Search

Background: Efficacy of necitumumab [recombinant human monoclonal antibody that blocks the ligand binding epidermal growth factor receptor (EGFR)] in patients with squamous (SQ) non-small-cell lung cancer (NSCLC) has been confirmed in two randomized clinical trials (SQUIRE and JFCM). This study evaluated the association between efficacy and initial skin toxicity with necitumumab treatment by analyzing pooled data from two clinical trials (SQUIRE and JFCM)., Materials and Methods: Data of 635 patients with SQ-NSCLC (intent-to-treat population) treated with necitumumab plus gemcitabine and cisplatin (N + GC) were pooled from two clinical trials (SQUIRE and JFCM). The relationship between skin toxicities developed by the end of the second cycle and efficacy was evaluated. Efficacy endpoints included overall survival (OS), progression-free survival (PFS), and objective response rate (ORR). Univariate and multivariate analyses were carried out for these endpoints., Results: OS and ORR were associated with skin toxicity, whereas PFS was not. Patients with grade ≥2 or grade 1 skin toxicity had significantly longer OS compared to patients without skin toxicity (grade 0) in the N + GC group [median = 15.0 (grade ≥2); 12.7 (grade 1); 9.4 (grade 0) months; hazard ratio (HR) = 0.51 (grade ≥2 to grade 0); 95% confidence interval (CI) 0.40-0.64, P < 0.001 and HR = 0.64 (grade 1 to grade 0); 95% CI 0.52-0.80, P < 0.001]. In multivariate analysis, OS was significantly associated with skin toxicity., Conclusions: A significant association was found between necitumumab-induced skin toxicity and efficacy. These results are consistent with the previously reported association between other EGFR inhibitors-induced skin toxicity and efficacy., Competing Interests: Disclosure SW reports receiving personal fees from Novartis Pharma, Chugai Pharmaceutical, Boehringer Ingelheim, Ono Pharmaceutical, Taiho Pharmaceutical, AstraZeneca, Bristol-Myers Squibb, MSD, and Daiichi Sankyo. HY reports receiving personal fees from Delta Fly Pharma, Chugai Pharmaceutical, MSD, AstraZeneca, Boehringer Ingelheim, Taiho Pharmaceutical, Ono Pharmaceutical, Bristol-Myers Squibb, Novartis Pharma, Kyowa Kirin, Nippon Kayaku, Eli Lilly, Otsuka Pharmaceutical, Daiichi Sankyo, Amgen, Pfizer, and Nipro Pharma. HS reports receiving personal fees from Merck, Ono Pharmaceutical, Bristol-Myers Squibb, Chugai Pharmaceutical, and AstraZeneca. KH reports receiving grants from MSD, AstraZeneca, Chugai Pharmaceutical, Eli Lilly, Bristol-Myers Squibb, and AbbVie; and personal fees from Pfizer, AstraZeneca, Chugai Pharmaceutical, Eli Lilly, Takeda Pharmaceutical, MSD, Bristol-Myers Squibb, Ono Pharmaceutical, Taiho Pharmaceutical, and Boehringer Ingelheim. MT reports receiving grants from Chugai Pharmaceutical, Ono Pharmaceutical, and Pfizer. KY reports personal fees from Healios, Chugai Pharmaceutical, AstraZeneca, and Bristol-Myers Squibb. SS reports receiving personal fees from MSD, Nippon Kayaku, Chugai Pharmaceutical, AstraZeneca, Ono Pharmaceutical, Bristol-Myers Squibb, Boehringer Ingelheim, Taiho Pharmaceutical, Eli Lilly, Novartis Pharma, Kyowa Kirin, Yakult Honsha, Takeda Pharmaceutical, Pfizer, Merck, Amgen, AbbVie, Otsuka Pharmaceutical, Thermo Fisher Scientific, and Towa Pharmaceutical. YT reports receiving grants from Ono Pharmaceutical, AstraZeneca, MSD, AbbVie, Bristol-Meyers Squib, Taiho Pharmaceutical, Chugai Pharmaceutical, Daiichi Sankyo, Eli Lilly, Boehringer Ingelheim, Eisai, Nippon Kayaku, and Takeda Pharmaceutical; and personal fees from Ono Pharmaceutical, AstraZeneca, Bristol-Meyers Squib, Taiho Pharmaceutical, Chugai Pharmaceutical, Daiichi Sankyo, Eli Lilly, Boehringer Ingelheim, Eisai, MSD, Takeda Pharmaceutical, Amgen, Novartis Pharma, Merck BioPharma, and Kyowa Kirin. YH reports receiving personal fees from AstraZeneca, Eli Lilly, Taiho Pharmaceutical, Chugai Pharmaceutical, Ono Pharmaceutical, Bristol-Myers Squibb, Kyowa Kirin, Nippon Kayaku, Takeda Pharmaceutical, Eisai, Novartis Pharma, and Pfizer. KT reports receiving personal fees from AstraZeneca, Boehringer Ingelheim, Chugai Pharmaceutical, Daiichi Sankyo, Kyowa Kirin, MSD, and Taiho Pharmaceutical. SN reports receiving grants from AstraZeneca, Merck BioPharma, Chugai Pharmaceutical, and GlaxoSmithKline; and personal fees from AstraZeneca, Ono Pharmaceutical, Chugai Pharmaceutical, Pfizer, Eli Lilly, Takeda Pharmaceutical, Merck BioPharma, Boehringer Ingelheim, Taiho Pharmaceutical, Novartis Pharma, Daiichi Sankyo, KYORIN Pharmaceutical, and MSD. MN reports receiving personal fees from Ono Pharmaceutical, Bristol-Myers Squibb, Pfizer, Chugai Pharmaceutical, Eli Lilly, Taiho Pharmaceutical, AstraZeneca, Astellas Pharma, Boehringer Ingelheim, MSD, Novartis Pharma, Daiichi Sankyo Healthcare, Taiho Pharmaceutical, and Merck Serono. TK reports receiving grants from AbbVie, Amgen, AstraZeneca, BeiGene, Blueprint Medicines, Boehringer Ingelheim, Chugai Pharmaceutical, Daiichi Sankyo, Eli Lilly, Haihe Biopharma, Merck, MSD, Novartis Pharma, Pfizer, Regeneron Pharmaceuticals, Takeda Pharmaceutical, and Turning Point Therapeutics; and personal fees from Amgen, AstraZeneca, BeiGene, Boehringer Ingelheim, Chugai Pharmaceutical, Daiichi Sankyo, Eli Lilly, GlaxoSmithKline, Janssen Pharmaceutical, Merck, MSD, Novartis Pharma, Ono Pharmaceutical, Pfizer, Taiho Pharmaceutical, and Takeda Pharmaceutical. TT reports receiving grants from AstraZeneca, Amgen, Boehringer Ingelheim, Merck Biopharma, Chugai Pharmaceutical, Eli Lilly, Ono Pharmaceutical, MSD, and Pfizer; and personal fees from AstraZeneca, Chugai Pharmaceutical, Eli Lilly, Ono Pharmaceutical, MSD, Pfizer, Boehringer Ingelheim, Roche Diagnostics, Takeda Pharmaceutical, and Yakult Honsha. HE reports receiving personal fees from Nippon Kayaku. MA reports receiving personal fees from Nippon Kayaku. NY reports receiving grants from Boehringer Ingelheim, Taiho Pharmaceutical, Chugai Pharmaceutical, Shionogi Pharma, Eli Lilly, Daiichi Sankyo, Tsumura, Nippon Kayaku, Asahikasei-pharma, AstraZeneca, Janssen Pharmaceutical, Sanofi, Amgen, Novartis Pharma, Astellas Pharma, MSD, Eisai, Bristol-Myers Squibb, AbbVie, and Tosoh; and personal fees from MSD, AstraZeneca, Amgen, Ono Pharmaceutical, Otsuka Pharmaceutical, Guardant Health, Tsumura, Kyowa Kirin, KYORIN Pharmaceutical, GlaxoSmithKline, Sanofi, Daiichi Sankyo, Taiho Pharmaceutical, Takeda Pharmaceutical, Chugai Pharmaceutical, Eli Lilly, Nippon Kayaku, Boehringer Ingelheim, Novartis Pharma, Pfizer, Bristol-Myers Squibb, Miyarisan Pharmaceutical, Merck, and Janssen Pharmaceutical. YO reports receiving grants from AstraZeneca, Chugai Pharmaceutical, Eli Lilly, Ono Pharmaceutical, Bristol-Myers Squibb, KYORIN Pharmaceutical, Sumitomo Pharma, Pfizer, Taiho Pharmaceutical, Novartis Pharma, Takeda Pharmaceutical, Kissei Pharmaceutical, Daiichi Sankyo, and Janssen Pharmaceutical; and personal fees from AstraZeneca, Chugai Pharmaceutical, Eli Lilly, Ono Pharmaceutical, Bristol-Myers Squibb, Boehringer Ingelheim, Bayer Yakuhin, Pfizer, MSD, Taiho Pharmaceutical, Nippon Kayaku, Kyowa Kirin, and Eisai. KN reports receiving grants from AstraZeneca, MSD, Ono Pharmaceutical, Boehringer Ingelheim, Novartis Pharma, Pfizer, Bristol-Myers Squibb, Eli Lilly, Chugai Pharmaceutical, Daiichi Sankyo, Merck Biopharma, PAREXEL International, PRA HEALTHSCIENCES, EPS, Kissei Pharmaceutical, EPS International, Taiho Pharmaceutical, PPD-SNBL, SymBio Pharmaceuticals, IQVIA Services, SYNEOS HEALTH CLINICAL, Nippon Kayaku, EP-CRSU, Mebix, Janssen Pharmaceutical, AbbVie, Bayer Yakuhin, Eisai, Mochida Pharmaceutical, Covance, Japan Clinical Research Operations, Takeda Pharmaceutical, GlaxoSmithKline, Sanofi, Sysmex, Medical Research Support, Otsuka Pharmaceutical, SRL, Pfizer R&D, and Amgen; and personal fees from Eli Lilly, KYORIN Pharmaceutical, Ono Pharmaceutical, Pfizer, Amgen, Nippon Kayaku, AstraZeneca, Chugai Pharmaceutical, MSD, Boehringer Ingelheim, Taiho Pharmaceutical, Bayer Yakuhin, CMIC ShiftZero, Life Technologies, Neo Communication, Roche Diagnostics, AbbVie, Merck Biopharma, Kyowa Kirin, Takeda Pharmaceutical, 3H Clinical Trial, Care Net, Medical Review, Medical Mobile Communications, YODOSHA, Nikkei Business Publications, Japan Clinical Research Operations, CMIC, Novartis Pharma, TAIYO Pharma, and Bristol-Myers Squibb., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background/aim: Adjuvant therapy using third-generation tyrosine kinase inhibitors (TKI) demonstrated improved central nervous system (CNS) disease-free survival after surgery in patients with epidermal growth factor receptor (EGFR) mutation-positive lung cancer. However, the prognostic impact of CNS recurrence in surgical patients remains unknown. We evaluated the effect of CNS recurrence on post-recurrence survival (PRS) in patients with postoperatively recurrent NSCLC., Patients and Methods: We assessed the prognostic impact of CNS recurrence using a cohort from a prospective observational study (Kyushu University Lung Surgery Group Study 2: KLSS-2). Based on data from 340 patients in whom EGFR mutations were assessed among 498 total patients in the KLSS-2 cohort, factors related to CNS recurrence and prognosis after postoperative recurrence were analyzed., Results: We noted no marked differences in the presence of EGFR mutations (p=0.14) between patients with CNS recurrence and those without CNS recurrence. Among the patients tested for EGFR mutations with stage IV recurrences (n=219), survival analysis of patients with EGFR mutations showed that the CNS group had a significantly poorer PRS than the no-CNS group (MST: 36.8 vs. 43.9 months, p=0.035). In multivariate survival analysis of stage IV EGFR mutation-positive cases, recurrence in multiple organs and recurrence of brain metastases were independent poor prognostic factors (hazard ratio=2.2, p=0.029; hazard ratio=3.2, p=0.0006, respectively)., Conclusion: Postoperative CNS recurrence was associated with a poor prognosis among patients with EGFR mutation-positive lung cancer in the period when third-generation EGFR-TKIs were not available. In EGFR mutation-positive lung cancer, prevention of CNS recurrence after surgery may improve post-recurrence prognosis., (Copyright © 2023 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Background: Previous trials suggest that older adults with non-small cell lung cancer (NSCLC) derive benefit from platinum doublet combination therapy, but its superiority is controversial. Although geriatric assessment variables are used to assess the individual risk of severe toxicity and clinical outcomes in older patients, the standard first-line treatment is still debated. Therefore, we aimed to identify the risk factors for clinical outcomes in older patients with NSCLC., Methods: Patients aged ≥75 years with advanced NSCLC treated at any of 24 National Hospital Organization institutions completed a pre-first-line chemotherapy assessment, including patient characteristics, treatment variables, laboratory test values, and geriatric assessment variables. We evaluated whether these variables were the risk factors for progression-free survival (PFS) and overall survival (OS)., Results: A total of 148 patients with advanced NSCLC were treated with combination therapy (n = 90) or monotherapy (n = 58). Median PFS was 5.3 months and OS was 13.6 months. We identified that hypoalbuminemia (hazard ratio [HR] 2.570, 95% confidence interval [CI]: 1.117-5.913, p = 0.0264) was a risk factor for PFS and monotherapy (HR 1.590, 95% CI: 1.070-2.361, p = 0.0217), lactate dehydrogenase (HR 3.682, 95% CI: 1.013-13.39, p = 0.0478), and high C-reactive protein (HR 2.038, 95% CI: 1.141-3.642, p = 0.0161) were risk factors for OS. The median OS was significantly longer in patients treated with combination therapy than in those who received monotherapy (16.5 months vs. 10.3 months; HR 0.684, 95% CI: 0.470-0.995, p = 0.0453)., Discussion: Platinum doublet combination therapy may be beneficial in older patients with NSCLC. Identification of risk factors will assist in the development of a personalized treatment strategy., (© 2023 The Authors. Thoracic Cancer published by China Lung Oncology Group and John Wiley & Sons Australia, Ltd.)

NK cells are major effector cells involved in the elimination of early tumors and prevent metastasis. They often have an impaired function in patients with cancer. Preclinical studies have demonstrated NK cell activation as the adjunctive effect of invariant NKT (iNKT) cells. Activation of iNKT cells after administration of the glycolipid ligand α-galactosylceramide, loaded with CD1d-expressing human PBMC-derived APCs (APC/Gal), is an attractive cancer therapy to optimize the use of NK cells. However, the subsets of NK cells that are activated following iNKT cell activation as well as the period of NK cell activation remain unclear. In this study, we report that the granzyme B-expressing NK cell response in postoperative lung cancer patients was enhanced 49 d after administration of APC/Gal in a phase II study. We found maximum IFN-γ production on day 49 in 13 out of 27 APC/Gal-treated patients. On day 49, 14 out of 27 patients (51.9%) had higher IFN-γ production by iNKT cells (>6-fold higher than the baseline level). This increment significantly correlated with granzyme B-expressing NK cells. Although IFN-γ production was lower in patients in the nontreated group, we detected maximum IFN-γ production 12 mo after the resection of lung cancer (9 out of 29 patients [31%]). These findings suggest that elimination of cancer cells leads to increased NK cell function, which can be further enhanced by APC/Gal therapy., (Copyright © 2023 The Authors.)

A 72-year-old woman underwent complete video-assisted thoracic surgical procedure for removal of a smooth, progressively contrasted, homogeneous 20-mm nodular anterior mediastinal tumor. The tumor was completely resected. The pathologic diagnosis was malignant melanoma, which was positive for HMB-45 and S-100. Postoperative positron emission tomography revealed no other lesions throughout the whole body. The tumor was therefore diagnosed as primary malignant melanoma of the thymus. The patient's postoperative course was good, and she had no recurrence. This tumor is reportedly highly malignant and prone to recurrence; hence, careful follow-up is necessary for this case., (© 2022 Published by Elsevier Inc. on behalf of The Society of Thoracic Surgeons.)

Introduction: Previous studies have developed risk stratification schemas to assess systemic therapy toxicity. However, it is controversial which geriatric assessment variables should be used to assess the individual risk of severe treatment-associated toxicity in older adult patients., Materials and Methods: Patients aged ≥70 years with advanced non-small cell lung cancer (NSCLC) treated at 24 National Hospital Organization institutions completed a pre-first-line systemic therapy assessment, including patient characteristics, treatment variables, laboratory test values, and geriatric assessment variables. Patients were followed through one cycle of systemic therapy to assess grade 3 (severe) to grade 5 (death) adverse events according to the National Cancer Institute Common Terminology Criteria for Adverse Events, version 4.0., Results: In total, 348 advanced NSCLC patients with a median age of 76 years (range, 70 to 95 years) joined this prospective study. Severe adverse events ≥grade 3 occurred in 136 patients (39.1%). Predictors of hematologic toxicity were treatment variables, body mass index, body weight loss, and limitation in daily living due to dementia. These predictors provided the predictive model of hematologic toxicity ≥grade 3; 0 point (22.2%), 1 point (33.8%), 2 points (59.6%), ≥3 points (73.3%). Sex, daily living independence level, and lactate dehydrogenase levels were associated with non-hematologic toxicity ≥grade 3 in multivariate analysis. A scoring system using these predictors distinguished the risk levels of non-hematologic toxicity ≥grade 3; 0 point (6.6%), 1 point (12.2%), 2 points (39.0%), 3 points (75.0%)., Discussion: A stratification using individual extracted risk factors may be useful to predict the vulnerability to systemic therapy in older adult NSCLC patients., 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 © 2022 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: In Japan, docetaxel, a cytotoxic monotherapy, is the standard drug administered to older patients with advanced non-small-cell lung cancer (NSCLC). Carboplatin plus nab-paclitaxel has shown a high objective response rate in patients with squamous histology and was suggested to improve overall survival in patients aged 70 years and older. The CAPITAL trial aimed to assess the safety and efficacy of carboplatin plus nab-paclitaxel versus docetaxel as first-line therapy for patients aged 70 years and older with advanced squamous NSCLC., Methods: This multicentre, open-label, randomised, phase 3 trial was carried out at 92 medical institutions in Japan. Eligible patients were aged 70 years and older, had advanced squamous NSCLC with no previous systemic chemotherapy, and had an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1. Using an electronic data capture system, patients were randomly assigned (1:1) to intravenous carboplatin (area under the concentration-time curve of 6 mg/mL per min for 30 min) on day 1 of a 21-day cycle and intravenous nab-paclitaxel (100 mg/m 2 for 60 min) on days 1, 8, and 15 every 3 weeks or intravenous docetaxel (60 mg/m 2 for 60 min) on day 1 every 3 weeks. Randomisation was computer-generated per participant and stratified by ECOG performance status, clinical stage, sex, age, and institution. The primary endpoint was overall survival, measured in the full analysis set and defined as the time from registration to the date of death due to any cause. Safety was assessed in all patients who received at least one dose of the trial treatment. This trial is registered with the UMIN Clinical Trials Registry, UMIN000019843, and the Japan Registry of Clinical Trials, jRCTs041180110. After the planned interim analysis in Aug 3, 2020, the independent data monitoring committee recommended that the trial be stopped early. This report represents the final analysis., Findings: Between Feb 24, 2016, and Aug 11, 2020, 196 patients were enrolled and were randomly assigned to the carboplatin plus nab-paclitaxel group (n=98) or the docetaxel group (n=98). Of these patients, four (carboplatin plus nab-paclitaxel group, n=3; docetaxel group, n=1) did not receive any treatment and two patients in the docetaxel group were excluded from the full analysis set. Median overall survival in the full analysis set was 16·9 months (95% CI 12·6-25·4) in the carboplatin plus nab-paclitaxel group and 10·9 months (8·5-12·4) in the docetaxel group (hazard ratio 0·52 [90% CI 0·38-0·70]; p=0·0003). Grade 3-4 adverse events occurred in 79 (83%) patients in the carboplatin plus nab-paclitaxel group and 77 (79%) patients in the docetaxel group (p=0·63). The most common grade 3-4 adverse events in the carboplatin plus nab-paclitaxel group and the docetaxel group were leukopenia (44 [46%] vs 55 [57%]; p=0·20), neutropenia (60 [63%] vs 75 [77%]; p=0·046), febrile neutropenia (nine [10%] vs 19 [20%]; p=0·073), and anaemia (37 [39%] vs two [2%]; p<0·0001). Serious treatment-related adverse events of all grades occurred in 13 (14%) patients in the carboplatin plus nab-paclitaxel group and 11 (11%) patients in the docetaxel group. Treatment-related deaths occurred in two (2%; respiratory failure n=1, visceral arterial ischaemia n=1) patients in the carboplatin plus nab-paclitaxel group and one (1%; sepsis) patient in the docetaxel group., Interpretation: Our study showed that overall survival was longer with carboplatin plus nab-paclitaxel than with docetaxel, suggesting that carboplatin plus nab-paclitaxel can be used as standard first-line treatment for patients aged 70 years and older with advanced squamous NSCLC., Funding: Taiho Pharmaceutical., Competing Interests: Declaration of interests YK reports grants from Taiho Pharmaceutical, during the conduct of the study; and grants and personal fees from MSD, personal fees from AstraZeneca, Chugai Pharmaceutical, Taiho Pharmaceutical, Eli Lilly, Boehringer Ingelheim, and Ono Pharmaceutical, outside the submitted work. SI reports grants and personal fees from Ono Pharmaceutical; and personal fees from Chugai Pharmaceutical, AstraZeneca, MSD, Bristol Myers Squibb, Taiho Pharmaceutical, and Daiichi Sankyo, outside the submitted work. HS reports grants from Taiho Pharmaceutical, during the conduct of the study; grants and personal fees from AstraZeneca, MSD, Ono Pharmaceutical; and personal fees from Boehringer Ingelheim, Chugai Pharma, and Kyorin, outside the submitted work. AK reports grants from Taiho Pharmaceutical, during the conduct of the study; and personal fees from Bayer Yakuhin, outside the submitted work. SA reports grants from the National Cancer Center Research and Development Fund (26-A-22, 29-A-15, 2020-A-13) and Taiho Pharmaceutical, during the conduct of the study; grants and personal fees from AstraZeneca, Ono Pharmaceutical, Taiho, Boehringer Ingelheim, Pfizer, Bristol Myers Squibb, MSD, Eli Lilly, Chugai, and Merck; grants and non-financial support from F Hoffmann-La Roche; and personal fees from Hisamitsu, Kyowa Hakko Kirin, Novartis Pharma, and Thermo Fisher Scientific, outside the submitted work. YT reports grants and personal fees from Taiho Pharmaceutical, during the conduct of the study; grants and personal fees from Eli Lilly, Ono Pharmaceutical, Chugai Pharmaceutical, MSD, and Takeda; grants from Daiichi Sankyo and Kyowa-Hakko Kirin; and personal fees from Novartis, Boehringer Ingelheim, and AstraZeneca, outside the submitted work. AI reports personal fees from AstraZeneca, Eli Lilly, Boehringer Ingelheim, Pfizer, Chugai Pharmaceutical, MSD, and Daiichi Sankyo, outside the submitted work. TK reports personal fees from AstraZeneca, MSD, Eli Lilly, Chugai, Ono Pharmaceutical, Bristol Myers Squibb, and Boehringer Ingelheim; grants from AstraZeneca, MSD, Ono Pharmaceuticals, Eli Lilly, and Takeda, outside the submitted work. IO reports grants from Boehringer Ingelheim, during the conduct of the study; grants and personal fees from AstraZeneca, Taiho Pharmaceutical, Boehringer Ingelheim, Ono Pharmaceutical, MSD Oncology, Eli Lilly, Bristol Myers Squibb, and Chugai Pharma; grants from Astellas Pharma, Novartis, and AbbVie; and personal fees from Pfizer, outside the submitted work. MY reports grants and personal fees from Chugai Pharmaceutical; and grants from Daiichi Sankyo, MSD, and Pfizer Japan, outside the submitted work. MS reports grants and personal fees from Taiho Pharmaceutical, Chugai Pharmaceutical, MSD, Boehringer Ingelheim, and Eli Lilly Japan; and personal fees from AstraZeneca, outside the submitted work. MA reports grants from Kyowa Kirin, outside the submitted work. KK reports grants and personal fees from Ono Pharmaceutical and Boehringer Ingelheim; and personal fees from Chugai, MSD, AstraZeneca, Eli Lilly, Daiichi Sankyo, Bristol Myers Squibb, Kyowa Hakko Kirin, and Taiho, outside the submitted work. MT reports grants and personal fees from AstraZeneca, Chugai Pharmaceutical, Covidien Japan, Eli Lilly Japan, Kyowa Hakko Kirin, MSD, Nippon Boehringer Ingelheim, Novartis Pharma, Ono Pharmaceutical, Pfizer Japan, and Taiho Pharmaceutical; personal fees from Bristol Myers Squibb, Johnson & Johnson, and Nippon Kayaku; and grants from KM Biologics, outside the submitted work. TS reports grants and personal fees from Chugai Pharmaceutical, Daiichi Sankyo, Eli Lilly Japan, MSD, Novartis Pharma, Pfizer Japan, and Takeda Pharmaceutical; grants from AbbVie, Kissei Pharmaceutical, LOXO Oncology, and Merck Biopharma; and personal fees from AstraZeneca, Bristol Myers Squibb, Covidien Japan, Kyowa Hakko Kirin, Mochida Pharmaceutical, Nippon Boehringer Ingelheim, Ono Pharmaceutical, Taiho Pharmaceutical, Thermo Fisher Scientific, and Precision Medicine Asia, outside the submitted work. NY reports grants and personal fees from MSD, Chugai Pharmaceutical, Ono Pharmaceutical, Daiichi Sankyo, Taiho Pharmaceutical, Takeda Pharmaceutical, Eli Lilly Japan, Boehringer Ingelheim, Novartis, Pfizer, and AstraZeneca; and personal fees from Thermo Fisher Scientific, Bristol Myers Squibb, Life Technologies, Nippon Kayaku, and Merk Biopharma; grants from Astellas Pharma, Tsumura & Co, Shionogi, AbbVie, Amgen, Kyorin Pharmaceutical, Eisai, Terumo, Toppan Printing, and TOSOH, outside the submitted work. AG reports personal fees from Taiho, Nihon Kayaku, AstraZeneca, Chugai, Ono Pharmaceutical, and Boehringer Ingelheim, outside the submitted work. All other authors declare no competing interests., (Copyright © 2021 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY-NC-ND 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

Immune checkpoint inhibitors (ICIs) targeting programmed cell death-1 (PD-1) and programmed cell death-ligand 1 (PD-L1) have markedly improved the prognosis of many patients with advanced non-small cell lung cancer (NSCLC). However, the relationship between the patient's nutritional/immunologic status and the outcomes of ICI treatment remains unclear. In previous retrospective studies, we reported that the controlling nutritional status (CONUT) score, skeletal muscle area, and neutrophil-to-lymphocyte ratio were independent predictors of the response of NSCLC patients to anti-PD-1 drugs. The aim of this prospective multi-center study is to investigate the clinical impact of pre-treatment nutritional/immunologic indices and early post-treatment changes in the indices on treatment outcomes in advanced NSCLC. The main inclusion criteria are: (1) stage IV NSCLC, or stage III NSCLC not applicable for definitive chemoradiotherapy; (2) treatment with ICIs (monotherapy or combined with chemotherapy) as first-line therapy; and (3) available data on PD-L1 expression on tumor cells. A total of 300 patients will be enrolled prospectively. Enrollment will begin in 2020 and the final analyses will be completed by 2025., Competing Interests: The authors declare no conflicts of interest in association with the present study.

Background: Video-assisted surgery helps surgeons learn surgical skills efficiently. The aim of this study was to evaluate the effect of mutual evaluation of trainees' surgical techniques using tabulated common evaluation criteria., Methods: We created a check sheet in which a standard pulmonary lobectomy procedure was divided into six parts and the checkpoints to note listed. Both the trainees and trainers used tabulated common evaluation criteria to evaluate lobectomies performed by the trainees., Results: From September 2019 to March 2020, 30 lobectomies were performed by three trainees. The trainee's evaluations of their own procedures were relatively high at first, then decreased, then gradually increased; however, the trainers' evaluations showed no such tendency., Conclusions: Mutual evaluation of surgery using tabulated common evaluation criteria enables trainees to review their own surgery objectively and receive evaluations by trainers, thus helping them to avoid the Dunning-Kruger effect and efficiently acquire basic surgical skills.

Background: Preoperative nutritional status is an important host-related prognostic factor for non-small cell lung carcinoma (NSCLC); however, the significance of postoperative changes in nutritional status remains unclear. This study aimed to elucidate the significance of postoperative decreases in serum albumin (ΔAlb) on the outcomes of early-stage NSCLC., Methods: We analyzed 443 training cohort (TC) and 642 validation cohort (VC) patients with pStage IA NSCLC who underwent surgery and did not recur within 1 year. We measured preoperative serum albumin levels (preAlb) and postoperative levels 1 year after surgery (postAlb), and calculated ΔAlb as (preAlb - postAlb)/preAlb × 100%. A cutoff value of 11% for ΔAlb was defined on the basis of the receiver operating characteristic curve for the TC., Results: Patients were divided into ΔAlb-Decreased and ΔAlb-Stable groups, including 100 (22.6%) and 343 (77.4%) in the TC, and 58 (9.0%) and 584 (90.1%) in the VC. ΔAlb-Decreased was associated with male sex (p = 0.0490), smoking (p = 0.0156), and non-adenocarcinoma (p<0.0001) in the TC, and pT1b (p = 0.0169) and non-adenocarcinoma (p = 0.0251) in the VC. Multivariable analysis identified ΔAlb as an independent prognostic factor for disease-free survival (DFS) and overall survival (OS) in both cohorts (VC: DFS, HR = 1.9, 95%CI: 1.10-3.15, p = 0.0197; OS, HR = 2.0, 95%CI: 1.13-3.45, p = 0.0173). Moreover, subgroup analysis demonstrated that the prognostic value of ΔAlb was consistent for age, sex, smoking history, surgical procedure, and histological type., Conclusion: We demonstrated a negative impact of postoperative decrease of the serum albumin on the prognosis of patients with early-stage NSCLC. Postoperative changes in nutritional status might be important in NSCLC outcomes., Competing Interests: The authors have declared that no competing interests exist.

Genetic alterations underlying the development of lung cancer in individuals with idiopathic pulmonary fibrosis (IPF) have remained unclear. To explore whether genetic alterations in IPF tissue contribute to the development of IPF-associated lung cancer, we here evaluated tumor mutation burden (TMB) and somatic variants in 14 paired IPF and tumor samples from patients with IPF-associated lung adenocarcinoma. We also determined TMB for 22 samples of lung adenocarcinoma from patients without IPF. TMB for IPF-associated lung adenocarcinoma was significantly higher than that for matched IPF tissue (median of 2.94 vs. 1.26 mutations/Mb, P = 0.002). Three and 102 somatic variants were detected in IPF and matched lung adenocarcinoma samples, respectively, with only one pair of specimens sharing one somatic variant. TMB for IPF-associated lung adenocarcinoma was similar to that for lung adenocarcinoma samples with driver mutations (median of 2.94 vs. 2.51 mutations/Mb) and lower than that for lung adenocarcinoma samples without known driver mutations (median of 2.94 vs. 5.03 mutations/Mb, P = 0.130) from patients without IPF. Our findings suggest that not only the accumulation of somatic mutations but other factors such as inflammation and oxidative stress might contribute to the development and progression of lung cancer in patients with IPF.

Background: Immune checkpoint inhibitors (ICIs) have become a standard therapy in non-small cell lung cancer (NSCLC). Although lung cancer adjoining emphysematous bullae (Ca-ADJ) were reported to express higher programmed cell death-ligand 1 (PD-L1), the predictive impact of Ca-ADJ on the response to ICIs is unknown., Methods: Two hundred and fifty-seven advanced or recurrent NSCLC patients treated with ICI monotherapy at Kyushu University Hospital and National Hospital Organization Kyushu Cancer Center were analyzed. To minimize the bias arising from the patients' background, adjusted Kaplan-Meier survival curves and Cox proportional hazards regression analyses using inverse probability of treatment weights (IPTW) were performed., Results: Of the 257 patients, 55 had Ca-ADJ. Patients with Ca-ADJ were significantly associated with younger age (P = 0.0343), male sex (P = 0.0070), and smoking (P = 0.0080). The objective response rate of cases with Ca-ADJ was significantly higher than that of those without Ca-ADJ (36.4% vs. 20.8%, respectively; P = 0.0167). The disease control rate of cases with Ca-ADJ was also significantly higher than tumors without Ca-ADJ (63.6% vs. 47.5%, respectively; P = 0.0341). The IPTW-adjusted Kaplan-Meier curves showed that patients with Ca-ADJ had significantly longer progression-free survival (PFS) and overall survival (OS) than those without Ca-ADJ (P = 0.0407 and P = 0.0126, respectively). On IPTW-adjusted Cox analysis, Ca-ADJ was an independent predictor of PFS and OS (P < 0.0001 and P < 0.0001, respectively)., Conclusions: Patients with Ca-ADJ may be good candidates for ICIs. These findings should be validated prospectively.

Introduction: YS110, a humanized monoclonal antibody with a high affinity to CD26, exhibited promising antitumor activity and was generally well-tolerated in the phase 1 part of a phase 1 and 2 Japanese trial in patients with malignant pleural mesothelioma (MPM). Here we report the results of the phase 2 part of the study., Methods: The patients included were aged 20 years and older, had histologically confirmed MPM, were refractory to or intolerant of existing antineoplastic agents, and were not candidates for standard therapy. YS110 6 mg/kg, determined in the phase 1 dose-determination part, was given in 6-weekly cycles (5 × once-weekly infusions, followed by a 1-wk rest)., Results: The study included 31 patients (median age = 68 y, 90.3% men); 64.5% had stage IV MPM, 90.3% had greater than or equal to 20% CD26 expression in tumor tissue, and 38.7% (12 patients) had previously received nivolumab. The 6-month disease control rate was 3.2%. The best overall response was partial response in one patient and stable disease in 14 patients. The median progression-free survival was 2.8 months (both in patients who had and had not previously received nivolumab-groups A and B, respectively). Respective progression-free survival rates at 6 months were 9.1% and 31.6% in groups A and B. The median overall survival was 9.7 months. A total of 30 patients (96.8%) had at least one adverse event. Common treatment-related adverse events were infusion-related reaction (16.1%), hiccups (9.7%), and interstitial lung disease (9.7%). There were no treatment-related deaths., Conclusions: The 6-month disease control rate did not exceed the predefined threshold, but YS110 revealed modest efficacy in response rate as salvage therapy in difficult-to-treat patients with MPM. YS110 was generally well tolerated., (© 2021 The Authors.)

Background: The pack-year index, which is calculated by multiplying a smoking period by the number of cigarette packs smoked per day, is frequently used to investigate the risk of developing lung cancer. Notably, however, whether the smoking period or the number of packs per day is more predictive of postoperative prognosis remains unclear in non-small cell lung cancer (NSCLC) patients who receive curative lung resection., Patients and Methods: Initial screening included 2055 consecutive lung cancer patients who had underwent curative lung resection between 2000 and 2016 at a single center in Japan. Data from 1134 NSCLC patients with smoking history were ultimately analyzed. Time-dependent areas under the curve (AUCs) were used to compare diagnostic accuracy., Results: On univariate analysis, the number of packs smoked per day was not a significant predictor of disease-free survival (DFS; p = 0.2387) or overall survival (OS; p = 0.1357). On multivariable analysis, smoking period was an independent predictor of DFS and OS (both p < 0.0001). Time-dependent smoking period AUCs were superior to those of number of packs smoked per day. On subgroup analyses, patients with a smoking period ≥ 40 years had significantly shorter DFS and OS than those with a smoking period of < 40 years, independent of sex, clinical stage, and histological type., Conclusions: Smoking period was a significant prognostic indicator in NSCLC patients who underwent curative lung resection, which should be validated in further prospective and/or multicenter studies with large sample sizes.

Background: Two phase II studies in Japan examined the efficacy and safety of nivolumab, a programmed cell death 1 receptor inhibitor, in patients with advanced squamous and non-squamous non-small cell lung cancer (ONO-4538-05 and ONO-4538-06). We examined the long-term efficacy and safety of nivolumab in these patients treated for up to 5 years., Methods: Patients with squamous (N = 35) or non-squamous (N = 76) non-small cell lung cancer received nivolumab (3 mg/kg every 2 weeks) until disease progression/death. Overall survival and progression-free survival were assessed at 5 years after starting treatment in separate and pooled analyses. Safety was evaluated in terms of treatment-related adverse events., Results: A total of 17 patients were alive at the database lock (26 July 2019). The median overall survival (95% confidence interval) and 5-year survival rate were 16.3 (12.4-25.2) months and 14.3% in squamous patients, 17.1 (13.3-23.0) months and 19.4% in non-squamous patients and 17.1 (14.2-20.6) months and 17.8% in the pooled analysis, respectively. Programmed death ligand-1 expression tended to be greater among 5-year survivors than in non-survivors (P = 0.0703). Overall survival prolonged with increasing programmed death ligand-1 expression, with 5-year survival rates of 11.8, 21.8 and 41.7% in patients with programmed death ligand-1 expression of <1, ≥1-<50 and ≥50%, respectively. Treatment-related adverse events in ≥10% of patients (pooled analysis) included rash (15.3%), malaise (14.4%), decreased appetite (14.4%), pyrexia (14.4%) and nausea (10.8%)., Conclusions: Long-term survival with nivolumab was observed in patients with squamous or non-squamous non-small cell lung cancer. No new safety signals were reported after ≥5 years of follow-up., (© The Author(s) 2020. Published by Oxford University Press.)

Background: Lymphovascular invasion (LVI), which includes vascular or lymphatic invasions, is a representative prognostic factor even in patients with resected stage IA non-small cell lung cancer (NSCLC). Because tegafur-uracil is effective on cancers with LVI, we conducted a multi-center single-arm phase II study to estimate the efficacy of adjuvant tegafur-uracil in patients with LVI-positive stage IA NSCLC., Methods: Patients with completely resected LVI-positive stage IA NSCLC were registered. LVI was diagnosed by consensus of two of three pathologists. Adjuvant chemotherapy consisted of 2 years of oral tegafur-uracil at 250 mg/m 2 /day. Fifty-five patients from 7 institutions were enrolled from June 2007 to September 2012., Results: Among the 52 eligible patients, 36 (69.2%) completed the treatment course. There were 39 male and 13 female patients. The observation period was calculated as 562 to 3107 days using the reverse Kaplan-Meier method. The 5-year overall and relapse free survival rates were 94.2 and 88.5% respectively, which were significantly better than that of any other studies conducted on patients with LVI-positive stage IA NSCLC. Notably, the overall survival rate was 15% better than that of our prior retrospective study. The retrospective analysis of stage IA NSCLC patients who had received an operation in the same period revealed that the 5-year overall survival rate of the LVI positive group was 73.6% when adjuvant chemotherapy was not applied. Among 55 safety analysis sets, 4 cases of grade 3 hepatic function disorder (9.1%) and 5 cases of grade 2 anorexia (10.9%) were most frequently observed. No grade 4 adverse effects were encountered., Conclusion: A 2-year course of oral tegafur-uracil administration is feasible and might have a significant benefit in the adjuvant treatment of LVI-positive stage IA NSCLC., Trial Registration: UMIN identifier: UMIN000005921 ; Date of enrolment of the first participant to the trial: 19 June 2007; Date of registration: 5 July 2011 (retrospectively registered).

Background: Smoking cessation is a highly important preparation before thoracic surgery. We examined the effects of short-term smoking cessation intervention before pulmonary resection on postoperative pulmonary complications (PPCs)., Methods: A retrospective analysis of prospectively collected data was performed for 753 patients who underwent curative surgical resection for thoracic malignancy at 3 institutions. Patients with a smoking history were instructed to quit smoking. After confirming smoking cessation by at least four weeks before surgery, surgical resection was performed. Subjects were classified into three groups based on their smoking status: abstainers (anyone who had stopped smoking for at least 4 weeks but less than 2 months), former smokers (anyone who had abstained from smoking for more than two months prior to surgery), and never smokers (those who had never smoked). We examined the relationship between the preoperative smoking status and PPCs., Results: Surgery was performed for 660 primary lung cancers and 93 metastatic lung tumors. The smoking statuses were classified as follows: abstainers (n=105, 14%), former smokers (n=361; 48%) and never smokers (n=287, 38%). The incidence of PPCs among abstainers, former smokers and never smokers was 15%, 8% and 6%, respectively (P=0.01). The mean duration of post-operative chest tube drainage among abstainers, former smokers and never smokers was 3.2, 2.2 and 2.2 days, respectively (P=0.04). The mean post-operative hospital stay among abstainers, former smokers and never smokers was 12.1, 10.6 and 10.2 days, respectively (P=0.07). There was no 30-day mortality in the cohort., Conclusions: Short-term smoking cessation intervention did not enough reduce the PPCs as much as in former or never smokers., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at http://dx.doi.org/10.21037/jtd-20-2574). The authors have no conflicts of interest to declare., (2020 Journal of Thoracic Disease. All rights reserved.)

Immunotherapy targeting programmed death-1 or programmed death-ligand 1 has become the standard of care for advanced non-small cell lung cancer (NSCLC). Several recent clinical trials have investigated the efficacy of immune checkpoint inhibitors (ICIs) as neoadjuvant treatment for early NSCLC. However, the safety and feasibility of pulmonary resection after ICIs remain unclear. We herein report a patient in whom cohesion between the left main pulmonary artery and left upper bronchus was found during left upper lobectomy following neoadjuvant ICI combined with chemotherapy. After both central and peripheral sides of the left main pulmonary artery were clamped with the aim of controlling hemorrhage in case of vascular injury, the left main pulmonary artery and left upper bronchus were divided and individually cut with staplers. The thoracoscopic procedure was otherwise uneventful. The patient was discharged from our hospital with no postoperative complications. Thoracic surgeons should anticipate the possible need for management of cohesion between a pulmonary artery and bronchus in patients who have received immune checkpoint inhibitors preoperatively., (© 2020 The Authors. Thoracic Cancer published by China Lung Oncology Group and John Wiley & Sons Australia, Ltd.)

Lessons Learned: This phase II trial evaluated the efficacy of erlotinib for patients with non-small cell lung cancer with leptomeningeal metastasis. The 17 cerebrospinal fluid specimens that were available for epidermal growth factor receptor mutation analysis were all negative for the resistance-conferring T790M mutation. The cytological objective clearance rate was 30.0% (95% confidence interval: 11.9%-54.3%). The median time to progression was 2.2 months. The rate of cerebrospinal fluid penetration among these patients was equivalent to those in previous reports regarding leptomeningeal metastasis., Background: Leptomeningeal metastases (LM) occur in approximately 5% of patients with non-small cell lung cancer (NSCLC) and are associated with a poor prognosis. However, no prospective study has identified an active chemotherapeutic drug in this setting., Methods: Patients were considered eligible to receive erlotinib if they had NSCLC with cytologically confirmed LM. The objective cytological clearance rate, time to LM progression (TTP), overall survival (OS), quality of life outcomes, and pharmacokinetics were analyzed. This study was closed because of slow accrual at 21 of the intended 32 patients (66%)., Results: Between December 2011 and May 2015, 21 patients (17 with activating epidermal growth factor receptor [EGFR] mutations) were enrolled. The 17 cerebrospinal fluid specimens available were all negative for the T790M mutation, which confers erlotinib resistance. The clearance rate was 30.0% (95% confidence interval [CI]: 11.9%-54.3%), the median TTP was 2.2 months, and the median OS was 3.4 months. Significantly longer TTP and OS times were observed in patients with mutant EGFR (p = .0113 and p < .0054, respectively). The mean cerebrospinal fluid penetration rate was 3.31% ± 0.77%. There was a good correlation between plasma and cerebrospinal fluid (CSF) concentrations, although there was no clear correlation between pharmacokinetic parameters and clinical outcome., Conclusion: Erlotinib was active for LM and may be a treatment option for patients with EGFR-mutated NSCLC and LM., (© AlphaMed Press; the data published online to support this summary are the property of the authors.)

Inflammatory biomarkers have been associated with clinical outcomes in non-small cell lung cancer (NSCLC). However, the best prognostic marker(s) has not been identified, and the association between inflammatory markers and clinical characteristics is poorly understood. We selected 1,237 patients with resected NSCLC from Kyushu University (2003-2015) and Kyushu Cancer Center (2009-2015) in Japan. Pearson product-moment correlation coefficient among inflammatory markers and area under curve (AUC) of receiver operating characteristic (ROC) curve analyses for overall survival (OS) were calculated. We analyzed the associations between inflammatory markers and clinical factors using Student's t-test. Univariate and multivariate analyses with Cox proportional hazards regression analyses were performed to evaluate the relationship between survival and clinical factors. The cut-off values for neutrophil-lymphocyte ratio (NLR), lymphocyte-monocyte ratio (LMR), platelet-lymphocyte ratio, and derived NLR (dNLR) were determined by ROC curve analyses for OS. We found a strong positive correlation between NLR and dNLR (r = 0.9629). The AUC of LMR was the highest amongst the measured metrics, and the AUC of NLR was higher than dNLR. Levels of some inflammatory markers were associated with sex, smoking, squamous cell carcinoma, and pathological stage. LMR ≥ 5.11 and lactate dehydrogenase (LDH) concentration ≥ 222 (U/L) were independent predictors of both disease-free survival (DFS) and OS (LMR; P = 0.0009 and 0.0008, LDH; P = 0.0195 and 0.0187, respectively). Certain inflammatory markers, potentially linked to smoking, were associated with an advanced pathological stage in NSCLC. LMR and LDH were independent predictors of both DFS and OS., Competing Interests: The authors have declared that no competing interests exist.

The present study analyzed the antitumor effect of γδT cells transduced with the TCR of cancer-specific CTLs to establish forceful cancer-specific adoptive immunotherapy. We cloned the TCRαβ genes from CTLs showing HLA-B15 restricted recognition of Kita-Kyushu lung cancer antigen-1 (KK-LC-1), a cancer/germline gene antigen, identified in a lung adenocarcinoma case (F1121). The TCRαβ and CD8 genes were transduced into γδT cells induced from PBLs of healthy volunteers stimulated with zoledronate and IL-2. The KK-LC-1-specific TCRαβ-CD8 γδT cells showed cytotoxic activity against the KK-LC-1 positive lung cancer cell line F1121L and produced IFN-γ against F1121L and KK-LC-1 peptide-pulsed F1121 EBV-B cells. These responses were blocked by HLA class I and HLA-B/C antibodies. An in vivo assay using NOD/SCID mice with xenotransplantation of human lung cancer cells was performed, and the TCRαβ-CD8 transduced γδT cells (TCRαβ-CD8 γδT cells) were intravenously injected. Growth inhibition of KK-LC-1 + , HLA-B15 + lung cancer cells was confirmed in mice with injection of the TCRαβ-CD8 γδT cells from 1 wk after xenotransplantation of cancer cells but not in those treated 2 wk after xenotransplantation. The resected specimens of the tumor, 2 wk after xenotransplantation, highly expressed FasL but not programmed death ligand-1 (PD-L1) by immunohistochemical staining. FasL highly expressed cancer cells xenotransplanted 2 wk ago were resistant to TCRαβ-CD8 γδT cells injection. These results suggested that apoptosis of Fas-positive TCRαβ-CD8 γδT cells may be induced by a Fas-mediated signal after interacting with FasL-positive cancer cells., (© 2020 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.)

Non-small cell lung cancer (NSCLC) patients are sometimes referred for thoracic surgical consultation to address the possibility of resecting second primary lung cancer. We report a case of pulmonary resection for second primary lung adenocarcinoma after 3 cycles of pembrolizumab under circumstances in which the primary metastatic lung adenocarcinoma was controlled. The tumor statuses, including programmed death-ligand 1, epidermal growth factor receptor, and CD8+ tumor-infiltrating lymphocytes, were different between the surgically resected specimen and the previously biopsied sample. Surgery should be considered for second primary NSCLC in cases in which the primary NSCLC are well controlled with immune checkpoint inhibitors., (Copyright © 2020 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.)