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Background: Recent advances in perioperative immunotherapies have led to a new era in the perioperative treatment of resectable, non-small cell lung cancer (NSCLC). Although the choice of neoadjuvant, adjuvant or perioperative immunotherapy remains controversial, few reports have compared programmed death ligand-1 (PD-L1) expression as a biomarker between preoperative biopsy specimens and surgical specimens., Methods: We retrospectively reviewed consecutive patients with NSCLC whose preoperative biopsy specimens and surgical specimens were tested for PD-L1 (22C3) and PD-L1 (SP263), respectively, from June 2022 to February 2024. The three categorical classifications of PD-L1 expression (negative [<1%], low [1-49%], and high [≥50%]) were compared between the two tests., Results: Of the 33 patients, 13 patients had negative PD-L1 expression, 9 patients had low PD-L1 expression and 11 patients had high PD-L1 expression with preoperative biopsy specimens, while 18 patients had negative PD-L1 expression, 10 patients had low PD-L1 expression and 5 patients had high PD-L1 expression with surgical specimens. The concordance rate for the three categorical classifications of PD-L1 expression between the preoperative biopsy specimens and surgical specimens was 57.6%., Conclusions: PD-L1 expression may differ between preoperative biopsy specimens and surgical specimens. PD-L1 expression evaluated using small biopsy specimens may be largely influenced by chance due to intra-tumoral heterogeneity.

Background: Presbyphagia, an age-related decline in swallowing function, is considered a precursor stage of dysphagia and a risk state that can lead to aspiration pneumonia and malnutrition. We examined factors associated with presbyphagia in patients with community-acquired pneumonia (CAP)., Methods: A cross-sectional study was conducted with 80 patients with CAP aged ≥65 years admitted to an acute care hospital between June 2021 and April 2024. Presbyphagia was assessed using the 10-item Eating Assessment Tool. The survey items included grip strength, body mass index, the Mini-Cog©, repetitive saliva swallowing test, tongue pressure, and evaluations for sarcopenia and frailty. Logistic regression analysis was performed to examine the factors associated with presbyphagia after adjusting for age and sex., Results: Of 80 patients, 44 (55%) had presbyphagia. The presbyphagia group was older, had lower Barthel Index scores, and had a higher proportion of history of cerebrovascular accident, sarcopenia and frailty than the non-presbyphagia group. Logistic regression analysis revealed frailty (adjusted odds ratio: 3.106, 95% confidence interval: 1.161-8.313, p = 0.024) was significantly associated with presbyphagia., Conclusions: Our results revealed a significant association between presbyphagia and frailty in patients with CAP. The relationship between presbyphagia and frailty suggests that these conditions are not caused by a single functional decline or structural change but by a combination of factors. Therefore, it is crucial to comprehensively evaluate presbyphagia in patients with CAP to provide appropriate interventions., Competing Interests: Declaration of competing interest Osamu Hataji received a research grant funding from AstraZeneca, GlaxoSmithKline, Boehringer Ingelheim, Sanofi, Eli Lilly and Novartis. Osamu Hataji received speaker fees as honoraria from AstraZeneca, GlaxoSmithKline, Diichi Sankyo, Janssen Pharmaceutical, Insmed Incorporated, Eli Lilly, Boehringer Ingelheim and FUJIFILM Toyama Chemical. Yasunori Imaoka has no conflict of interest., (Copyright © 2024 [The Author]. Published by Elsevier B.V. All rights reserved.)

Idiopathic pulmonary fibrosis (IPF) is a progressive, often fatal lung disease characterized by tissue scarring and declining lung function. The MUC5B promoter polymorphism rs35705950, a significant genetic predisposition for IPF, paradoxically associates with better survival and slower disease progression than other IPF genotypes. This study investigates the potential paradoxical protective effects of this MUC5B variant in lung fibrosis. For this purpose, we developed a transgenic mouse model overexpressing the human MUC5B rs35705950 variant in the proximal large airways. Lung fibrosis was induced through subcutaneous injection of bleomycin. Results demonstrated significantly reduced lung fibrosis severity in transgenic mice compared to wild-type mice, assessed by trichrome staining, Ashcroft scoring, and hydroxyproline levels. Additionally, transgenic mice showed significantly lower levels of inflammatory cells and cytokines (TNFα, IL-6, IFNγ) and growth factors (PDGF, CTGF, IL-13) in the bronchoalveolar lavage fluid and lung tissues. There was also a significant decrease in mRNA expressions of fibrosis-related markers (periostin, fibronectin, Col1a1). In summary, this study reveals that mucin overexpression related to the MUC5B rs35705950 variant in the large airways significantly attenuates lung fibrosis and inflammatory responses in transgenic mice. These findings suggest that the rs35705950 variant modulates inflammatory and fibrotic responses in the proximal airways, which may contribute to the slower disease progression observed in IPF patients carrying this variant. Our study offers a possible explanation for the paradoxical beneficial effects of the MUC5B variant despite its role as a significant predisposing factor for IPF.

Objectives: This study aimed to assess the intrinsic impacts of the expression of PD-L1 on postoperative recurrence and the prognosis in patients with epidermal growth factor receptor ( EGFR )-mutated lung adenocarcinomas., Patients and Methods: Data from 221 surgically resected pathological stage IA-IIIA lung adenocarcinomas, collected between 2017 and 2019, were analyzed. This included measurements of EGFR mutations and the PD-L1 expression. Recurrence-free survival (RFS) and overall survival (OS) were estimated using a Kaplan-Meier analysis and log-rank test. The independent risk factors for RFS were assessed using univariate and multivariate analyses., Results: Among the patients, 140 were PD-L1-negative (<1%), while 81 were PD-L1-positive (≥1%). PD-L1 positivity was significantly associated with male sex (p=0.038), smoking habit (p=0.005), ND2 lymph node dissection (p=0.013), higher malignant subtype (p=0.003), higher histological grade (p=0.001), and advanced pathological stage (p=0.004). Conversely, EGFR mutations were more common in the PD-L1-negative group than in the PD-L1-positive group (p=0.006). Patients were categorized into four groups based on their EGFR mutation status and PD-L1 expression status: PD-L1-positive (≥1%) with or without EGFR mutations ( EGFR (+)/PD-L1≥1% or EGFR ( -)/PD-L1≥1%), and PD-L1-negative (<1%) with or without EGFR mutations ( EGFR (+)/PD-L1<1% or EGFR ( -)/PD-L1<1%). Among these groups, EGFR (+)/PD-L1≥1% cases exhibited the worst 5-year RFS (log-rank, p=0.010), while there was no significant difference in 5-year OS (log-rank, p=0.122). Furthermore, a multivariate analysis revealed that PD-L1 positivity was an independent significant factor for RFS in EGFR -mutated lung adenocarcinoma (p=0.013)., Conclusion: PD-L1 positivity emerged as an independent risk factor for RFS in patients with EGFR -mutant resected lung adenocarcinoma. These findings may provide valuable insights into the prognostic impact of PD-L1 expression and guide the implementation of postoperative adjuvant therapy in this patient population., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Ito, Kano, Tarukawa, Suzuki, Sakaguchi, Ito, Nishii, Taguchi, Yasui, Takao and Hataji.)

Importance: The Eastern Cooperative Oncology Group Performance Status (ECOG PS) is extensively used to guide treatment decisions in patients with advanced lung cancer. However, its assessment is subjective, potentially leading to discordance among observers., Objective: To investigate the association between measured physical activity and ECOG PS, as well as the potential prognostic value of physical activity measurements in patients with advanced lung cancer., Design, Setting, and Participants: This single-institution, prospective observational study enrolled 119 patients with advanced lung cancer scheduled to receive systemic therapy as outpatients at Matsusaka Municipal Hospital in Mie, Japan. Participants wore the wearable device amuelink (Sony) for up to 14 days to measure physical activity, including metabolic equivalent tasks, distance walked, and number of steps taken. ECOG PS was assessed at enrollment, which took place from December 2021 to August 2022., Main Outcomes and Measures: The primary end point was estimating the area under the curve (AUC) for classification into ECOG PS of 2 or higher using physical activity measurements. An analysis of the association with survival was also conducted., Results: Among the 119 patients (median [range] age, 72 (32-88) years; 71 [59.7%] male), mean distance walked (MDW) had the highest diagnostic value for classifying an ECOG PS of 2 or greater, with an AUC of 0.818 (95% CI, 0.703-0.934). Moreover, MDW was also associated with 6-month survival, with an AUC of 0.806 (95% CI, 0.694-0.918). Survival curves significantly diverged based on the MDW threshold, indicating a potential association with survival outcome (hazard ratio, 0.17; 95% CI, 0.05-0.57)., Conclusions and Relevance: The cohort study suggests that MDW, as measured by a wearable device, was associated with ECOG PS and may serve as a predictor of health status alongside ECOG PS categories. It demonstrates the potential of objectively measured physical activity in complementing subjective ECOG PS assessments in patients with advanced lung cancer. Further research is needed to confirm the prognostic value of physical activity measurements.

Background: There are no reports of exercise-induced hypoxemia in patients with coronavirus disease 2019 (COVID-19). Additionally, the predictive factors and prevalence of exercise-induced hypoxemia are unknown. This study investigated the incidence and predictive factors of exercise-induced hypoxemia before and after discharge in patients with COVID-19., Methods: We enrolled 77 patients diagnosed with COVID-19 who were hospitalized between November 2020 and October 2021 and who underwent a 6-min walk test before and after discharge. Based on the test results, we classified patients into exercise-induced and non-exercise-induced hypoxemia groups and investigated the predictive factors of exercise-induced hypoxemia using logistic regression analysis., Results: The incidences of exercise-induced hypoxemia in patients with COVID-19 were 37.7% and 19.5% before and after discharge, respectively. At admission, the Krebs von den Lungen-6 levels was the associated factor for exercise-induced hypoxemia in patients with COVID-19 before and after discharge, with cut-off values of 314 U/mL and 367 U/mL, respectively. Age and lactate dehydrogenase levels were the associated factors for exercise-induced hypoxemia in patients with COVID-19 before discharge, with cut-off values of 61 years and 492 U/L, respectively., Conclusions: Some patients with COVID-19 may continue to experience exercise-induced hypoxemia after discharge. Age, lactate dehydrogenase, and Krebs von den Lungen-6 levels at admission could serve as predictive markers of exercise-induced hypoxemia before and after discharge in these patients., Competing Interests: Declaration of competing interest Osamu Hataji received a research grant funding from AstraZeneca, United Kingdom; GlaxoSmithKline, United Kingdom; Chugai Pharmaceutical, Japan; Boehringer Ingelheim, Janssen Pharmaceutical, Insmed Incorporated, IQVIA, Diichi Sankyo and FUJIFILM Toyama Chemical, Japan. Osamu Hataji received speaker fees as honoraria from AstraZeneca, GlaxoSmithKline, Boehringer Ingelheim, Sanofi and Eli Lilly in Japan. The other authors have no conflicts of interest., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Some multi-gene panel tests have been implemented in clinical settings to guide targeted therapy in non-small-cell lung cancer (NSCLC) in Japan. The current performance of multi-gene panel tests under the condition that the Oncomine Dx Target Test (ODxTT) and Amoy Dx ® Pan Lung Cancer PCR panel (AmoyDx-multi) are available remains relatively unknown. We retrospectively reviewed consecutive patients with NSCLC, whose FFPE samples were considered for genetic testing. We assessed the submission rates, the success rates, and the driver oncogene detection rates of multi-gene panel tests. A total of 225 patients were histologically newly diagnosed with NSCLC or diagnosed with a recurrence of NSCLC without a previous multi-gene panel test at our institution. Among the 225 patients, the FFPE samples of 212 patients (94.2%) were submitted for multi-gene panel testing, including 191 samples (84.9%) for the ODxTT and 21 samples (9.3%) for the AmoyDx-multi. Among the 212 samples submitted to multi-gene panel tests, the success rate was 99.5% (211/212). The detection rate of driver oncogene alterations for all histologies was 52.4% (111/212), and that for adenocarcinoma was 69.7% (106/152). A favorable submission rate and success rate of multi-gene panel tests were shown, along with a favorable detection rate in recent clinical settings., Competing Interests: Matsusaka Municipal Hospital received research grant funding from Novartis, GlaxoSmithKline, AstraZeneca, Daiichi Sankyo, Bayer, and Boehringer Ingelheim. K. Ito has received speaker fees as honoraria from Eli Lilly Japan, Chugai, AstraZeneca, MSD, Boehringer Ingelheim Japan, Ono, and Pfizer Japan. O. Taguchi received speaker fees as honoraria from AstraZeneca. O. Hataji received speaker fees as honoraria from Novartis Pharma, AstraZeneca, and Boehringer Ingelheim Japan. The remaining authors declare no conflicts of interest.

Objective: As first-line treatment for stage IV or recurrent non-small cell lung cancer, combination immunotherapy with nivolumab and ipilimumab, with or without chemotherapy, had demonstrated survival benefits over chemotherapy; however, data on Japanese patients are limited., Methods: LIGHT-NING was a multicenter, observational study and retrospectively collected data. In this interim analysis, we analyzed patients who received combination immunotherapy between 27 November 2020 and 31 August 2021 for the treatment status, safety objectives (treatment-related adverse events and immune-related adverse events incidences), and effectiveness objectives (objective response rate and progression-free survival) to determine the characteristics and early safety information., Results: We analyzed 353 patients, with a median follow-up of 7.1 (interquartile range, 5.0-9.7) months. Overall, 60.1 and 39.9% received nivolumab plus ipilimumab with and without chemotherapy, respectively. In these cohorts, the median age was 67 and 72 years; 10.8 and 35.5% were aged ≥75 years; 80.2 and 79.4% were male; 5.2 and 13.5% had a performance score ≥ 2; 32.1 and 27.0% developed grade 3-4 immune-related adverse events; treatment-related deaths were observed in 6 (2.8%) and 5 (3.5%) patients, respectively. Grade 3-4 immune-related adverse event incidence was the highest within the first month of treatment in both cohorts, although the immune-related adverse event risk persisted throughout. No new safety signals were observed at this interim analysis. The median progression-free survival was 6.0 (95% confidence interval, 5.2-7.6) and 5.8 (4.3-7.0) months in nivolumab plus ipilimumab with and without chemotherapy cohorts, respectively., Conclusions: LIGHT-NING offers valuable insights into combination immunotherapy for untreated patients with stage IV or recurrent non-small cell lung cancer in Japanese real-world settings., (© The Author(s) 2024. Published by Oxford University Press.)

Background: Immune checkpoint inhibitors have recently become the standard of care in the first-line treatment of extensive-stage small cell lung cancer. Although immune-related adverse events have been reported to influence prognosis in non-small cell lung cancer patients, few studies have investigated the prognostic value of immune-related adverse events in small cell lung cancer patients. In this study, we evaluated the prognosis of patients who developed immune-related adverse events after first-line treatment with immune checkpoint inhibitor-based chemotherapy for extensive-stage small cell lung cancer., Methods: We enrolled 90 patients with extensive-stage small cell lung cancer who received immune checkpoint inhibitor-based chemotherapy as first-line treatment from September 2019 to December 2022 in six hospitals in Japan. The patients were categorized into groups with and without immune-related adverse events., Results: There were 23 patients with and 67 without immune-related adverse events. Seventeen patients had grade 1-2 immune-related adverse events, and nine (including overlapping cases) had grade ≥3. The most frequent immune-related adverse event was a skin rash. The median survival time was 22 months in patients with immune-related adverse events and 9.3 months in patients without immune-related adverse events. The hazard ratio was 0.40 (95% confidence interval: 0.19-0.83, p = 0.013)., Conclusions: The results of this study show that immune-related adverse events are associated with improved survival outcomes in patients with extensive-stage small cell lung cancer., (© 2024 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

Background: A previous longitudinal study of chronic obstructive pulmonary disease (COPD) Assessment Test (CAT) score changes suggested patients fall into 3 patterns: stable, improving, and worsening. This study assessed the evolution of CAT scores over time and its relationship to exacerbations., Methods: In total, 84 participants used a telemedicine platform to complete CAT weekly for 52 weeks. Completion rates, annualized change in CAT scores, and learning effects were measured, as well as CAT changes of >4 units during look-back periods of 4 and 8 weeks. In a subgroup of participants with at least a 25% completion rate (adherent group, n=68 [81%]), the relationship between change in CAT score and exacerbations at any time during the study was examined post hoc., Results: Linear regression showed that 50%, 22%, and 28% of the adherent subgroup had CAT scores indicating worsening, stable, and improving health status, respectively. In the adherent subgroup, 70% (n=7/10) of participants who had an exacerbation during the study had worsening CAT scores, versus 47% (n=27/58) without an exacerbation. The hazard ratio association between CAT score increase and moderate exacerbation was 1.13 (95% confidence interval: 1.03-1.24). Most participants experienced at least one CAT score change of >4 units, and 7% showed an initial learning effect with a median of 2 weeks., Conclusion: Measuring trends in CAT scores may allow future studies to group patients into 3 defined categories of change over time and quantify CAT change trajectories to assess treatment response and potentially predict medium-term outcomes within individual patients., (JCOPDF © 2024.)

Importance: The combination of an antibody to programmed cell death-1 (PD-1) or to its ligand (PD-L1) with chemotherapy is the standard first-line treatment for metastatic non-small cell lung cancer (NSCLC). Bevacizumab is expected to enhance the efficacy not only of chemotherapy but also of PD-1/PD-L1 antibodies through blockade of vascular endothelial growth factor-mediated immunosuppression, but further data are needed to support this., Objective: To evaluate the efficacy and safety of bevacizumab administered with platinum combination therapy and atezolizumab in patients with advanced nonsquamous NSCLC., Design, Setting, and Participants: An open-label phase 3 randomized clinical trial was conducted at 37 hospitals in Japan. Patients with advanced nonsquamous NSCLC without genetic driver alterations or those with genetic driver alterations who had received treatment with at least 1 approved tyrosine kinase inhibitor were enrolled between January 20, 2019, and August 12, 2020., Interventions: Patients were randomly assigned to receive either atezolizumab plus carboplatin with pemetrexed (APP) or atezolizumab, carboplatin plus pemetrexed, and bevacizumab (APPB). After 4 cycles of induction therapy, maintenance therapy with atezolizumab plus pemetrexed or with atezolizumab, pemetrexed, and bevacizumab was administered until evidence of disease progression, development of unacceptable toxic effects, or the elapse of 2 years from the initiation of protocol treatment., Main Outcomes and Measures: The primary end point was progression-free survival (PFS) as assessed by blinded independent central review (BICR) in the intention-to-treat (ITT) population., Results: A total of 412 patients were enrolled (273 men [66%]; median age, 67.0 [range, 24-89] years) and randomly assigned, with 205 in the APPB group and 206 in the APP group of the ITT population after exclusion of 1 patient for good clinical practice violation. The median BICR-assessed PFS was 9.6 months with APPB vs 7.7 months with APP (stratified hazard ratio [HR], 0.86; 95% CI, 0.70-1.07; 1-sided stratified log-rank test; P = .92). According to prespecified subgroup analysis of BICR-assessed PFS, an improved PFS with APPB vs APP was apparent specifically in driver oncogene-positive patients (median, 9.7 vs 5.8 months; stratified HR, 0.67; 95% CI, 0.46-0.98). Toxic effects related to bevacizumab were increased in the APPB group., Conclusions and Relevance: The findings of this trial did not show superiority of APPB over APP for patients with nonsquamous NSCLC; however, this regimen showed a similar tolerability and improved survival relative to APP in patients with driver oncogenes., Trial Registration: Japan Registry of Clinical Trials Identifier: jRCT2080224500.

Tracheal AERO stent collapse is a rare complication compared to bronchial AERO stent collapse due to differences in the nitinol framework thickness. A 58-year-old man with a bulky anaplastic thyroid carcinoma was referred to our hospital due to exacerbation of tracheal stenosis despite the administration of lenvatinib. His tracheal stenosis exhibited a severe extrinsic compression pattern with a length of 8 cm. Because tracheotomy was inappropriate, we placed an 18 × 80 mm AERO stent. Five months later, he was readmitted with severe dyspnea due to collapse of the distal portion of the stent caused by tumor growth. Because stent removal was difficult, we placed an additional AERO stent (18 × 60 mm) to cover the collapsed portion. The additional stent successfully expanded the collapse and improved his dyspnea. To our knowledge, this is the first case where a tracheal AERO stent collapse due to a poor prognosis tumor was treated with the stent-in-stent method., (© 2023 The Authors. Thoracic Cancer published by John Wiley & Sons Australia, Ltd.)

In Japan, exacerbations are underreported compared with other countries, possibly due in part to a failure to recognize them. This study aimed to create a simple chronic obstructive pulmonary disease (COPD) Exacerbation Recognition Tool (CERT-J) specifically for Japanese patients. Patients ≥40 years with confirmed COPD or asthma-COPD overlap were included. Focus groups were held to identify words and phrases used by patients to describe symptoms associated with an exacerbation, resulting in candidate items being identified. Following cognitive debriefing, the items were refined based on item frequency, level of endorsement and effect of demographic factors. Exploratory factor analysis (EFA) was then performed to inform an expert panel's choice of items to form the new tool. A total of 41 patients were included in the focus groups and nine patients performed the cognitive debrief. Following this, the expert panel identified 26 items for testing in a further 100 patients (mean age 72 years, forced expiratory volume in 1 s 54.8% predicted and 1.8 exacerbations in the preceding 12 months). Eleven items were associated with breathlessness or activity limitation and seven of these were the most frequently endorsed. EFA identified four factors, with one (breathlessness) being dominant. The expert panel recommended that the CERT-J should include six items: breathlessness and activity limitation (3 items), cough (1 item) and phlegm (2 items). The final CERT-J should benefit patients with COPD by providing them with an increased understanding and recognition of exacerbations. Clinical Trial Registration: GSK K.K (jRCT1080224526).

Background: Immune checkpoint inhibitors (ICI) plus platinum-based chemotherapy has been recognized as a standard first-line therapy in non-small cell lung cancer (NSCLC); however, no prospective clinical trials of docetaxel (DTX) plus ramucirumab (RAM) following first-line ICI plus platinum-based chemotherapy has been reported., Methods: In this multicentre, open-label, single-arm, phase 2 trial, we enrolled patients with NSCLC from eight centres in Japan. Patients with metastatic NSCLC with disease progression after platinum-based chemotherapy plus ICI were eligible for the study. Patients were intravenously treated with 60 mg/m 2 of DTX and 10 mg/kg of RAM on day 1 with a strong recommendation of pegfilgrastim administration on day 2 every 3 weeks. The primary end point was objective response rate (ORR) in efficacy analysis population. Safety was assessed in all patients treated at least one dose. The ORR of the null and alternative hypotheses were 10% and 30%, with α error of 0.1 and β error of 0.1. This trial is registered with the Japan Registry for Clinical Trials, jCRTs041190077., Findings: Between 16 January, 2020, and 24 August, 2021, 33 patients (median age 66 [range 42-79] years) were enrolled. Thirteen patients (41%) had Eastern Cooperative Oncology Group performance status of 1. Twenty-five patients (78%) had an interval of <60 days after the last administration of ICI. In the efficacy analysis population (n = 32), the primary endpoint was met as 11 patients achieved partial response (PR), with ORR of 34.4% (80% CI, 23.1-47.2). Grade ≥3 anaemia and febrile neutropenia were observed in 2 (6%) and 3 (9%) patients, respectively. No treatment-related deaths and no new safety signals were observed., Interpretation: DTX plus RAM demonstrated encouraging antitumor activity with a manageable safety profile in patients who have progressed on front-line ICIs plus platinum-based chemotherapy. The results of this trial can be a helpful reference in conducting further phase III trials of new second-line treatment options., Funding: Eli Lilly Japan K.K., Competing Interests: RM received personal fees from Boehringer Ingelheim, AstraZeneca, Pfizer, Eli Lilly, Chugai Pharmaceutical, Merk Sharp & Dohme (MSD), Ono Pharmaceutical, and Taiho Pharmaceutical. MM received grants from Boehringer Ingelheim and Eli Lilly; personal fees from Eli Lilly, Chugai, Astra Zeneca, Ono, Pfizer, and MSD; non-financial support from F. Hoffmann-La Roche; others from Chugai, Astra Zeneca, Pfizer, Merk Serono, Kissei, Taiho, and Novartis. KI received personal fees from Boehringer Ingelheim, AstraZeneca, Pfizer, Eli Lilly, Chugai, MSD, Ono, Taiho, Takeda, and Daiichi Sankyo. OH received grants from AstraZeneca, Novartis, MSD, Daiichi Sankyo, Bayer Yakuhin, AbbVie, Eli Lilly, Janssen, and Ono; personal fees from AstraZeneca, Chugai, Takeda, MSD, Merck, Daiichi Sankyo, Eli Lilly, AbbVie, Boehringer Ingelheim, Nippon Kayaku, and Taiho. KT received personal fees from AstraZeneca, Boehringer Ingelheim, Chugai, Eli Lilly, GlaxoSmithKline (GSK), MSD, Nippon Kayaku, Novartis, Pfizer, Taiho, and Takeda. YG received personal fees from Taiho, Boehringer Ingelheim, Chugai, MSD, GSK, Pfizer, Takeda, Nippon Kayaku, Novartis, Bristol-Meyers Squibb, Kyowa Hakko Bio, and Eli Lilly. HI received personal fees from Eli Lilly. TY received personal fees from Ono, Chugai, Eli Lilly, Taiho, AstraZeneca, MSD, and Bristol-Meyers Squibb. YZ received grants from AstraZeneca, MSD, Daiichi-Sankyo, Merck and Amgen; personal fees from AstraZeneca, Eli Lilly, Chugai, Ono, Bristol-Meyers Squibb, Takeda, Boehringer-Ingelheim, Taiho, MSD, Novartis, Pfizer, Nihon Kayaku, Kyowa Kirin, and Amgen. MO received grants from AbbVie, Chugai, GSK, MSD, Parexel, Sanofi, AstraZeneca, Fujifilm Toyama Chemical, Janssen, Ono and Pfizer; personal fees from AMCO, Canon Medical Systems, Fujifilm Toyama Chemical, Merit Medical Japan, Olympus, AstraZeneca, Chugai, Kaneka Medix, Novartis, and Sanofi. MI received personal fees from AstraZeneca, GlaxoSmithKline, Pfizer, Shionogi, Sanofi, Insmed, Asahi Kasei Pharma, Kyorin pharmaceutical, Chugai pharmaceutical, Boehringer Ingelheim, Eli Lilly, Daiichi Sankyo, MSD, Abbott, Taiho pharmaceutical, Amgen, and Novartis., (© 2023 The Authors.)

Background/aim: Lung adenocarcinoma and lung squamous cell carcinoma represent the most prevalent subtypes of non-small cell lung cancer eligible for surgery in the early stages. The emergence of immune checkpoint inhibitors as adjuvant therapy has shown promising potential in improving the postoperative prognosis of patients with lung cancer. Hence, a comprehensive understanding of the clinicopathological and molecular features of programmed cell death ligand-1 (PD-L1) expression in lung adenocarcinoma and squamous cell carcinoma is crucial., Patients and Methods: In this retrospective study, we conducted a comparative analysis of clinicopathological features associated with the expression of PD-L1, stratifying patients who underwent surgical resection into two distinct groups: 289 patients with lung adenocarcinoma and 66 with lung squamous cell carcinoma. Furthermore, we investigated the associations between the expression of PD-L1 and genetic alterations in well-established oncogenic driver mutations., Results: Among the cases, 52.9% exhibited negative PD-L1 expression, 32.9% had low PD-L1 expression, and 12.3% had high PD-L1 expression in adenocarcinoma, while the PD-L1 expression in squamous cell carcinoma showed a near-even distribution. Notably, male sex, smoking history, the presence of invasive pathological factors, and disease progression significantly influenced PD-L1 expression in adenocarcinoma, whereas none of these factors were associated with PD-L1 expression in squamous cell carcinoma. Additionally, the distribution of PD-L1 expression varied based on the type of specific driver gene mutation in adenocarcinoma., Conclusion: The present study revealed clinicopathological and molecular differences between lung adenocarcinoma and squamous cell carcinoma patients promoting the expression of PD-L1., (Copyright © 2023 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Bronchoscopy with radial-probe endobronchial ultrasound, a guide sheath, and electromagnetic navigation can improve the diagnostic yield of peripheral lung nodules. However, the suitability of specimens for genetic analysis remains unsatisfactory. We hypothesized that a transbronchial biopsy performed after closely approaching the bronchoscope tip to the lesion might provide more suitable specimens for genetic analysis. We enrolled 155 patients with peripheral pulmonary lesions who underwent bronchoscopy with a thin or ultrathin bronchoscope. Bronchoscopy was performed using virtual bronchoscopic navigation and radial-probe endobronchial ultrasound with a guide sheath. The bronchoscope tip was placed closer to the lesion during bronchoscopy to collect larger specimens with higher malignant cell content. The patients who underwent a close-to-lesion biopsy had higher rates of overall diagnostic yield, histopathological diagnostic yield, and specimen quality for genetic testing than those who did not. The significant determinants of the specimen's suitability were the close-to-lesion approach, within-the-lesion image, the use of standard 1.9-mm-forceps, and the number of cancer-cell-positive specimens. The significant predictors of the specimen's suitability for genetic analysis were close-to-lesion biopsy and the number of malignant cell-positive tissue samples. This study demonstrates that the close-to-lesion transbronchial biopsy significantly improves the suitability of bronchoscopic specimens for genetic analysis., (© 2023. Springer Nature Limited.)

Entrectinib, a ROS-1 inhibitor, has been shown to be effective for patients with ROS-1 fused NSCLC, and has been established as the standard of care for this population. Entrectinib has been shown to achieve a better response to brain metastasis due to the characteristic of the drug having a weak interaction with P-glycoprotein and, even in prospective studies, the intracranial response is higher. Patients have been known to acquire resistance to molecularly targeted drugs such as EGF-TKIs or ALK-TKIs during targeted therapy. Similarly, the mechanisms of resistance to entrectinib have been reported, but information about the effects of TP53 mutation with entrectinib are still limited. Here, we experienced a case of a patient with ROS-1 fusion and concurrent TP53 mutation who was treated with entrectinib, resulting in a response to brain metastasis but rapid resistance to entrectinib. Our case demonstrates both the intracranial activity of entrectinib and the potential for resistance to entrectinib due to TP53 mutation., (© 2023 The Authors. Thoracic Cancer published by China Lung Oncology Group and John Wiley & Sons Australia, Ltd.)

Although we have experienced some cases with discordant results between the Oncomine Dx target test (ODxTT) and conventional single gene tests for detecting EGFR alterations, the clinical efficacy of EGFR-TKIs in these discordant cases remains little known. We retrospectively reviewed consecutive patients with non-small-cell lung cancer whose FFPE samples were simultaneously submitted for the ODxTT, and a PNA-LNA PCR clamp test. We evaluated the clinical efficacy of EGFR-TKIs in patients with discordant results between the two tests, focusing on the common EGFR mutations. Among 444 successful results, 10 patients had discordant results for common EGFR mutations (9 Ex 19 deletion and 1 Ex 21 L858R mutation), and all of these were detected only by the PNA-LNA PCR clamp test. Among six discordant cases treated with EGFR-TKI, the mutations detected in 3 patients were not included in the list of detectable variants that are reportable by the ODxTT, while the mutations detected in the other 3 patients were included in the list. For all three discordant cases harboring the mutations not reportable by the ODxTT, good clinical responses were demonstrated. However, among the other three discordant cases harboring the mutations reportable by the ODxTT, only one patient had a clinical response with short duration. Among the discordant cases for common EGFR mutations between the ODxTT and the conventional single gene test, there are a certain number of suitable patients responsive to EGFR-TKIs, especially when the cause of the discordant results comes from the difference in the range of detectable variants that are reportable between the tests., (© 2023. Springer Nature Limited.)

Background: Idiopathic pulmonary fibrosis (IPF) is characterised by worsening dyspnoea and exercise intolerance., Research Question: Does a long-term pulmonary rehabilitation improve exercise tolerance in patients with IPF treated with standard antifibrotic drugs, which are expected to reduce disease progression?, Methods: This open-label randomised controlled trial was performed at 19 institutions. Stable patients receiving nintedanib were randomised into pulmonary rehabilitation and control groups (1:1). The pulmonary rehabilitation group underwent initial rehabilitation which included twice-weekly sessions of monitored exercise training for 12 weeks, followed by an at-home rehabilitation programme for 40 weeks. The control group received usual care only, without pulmonary rehabilitation. Both groups continued to receive nintedanib. The primary and main secondary outcomes were change in 6 min walking distance (6MWD) and change in endurance time (using cycle ergometry) at week 52., Results: Eighty-eight patients were randomised into pulmonary rehabilitation (n=45) and control (n=43) groups. Changes in 6MWD were -33 m (95% CI -65 to -1) and -53 m (95% CI -86 to -21) in the pulmonary rehabilitation and control groups, respectively, with no statistically significant difference (mean difference, 21 m (95% CI -25 to 66), p=0.38). Changes in endurance time were significantly better in the pulmonary rehabilitation (64 s, 95% CI -42.3 to 171)) than in the control (-123 s (95% CI -232 to -13)) group (mean difference, 187 s (95% CI 34 to 153), p=0.019)., Interpretation: Although pulmonary rehabilitation in patients taking nintedanib did not improve 6MWD in the long term, it led to prolonged improvement in endurance time., Trial Registration Number: UMIN000026376., Competing Interests: Competing interests: The following authors received payment or honoraria for lectures, presentations, speaker bureaus, manuscript writing or educational events outside the submitted work: KK and ON (Nippon Boehringer Ingerheim); TaO (Nippon Boehringer Ingerheim; Shionogi; Eisai; Astellas Pharma; Bristol-Myers Squibb; Taiho Pharmaceutical); TT and HT (Nippon Boehringer Ingerheim; KYORIN Pharmaceutical; AstraZeneca K.K.; Teijin Pharma Limited), KT (Nippon Boehringer Ingerheim; Teijin Pharma); HIs, KI and HaS (Nippon Boehringer Ingerheim); YK (Nippon Boehringer Ingerheim; Asahi Kasei Pharma Corp.; Shionogi; Janssen Pharmaceutical K.K.; Healios K.K.; Taiho Pharmaceutical; AstraZeneca K.K.; Eisai; KYORIN Pharmaceutical; Mitsubishi Tanabe Pharma; Novartis Pharma K.K.)., (© Author(s) (or their employer(s)) 2023. No commercial re-use. See rights and permissions. Published by BMJ.)

Background. Physical activity is a potential parameter to assess the severity or prognosis of lung disease. However, the differences in physical activity between healthy individuals and patients with lung disease remain unclear. Methods. The analyses in this report are a combined analysis of four cohorts, including a healthy control cohort, in a prospective study designed to evaluate wearable device-estimated physical activity in three cohorts: the lung cancer cohort, the interstitial pneumonia cohort, and the COPD cohort (UMIN000047834). In this report, physical activity in the lung disease cohort was compared with that in the healthy cohort. Subgroup analyses were performed based on age, sex, duration of wearable device use, and lung disease subtype. Results. A total of 238 cases were analyzed, including 216 patients with lung disease and 22 healthy cases. Distance walked and number of steps were significantly lower in the patient group compared to the healthy control group. ROC analysis for the diagnostic value of lung disease by mean distance walked and mean number of steps showed AUC of 0.764 (95%CI, 0.673 to 0.856) and 0.822 (95%CI, 0.740 to 0.905), respectively. There was a significant difference in physical activity by age, but not by gender nor by duration based on the threshold of 7 days of wearing the device. Conclusions. Lung disease decreases physical activity compared to healthy subjects, and aging may bias the estimation of physical activity. The distance walked or number of steps is recommended as a measure of physical activity, with a period of approximately one week and adjusted for age for future investigation.

Objectives: To evaluate the efficacy and safety of nafamostat combined with favipiravir for the treatment of COVID-19., Methods: We conducted a multicenter, randomized, single-blind, placebo-controlled, parallel assignment study in hospitalized patients with mild-to-moderate COVID-19 pneumonia. Patients were randomly assigned to receive favipiravir alone (n = 24) or nafamostat with favipiravir (n = 21). The outcomes included changes in the World Health Organization clinical progression scale score, time to improvement in body temperature, and improvement in oxygen saturation (SpO 2 )., Results: There was no significant difference in the changes in the clinical progression scale between nafamostat with favipiravir and favipiravir alone groups (median, -0.444 vs -0.150, respectively; least-squares mean difference, -0.294; P = 0.364). The time to improvement in body temperature was significantly shorter in the combination group (5.0 days; 95% confidence interval, 4.0-7.0) than in the favipiravir group (9.0 days; 95% confidence interval, 7.0-18.0; P =0.009). The changes in SpO 2 were greater in the combination group than in the favipiravir group (0.526% vs -1.304%, respectively; least-squares mean difference, 1.831; P = 0.022). No serious adverse events or deaths were reported, but phlebitis occurred in 57.1% of the patients in the combination group., Conclusion: Although our study showed no differences in clinical progression, earlier defervescence, and recovery of SpO 2 were observed in the combination group., Competing Interests: Declaration of competing interest JI, YS, and KM are co-inventors on patent applications of nafamostat as an antiviral agent (PCT/JP2021/9968, patent applicant: the University of Tokyo). All other authors declare no competing interests. FUJIFILM Toyama Chemical and Nichi-Iko supplied the favipiravir and nafamostat mesilate, respectively., (Copyright © 2022. Published by Elsevier Ltd.)

Introduction: The efficacy and safety of atezolizumab in previously treated patients with NSCLC have been established in the registrational phase 3 OAK trial. In this study, we evaluated the effectiveness and safety of atezolizumab monotherapy in a large real-world cohort to confirm the reproducibility of the results of the registrational trial., Methods: This was a multicenter, prospective, single-arm observational study. Consecutive patients with previously treated NSCLC scheduled to receive atezolizumab monotherapy were enrolled. The primary end point was the 18-month overall survival (OS) rate. The incidence of adverse events (AEs) and immune-related AEs was evaluated., Results: Overall, 1002 patients were included in the safety analysis set and 1000 in the full analysis set. Median follow-up was 11.5 months. Of the full analysis set, 62% were ineligible for the OAK trial (OAK-unlike subpopulation). The 18-month OS rate was 41.1%, with a median OS of 13.0 months (95% confidence interval: 12.2-15.1). The 18-month OS rate was 49.4% and 36.1% in OAK-like and OAK-unlike subpopulations, respectively; that in patients with Eastern Cooperative Oncology Group performance status greater than or equal to 2 was 14.3%. The incidence of AEs overall, in the OAK-like, and OAK-unlike subpopulations was 43.9%, 46.2%, and 42.5%; that of immune-related AEs was 19.0%, 20.1%, and 18.3%, respectively., Conclusions: The findings suggest that atezolizumab may be effective and safe for previously treated patients with NSCLC in real-world settings; however, atezolizumab administration should be considered carefully regarding the benefit-risk balance for the OAK-unlike subpopulation, especially in patients with Eastern Cooperative Oncology Group performance status greater than or equal to 2., (© 2023 The Authors.)

Rationale: The long-term effects of using a high-flow nasal cannula for chronic hypercapnic respiratory failure caused by chronic obstructive pulmonary disease remain unclear. Objectives: To assess whether long-term high-flow nasal cannula use reduces the number of exacerbations and improves other physiological parameters in patients with chronic hypercapnic respiratory failure caused by chronic obstructive pulmonary disease. Methods: We enrolled 104 participants (aged ⩾40 yr) with daytime hypercapnia (Global Initiative for Chronic Obstructive Lung Disease stages 2-4) receiving long-term oxygen therapy (⩾16 h/d for ⩾1 mo) and randomly assigned them to high-flow nasal cannula/long-term oxygen therapy and long-term oxygen therapy groups. The primary endpoint was the moderate or severe exacerbation rate. We compared changes from baseline in arterial blood gas values, peripheral oxygen saturation, pulmonary function, health-related quality-of-life scores, and the 6-minute-walk test. Measurements and Main Results: High-flow nasal cannula use significantly reduced the rate of moderate/severe exacerbations (unadjusted mean count 1.0 vs. 2.5, a ratio of the adjusted mean count between groups [95% confidence interval] of 2.85 [1.48-5.47]) and prolonged the duration without moderate or severe exacerbations. The median time to first moderate or severe exacerbation in the long-term oxygen therapy group was 25 (14.1-47.4) weeks; this was not reached in the high-flow nasal cannula/long-term oxygen therapy group. High-flow nasal cannula use significantly improved health-related quality of life scores, peripheral oxygen saturation, and specific pulmonary function parameters. No safety concerns were identified. Conclusions: A high-flow nasal cannula is a reasonable therapeutic option for patients with stable hypercapnic chronic obstructive pulmonary disease and a history of exacerbations. Clinical trial registered with www.umin/ac.jp (UMIN000028581) and www.clinicaltrials.gov (NCT03282019).

Background: Telemedicine may help the detection of symptom worsening in patients with chronic obstructive pulmonary disease (COPD), potentially resulting in improved outcomes. This study aimed to determine the feasibility and acceptability of telemedicine among patients with COPD and physicians and facility staff in Japan., Methods: This was a 52-week multicenter, prospective, single-arm, feasibility and acceptability cohort study of Japanese patients ≥40 years of age with COPD or asthma-COPD overlap. Participants underwent training to use YaDoc, a telemedicine smartphone App, which included seven daily symptom questions and weekly COPD Assessment Test (CAT) questions. The primary endpoint was participant compliance for required question completion. The secondary endpoint was participant and physician/facility staff acceptability of YaDoc based on questionnaires completed at Week 52. The impact of the Japanese COVID-19 pandemic state of emergency on results was also assessed., Results: Of the 84 participants enrolled (mean age: 68.7 years, 88% male), 72 participants completed the study. Completion was high in the first six months but fell after that. Median (interquartile range [IQR]) compliance for daily questionnaire entry was 66.6% (31.0-91.8) and 81.0% (45.3-94.3) for weekly CAT entry. Positive participant responses to the exit questionnaire were highest regarding YaDoc ease of use (83.8%), positive impact on managing health (58.8%), and overall satisfaction (53.8%). Of the 26 physicians and facility staff enrolled, 24 completed the study. Of these, the majority (66.7%) responded positively regarding app facilitation of communication between physicians and participants to manage disease. Compliance was similar before and after the first COVID-19 state of emergency in Japan., Conclusion: Daily telemedicine monitoring is potentially feasible and acceptable to both patients and physicians in the management of COPD. These results may inform potential use of telemedicine in clinical practice and design of future studies., Clinical Trial Registration: JapicCTI-194916., Competing Interests: No authors received payment for the development of the manuscript. Masahiro Shinoda, Osamu Hataji, Motohiko Miura, Masaharu Kinoshita, Akira Mizoo and Kazunori Tobino report having received grants from the GSK group of companies for the conduct of this study. Osamu Hataji also reports personal fees from AstraZeneca, Novartis Pharma, and Boehringer Ingelheim for research funding consulting fee, outside the submitted work. Yoko Shibata reports having received personal fees from the GSK group of companies during the conduct of the study, and lecture fees from AstraZeneca, Novartis and Boehringer Ingelheim. Takanobu Nishi is an employee of GSK. Takeo Ishii, Ryan Tomlinson, Taizo Matsuki and Paul W Jones are employees of GSK and hold stocks/shares. Bruce E. Miller, Toru Soutome and Ruth Tal-Singer are former employees at the time of the study and shareholders of GSK. Ruth Tal-Singer is a Board member of ENA Respiratory and holds stock options from ENA Respiratory, she reports honorarium for conference talks from AAAAI and ATS, travel reimbursement from AAAAI, and personal fees from Immunomet, VOCALIS Health, ENA Respiratory, and Teva until January 2021. The authors report no other conflicts of interest in this work., (© 2022 Shinoda et al.)

Adding an immune checkpoint inhibitor to chemotherapy to treat extensive-stage small cell lung cancer is effective. However, there are no reports of an effective second-line treatment in patients previously treated with chemotherapy and immune checkpoint inhibitors as a first-line treatment. Here, we assessed the efficacy and safety of amrubicin as a second-line treatment for extensive-stage small cell lung cancer after chemotherapy and immune checkpoint inhibitor combination therapy. The study enrolled 150 patients with extensive-stage small cell lung cancer. The efficacy and the incidence of adverse events were compared between patients previously treated with immune checkpoint inhibitors and patients without previous immune checkpoint inhibitor treatment. One hundred and twenty-three patients were eligible. There was no difference in objective response rate, time-to-treatment failure, progression-free survival, and overall survival between both groups. The incidence of adverse events was similar in both treatment groups. Pretreatment with immune checkpoint inhibitors was not associated with an increase in amrubicin-related adverse events. This study shows that the efficacy of amrubicin in extensive-stage small cell lung cancer remains unchanged irrespective of previous treatment with immune checkpoint inhibitors. Amrubicin-related adverse events did not increase in patients previously treated with immune checkpoint inhibitors.

The abscopal effect without concomitant immunotherapy is a rare event, including among cases of lung cancer. Furthermore, the occurrence of limited abscopal effect for only a single lesion in the metastatic organ consistent with the irradiated organ would be an even more rare event. A 94-year-old man was diagnosed with advanced lung cancer with osteolytic bone metastases in his right iliac bone, and the right side of his axial vertebrae. After palliative radiation therapy to the right iliac lesion for pain relief without other anticancer therapy, the axial vertebral osteolytic lesion disappeared despite no reduction in the other lesions. This case furthers our understanding of the pathogenesis of the abscopal effect., (© 2022 The Authors. Thoracic Cancer published by China Lung Oncology Group and John Wiley & Sons Australia, Ltd.)

Thymic carcinoma is a rare malignant tumor with a poor prognosis. No standard treatment is currently available. The present case was a 64-year-old male smoker with no symptoms referred to our hospital because of abnormal chest radiological findings. The CT study showed a tumor between the anterior mediastinum and the right lung upper lobe, multiple nodular shadows along the right pleura, and pleural effusion. A CT-guided needle biopsy revealed squamous cell carcinoma. However, the differential diagnosis between thymic carcinoma and primary lung cancer was difficult. Treatment with carboplatin, nanoparticle albumin-bound paclitaxel, and pembrolizumab was initiated. The CT scan showed tumor shrinkage and good clinical response after four treatment cycles. Therapy was switched to maintenance therapy with pembrolizumab alone. Imaging studies showed further tumor shrinkage after twelve cycles of maintenance therapy with pembrolizumab. Sixteen cycles of maintenance therapy were continued without performance status deterioration. An abnormal radiological finding was detected after a twelve-month exacerbation-free period. The diagnosis was thymic carcinoma. Treatment with lenvatinib was initiated, and tumor-size reduction was observed. This is the first report of a case showing a successful maintenance therapy with pembrolizumab after effective first-line therapy with a combination of carboplatin-based chemotherapy plus pembrolizumab in advanced thymic carcinoma.

A 74-year-old Asian man was referred for numb and painful sensation in the right upper limb. He was diagnosed with lung large cell neuroendocrine carcinoma and started receiving durvalumab therapy as second-line treatment. Sixteen days after the first dose, laboratory examination revealed increased liver enzyme levels and a marked inflammatory response. Contrast-enhanced computed tomography revealed an unenhanced tumor measuring approximately 25 mm in the head of pancreas and dilation of the intra- and extra-hepatic bile ducts. Magnetic resonance cholangiopancreatography confirmed stricture in the lower common bile duct and main pancreatic duct. We suspected acute cholangitis caused by a pancreatic cancer and performed an endoscopic biliary drainage. Two weeks after the procedure, computed tomography revealed significant shrinkage of the tumor. The tumor gradually reduced and pseudoprogression in lung large cell neuroendocrine carcinoma was ultimately diagnosed. Acute cholangitis caused by pseudoprogression resembling pancreatic cancer during immune therapy has not yet been reported. We are mindful that pseudoprogression should be considered as a differential diagnosis if a rapidly developing pancreatic tumor is observed during immunotherapy., (© 2022. Japanese Society of Gastroenterology.)

Introduction: Alternation of osimertinib and afatinib is a potential approach to overcome osimertinib resistance and to allow complementation of drug efficacy without compromising safety in patients with epidermal growth factor receptor gene (EGFR)-mutated non-small cell lung cancer (NSCLC)., Methods: Treatment-naive patients with stage IV NSCLC harboring an activating EGFR mutation (L858R or exon-19 deletion) were enrolled. Alternating cycles of osimertinib at 80 mg/day for 8 weeks followed by afatinib at 20 mg/day for 8 weeks were administered. The primary end point was 12-month progression-free survival (PFS) probability., Results: Forty-six patients were enrolled and treated with study therapy. The 12-month PFS probability was 70.2% (60% confidence interval [CI], 63.9-75.6%; 95% CI, 54.2-81.5%), which did not meet the primary end point. After a median follow-up time of 25.7 months, the median PFS was 21.3 months (95% CI, 16.3 months-not reached). The overall response rate was 69.6% (95% CI, 54.2-82.3%). The most common treatment-related adverse events (any grade or grade ≥ 3, respectively) were diarrhea (73.9%, 4.3%), rash acneiform (63.0%, 2.2%), and paronychia (52.2%, 0%). Five cases of pneumonitis, two of grade 2 and thres of grade 3, were apparent, all of which developed during osimertinib treatment. Exploratory evaluation of circulating tumor DNA suggested that coexisting TP53 mutations did not influence PFS for the alternating therapy., Conclusions: Alternating therapy with osimertinib and afatinib for treatment-naive patients with EGFR- mutated advanced NSCLC did not meet its primary end point, despite the encouraging efficacy and safety profile of this treatment strategy., (Copyright © 2022 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: Next-generation sequencing (NGS) has been implemented in clinical oncology to analyze multiple genes and to guide targeted therapy. Although the pathological diagnosis and biomarker tests for patients with advanced lung cancer have mostly been obtained with small biopsy samples, especially with bronchoscopic approaches, the performance for NGS with respect to the different sizes of biopsy forceps remains little known., Methods: We retrospectively reviewed consecutive patients with non-small cell lung cancer, whose FFPE samples were obtained by endobronchial biopsy/transbronchial biopsy and were submitted for the Oncomine Dx Target Test (ODxTT). We compared the analytical performance for ODxTT with respect to the size of biopsy forceps., Results: A total of 103 samples were identified. The success rate of the ODxTT for the group with all samples obtained with small forceps biopsies (70%) was lower than that of the group with some or all samples obtained with standard forceps biopsies (83%), although without a statistically significant difference (p = 0.20). With regard to the reason for unsuccessful analysis, the proportion of the samples which did not pass the nucleic acid concentration threshold in the former group (15%) was higher compared with that of the latter group (4%) (p = 0.08). The proportion of tissue size 4 mm 2 or larger in the former group (70%) was lower than that in the latter group (93%) (p = 0.01)., Conclusion: The analysis of ODxTT for specimens biopsied using only small forceps is prone to be unsuccessful due to an insufficient amount of nucleic acid., (© 2022 The Authors. Thoracic Cancer published by China Lung Oncology Group and John Wiley & Sons Australia, Ltd.)

Idiopathic pulmonary fibrosis is an incurable disease of unknown etiology. Acute exacerbation of idiopathic pulmonary fibrosis is associated with high mortality. Excessive apoptosis of lung epithelial cells occurs in pulmonary fibrosis acute exacerbation. We recently identified corisin, a proapoptotic peptide that triggers acute exacerbation of pulmonary fibrosis. Here, we provide insights into the mechanism underlying the processing and release of corisin. Furthermore, we demonstrate that an anticorisin monoclonal antibody ameliorates lung fibrosis by significantly inhibiting acute exacerbation in the human transforming growth factorβ1 model and acute lung injury in the bleomycin model. By investigating the impact of the anticorisin monoclonal antibody in a general model of acute lung injury, we further unravel the potential of corisin to impact such diseases. These results underscore the role of corisin in the pathogenesis of acute exacerbation of pulmonary fibrosis and acute lung injury and provide a novel approach to treating this incurable disease., (© 2022. The Author(s).)

Introduction: Many patients with nontuberculous mycobacteria pulmonary disease are asymptomatic. The disease diagnosis is confirmed in only a small proportion of patients with radiological findings suspicious for nontuberculous mycobacteria pulmonary disease. Thus, many patients remained undiagnosed. Here, we evaluated the diagnostic value of digital polymerase chain reaction (PCR) in nontuberculous mycobacteria pulmonary disease., Methods: We prospectively evaluated 123 patients with radiological findings suspicious for nontuberculous mycobacteria pulmonary disease. Digital PCR was performed using bronchial lavage fluid, sputum, saliva, blood, and urine., Results: The culture of bronchial washing fluid was positive for nontuberculous mycobacteria in 53 patients and negative in 70. The positive detection rate of nontuberculous mycobacteria by digital PCR in patients with positive culture (n = 53) was as follows: bronchial lavage fluid 100%, sputum 62.9%, saliva 41.5%, blood 7.5%, and urine 3.8%. All patients with two or more positive partitions for nontuberculous mycobacteria in the digital PCR of bronchial lavage fluid showed nontuberculous mycobacteria growth in the bronchial lavage fluid culture. The digital PCR analysis of the bronchial lavage fluid showed a high sensitivity (100%), specificity (85.7%), positive predictive value (84.1%), negative predictive value (100%), and a high concordance rate (91.9%) with the bronchial lavage fluid culture results. In addition, the culture of bronchial lavage fluid was positive for nontuberculous mycobacteria in patients with two or more positive partitions in the digital PCR of sputum and saliva with a combined positive predictive value of 81.1%., Conclusion: Digital PCR analysis of nontuberculous mycobacteria in bronchial lavage fluid shows a high concordance rate with the bronchial lavage fluid culture results and a high positive predictive value using both sputum and saliva, suggesting the potential usefulness of dPCR for diagnosis of nontuberculous mycobacteria pulmonary disease in clinical practice., Competing Interests: Dr Yoichi Nishii reports grants from AstraZeneca, Daiichi Sankyo, Takeda Pharmaceutical, Novartis Pharma, Boehringer Ingelheim, Kyowa Hakko Kirin, Sumitomo Dainippon Pharma, MSD, GlaxoSmithKline, Olympus, Bristol-Myers Squibb, Ono Pharmaceutical, Chugai Pharmaceutical, Eli Lilly, AbbVie, Taisho Pharmaceutical, and Celgene, outside the submitted work. Dr Kazuki Furuhashi reports grants from AstraZeneca, Daiichi Sankyo, Takeda Pharmaceutical, Novartis Pharma, Boehringer Ingelheim, Kyowa Hakko Kirin, Sumitomo Dainippon Pharma, MSD, GlaxoSmithKline, Olympus, Bristol-Myers Squibb, Ono Pharmaceutical, Chugai Pharmaceutical, Eli Lilly, AbbVie, Taisho Pharmaceutical, and Celgene, outside the submitted work. Dr Yuki Nakamura reports grants from AstraZeneca, Daiichi Sankyo, Takeda Pharmaceutical, Novartis Pharma, Boehringer Ingelheim, Kyowa Hakko Kirin, Sumitomo Dainippon Pharma, MSD, GlaxoSmithKline, Olympus, Bristol-Myers Squibb, Ono Pharmaceutical, Chugai Pharmaceutical, Eli Lilly, AbbVie, Taisho Pharmaceutical, and Celgene, outside the submitted work. Dr Tadashi Sakaguchi reports grants from AstraZeneca, Daiichi Sankyo, Takeda Pharmaceutical, Novartis Pharma, Boehringer Ingelheim, Kyowa Hakko Kirin, Sumitomo Dainippon Pharma, MSD, GlaxoSmithKline, Olympus, Bristol-Myers Squibb, Ono Pharmaceutical, Chugai Pharmaceutical, Eli Lilly, AbbVie, Taisho Pharmaceutical, and Celgene, outside the submitted work. Dr Yuta Suzuki reports grants from AstraZeneca, Daiichi Sankyo, Takeda Pharmaceutical, Novartis Pharma, Boehringer Ingelheim, Kyowa Hakko Kirin, Sumitomo Dainippon Pharma, MSD, GlaxoSmithKline, Olympus, Bristol-Myers Squibb, Ono Pharmaceutical, Chugai Pharmaceutical, Eli Lilly, AbbVie, Taisho Pharmaceutical, and Celgene, outside the submitted work. Dr Kentaro Fujiwara reports grants from AstraZeneca, Daiichi Sankyo, Takeda Pharmaceutical, Novartis Pharma, Boehringer Ingelheim, Kyowa Hakko Kirin, Sumitomo Dainippon Pharma, MSD, Glaxo Smith Kline, Olympus, Bristol-Myers Squibb, Ono Pharmaceutical, Chugai Pharmaceutical, Eli Lilly, AbbVie, Taisho Pharmaceutical, and Celgene, outside the submitted work. Dr Esteban C Gabazza reports grants from Shionogi pharmaceuticals and Astellas Pharmaceuticals, outside the submitted work. Dr Osamu Hataji reports grants, personal fees from AstraZeneca, Daiichi Sankyo, Takeda Pharmaceutical, Novartis Pharma, Boehringer Ingelheim, MSD, Glaxo Smith Kline, Olympus, Bristol-Myers Squibb, Ono Pharmaceutical, Chugai Pharmaceutical, Eli Lilly; personal fees from Pfizer, Kyorin Pharmaceutical, Taiho Pharmaceutical, Astellas Pharmaceutical, Meiji, Mitsubishi Tanabe Pharma, Sanofi; grants from Kyowa Hakko Kirin, Sumitomo Dainippon Pharma, AbbVie, Taisho Pharmaceutical, and Celgene, outside the submitted work. The authors report no other conflicts of interest in this work., (© 2021 Nishii et al.)

Background: Atezolizumab combined with bevacizumab plus platinum-based chemotherapy is a standard treatment for advanced non-squamous non-small-cell lung cancer (nsNSCLC). We aimed to determine the most effective platinum-based combination, such that future studies with atezolizumab can be conducted to further improve patient outcomes., Methods: This phase 2 study enrolled treatment-naïve patients with advanced or recurrent nsNSCLC who were randomly assigned to either cisplatin (75 mg/m 2 ) + pemetrexed (500 mg/m 2 ) + bevacizumab (15 mg/kg) (CisPemBev) followed by maintenance PemBev (N=132) or carboplatin (area under the concentration-time curve of 6 mg/mL/min) + paclitaxel (200 mg/m 2 ) + bevacizumab (15 mg/kg) (CarPacBev) followed by maintenance Bev (N=67). The primary endpoint was progression-free survival (PFS, by central review). Secondary endpoints included overall survival (OS) and overall response rate (ORR). Adverse events (AEs) were evaluated for safety. This study was designed with the point estimate of the hazard ratio (HR) for PFS calculated based on an expected HR <0.830 with a probability ≥80%., Results: The HR for PFS (CisPemBev/CarPacBev) was 0.825 [95% confidence interval (CI), 0.600-1.134, median PFS, 7.6 vs . 7.0 months]. Because the observed point estimate of the HR for PFS was <0.830, the primary endpoint was met, and CisPem doublet therapy was deemed to be more effective than CarPac in terms of PFS. Median OS was 23.4 months for CisPemBev and 21.6 months for CarPacBev (HR 0.845; 95% CI, 0.583-1.242). The ORR was 57% for CisPemBev and 55% for CarPacBev. Both CisPemBev and CarPacBev were well tolerated; grade ≥3 AEs were reported in 67% and 82% of patients, respectively., Conclusions: CisPem combined with Bev was more effective in improving PFS compared with CarPacBev in patients with advanced nsNSCLC. CisPemBev was also well tolerated by this patient population. A study to evaluate the efficacy of atezolizumab plus CisPemBev is warranted., Trial Registration: University hospital Medical Information Network Clinical Trial Registry (ID: UMIN000013354)., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://dx.doi.org/10.21037/tlcr-21-240). SW, FT, MS, HY, TY and KG have received honoraria from Chugai Pharmaceutical Co., Ltd. SA and KG have received research funds from Chugai Pharmaceutical Co., Ltd. FT, MS and TY have received scholarship endowments from Chugai Pharmaceutical Co., Ltd. The authors have no other conflicts of interest to declare., (2021 Translational Lung Cancer Research. All rights reserved.)

Background: Consolidation therapy with durvalumab after concurrent chemoradiotherapy has been reported to significantly prolong progression-free survival and overall survival in patients with stage III unresectable non-small cell lung cancer (NSCLC). However, which chemotherapy regimen should be selected for consolidation therapy with durvalumab is currently unknown., Methods: We retrospectively reviewed consecutive patients with unresectable stage III NSCLC who received concurrent definitive chemoradiotherapy with platinum-based chemotherapy. We reviewed the timing and severity of radiation pneumonitis by assessing chemotherapy regimens and histology., Results: A total of 103 patients were identified. Fourteen patients (13.6%) developed grade 2 or greater radiation pneumonitis within 42 days after chemoradiotherapy. No adenocarcinoma patients treated with a regimen of cisplatin plus pemetrexed developed grade 2 or greater radiation pneumonitis within 42 days; however, 20% of patients who were treated with carboplatin plus paclitaxel developed grade 2 or greater radiation pneumonitis. Furthermore, the objective response rates and disease control rates of cisplatin plus pemetrexed were equal to or greater than those of carboplatin plus paclitaxel in adenocarcinoma patients., Conclusion: Cisplatin plus pemetrexed regimen may be a preferable option to consider for subsequent consolidation therapy with durvalumab in patients with unresectable stage III adenocarcinoma., (© 2021 The Authors. Thoracic Cancer published by China Lung Oncology Group and John Wiley & Sons Australia, Ltd.)