients with NSCLC diagnosed with locoregional recurrence after complete resection who subsequently underwent concurrent CRT followed by durvalumab (CRT-D group) or CRT alone (CRT group). We employed propensity score analysis with inverse probability treatment weighting (IPTW) to adjust for various confounders and evaluate efficacy in the CRT-D group. After IPTW adjustment, the CRT-D group contained 119 patients (64.7% male; 69.7% adenocarcinoma), and the CRT group contained 111 patients (60.5% male; 73.4% adenocarcinoma). Their mean ages were 66 and 65 years, respectively. The IPTW-adjusted median progression-free survival was 25.4 and 11.5 months for the CRT-D and CRT groups, respectively (hazard ratio, 0.44; 95% confidence interval, 0.30-0.64); the median overall survival was not reached in either group favoring CRT-D (hazard ratio, 0.49; 95% confidence interval, 0.24-0.99). Grade 3 or 4 adverse events were observed in 48.8% of patients during CRT, 10.7% after initiating durvalumab maintenance therapy in the CRT-D group, and 57.3% in the CRT group. Overall, the sequential approach of CRT followed by durvalumab is a promising treatment strategy for locoregional recurrence of NSCLC after complete resection., (© 2024 The Author(s). Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.)

Background: The optimal subsequent treatment strategy for locally advanced non-small cell lung cancer (LA-NSCLC) after chemoradiotherapy (CRT) and consolidative durvalumab therapy remains unknown. We aimed to determine the optimal subsequent treatment strategy for this clinical population., Materials and Methods: We retrospectively enrolled 523 consecutive patients with LA-NSCLC treated with CRT and analyzed the treatment outcomes of subsequent therapy after progression following CRT and consolidative durvalumab therapy. Patients who received tyrosine kinase inhibitors as subsequent therapy were excluded., Results: Out of 122 patients who received subsequent chemotherapy, 55% underwent platinum-based, 25% non-platinum-based, and 20% immune checkpoint inhibitor (ICI)-containing therapies. In the platinum-based group, patients with a durvalumab-progression-free survival (Dur-PFS) ≥ 1 year had a significantly longer median subsequent therapy-PFS (SubTx-PFS) than those with Dur-PFS < 1 year (13.2 months vs. 4.7 months; hazard ratio, 0.45; 95% confidence interval, 0.21-0.97; P = .04). Furthermore, among patients receiving non-platinum-based chemotherapy, the median SubTx-PFS was longer in the combined with angiogenesis inhibitor group than in the without group, although the difference was not statistically significant. No significant difference of SubTx-PFS was observed between the reason for durvalumab discontinuation and the outcomes of ICI-containing therapy., Conclusion: In clinical practice, platinum-based chemotherapy rechallenge is frequently employed following progression subsequent to CRT and consolidative durvalumab therapy for LA-NSCLC. Optimal treatment strategies may consider Dur-PFS and angiogenesis inhibitor feasibility. Further research is warranted to identify clinical biomarkers that can help identify patients who would benefit from ICI rechallenge., Competing Interests: Disclosure Hayato Kawachi reported receiving personal fees from AstraZeneca, Bristol-Myers Squibb, Chugai Pharmaceutical, Eli Lilly, MSD, Ono Pharmaceutical, and Taiho Pharmaceutical outside the submitted work. Motohiro Tamiya reported receiving personal fees from Amgen, Asahi Kasei Pharmaceutical, AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, Chugai Pharmaceutical, Eli Lilly, MSD, Ono Pharmaceutical, Pfizer, and Taiho Pharmaceutical outside the submitted work. Yuko Oya reported receiving personal fees from Amgen, AstraZeneca, Bristol Myers Squibb, Chugai Pharmaceutical, Eli Lilly, MSD, Novartis Pharma KK, Pfizer, Taiho Pharmaceutical, Daiichi Sankyo, and Takeda Pharmaceutical Company Limited outside the submitted work. Go Saito reported receiving personal fees from AstraZeneca, Chugai Pharmaceutical, Daiichi Sankyo Company, MSD, Novartis Pharma KK, Ono Pharmaceutical, Pfizer, and Taiho Pharmaceutical outside the submitted work. Yoshihiko Taniguchi reports receiving personal fees from AstraZeneca, Bristol Myers Squibb, Chugai Pharmaceutical, MSD, and Ono Pharmaceutical outside the submitted work. Hirotaka Matsumoto reported receiving personal fees from AstraZeneca, Boehringer Ingelheim, Chugai Pharmaceutical, Kyowa Kirin, MSD, Nippon Kayaku Co. Ltd., Ono Pharmaceutical, Taiho Pharmaceutical, and Takeda Pharmaceutical Company Limited outside the submitted work. Yuki Sato reported receiving personal fees from AstraZeneca, Bristol Myers Squibb, Chugai Pharmaceutical, Eli Lilly, MSD, Novartis Pharma KK, Ono Pharmaceutical, Pfizer, Taiho Pharmaceutical, Nippon Kayaku, Kyowa Kirin, and Takeda Pharmaceutical Company Limited outside the submitted work. Taiichiro Otsuki reported receiving personal fees from AstraZeneca, Bristol Myers Squibb, Chugai Pharmaceutical, Eisai Co. Ltd., MSD, Nippon Kayaku Co. Ltd., Ono Pharmaceutical, Takeda Pharmaceutical Company Limited, and Tsumura & Co. outside the submitted work. Hidekazu Suzuki reported receiving personal fees from AstraZeneca, Chugai Pharmaceutical, MSD, and Takeda Pharmaceutical Company Limited outside the submitted work. Yasushi Fukuda reported receiving personal fees from AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Chugai Pharmaceutical, Daiichi Sankyo, Merck Biopharma, MSD, Novartis, Ono Pharmaceutical, and Taiho Pharmaceutical outside the submitted work. Satoshi Tanaka declares that he has no competing financial interests or personal relationships that would affect the research reported in this paper. Yoko Tsukita reported receiving personal fees from AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, Chugai Pharmaceutical, Daiichi Sankyo, Eisai, Eli Lilly, MSD, and Taiho Pharmaceutical outside the submitted work. Junji Uchida declares that he has no competing financial interests or personal relationships that would affect the research reported in this paper. Yoshihiko Sakata reported receiving personal fees from AstraZeneca, Amgen, Boehringer Ingelheim, Bristol Myers Squibb, Chugai Pharmaceutical Co Ltd, Eli Lilly, Kyowa KIRIN, MSD, Novartis Pharma KK, Taiho Pharmaceutical, Takeda Pharmaceutical Company Limited outside the submitted work. Yuki Nakatani declares that he has no competing financial interests or personal relationships that would affect the research reported in this paper. Ryota Shibaki reported receiving personal fees from AstraZeneca, Chugai Pharmaceutical, MSD, and Taiho Pharmaceutical outside of the submitted work. Daisuke Arai reported receiving personal fees from AstraZeneca, Chugai Pharmaceutical, Merck Biopharma Co. Ltd., MSD, Nippon Kayaku Co. Ltd., Ono Pharmaceutical, Taiho Pharmaceutical, and Takeda Pharmaceutical Company Limited outside the submitted work. Asuka Okada reported receiving personal fees from AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, Chugai Pharmaceutical, Eli Lilly, Kyowa KIRIN, MSD, and Nippon Kayaku Co. Ltd. outside the submitted work. Satoshi Hara declares that he has no competing financial interests or personal relationships that would affect the research reported in this paper. Koichi Takayama reported receiving research grants from Chugai Pharmaceutical and Ono Pharmaceutical and personal fees from AstraZeneca, Boehringer Ingelheim, Chugai Pharmaceutical, Daiichi-Sankyo, Eli Lilly, MSD, and Merck outside the purview of the submitted work. Kazumi Nishino reported receiving grants from Ono, TAIHO, MSD, AbbVie, DAIICHI SANKYO, Amgen, Eisai, Sanofi, Janssen, Novartis, Pfizer, Eli Lilly, Merck, Takeda, Chugai, and Merus; and personal fees from AstraZeneca, Bristol Myers Squibb, Chugai, Eli Lilly, Janssen, Nippon Boehringer Ingerheim, Nippon Kayaku, Merck, Novartis, Pfizer, and Roche outside the submitted work., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Background: The effect of dual immunotherapy combined with platinum-based chemotherapy on untreated brain metastases derived from non-small cell lung cancer (NSCLC) has remained unclear., Methods: This multicenter single-arm phase 2 study enrolled patients with chemotherapy-naïve advanced NSCLC and at least one brain metastasis ≥ 5 mm in size that had not been previously treated. Patients received nivolumab plus ipilimumab combined with platinum-doublet chemotherapy (two cycles), followed by nivolumab-ipilimumab alone. The primary endpoint of the study was intracranial response rate as determined by modified Response Evaluation Criteria in Solid Tumors (RECIST) for brain metastases of ≥ 5 mm as target lesions., Results: A total of 30 patients from 18 institutions was enrolled in this study. The median age was 66.5 years (range, 47-83 years), and 26 patients (87 %) had a non-squamous cell carcinoma histology. The median size of all target brain lesions was 8.4 mm, with a range of 5-39 mm. The intracranial response rate assessed by modified RECIST was 50.0 % (95 % CI, 33.2-66.8 %), with the rate of complete response being 20.0 %, and the study met its primary endpoint. The systemic response rate was 53.3 % (95 % CI, 36.1-69.8 %), and responses for intracranial and extracranial lesions were generally consistent. The median intracranial progression-free survival was 8.1 months, and both the median intracranial duration of response and time to brain radiotherapy were not reached., Conclusion: Nivolumab plus ipilimumab combined with platinum-based chemotherapy showed promising intracranial activity in NSCLC patients with untreated brain metastases., Trial Registration: jRCT071210019., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Y Tsuchiya-Kawano has received personal fees from Bristol-Myers Squibb, Taiho Pharmaceutical, Chugai Pharmaceutical, AstraZeneca, Kyowa hakko Kirin, MSD, Ono Pharmaceutical, and Takeda Pharmaceutical outside the submitted work. Y Shiraishi has received grants and personal fees from Chugai Pharmaceutical as well as personal fees from Ono Pharmaceutical, Taiho Pharmaceutical, AstraZeneca, Bristol-Myers Squibb, and Kyowa Kirin outside the submitted work. K Tanaka has received personal fees from Chugai Pharmaceutical, Ono Pharmaceutical, AstraZeneca, Daiichi Sankyo, Eli Lilly, Merck, Takeda Pharmaceutical, Pfizer, MSD, Novartis, and Bristol-Myers Squibb outside the submitted work. M Tachihara has received grants from AstraZeneca, Chugai Pharmaceutical, and Eli Lilly as well as personal fees from Eli Lilly, Ono Pharmaceutical, Bristol-Myers Squibb, Chugai Pharmaceutical, AstraZeneca, MSD, Novartis Pharmaceuticals, Takeda Pharmaceutical, Taiho Pharmaceutical, Boehringer Ingelheim, Daiichi Sankyo, Pfizer, and Janssen Pharmaceutical outside the submitted work. T Okamoto has received grants from Chugai Pharmaceutical, AstraZeneca, Boehringer Ingelheim, MSD, Eli Lilly, and Bristol-Myers Squibb as well as personal fees from AstraZeneca, Boehringer Ingelheim, Chugai Pharmaceutical, Ono Pharmaceutical, MSD, Eli Lilly, and Bristol-Myers Squibb outside the submitted work. I Okamoto has received grants from Chugai Pharmaceutical, AstraZeneca, Taiho Pharmaceutical, Boehringer Ingelheim, Ono Pharmaceutical, MSD, Eli Lilly, Astellas, Bristol-Myers Squibb, Novartis, Pfizer, and AbbVie; consulting fees from AstraZeneca, Bristol-Myers Squibb, and AbbVie; and personal fees from AstraZeneca, Taiho Pharmaceutical, Boehringer Ingelheim, Chugai Pharmaceutical, Ono Pharmaceutical, MSD, Eli Lilly, Bristol-Myers Squibb, Novartis, and Pfizer outside the submitted work. All other authors declare no competing interests., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Background: We aimed to examine the effectiveness of a nurse-led, screening-triggered early specialized palliative care intervention program for patients with advanced lung cancer., Methods: Patients with advanced lung cancer who underwent initial chemotherapy were randomized to intervention and usual care groups between January 2017 and September 2019. The intervention comprised comprehensive needs assessments, counseling, and service coordination by advanced-level nurses. Patients in the usual care group received the usual oncological care. The primary end point was a change in the trial outcome index (TOI) scores from baseline to 12 weeks. The secondary end-points were TOI scores at week 20, depression, anxiety, and survival., Results: In total, 102 patients were assigned to each group. Compared with the usual care group, no significant improvement in TOI scores was observed at 12 weeks in the intervention group (mean group difference: 2.13; 90% confidence interval: -0.70, 4.95; p = 0.107, one-sided), whereas significant improvement was observed at 20 weeks (3.58; 90% confidence interval: 0.15, 7.00; p = 0.043). There were no significant differences in the change from baseline depression and anxiety between the groups from baseline at week 12 and 20 weeks (depression: p = 0.60 and 0.10, anxiety: p = 0.78 and 0.067). Survival did not significantly differ between the groups (median survival time: 12.1 vs. 11.1 months; p = 0.302)., Conclusions: Nurse-led, screening-triggered, early specialized palliative care did not show significant superiority over usual care during the 12-week study period. However, it may have yielded delayed clinical benefits, such as improved quality of life and this feasible model can be acceptable in clinical practice., Trial Registration: The University Hospital Medical Information Network Clinical Trials Registry: UMIN000025491., (© 2024 The Author(s). Cancer Medicine published by John Wiley & Sons Ltd.)

Objectives: Certain guidelines recommend caution when administering immunotherapy in patients with pre-existing interstitial lung disease (ILD) owing to the high incidence of pneumonitis induced by anti-cancer therapy. A prospective clinical trial assessing the safety of chemoimmunotherapy in patients with small-cell lung cancer (SCLC) and pre-existing ILD is warranted. Therefore, this study evaluated the safety and efficacy of chemoimmunotherapy in patients with extensive-stage (ES)-SCLC and mild idiopathic interstitial pneumonia (IIP)., Methods: In this multicenter prospective trial, patients with ES-SCLC and pre-existing mild chronic fibrosing IIP were recruited. Mild IIP was defined as the exclusion of poor pulmonary function, a definite usual interstitial pneumonia (UIP) pattern, and positivity for autoantibodies in blood tests. The patients received durvalumab, etoposide, and carboplatin every three weeks (induction phase), followed by 1,500 mg durvalumab every four weeks (maintenance phase). The primary endpoint was severe pneumonitis-free rate., Results: Twenty-one patients were included in the analysis. Among them, 13 patients displayed a probable UIP pattern, whereas eight patients exhibited an indeterminate for UIP pattern. Two patients (9.5 %) had pneumonitis of any grade during the induction phase; one had Grade 1 and the other had Grade 5 pneumonitis. No other patient developed pneumonitis during the maintenance phase. The severe pneumonitis-free rate was 95.2 % (95 % confidence interval (CI): 77.3-99.2 %). The median progression-free survival was 5.5 months (95 % CI: 3.6-6.4 months). Median overall survival was 10.7 months (95 % CI: 6.0 months to not reached)., Conclusions: Chemoimmunotherapy is a feasible treatment approach for patients with ES-SCLC and mild IIP., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: [Daichi Fujimoto reports financial support provided by AstraZeneca K.K. Ryota Shibaki received personal fees from AstraZeneca KK, Taiho Pharmaceutical Co. Ltd., Chugai Pharmaceutical Co. Ltd., and MSD KK outside the submitted work. Daichi Fujimoto received grants from AstraZeneca K.K. during the study and personal fees from AstraZeneca KK, Boehringer Ingelheim Japan Inc., Ono Pharmaceutical Co. Ltd., Bristol-Myers Squibb Co. Ltd., Taiho Pharmaceutical Co. Ltd., Chugai Pharmaceutical Co. Ltd., MSD KK, Eli Lilly Japan KK, Kyowa Kirin Co. Ltd., Janssen Pharmaceutical KK, Daiichi Sankyo Co. Ltd., Takeda Pharmaceutical Co. Ltd., and Novartis Pharma KK outside of the submitted work. Eisaku Miyauchi received personal fees from AstraZeneca KK, Boehringer Ingelheim Japan Inc., Ono Pharmaceutical Co. Ltd., Bristol-Myers Squibb Co. Ltd., Taiho Pharmaceutical Co. Ltd., Chugai Pharmaceutical Co. Ltd., MSD KK, Eli Lilly Japan KK, Kyowa Kirin Co. Ltd., Daiichi Sankyo Co. Ltd., Takeda Pharmaceutical Co. Ltd., Merck Biopharma Co. Ltd., Pfizer Inc., Eisai Co. Ltd., Otsuka Pharmaceutical Co. Ltd., Amgen Inc., Thermo Fisher Scientific KK, Nippon Kayaku Co. Ltd., Sysmex Co. Ltd., KYORIN Pharmaceutical Co. Ltd., and Novartis Pharma KK outside the submitted work. Yoko Tsukita received personal fees from AstraZeneca KK, Bristol-Myers Squibb Co. Ltd., Taiho Pharmaceutical Co. Ltd., Chugai Pharmaceutical Co. Ltd., MSD KK, Eli Lilly Japan KK, Daiichi Sankyo Co. Ltd., Eisai Co. Ltd., and Boehringer Ingelheim Japan Inc. outside the submitted work. Daisuke Arai has received personal fees from AstraZeneca KK, Taiho Pharmaceutical Co. Ltd., Chugai Pharmaceutical Co. Ltd., MSD KK, Eli Lilly Japan KK, Ono Pharmaceutical Co. Ltd., Takeda Pharmaceutical Co. Ltd., Merck, and Nippon Kayaku Co. outside the submitted work. Yoshihiko Sakata received personal fees from AstraZeneca KK, Amgen, Boehringer Ingelheim Japan Inc., Bristol-Myers Squibb Co. Ltd., Taiho Pharmaceutical Co. Ltd., Chugai Pharmaceutical Co. Ltd., MSD KK, Eli Lilly Japan KK, Kyowa Kirin Co. Ltd., Takeda Pharmaceutical Co., Ltd., and Novartis Pharma KK outside the submitted work. Naoki Shingu received personal fees from AstraZeneca KK, Chugai Pharmaceutical Co. Ltd., Bristol-Myers Squibb Co. Ltd., Takeda Pharmaceutical Co. Ltd., and MSD KK outside the submitted work. Takashi Kijima received personal fees from Chugai Pharmaceutical Co. Ltd. outside the submitted work. Go Saito received personal fees from AstraZeneca KK, Taiho Pharmaceutical Co. Ltd., Chugai Pharmaceutical Co. Ltd., MSD KK, Ono Pharmaceutical Co. Ltd., Pfizer, Daiichi Sankyo Company, and Novartis Pharma KK outside the submitted work. Yuki Sato received personal fees from AstraZeneca KK, Ono Pharmaceutical Co. Ltd., Bristol-Myers Squibb Co. Ltd., Taiho Pharmaceutical Co. Ltd., Chugai Pharmaceutical Co. Ltd., MSD KK, Eli Lilly Japan KK, Kyowa Kirin Co. Ltd., Daiichi Sankyo Co. Ltd., and Takeda Pharmaceutical Co. Ltd., Pfizer Inc., Nippon Kayaku Co., Ltd., and Novartis Pharma KK outside the submitted work. Shinya Sakata received personal fees from AstraZeneca KK, Taiho Pharmaceutical Co. Ltd., Chugai Pharmaceutical Co. Ltd., and Takeda Pharmaceutical Co. Ltd. outside the submitted work. Yoshihiko Taniguchi received personal fees from AstraZeneca KK, Bristol-Myers Squibb Co. Ltd., and Chugai Pharmaceutical Co. Ltd. outside the submitted work. Akito Hata has received personal fees from AstraZeneca KK, Taiho Pharmaceutical Co. Ltd., Chugai Pharmaceutical Co. Ltd., Eli Lilly Japan KK, Pfizer Inc., and Boehringer Ingelheim outside the submitted work. Hirotaka Matsumoto received personal fees from AstraZeneca KK, Taiho Pharmaceutical Co. Ltd., Chugai Pharmaceutical Co. Ltd., MSD KK, Takeda Pharmaceutical Co. Ltd., Nippon Kayaku Co. Ltd., Ono Pharmaceutical Co. Ltd., and Boehringer Ingelheim outside the submitted work. Nobuyuki Yamamoto has received personal fees from AstraZeneca KK, Chugai Pharmaceutical Co. Ltd., MSD KK, Ono Pharmaceutical Co. Ltd., Daiichi Sankyo, Taiho Pharmaceutical Co. Ltd., Takeda Pharmaceutical Co. Ltd., Boehringer Ingelheim Japan Inc., Pfizer Inc., Amgen Inc., Janssen Pharmaceutical KK, Terumo, Eli Lilly Japan KK, Novartis Pharma KK, Merck Biopharma, Guardant Health Japan, Accuray Inc., AbbVie, Kyorin Pharmaceutical Co. Ltd., Tsumura & Co., and Miyarisan Pharmaceutical outside the submitted work. Other authors declare that they have no competing financial interests or personal relationships that could have influenced the work reported in this study.]., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Lung cancer remains the leading cause of cancer death. Treatment with immune checkpoint inhibitor (ICI) alone or combination with chemotherapy served as first-line therapy in non-small cell lung cancer (NSCLC). However, only 20-50% of NSCLC patients respond to ICI. Necroptosis, an inflammatory form of cell death plays an important role in the regulation of tumor immune microenvironment which may affect prognosis and ICI response but its clinical significance in NSCLC patients has remained largely unknown. Therefore, we aimed to analyze the correlation between key necroptotic proteins and necroptosis and clinical outcomes, the status of tumor-infiltrating immune cells, and response to ICI in NSCLC patients. The expression of receptor-interacting protein kinase 3 (RIPK3), mixed lineage kinase domain-like protein (MLKL) and phosphorylated MLKL (pMLKL) were immunolocalized in 125 surgically resected NSCLC patients and 23 NSCLC patients administered with ICI therapy. CD8 + and FOXp3 + T cells and CD163 + M2 macrophages were also immunolocalized. High RIPK3 status was positively correlated with survival of the patients and RIPK3 turned out an independent favorable prognostic factor of the patients. RIPK3 was negatively correlated with CD8 + T cells, while MLKL positively correlated with CD163 + M2 macrophages, suggesting the possible involvement of RIPK3 and MLKL in formulating immunosuppressive microenvironment. In addition, high RIPK3 status tended to be associated with clinical resistance to ICI therapy (P-value = 0.057). Furthermore, NSCLC cells-expressing RIPK3 suppressed T cells response to ICI therapy in vitro. Therefore, RIPK3 and MLKL could induce an immunosuppressive microenvironment, resulting in low response to ICI therapy in NSCLC., (© 2024. The Author(s).)

This single-arm multi-institutional prospective study aimed to evaluate the 10-year outcomes of sublobar resection for small-sized ground-glass opacity-dominant lung cancer. Among 73 patients prospectively enrolled from 13 institutions between November 2006 and April 2012, 53 ground-glass opacity-dominant lung cancer patients underwent sublobar resection with wedge resection as the first choice. The inclusion criteria were maximum tumor size of 8-20 mm; ≥ 80% ground-glass opacity ratio on high-resolution computed tomography; lower 18 F-fluorodeoxyglucose accumulation than the mediastinum; intraoperative pathological diagnosis of adenocarcinoma in situ; and no cancer cells on intraoperative cut margins. The primary endpoint was a 10-year disease-specific survival. The 53 eligible patients had a mean tumor size of 14 ± 3.4 mm and a mean ground-glass opacity ratio of 95.9 ± 7.2%. Wedge resection and segmentectomy were performed in 39 and 14 patients, respectively. The final pathological diagnoses were adenocarcinoma in situ in 47 patients (88.7%) and adenocarcinoma with mixed subtype in 6 patients (11.3%). The 10-year disease-specific survival and overall survival were 100% and 96.2%, respectively, during a median follow-up period of 120 months (range, 37-162 months). Ground-glass opacity-dominant small lung cancer is cured by sublobar resection when patients are strictly selected by the inclusion criteria of this study., (© 2024. The Author(s).)

Purpose: This single-institution retrospective cohort study was conducted to assess the prognostic significance of perioperative changes in the prognostic nutritional index (PNI) in patients who underwent surgery for non-small cell lung cancer (NSCLC)., Methods: Clinicopathological data were collected from 441 patients who underwent lobectomy for NSCLC between 2010 and 2016.The PNI ratio (postoperative PNI/preoperative PNI) was used as an indicator of perioperative PNI changes. Prognostic differences were investigated based on PNI ratios., Results: The optimal cut-off value of the PNI ratio for overall survival (OS) was set at 0.88 using a receiver operating characteristic curve. The PNI ratio was inversely related to a high smoking index, interstitial lung disease, and postoperative pulmonary complications. The 5-year OS rates for the high vs. low PNI ratio groups were 88.2% vs. 68.5%, respectively (hazard ratio [HR]: 3.04, 95% confidence interval [CI]: 1.90-4.86). Multivariable analysis revealed that a low PNI ratio was significantly associated with poor prognosis (HR: 2.94, 95% CI: 1.77-4.87). The PNI ratio was a more sensitive indicator than postoperative PNI status alone for identifying patients at high risk of mortality, particularly those with non-lung cancer causes., Conclusion: The perioperative PNI change is a significant prognostic factor for patients with NSCLC., (© 2024. The Author(s).)

Cancer-associated fibroblasts (CAFs) are a heterogeneous population of fibroblasts with various features in the cancer stroma and have been reported to influence cancer progression through cell-cell interactions in various types of malignancies, including lung adenocarcinoma (LUAD). Dipeptidyl peptidase 4 (DPP4) is a transmembrane protein with serine protease activity and is involved in the progression of tumors, metabolic diseases, and autoimmune diseases. In the present study, we focused on the role of DPP4-positive CAFs in LUAD. Immunohistochemistry revealed that 38 of 89 LUAD patients showed DPP4 expression in the fibrous stroma, and patients harboring DPP4-positive CAFs were more often male, had a higher Brinkman index, and had a higher Ki-67 labeling index of tumor cells than those with DPP4-negative CAFs. DPP4-positivity was associated with the expression of other CAF markers, α-SMA, periostin, and podoplanin, as well as a cellular senescence marker, p16. In the in vitro study, conditioned media collected from pulmonary fibroblast (OUS-11, HPF, and HPF-C)-induced overexpression of DPP4 significantly promoted the proliferation of LUAD cells (A549 and PC-9) and increased the expression levels of MCP-1, IL-8, IL-6, and GCSF in the media compared to those in controls. In addition, OUS-11 overexpression in DPP4 overexpression increased periostin expression. In conclusion, DPP4-positive CAFs could promote lung adenocarcinoma cell growth by producing soluble factors, and DPP4 inhibition may inhibit cancer progression., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Hironobu Sasano and Chihiro Inoue report financial support was provided by Astellas Pharma, Inc. If there are other authors, they 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 The Authors. Published by Elsevier GmbH.. All rights reserved.)

Background: The risk and survival of patients with non-small cell lung cancer (NSCLC) with pre-existing autoimmune disorders (AIDs) receiving immune checkpoint blockade (ICB) therapy have not been clearly established., Patients and Methods: This multi-institutional, retrospective cohort study was conducted in collaboration with 20 centers in Japan., Results: In total, 229 patients with advanced or recurrent NSCLC and pre-existing AID, with or without ICB treatment from January 2010-February 2020, were included and analyzed. Among 69 patients who received ICB, 2 received two lines of ICBs with a total of 71 ICB treatments; 57 (80.3 %) and 14 (19.7 %) patients received ICB monotherapy and combination therapy, respectively. AID flares were observed in 18 patients (25.4 %, 95 % confidence interval [CI], 15.8-37.1 %) receiving ICB. AID exacerbations were more likely when NSCLC was diagnosed less than 1 year after the AID diagnosis (odds ratio 5.26 [95 % CI, 1.40-21.61]; P = 0.016). Immune-related adverse events were observed in 32 patients (45.1 %, 95 % CI, 33.2-57.3 %); 17 had grade 3 or higher. The safety profile of combination immunotherapy was not significantly different from that of the monotherapy. After inverse probability weighting, the use of ICB prolonged survival (hazard ratio 0.43 [95 % CI, 0.26-0.70]; P = 0.0006)., Conclusions: These findings revealed a novel risk factor for AID flares following ICB treatment, that is the diagnosis of NSCLC within 1 year of AID diagnosis, and showed that ICBs may improve survival in this population. These results support the utilization of ICB in patients with NSCLC and pre-existing AID., 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. Dr. Asao reported receiving personal fees from AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, Chugai Pharmaceutical, Daiichi Sankyo, Eli Lilly Japan, Merck Biopharma, MSD, Nippon Kayaku, Ono Pharmaceutical, Pfizer, Taiho Pharmaceutical, and Takeda Pharmaceutical outside the submitted work. Dr. Shukuya reported receiving grants from AstraZeneca, Boehringer Ingelheim, Chugai Pharmaceutical, MSD, and Novartis, outside the submitted work; and personal fees from AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Chugai Pharmaceutical, Daiichi Sankyo, Eli Lilly, MSD, Nippon Kayaku, Novartis, Ono Pharmaceutical, Pfizer, Taiho Pharmaceutical, Takeda Pharmaceutical, outside the submitted work. Dr. Mouri reported receiving personal fees from Chugai Pharmaceutical and Eli Lilly, outside the submitted work. Dr. Tsukita reported receiving personal fees from AstraZeneca, Boehringer Ingelheim, Bristol-Meyers Squibb, Chugai Pharmaceutical, Daiichi-Sankyo, Eisai, Eli Lilly, MSD, and Taiho Pharmaceutical, outside the submitted work. Dr. Watanabe reported receiving grants from Nippon Kayaku outside the submitted work, personal fees from AstraZeneca, Bristol-Meyers Squibb, Celltrion, Chugai Pharmaceutical, Daiichi-Sankyo, Eli Lilly, Kyowa Kirin, MSD, Nippon Kayaku, Novartis, Ono Pharmaceutical, Taiho Pharmaceutical, Takeda Pharmaceutical, outside the submitted work. Dr. Morita reported receiving personal fees from Amgen, AstraZeneca, Bristol-Meyers Squibb, Chugai Pharmaceutical, Daiichi-Sankyo, Eli Lilly, MSD, Nippon Kayaku, Novartis, Pfizer, Taiho Pharmaceutical, Takeda Pharmaceutical, and ThermoFisher Scientific, outside the submitted work. Dr. Yoshioka reported receiving grants from AstraZeneca, Boehringer Ingelheim, Daiichi Sankyo, Delta Fly Pharma, Janssen Pharmaceutical, MSD, and Novartis, outside the submitted work; and personal fees from AstraZeneca, Amgen, Boehringer Ingelheim, Bristol-Myers Squibb, Chugai Pharmaceutical, Daiichi Sankyo, Eli Lilly, Kyowa Kirin, MSD, Nippon Kayaku, Nipro Pharma, Novartis, Ono Pharmaceutical, Otsuka Pharmaceutical, Pfizer, Taiho Pharmaceutical, outside the submitted work. Dr. Namba reported receiving personal fees from Chugai Pharmaceutical, Kyowa Kirin, MSD, and Taiho Pharmaceutical, outside the submitted work. Dr. Nakagawa reported receiving personal fees from AstraZeneca, Chugai Pharmaceutical, Eli Lilly Japan, Japan Blood Products Organization, MSD, Nippon Kayaku, Novartis Pharma, Ono Pharmaceutical, Pfizer Japan, and Taiho Pharmaceutical, outside the submitted work. Dr. Watanabe reported receiving grants from MSD, outside the submitted work. Dr. Kobayashi reported receiving personal fees from AstraZeneca and Takeda Pharmaceutical, outside the submitted work. Dr. Takahashi reports grant support from Asahi Kasei Pharma, Bayer, Boehringer Ingelheim, Chugai Pharmaceutical, Daiichi Sankyo, Eli-Lilly, Kyorin Pharmaceutical, Kyowa Kirin, Nippon Kayaku, Nippon Shinyaku, Nipro Pharma, Novartis, Ono Pharmaceutical, Pfizer, Sanofi, Shionogi, Takeda Pharmaceutical, Taiho Pharmaceutical, Teijin Pharma, and Tsumura, outside the submitted work; personal fees from Abbott Japan, AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Chugai Pharmaceutical, Eli Lilly, Janssen Pharmaceutical, Meiji Seika Pharma, Merck Biopharma, MSD, Kyorin Pharmaceutical, Nippon Kayaku, Novartis, Ono Pharmaceutical, Pfizer, Sumitomo Dainippon Pharma, Taiho Pharmaceutical, Takeda Pharmaceutical, ThermoFisher Scientific and Viatris, outside the submitted work.; and serving as a board member of director of the Japan Lung Cancer Society and The Japanese Respiratory Society. No other disclosures were reported., (Copyright © 2024. Published by Elsevier B.V.)

Background: Selecting pembrolizumab monotherapy (MONO) or pembrolizumab plus platinum-based chemotherapy (COMB) for patients with nonsmall cell lung cancer (NSCLC) and high programmed death-ligand 1 (PD-L1) expression is an important issue in clinical practice. We previously conducted a retrospective multicenter observational study of patients with NSCLC and high PD-L1 expression who received MONO or COMB as a first-line treatment. Here, we report updated data and evaluate the long-term outcomes., Methods: We performed a retrospective multicenter study of 298 patients with NSCLC and high PD-L1 expression who received MONO or COMB as first-line treatment between December 2018 and January 2020. We reviewed the medical records and assessed the clinical efficacy and toxicity using a prolonged data cutoff., Results: In total, 164 (median age: 74 years) and 134 (median age: 68 years) patients received MONO and COMB, respectively; patients who received COMB were younger and had better performance statuses (0-1). At the prolonged data cutoff, the median follow-up was 20.2 (range: 0.1-41.4) months. The median progression-free survivals were 7.5 and 13.1 months, and overall survivals (OSs) were 17.2 and 33.7 months for MONO and COMB, respectively. Treatment discontinuation rates were 21.9% and 20.1% for the MONO and COMB, respectively. With prolonged follow-up, although COMB demonstrated an OS benefit and higher objective response rate than MONO, in the propensity score matching analysis COMB didn't demonstrate a significant benefit compared to the MONO., Conclusions: COMB may be effective as a first-line treatment for NSCLC with high PD-L1 expression in a selected subset of patients., (© 2024 The Author(s). Cancer Medicine published by John Wiley & Sons Ltd.)

Previous studies have investigated the association between reproductive factors and lung cancer risk; however, findings have been inconsistent. In order to assess this association among Asian women, a total of 308,949 female participants from 11 prospective cohorts and four Asian countries (Japan, Korea, China, and Singapore) were included. Cox proportional hazards regression models were used to estimate the hazard ratios (HR) and 95% confidence intervals (CIs). A total of 3,119 primary lung cancer cases and 2247 lung cancer deaths were identified with a mean follow-up of 16.4 years. Parous women had a lower risk of lung cancer incidence and mortality as compared with nulliparous women, with HRs of 0.82 (95% CI = 0.70-0.96) and 0.78 (95% CI = 0.65-0.94). The protective association of parity and lung cancer incidence was greater among ever-smokers (HR = 0.66, 95% CI = 0.49-0.87) than in never-smokers (HR = 0.90, 95% CI = 0.74-1.09) (P-interaction = 0.029). Compared with age at first delivery ≤20 years, older age at first delivery (21-25, ≥26 years) was associated with a lower risk of lung cancer incidence and mortality. Women who ever used hormone replacements had a higher likelihood of developing non-small cell lung cancer (HR = 1.31, 95% CI = 1.02-1.68), compared to those who never used hormone replacements. Future studies are needed to assess the underlying mechanisms, the relationships within these female reproductive factors, and the potential changes in smoking habits over time., (© 2024 UICC.)

Purpose: The current study was designed to analyze the impact of the COVID-19 pandemic on general thoracic surgeries in Japan., Methods: Changes in surgeries for lung cancer and metastatic lung tumors were evaluated based on National Clinical Database data regarding cancer screening., Results: In 2021, surgeries for primary lung cancer increased by 3.4% compared to 2020, which, given the increase from 2014 to 2019, indicates an overall 11.1% decrease. In contrast, surgeries for metastatic lung tumors in 2021 decreased by 5.8% compared to 2020, which, given the increase from 2014 to 2020, indicates an overall 9.2% decrease. Half of the primary diseases for metastatic lung tumor were cases of colorectal cancer. Low anterior resection procedures in 2020 decreased by 5.5% compared to 2019. Lung and colon cancer screening examinees in 2021 were increased compared to 2020; however, they still showed respective decreases of 11% and 9.0% compared to 2019., Conclusions: Surgeries for primary lung cancer still decreased substantially during the COVID-19 pandemic. The continued stagnation of screening was responsible for this decrease. Surgeries for metastatic lung tumors decreased profoundly, and the decrease in screening for primary tumors was responsible for this reduction. Our findings emphasize the significance of maintaining cancer screening efforts, even during a pandemic., (© 2023. The Author(s) under exclusive licence to Springer Nature Singapore Pte Ltd.)

Osimertinib is the standard of care for patients with epidermal growth factor receptor-activating mutation-positive non-small cell lung cancer. Dose-toxicity has been previously reported, but no dose-response data within the range of 20-240 mg daily (mg/d). Thus, the current 80 mg/d dosing might be too high for elderly Japanese patients with an average body weight of only 50 kg, resulting in excessive toxicity and cost. We therefore initiated a study to investigate whether osimertinib at 40 mg/d is non-inferior to 80 mg/d in patients with advanced or recurrent epidermal growth factor receptor-activating mutation-positive non-small cell lung cancer aged ≥70 years, using a regression discontinuity design. Osimertinib is administered at 40 mg/d for body weight ≤50 kg, and 80 mg/d for body weight >50 kg. The primary endpoint is progression-free survival. Sample size is 550 patients, based on a non-inferiority margin of the progression-free survival hazard ratio 1.333, 0.10 one-sided type I error and 80% power., (© The Author(s) 2024. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: In advanced non-small cell lung cancer (NSCLC) patients harboring epidermal growth factor receptor (EGFR) mutations, those with impaired performance status (PS) treated with EGFR-tyrosine kinase inhibitors (TKIs) have demonstrated comparable activities to good-PS patients. Due to the limited sample size and inclusion of older adult patients with good PS, these findings may not accurately depict the efficacy of EGFR-TKI in poor-PS patients. We investigated the benefit of EGFR-TKIs in this population and identified relevant prognostic factors., Patients and Methods: This nationwide prospective registry study included 9872 patients with local or advanced NSCLC. Outcomes were compared between poor- and good-PS patients treated with EGFR-mutated lung cancer therapies., Results: Of 9872 NSCLC patients, 1965 (19.9%) had EGFR mutations, with 1846 (93.9%) presenting common EGFR mutations. Poor PS (PS score ≥ 3) was noted in 171 patients (8.7%) and identified as an independent prognostic factor; those with poor PS had a significantly lower 1-year survival rate. The median overall survival (OS) for EGFR-TKI-treated good-PS patients was 31.5 (95% confidence interval, 29.6-33.4) months. Among poor-PS patients with EGFR mutations, 135 (78.9%) of whom were treated with EGFR-TKI had an OS of 15.5 (12.7-18.3) months, while those receiving only supportive care had an OS of 2.5 (1.4-3.6) months (P < .001). Hypoalbuminemia (< 3.5 g/dL), liver metastasis, and uncommon EGFR mutations were associated with poor prognosis., Conclusion: Poor PS at diagnosis was rare and associated with limited EGFR-TKI efficacy and a dismal prognosis. Liver metastasis and hypoalbuminemia may reduce EGFR-TKI efficacy in these patients., Competing Interests: Disclosure 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 Inc. All rights reserved.)

Recent advancements in computed tomography (CT) scanning have improved the detection rates of peripheral pulmonary nodules, including those with ground-glass opacities (GGOs). This study focuses on part-solid pure ground-glass nodules (GGNs) and aims to identify imaging predictors that can reliably differentiate primary lung cancer from nodules with other diagnoses among part-solid GGNs on high-resolution CT (HRCT). A retrospective study was conducted on 609 patients who underwent surgical treatment or observation for lung nodules. Radiological findings from pre-operative HRCT scans were reviewed and several CT imaging features of part-solid GGNs were examined for their positive predictive value to identify primary lung cancer. The proportions of the nodules with a final diagnosis of primary lung cancer were significantly higher in part-solid GGNs (91.9%) compared with solid nodules (70.3%) or pure GGNs (66.7%). Among CT imaging features of part-solid GGNs that were evaluated, consolidation-to-tumor ratio (CTR) < 0.5 (98.1%), pleural indentation (96.4%), and clear tumor border (96.7%) had high positive predictive value to identify primary lung cancer. When two imaging features were combined, the combination of CTR < 0.5 and a clear tumor border was identified to have 100% positive predictive values with a sensitivity of 40.8%. Thus we conclude that part-solid GGNs with a CTR < 0.5 accompanied by a clear tumor border evaluated by HRCT are very likely to be primary lung cancers with an acceptable sensitivity. Preoperative diagnostic procedures to obtain a pathological diagnosis may potentially be omitted in patients harboring such part-solid GGNs.

Background: Immune-related adverse events (irAEs) have been found to predict PD-L1 inhibitor efficacy in metastatic NSCLC. However, the relation of irAEs to clinical outcome for nonmetastatic NSCLC has remained unknown., Methods: In this multicenter prospective study of Stage III NSCLC treated with PACIFIC regimen, the relation of irAEs to PFS was evaluated by 8-week landmark analysis to minimise lead-time bias as well as by multivariable analysis adjusted for baseline factors. irAEs were categorised as mild or nonmild according to whether they were treated with systemic steroid., Results: Median PFS was 16.0 months, not reached, and 9.7 months for patients without (85 cases) or with mild (21 cases) or nonmild (21 cases) irAEs, respectively. Multivariable analysis indicated that nonmild irAEs were associated with poor PFS, with HRs of 3.86 (95% CI, 1.31-11.38) compared with no irAEs and 11.58 (95% CI, 2.11-63.63) compared with mild irAEs. This pattern was consistent after irAE grade, the number of durvalumab doses and immune profiles (PD-L1 score, CD8 + tumour-infiltrating lymphocyte density, and tumour mutation burden) were taken into consideration., Conclusions: The development of mild irAEs might predict a better survival outcome, whereas immunosuppressive steroid-treated irAEs were associated with a worse outcome, regardless of baseline clinical and immune profiles., (© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)

Objectives: Although several societies recommend regular chest computed tomography (CT) scans for the surveillance of surgically resected non-small cell lung cancer (NSCLC), there is paucity of evidence to support these statements. This study aimed to clarify whether regular CT scans improved the prognosis of patients with surgically resected NSCLC based on TNM 8th classification., Methods: Patients with pathologic Stage 0-III NSCLC who underwent complete surgical resection other than sublobar resection procedures were enrolled in the study. For these patients, clinicopathological data and postoperative surveillance data were collected by the retrospective review of medical records. Patients were categorized into the chest X-ray (CXR) group or the CT group according to whether they were followed-up with basic examinations including CXR or basic examinations plus regular chest CT. Postoperative overall survival was compared between the two groups., Results: Six hundred sixty five patients were categorized into the CXR (n = 245) and CT (n = 420) groups. The clinicopathological backgrounds did not differ to a statistically significant extent. Recurrence was seen in 68 (27.3%) patients in the CXR group and 117 (27.8%) patients in the CT group. The 5-year overall survival rates of the two groups did not differ to a statistically significant extent (CXR, 76.5%; CT, 78.3%, P = 0.22)., Conclusion: Regular chest CT scans may not improve the prognosis of surgically resected NSCLC. Further study is warranted to precisely evaluate the benefit of CT-based postoperative surveillance of NSCLC., (© 2023. The Author(s), under exclusive licence to The Japanese Association for Thoracic Surgery.)

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

Immune checkpoint inhibitor (ICI) therapy has been established as one of the key treatment strategies for lung squamous cell carcinoma (LUSQ). The status of programmed death-ligand 1 (PD-L1) in tumor cells and/or immune cells using immunohistochemistry has been primarily used as a surrogate marker for determining ICI treatment; however, when the tissues to be examined are small, false-negative results could be unavoidable due to the heterogeneity of PD-L1 immunoreactivity. To overcome this practical limitation, we attempted to explore the status of nuclear atypia evaluated using morphometry as a potential predictor of PD-L1 status in LUSQ. We correlated the parameters related to nuclear atypia with PD-L1 status using two different cohorts of LUSQ patients (95 cases from The Cancer Genome Atlas database and 30 cases from the Miyagi Cancer Center). Furthermore, we studied the gene mutation status to elucidate the genetic profile of PD-L1 predictable cases. The results revealed that nuclear atypia, especially morphometric parameters related to nuclear shape irregularity, including aspect ratio, circularity, roundness, and solidity, were all significantly associated with PD-L1 status. Additionally, LUSQ cases with high PD-L1 expression and pronounced nuclear atypia were significantly associated with C10orf71 and COL14A1 mutations compared with those with low PD-L1 expression and mild nuclear atypia. We demonstrated for the first time that nuclear shape irregularity could represent a novel predictor of PD-L1 expression in LUSQ. Including the morphometric parameters related to nuclear atypia in conjunction with PD-L1 status could help determine an effective ICI therapeutic strategy; however, further investigation is required., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Mounting evidence suggests that body mass index (BMI) is inversely associated with the risk of lung cancer. However, relatively few studies have explored this association in Asian people, who have a much lower prevalence of obesity than Caucasians. We pooled data from 10 prospective cohort studies involving 444,143 Japanese men and women to address the association between BMI and the risk of lung cancer. Study-specific hazard ratios (HRs) and 95% confidence intervals (CIs) were calculated in each cohort using the Cox proportional hazards model. A meta-analysis was undertaken by combining the results from each cohort. Heterogeneity across studies was evaluated using Cochran's Q and I 2 statistics. During 5,730,013 person-years of follow-up, 6454 incident lung cancer cases (4727 men and 1727 women) were identified. Baseline BMI was inversely associated with lung cancer risk in men and women combined. While leanness (BMI <18.5) was associated with a higher risk of lung cancer (HR 1.35; 95% CI, 1.16-1.57), overweight and obesity were associated with a lower risk, with HRs of 0.77 (95% CI, 0.71-0.84) and 0.69 (95% CI, 0.45-1.07), respectively. Every 5 kg/m 2 increase in BMI was associated with a 21% lower risk of lung cancer (HR 0.79; 95% CI, 0.75-0.83; p < 0.0001). Our pooled analysis indicated that BMI is inversely associated with the risk of lung cancer in the Japanese population. This inverse association could be partly attributed to residual confounding by smoking, as it was more pronounced among male smokers., (© 2024 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.)

Importance: Immune checkpoint inhibitor (ICI) plus chemotherapy combination treatment (ICI-chemotherapy) is now a standard treatment for non-small cell lung cancer (NSCLC) without targetable oncogene alterations, but there are few data on ICI-chemotherapy for patients 75 years and older., Objective: To inform the choice of first-line drugs in clinical practice and assess the safety and efficacy of ICI-chemotherapy combination treatment in older adult patients with previously untreated advanced NSCLC., Design, Setting, and Participants: This retrospective cohort study included 58 centers in Japan. The cohort consisted of patients 75 years and older with clinical stage IIIB, IIIC, IV, postoperative or radiotherapy recurrent NSCLC. Patients started first-line systemic therapy between December 2018 and March 2021. Those receiving first-line molecular targeted drugs were excluded. The data were analyzed from February 2022 to October 2022., Exposures: Systemic therapy., Main Outcomes and Measures: The main outcomes were overall survival (OS), progression-free survival (PFS), and safety., Results: A total of 1245 patients (median [range] age, 78 [75-95] years; 967 [78%] male) with NSCLC were included in the cohort. Programmed death ligand-1 (PD-L1) expression of less than 1% occurred in 268 tumors (22%); 1% to 49% in 387 tumors (31%); 50% and higher in 410 tumors (33%), and unknown expression in 180 tumors (14%). Median OS was 20.0 (95% CI, 17.1-23.6) months for the 354 patients receiving ICI-chemotherapy (28%); 19.8 (95% CI, 16.5-23.8) months for the 425 patients receiving ICI alone (34%); 12.8 (95% CI, 10.7-15.6) months for the 311 patients receiving platinum-doublet chemotherapy (25%); and 9.5 (95% CI, 7.4-13.4) months for the 155 patients receiving single-agent chemotherapy (12%). After propensity score matching, no differences in OS and PFS were found between the patients receiving ICI-chemotherapy vs ICI alone. Each group consisted of 118 patients. For PD-L1 expression of 1% and higher the OS hazard ratio (HR) was 0.98 (95% CI, 0.67-1.42; P = .90), and the PFS HR was 0.92 (95% CI, 0.67-1.25; P = .59). Significance was also not reached when separately analyzed for lower or higher PD-L1 expression (1%-49% or ≥50%). However, grade 3 or higher immune-related adverse events occurred in 86 patients (24.3%) treated with ICI-chemotherapy and 76 (17.9%) with ICI alone (P = .03)., Conclusions and Relevance: In this study, ICI-chemotherapy combination treatment did not improve survival and increased the incidence of grade 3 and higher immune-related adverse events compared with ICI alone in patients 75 years and older. Based on these results, ICI alone may be recommended for older adult patients with PD-L1-positive NSCLC.

Durvalumab has been administered to patients with unresectable stage III non-small cell lung cancer (NSCLC). However, it remains unclear whether durvalumab benefits these patients with epidermal growth factor receptor (EGFR) mutation. We conducted a retrospective, multicenter study of patients with EGFR mutation who received chemoradiotherapy (CRT) between June 2018 and March 2021. We assessed patient characteristics, efficacy of durvalumab, and durvalumab safety before and after targeted therapy. We collected data on a total of 673 patients, of whom 401 (59.6%) underwent EGFR mutation testing. Fifty-one patients were EGFR positive and 311 were EGFR negative. In the EGFR-positive group, there were higher proportions of females, never-smokers, and patients with adenocarcinoma histology. Of the 51 patients in the positive group and 311 in the negative group who received CRT, 45 (88.2%) and 247 (79.4%) received durvalumab, with median progression-free survival of 23.0 and 24.2 months in the positive and negative groups, respectively (hazard ratio 1.03; 95% confidence interval: 0.64-1.67). The main adverse event was pneumonitis (positive group: 62.2%; 4.4% grade 3; negative group: 62.3%; 6.9% grade 3). No treatment-related deaths were observed. Of the 45 patients in the positive group who received durvalumab, 14 (31.1%) received targeted therapy after durvalumab at the data cutoff. One patient discontinued targeted therapy after developing pneumonitis. In patients with unresectable stage III NSCLC with EGFR mutation, durvalumab after CRT is potentially safe and effective. This may be a suitable treatment sequence for these patients., (© 2024 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.)

Nuclear receptor interacting protein 1 (NRIP1) is a transcription cofactor that regulates the activity of nuclear receptors and transcription factors. Functional expression of NRIP1 has been identified in multiple cancers. However, the expression and function of NRIP1 in lung adenocarcinoma have remained unclear. Thus, we aimed to clarify the NRIP1 expression and its functions in lung adenocarcinoma cells. NRIP1 and Ki-67 were immunostained in the tissue microarray section consisting of 64 lung adenocarcinoma cases, and the association of NRIP1 immunoreactivity with clinical phenotypes was examined. Survival analysis was performed in lung adenocarcinoma data from The Cancer Genome Atlas (TCGA). Human A549 lung adenocarcinoma cell line with an NRIP1-silencing technique was used in vitro study. Forty-three of 64 cases were immunostained with NRIP1. Ki-67-positive cases were more frequent in NRIP1-positive cases as opposed to NRIP1-negative cases. Higher NRIP1 mRNA expression was associated with poor prognosis in the TCGA lung adenocarcinoma data. NRIP1 was mainly located in the nucleus of A549 cells. NRIP1 silencing significantly reduced the number of living cells, suppressed cell proliferation, and induced apoptosis. These results suggest that NRIP1 participates in the progression and development of lung adenocarcinoma. Targeting NRIP1 may be a possible therapeutic strategy against lung adenocarcinoma., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Japanese Biochemical Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Introduction: Although lung cancer prediction models are widely used to support risk-based screening, their performance outside Western populations remains uncertain. This study aims to evaluate the performance of 11 existing risk prediction models in multiple Asian populations and to refit prediction models for Asians., Methods: In a pooled analysis of 186,458 Asian ever-smokers from 19 prospective cohorts, we assessed calibration (expected-to-observed ratio) and discrimination (area under the receiver operating characteristic curve [AUC]) for each model. In addition, we developed the "Shanghai models" to better refine risk models for Asians on the basis of two well-characterized population-based prospective cohorts and externally validated them in other Asian cohorts., Results: Among the 11 models, the Lung Cancer Death Risk Assessment Tool yielded the highest AUC (AUC [95% confidence interval (CI)] = 0.71 [0.67-0.74] for lung cancer death and 0.69 [0.67-0.72] for lung cancer incidence) and the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial Model had good calibration overall (expected-to-observed ratio [95% CI] = 1.06 [0.90-1.25]). Nevertheless, these models substantially underestimated lung cancer risk among Asians who reported less than 10 smoking pack-years or stopped smoking more than or equal to 20 years ago. The Shanghai models were found to have marginal improvement overall in discrimination (AUC [95% CI] = 0.72 [0.69-0.74] for lung cancer death and 0.70 [0.67-0.72] for lung cancer incidence) but consistently outperformed the selected Western models among low-intensity smokers and long-term quitters., Conclusions: The Shanghai models had comparable performance overall to the best existing models, but they improved much in predicting the lung cancer risk of low-intensity smokers and long-term quitters in Asia., (Copyright © 2023. Published by Elsevier Inc.)

The pathogenesis of malignant mesothelioma (MM) has been extensively investigated, focusing on stress derived from reactive oxygen species. We aimed to identify diagnostic biomarkers of MM by analyzing proteins in formalin-fixed paraffin-embedded specimens using liquid chromatography-mass spectrometry. We extracted proteins from formalin-fixed paraffin-embedded sections of MM tissues (n = 7) and compared their profiles with those of benign mesothelial tissues (n = 4) and alveolar tissue (n = 1). Proteomic data were statistically assessed and profiled using principal component analysis. We were successful in the classification of MM and healthy tissue. The levels of superoxide dismutase 2 (SOD2), an enzyme that converts superoxide anion into oxygen and hydrogen peroxide, and thioredoxin (TXN), which plays a crucial role in reducing disulfide bonds in proteins, primarily contributed to the classification. Other redox-related proteins, such as pyruvate dehydrogenase subunit X, and ceruloplasmin also contributed to the classification. Protein-protein interaction analysis demonstrated that these proteins play essential roles in MM pathogenesis. Immunohistochemistry revealed that TXN levels were significantly lower, whereas SOD2 levels were significantly higher in MM and lung cancer tissues than in controls. Proteomic profiling suggested that MM tissues experienced increased exposure to hydrogen peroxide and other reactive oxygen species. Combining immunohistochemistry for TXN and SOD2 allows for differentiation among MM, lung cancer, and control tissues; hence, TXN and SOD2 may be promising MM biomarkers and therapeutic targets., (Copyright © 2023 United States & Canadian Academy of Pathology. Published by Elsevier Inc. All rights reserved.)

Background: The factors that predict the clinical response to ramucirumab plus docetaxel (RD) after first-line chemoimmunotherapy are unresolved. We explored whether the therapeutic efficacy of prior chemoimmunotherapy could predict the outcome of RD as sequential therapy in patients with advanced non-small cell lung cancer (NSCLC)., Methods: Our study comprised 288 patients with advanced NSCLC who received RD as the second-line treatment after first-line chemoimmunotherapy at 62 Japanese institutions. Chemoimmunotherapy consisted of a platinum-based regimen and immune checkpoint inhibitors (ICIs). The association between several variables and the therapeutic outcome of RD was determined via logistic regression analysis., Results: Of the 288 patients, 225 (78.1%) received maintenance therapy and 108 (37.5%) received both ICI treatment for >180 days and maintenance therapy. All of 108 patients having ICIs for >180 days received maintenance therapy. Univariate analysis identified performance status, histology (adenocarcinoma), maintenance therapy, and ICI treatment >180 days as significant predictors of better progression-free survival (PFS) and overall survival (OS) after RD administration. Multivariate analysis confirmed that these factors independently predicted favorable PFS and OS. The therapeutic response and PD-L1 expression were not closely associated with outcome after RD treatment. In particular, maintenance therapy >4 cycles was more predictive of the better prognosis for RD treatment., Conclusion: Extended ICI treatment after chemoimmunotherapy and maintenance therapy enhanced the efficacy of second-line RD treatment in patients with advanced NSCLC., (© 2023 The Authors. Thoracic Cancer published by China Lung Oncology Group and John Wiley & Sons Australia, Ltd.)

Purpose: The purpose of this study is to identify the clinical, genomic, and transcriptomic features of patients with lung adenocarcinoma (LUAD) harboring uncommon epidermal growth factor receptor (EGFR) mutations (UCM) compared with common EGFR mutations (CM)., Materials and Methods: In this multicenter retrospective cohort study, clinicopathological data were collected from 1047 consecutive patients who underwent complete surgical resection for LUAD, as well as EGFR mutation analysis, between 2005 and 2012 at 4 institutions. Differences in postoperative overall survival (OS) and recurrence-free survival (RFS) according to EGFR mutation status were evaluated. For the genomic and transcriptomic analyses, 5 cohorts from public databases were evaluated., Results: Of 466 eligible patients, 415 (89.1%) and 51 (10.9%) had CM and UCM, respectively. The 5-year OS and RFS rates in the CM/UCM groups were 86.8%/77.0% and 74.8%/59.0%, respectively. OS and RFS were significantly shorter in the UCM than CM group (both P < .01). Multivariable analysis of OS showed that UCM was an independent prognostic factor (hazard ratio 1.72, 95% confidential interval 1.01-2.93). According to the genomic analysis, tumors with UCM had a significantly higher tumor mutation burden and TP53 mutation frequency. Transcriptomic analysis showed that the T-cell-inflamed gene signature, a biomarker of the treatment for immunotherapy, was significantly associated with tumors with UCM., Conclusion: UCM were associated with a poor prognosis in patients with surgically resected EGFR-mutated LUAD. Tumors with UCM had unique genomic and transcriptomic features suggestive of a tumor microenvironment responsive to immunotherapy., Competing Interests: Disclosure The authors have stated that they have no conflicts of interest., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Introduction: Evidence is limited on preferences of Japanese patients and physicians in treatment for epidermal growth factor receptor (EGFR)-mutant non-small cell lung cancer (NSCLC). Several oral or intravenous novel agents for EGFR exon 20 insertions are under development. The aim of our study was to investigate which attributes of novel treatments influenced selection of oral or intravenous agents among treated patients and treating physicians in Japan., Methods: The study was designed by board-certified oncologists, patient representatives, and analytics specialists. Eligible participants completed an online survey with a discrete choice experiment presenting two treatment profiles described by attributes: mode of administration (oral or intravenous); frequency of administration; overall response rate (ORR); average progression-free survival (PFS); chance of experiencing severe side effects (SEs); mild-moderate gastrointestinal SEs; mild-moderate skin-related SEs; and patient out-of-pocket costs., Results: Fifty-four patients (all self-reported EGFR-mutant) and 74 physicians participated from December 2021 to August 2022. All attributes being equal, there was greater preference for oral administration. However, there was greater preference for intravenous over oral, when ORR and PFS improved by 10% and 1 month, and severe SEs reduced by 10%. Physicians exhibited greater preference for PFS compared to patients (p < 0.01). Ranked order of attribute importance was as follows: (1) PFS; (2) ORR; (3) severe SEs, expressed by patients and physicians alike., Conclusions: Our study revealed Japanese physician and patient preferences in treatment options for EGFR-mutant NSCLC. Compared to the strong preference for a more efficacious drug, the preference of oral versus intravenous revealed a smaller impact., (© 2023 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

Objectives: Osimertinib is the primary treatment for patients with epidermal growth factor receptor (EGFR) mutation-positive advanced non-small cell lung cancer. However, evidence of the outcomes of osimertinib treatment in patients over 75 years of age in the real-world setting is limited., Materials and Methods: This retrospective study analyzed the data of 538 patients (203 elderly and 335 non-elderly) with EGFR mutation-positive lung cancer in whom osimertinib was initiated as first-line treatment between August 2018 and December 2019. Patients over 75 years of age were classified as elderly. The data cut-off date was February 28, 2022., Results: The progression-free survival (PFS) did not significantly differ between the elderly and non-elderly groups [elderly group: median PFS, 16.9 months (95 % confidence interval (CI), 14.3-20.2); non-elderly group: median PFS, 22.1 months (95 % CI: 19.5-26.3); hazard ratio (HR) for the elderly against the non-elderly: 1.21 (95 % CI: 0.98-1.50), p = 0.079]. However, the time to treatment failure (TTF) was significantly shorter in the elderly than in the non-elderly [elderly group: median TTF, 14.0 months (95 % CI: 0.98-1.50); non-elderly group: median TTF, 21.8 months (95 % CI: 18.2-24.6); HR for the elderly against the non-elderly: 1.46 (95 % CI: 1.20-1.77), p < 0.001]. Furthermore, the rate of treatment discontinuation because of adverse events was 28.6 % in the elderly and 14.9 % in the non-elderly (p < 0.001). Among patients who discontinued treatment, the conversion rate to second-line treatment was 39.6 % in the elderly and 72.8 % in the non-elderly. In addition, the median overall survival was 30 months (95 % CI: 25.8-37.7) in the elderly and not reached (NR) (95 % CI: NR-NR) in the non-elderly (p < 0.001)., Conclusion: In a real-world clinical setting, elderly patients receiving osimertinib as first-line treatment should be aware of the frequent inability to transition to second-line treatment due to adverse events., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Dr. Yoshihiko Sakata reported receiving personal fees from AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, Chugai Pharmaceutical, Eli Lilly, Kyowa KIRIN, MSD, Novartis Pharma KK, Pfizer, Taiho Pharmaceutical, and Takeda Pharmaceutical Company Limited outside the submitted work. Dr. Saito reported receiving personal fees from AstraZeneca, Chugai Pharmaceutical, Daiichi Sankyo Company, MSD, Novartis Pharma KK, Ono Pharmaceutical, Pfizer, and Taiho Pharmaceutical outside the submitted work. Dr. Shinya Sakata reported receiving personal fees from AstraZeneca, Chugai Pharmaceutical, Taiho Pharmaceutical, and Takeda Pharmaceutical Company Limited outside the submitted work. Dr. Oya reported receiving personal fees from Amgen, AstraZeneca, Bristol Myers Squibb, Chugai Pharmaceutical, Eli Lilly, MSD, Novartis Pharma KK, Pfizer, Taiho Pharmaceutical, and Takeda Pharmaceutical Company Limited outside the submitted work. Dr. Tamiya reported receiving personal fees from Amgen, Asahi Kasei Pharmaceutical, AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, Chugai Pharmaceutical, Eli Lilly, MSD, Ono Pharmaceutical, Pfizer, and Taiho Pharmaceutical outside the submitted work. Dr. Suzuki reported receiving personal fees from AstraZeneca, Chugai Pharmaceutical, MSD, and Takeda Pharmaceutical Company Limited outside the submitted work. Dr. Shibaki declares that he has no competing financial interests or personal relationships that would affect the research reported in this paper. Dr. Okada reported receiving personal fees from AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, Chugai Pharmaceutical, Eli Lilly, Kyowa KIRIN, MSD, and Nippon Kayaku Co. Ltd. outside the submitted work. Dr. Yokoyama reported receiving personal fees from AstraZeneca, Bristol Myers Squibb, Chugai Pharmaceutical, Eli Lilly, Merck Biopharma Co. Ltd., MSD, Nippon Kayaku Co. Ltd., Novartis Pharma KK, Ono Pharmaceutical, Pfizer, and Takeda Pharmaceutical Company Limited outside the submitted work. Dr. Matsumoto reported receiving personal fees from AstraZeneca, Boehringer Ingelheim, Chugai Pharmaceutical, MSD, Nippon Kayaku Co. Ltd., Ono Pharmaceutical, Taiho Pharmaceutical, and Takeda Pharmaceutical Company Limited outside the submitted work. Dr. Otsuki reported receiving personal fees from AstraZeneca, Bristol Myers Squibb, Chugai Pharmaceutical, Eisai Co. Ltd., MSD, Nippon Kayaku Co. Ltd., Ono Pharmaceutical, and Tsumura & Co. outside the submitted work. Dr. Sato reported receiving personal fees from AstraZeneca, Bristol Myers Squibb, Chugai Pharmaceutical, Eli Lilly, MSD, Novartis Pharma KK, Ono Pharmaceutical, Pfizer, Taiho Pharmaceutical, Nippon Kayaku, Kyowa Kirin, and Takeda Pharmaceutical Company Limited outside the submitted work. Dr. Uchida reported receiving personal fees from AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, Chugai Pharmaceutical, Eli Lilly, Kyowa KIRIN, MSD, Novartis Pharma KK, Taiho Pharmaceutical, and Takeda Pharmaceutical Company Limited outside the submitted work. Dr. Tsukita reported receiving personal fees from AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, Chugai Pharmaceutical, Daiichi Sankyo, Eisai, Eli Lilly, MSD, and Taiho Pharmaceutical outside the submitted work. Dr. Inaba reported receiving personal fees from AstraZeneca, Boehringer Ingelheim, Chugai Pharmaceutical, MSD, and Takeda Pharmaceutical Company Limited outside the submitted work. Dr.Ikeda declares that he has no competing financial interests or personal relationships that would affect the research reported in this paper. Dr. Arai reported receiving personal fees from AstraZeneca, Chugai Pharmaceutical, Merck Biopharma Co. Ltd., MSD, Nippon Kayaku Co. Ltd., Ono Pharmaceutical, Taiho Pharmaceutical, and Takeda Pharmaceutical Company Limited outside the submitted work. Dr. Maruyama reported receiving personal fees from AstraZeneca, Bristol Myers Squibb, Chugai Pharmaceutical, Eli Lilly, and Taiho Pharmaceutical outside the submitted work. Dr. Hara declares that he has no competing financial interests or personal relationships that would affect the research reported in this paper. Dr. Tsumura declares that he has no competing financial interests or personal relationships that would affect the research reported in this paper. Dr. Morinaga declares that he has no competing financial interests or personal relationships that would affect the research reported in this paper. Dr. Sakagami reported receiving personal fees from AstraZeneca, Boehringer Ingelheim, Chugai Pharmaceutical, Eli Lilly, GlaxoSmithKline, MSD, Novartis Pharma KK, Taiho Pharmaceutical, Takeda Pharmaceutical Company Limited, and Sanofi outside the submitted work., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Background: This study aimed to investigate the effectiveness of anticholinergics (AC) for death rattle in dying patients with cancer., Methods: This is a prospective cohort study enrolled Terminally ill adult (20 years or older) patients with cancer who developed substantial death rattle (Back score ≥2) from 23 palliative care units in Japan. AC treatment for death rattle was prescribed according to primary physician's decision. The primary outcome was the proportion of patients whose death rattle improved, which was defined as a Back score of ≤1. We compared the proportion of improved cases in patients treated with (AC group) and without (non-AC group) AC, controlling potential confounders by employing propensity score weighting., Results: Of the 1896 patients enrolled, we included 196 who developed a substantial death rattle. Of these, 81 received AC. 56.8% in the AC group and 35.4% in the non-AC group had an improved death rattle at 8 hours after baseline. In the weighted analysis, AC group showed significant improvements in death rattle, with an adjusted OR of 4.47 (95% CI 2.04 to 9.78; p=0.0024). All sensitivity analyses achieved essentially the same results. In the subgroup analysis, ACs were strongly associated with death rattle improvement in men, patients with lung cancer, and type 1 death rattle (adjusted OR 5.81, 8.38 and 9.32, respectively)., Conclusions: In this propensity score-weighted analysis, ACs were associated with death rattle improvement in terminally ill patients with cancer who developed substantial death rattle., Trial Registration Number: UMIN-CTR (UMIN00002545)., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2023. No commercial re-use. See rights and permissions. Published by BMJ.)

Objectives: The aim of this study was to examine the performance of a convolutional neural network (CNN) combined with exponentiating each pixel value in classifying benign and malignant lung nodules on computed tomography (CT) images., Materials and Methods: Images in the Lung Image Database Consortium-Image Database Resource Initiative (LIDC-IDRI) were analyzed. Four CNN models were then constructed to classify the lung nodules by malignancy level (malignancy level 1 vs. 2, malignancy level 1 vs. 3, malignancy level 1 vs. 4, and malignancy level 1 vs. 5). The exponentiation method was applied for exponent values of 1.0 to 10.0 in increments of 0.5. Accuracy, sensitivity, specificity, and area under the curve of receiver operating characteristics (AUC-ROC) were calculated. These statistics were compared between an exponent value of 1.0 and all other exponent values in each model by the Mann-Whitney U-test., Results: In malignancy 1 vs. 4, maximum test accuracy (MTA; exponent value = 2.0, 3.0, 3.5, 4.5, 5.0, 5.5, 6.0, 6.5, 7.0, 7.5, 8.0, 8.5, 9.0, 9.5, and 10.0) and specificity (6.5, 7.0, and 9.0) were improved by up to 0.012 and 0.037, respectively. In malignancy 1 vs. 5, MTA (6.5 and 7.0) and sensitivity (1.5) were improved by up to 0.030 and 0.0040, respectively., Conclusions: The exponentiation method improved the performance of the CNN in the task of classifying lung nodules on CT images as benign or malignant. The exponentiation method demonstrated two advantages: improved accuracy, and the ability to adjust sensitivity and specificity by selecting an appropriate exponent value., Clinical Relevance Statement: Adjustment of sensitivity and specificity by selecting an exponent value enables the construction of proper CNN models for screening, diagnosis, and treatment processes among patients with lung nodules., Key Points: • The exponentiation method improved the performance of the convolutional neural network. • Contrast accentuation by the exponentiation method may derive features of lung nodules. • Sensitivity and specificity can be adjusted by selecting an exponent value., (© 2023. The Author(s), under exclusive licence to European Society of Radiology.)

Introduction: The use of immune checkpoint inhibitors (ICIs) is rapidly expanding in cancer treatment. ICIs have a unique safety profile, characterised by immune-related adverse events (irAEs). The safety profile of ICIs lacks patient experience and perspectives. This study primarily aims to obtain a database for descriptive research on the status of irAEs using the Patient-Reported Outcomes version of the Common Terminology Criteria (PRO-CTCAE) in patients with gastrointestinal cancer, lung cancer and malignant pleural mesothelioma treated with regimens containing ICIs., Methods and Analysis: This is an ongoing, multicentre, observational study in Japan. Eligible patients must be at least 20 years old and have been diagnosed with lung cancer, malignant pleural mesothelioma or gastrointestinal cancer and plan to use ICIs. Participants will install the electronic PRO (ePRO) application and report adverse events via ePRO using PRO-CTCAE once weekly for up to 48 weeks. A registry will be established using background information obtained from medical records. The sample size is determined by 1 year projection without using statistical methods. Statistical analyses will include point estimates and 95% CIs for the incidence of each adverse event by cancer type and regimen at each time point., Ethics and Dissemination: This research will be conducted per the Declaration of Helsinki, the Ethical Guidelines for Life Science and Medical Research Involving Human Subjects issued by the Ministry of Education, Culture, Sports, Science and Technology and the Ministry of Health, Labor and Welfare, and the revised Personal Information Protection Law. The study protocol was approved by the Ethics Committee (approval ID T2021-0180) of Tokyo Medical University Hospital on 15 October 2021., Registration Details: The study began enrolling patients in December 2021. The target enrolment is 260; as of October 2022, 141 have been enrolled, and the enrolment is scheduled to end on 30 June 2023., Trial Registration Number: UMIN000046418., Competing Interests: Competing interests: None declared., (© 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: Evidence for use of second-line immunosuppressants for immune-related adverse events (irAEs) is inadequate. Therefore, a multicenter analysis should assess the efficacy of second-line immunosuppressants for severe irAEs associated with different malignant diseases., Methods: This descriptive study aims to investigate the effects of second-line immunosuppressants on corticosteroid-refractory irAEs in patients with lung cancer. We analyzed the effects of second-line immunosuppressants on underlying lung cancer and associated adverse effects., Results: Our study included 4589 patients who had received immune checkpoint inhibitor treatment, with 73 patients (1.6%) developing irAEs requiring second-line immunosuppressants. The most commonly observed irAE was pneumonitis (26 patients), followed by hepatobiliary disorders (15 patients) and enteritis (14 patients). We found a confirmed response rate of 42.3% for pneumonitis, which was lower than the response rates of 86.7% for hepatobiliary disorders and 92.9% for enteritis. The time from the start of corticosteroid therapy to the addition of a second-line immunosuppressant correlated significantly with the resolution of irAE to Grade 1 (correlation coefficients of r = 0.701, p < 0.005). The median progression-free survival and duration of response of underlying lung cancer from second-line immunosuppressant administration were 2.1 and 3.0 months, respectively. Of the patients with irAE, 27.4% developed infections and 5.5% might die due to infection., Conclusion: Second-line immunosuppressant response was confirmed in 72.2% of irAEs in patients with lung cancer, with lower response rates observed in irAE pneumonitis compared to other irAEs., (© 2023. The Author(s).)

Background: Previous studies have shown that socioeconomic factors are associated with cancer incidence and stage at diagnosis; however, relevant findings in Japan are limited. We examined the association between socioeconomic status and cancer incidence, stage at diagnosis, and detection status by screening, as assessed using the areal deprivation index (ADI), in population-based cancer registry data., Methods: A total of 79,816 cases, including stomach, colorectal, lung, female breast, and cervical cancer diagnosed in Miyagi Prefecture between 2005 and 2010, were analyzed. After calculating the ADI at the place of residence in each case, we examined the association between quintiles of ADI and age-adjusted incidence rates of all stages and advanced stages by sex and site using Poisson regression analysis. The association between the ADI and the proportion of screen-detected cancers was also examined using logistic regression analysis., Results: The age-adjusted incidence rates of all sites and lung cancer in men and lung cancer and cervical cancer in women tended to increase significantly in areas with a higher ADI. The age-adjusted incidence rates of advanced-stage cancers were significantly higher for all sites and lung cancer in both sexes, and for stomach and colorectal cancer in men. The proportion of screen-detected cancer tended to be significantly lower in areas with a higher ADI for stomach and colorectal cancer in men., Conclusion: Our results indicate that socioeconomic disparities may affect cancer incidence and early diagnosis in Japan. These results suggest the importance of cancer control measures targeting people with low socioeconomic status in Japan.

Introduction: The PACIFIC regimen of consolidation therapy with the programmed cell death-ligand 1 inhibitor durvalumab after definitive concurrent chemoradiation therapy has become a standard of care for individuals with unresectable stage III NSCLC. Nevertheless, approximately half of the treated patients experience disease progression within 1 year, with the mechanisms of treatment resistance being poorly understood. We here performed a nationwide prospective biomarker study to explore the resistance mechanisms (WJOG11518L:SUBMARINE)., Methods: A total of 135 patients with unresectable stage III NSCLC who received the PACIFIC regimen were included for comprehensive profiling of the tumor microenvironment by immunohistochemistry, transcriptome analysis, and genomic sequencing of pretreatment tumor tissue and flow cytometric analysis of circulating immune cells. Progression-free survival was compared on the basis of these biomarkers., Results: The importance of preexisting effective adaptive immunity in tumors was revealed for treatment benefit regardless of genomic features. We also identified CD73 expression by cancer cells as a mechanism of resistance to the PACIFIC regimen. Multivariable analysis of immunohistochemistry data with key clinical factors as covariables indicated that low CD8 + tumor-infiltrating lymphocyte density and the high CD73 + cancer cells were independently associated with poor durvalumab outcome (hazard ratios = 4.05 [95% confidence interval: 1.17-14.04] for CD8 + tumor-infiltrating lymphocytes; 4.79 [95% confidence interval: 1.12-20.58] for CD73). In addition, whole-exome sequencing of paired tumor samples suggested that cancer cells eventually escaped immune pressure as a result of neoantigen plasticity., Conclusions: Our study emphasizes the importance of functional adaptive immunity in stage III NSCLC and implicates CD73 as a promising treatment target, thus providing insight forming a basis for development of a new treatment approach in NSCLC., (Copyright © 2023 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.)

Background: This phase II trial was designed to evaluate the efficacy and safety of S-1 combined with weekly irinotecan as a second- or third-line treatment for patients with advanced or recurrent squamous cell lung cancer., Methods: Patients with a body surface area <1.25, 1.25-1.50, and >1.50 m 2 received oral S-1 on days 1-14 at 80, 100, and 120 mg/day, respectively, and irinotecan on days 1 and 8 at 70 mg/m 2 every 3 weeks. The primary endpoint was the overall response rate, and the secondary endpoints were progression-free survival, overall survival, and the incidence and severity of adverse effects., Results: Between September 2011 and December 2014, 30 patients were enrolled in this study. The overall response rate was 6.7% (95% confidence interval [CI]: 0.8%-22.1%), and the disease control rate was 73.3%. The median progression-free survival was 3.0 months (95% CI: 2.5-3.4 months), and the median overall survival was 10.5 months (95% CI: 5.6-13.7 months). Grade 3/4 treatment-related adverse events were reported in ≥10% of the patients, including leukopenia (21%), neutropenia (21%), anemia (17%), anorexia (10%), and hypokalemia (10%)., Conclusions: Although the treatment-related adverse events were manageable, the combination of weekly irinotecan and S-1 did not have the expected effect., (© 2023 The Authors. Thoracic Cancer published by China Lung Oncology Group and John Wiley & Sons Australia, Ltd.)

Leucine zipper-like transcriptional regulator 1 (LZTR1), a substrate adaptor of Cullin 3 (CUL3)-based E3 ubiquitin ligase, regulates proteostasis of the RAS subfamily. Mutations in LZTR1 have been identified in patients with several types of cancer. However, the role of LZTR1 in tumor metastasis and the target molecules of LZTR1, excluding the RAS subfamily, are not clearly understood. Here, we show that LZTR1 deficiency increases tumor growth and metastasis. In lung adenocarcinoma cells, LZTR1 deficiency induced the accumulation of the RAS subfamily and enhanced cell proliferation, invasion, and xenograft tumor growth. Multi-omics analysis to clarify the pathways related to tumor progression showed that MAPK signaling, epithelial-mesenchymal transition (EMT), and extracellular matrix (ECM) remodeling-related gene ontology terms were enriched in LZTR1 knockout cells. Indeed, LZTR1 deficiency induced high expression of EMT markers under TGF-β1 treatment. Our search for novel substrates that interact with LZTR1 resulted in the discovery of a Kelch-like protein 12 (KLHL12), which is involved in collagen secretion. LZTR1 could inhibit KLHL12-mediated ubiquitination of SEC31A, a component of coat protein complex II (COPII), whereas LZTR1 deficiency promoted collagen secretion. LZTR1-RIT1 and LZTR1-KLHL12 worked independently regarding molecular interactions and did not directly interfere with each other. Further, we found that LZTR1 deficiency significantly increases lung metastasis and promotes ECM deposition around metastatic tumors. Since collagen-rich extracellular matrix act as pathways for migration and facilitate metastasis, increased expression of RAS and collagen deposition may exert synergistic or additive effects leading to tumor progression and metastasis. In conclusion, LZTR1 deficiency exerts high metastatic potential by enhancing sensitivity to EMT induction and promoting collagen secretion. The functional inhibition of KLHL12 by LZTR1 provides important evidence that LZTR1 may be a repressor of BTB-Kelch family members. These results provide clues to the mechanism of LZTR1-deficiency carcinogenesis., (© 2023. The Author(s).)