Language：English   Publisher：Scientific Reports  

Osimertinib, a third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor, effectively treats EGFR-mutated non-small cell lung cancer. Drug-induced interstitial lung disease, a potentially fatal complication of osimertinib, involves an increase in lymphocytes in the bronchoalveolar lavage fluid (BALF). As the precise role of these lymphocytes is unknown, we investigated the pathogenesis of osimertinib-induced pneumonitis using BALF obtained from patients, and an osimertinib-induced pneumonitis mouse model. Mass cytometry revealed the presence of CCR7+ CD45RA+ naïve T cells in the BALF of patients with osimertinib-induced pneumonitis. Body weight measurements, BALF analysis, histopathological evaluation and RNA sequencing of mouse lung tissue were performed to investigate immune cell involvement and the mechanisms underlying osimertinib-induced pneumonitis. In the mouse model, administration of osimertinib after naphthalene-induced damage to the bronchiolar epithelium exacerbated lung inflammation and resulted in significant weight loss. Immunofluorescence staining revealed the infiltration of CCR7+ cells into the lungs of mice treated with naphthalene and osimertinib. Bulk RNA sequencing identified an upregulation of chemokine-related biological processes, with increased expression of C–C motif chemokine ligand 21 (Ccl21) and C–C motif chemokine ligand 8 (Ccl8) in the lung tissue. Additionally, immunofluorescence staining confirmed elevated expression of Ccl21 and Ccl8 in the distal bronchiolar epithelium. This study provides insights into the mechanisms underlying osimertinib-induced pneumonitis.

DOI： 10.1038/s41598-025-95271-9

Web of Science

Scopus

PubMed

Language：Japanese   Publishing type：Research paper (scientific journal)  

Language：English   Publisher：Journal of Clinical Medicine  

Background: Lung malignancies, including cancerous lymphangitis and lymphomas, can mimic interstitial lung diseases like cryptogenic organizing pneumonia (COP) on imaging, leading to diagnostic delays. We aimed to identify potential biomarkers to distinguish between these conditions. Methods: We analyzed bronchoalveolar lavage fluid from 8 patients (4 COP, mean age 59.8 ± 13.5 years; 4 lung malignancies including 2 cancerous lymphangitis, 1 MALT lymphoma, and 1 diffuse large B cell lymphoma, mean age 67.8 ± 4.5 years) using mass cytometry with 35 T cell markers. Data were analyzed using principal component analysis (PCA) and unsupervised Citrus clustering. Results: PCA of T cell marker intensities effectively separated the two groups, with IL-2Rα, PD-L2, CD45RA, CD44, and OX40 being the top discriminating markers. Citrus analysis showed a significant increase in the CD16+ CD4+ and CD16+ CD8+ T cell populations in the COP group compared to lung malignancies. Conclusions: Our findings reveal distinct T cell immunophenotypes in COP versus lung malignancies, particularly increased CD16+ T cells in COP, which could serve as potential diagnostic biomarkers.

DOI： 10.3390/jcm14020316

Web of Science

Scopus

PubMed

Language：Japanese   Publishing type：Research paper (scientific journal)  

Language：English   Publisher：Journal for Immunotherapy of Cancer  

Background The immune-related adverse event (irAE), pneumonitis, is a potentially fatal complication of immune checkpoint inhibitors (ICIs). Preventing its progression is crucial, emphasizing the need for effective screening tests. We evaluated the feasibility of using Krebs von den Lungen-6 (KL-6), a marker for interstitial pneumonitis, as a screening tool for pneumonitis. Methods We examined 500 patients with cancer divided into two groups: those with cancer other than non-small cell lung cancer (NSCLC) (Group 1, n=382) and those with NSCLC (Group 2, n=118). KL-6 levels were monitored before and during ICI treatment and analyzed for their correlation with pneumonitis. Results In Group 1, 37 patients (9.7%) developed pneumonitis. KL-6 levels were significantly elevated at irAE onset (pre: 222.0 U/mL, post: 743.0 U/mL, p<0.0001). Receiver operating characteristic curve analysis showed an area under the curve (AUC) of 0.903 (sensitivity 81.1%, specificity 91.6%) with a cut-off value 1.52 times pre-KL-6 levels, indicating that KL-6 is a reliable biomarker for pneumonitis. In these patients, the KL-6 level increased regardless of pneumonitis severity and was significantly elevated in patients with both symptomatic (pre: 205.0 U/mL, post: 674.5 U/mL, p<0.0001) and asymptomatic pneumonitis (pre: 314.0 U/mL, post: 743.0 U/mL, p<0.0001) at irAE onset. After irAE treatment, KL-6 levels in steroid-responsive patients remained unchanged; however, steroid-unresponsive patients had a significant increase in KL-6 levels at 1 month (1078 U/mL, p=0.031) compared with at irAE onset (678.0 U/mL). In Group 2, 24 patients (20.3%) developed irAE pneumonitis, with KL-6 levels elevated (pre: 360.5 U/mL, post: 506.5 U/mL, p=0.029) and an AUC of 0.683, indicating that KL-6 was less reliable in patients with NSCLC. Conclusions KL-6 is a viable screening biomarker in ICI-induced pneumonitis, particularly in patients without NSCLC. In patients with NSCLC, the significance of KL-6 monitoring is limited as it is not effective for detecting ICI-induced pneumonitis; their treatment is typically managed by pulmonary specialists. Early detection through KL-6 monitoring facilitates timely intervention for ICI-induced pneumonitis, potentially preventing treatment interruptions and reducing the need for immunosuppressants.

DOI： 10.1136/jitc-2024-010114

Web of Science

Scopus

PubMed

Language：English   Publisher：The Japanese Society of Internal Medicine  

<p>Nodal T-follicular helper cell lymphoma (nTFHL), a hematologic neoplasm originating from T-follicular helper (TFH) cells, occasionally presents with pulmonary radiographic abnormalities, without neoplastic cellular infiltration. However, the precise mechanisms underlying non-neoplastic pulmonary opacities in patients with nTFHL remain unclear. Previous reports have shown that TFH cell abnormalities are associated with collagen disease and interstitial pneumonia with autoimmune features (IPAF). We herein report a patient with nTFHL accompanied by interstitial pneumonia diagnosed via lung and lymph node biopsies. These findings suggest the need to rule out nTFHL before diagnosing IPAF. </p>

DOI： 10.2169/internalmedicine.3601-24

Web of Science

Scopus

PubMed

CiNii Research

Language：English   Publisher：(一社)日本内科学会  

症例は72歳男性で、夜間の乾性咳嗽と3ヵ月で5kgの体重減少を認めた。免疫グロブリン(Ig)G、IgG4、IgE、可溶性インターロイキン-2受容体の血清レベルが高値で、抗核抗体、リウマトイド因子、ミエロペルオキシダーゼ抗好中球細胞質抗体が陽性であった。高解像度CTの所見では、可能性の高い通常型間質性肺炎パターンが示された。FDG-PET検査で、両側肺門および縦隔リンパ節を包囲する全身性リンパ節腫脹が判明した。気管支肺胞洗浄、経気管支針生検、皮膚生検、胸腔鏡下気管分岐部リンパ節生検および右下葉部分切除術を行い、節性濾胞性ヘルパーT細胞リンパ腫(nTFHL)・非特定型と診断した。右下葉生検の所見では、部分的器質化肺炎を伴う非特異性間質性肺炎パターンが認められた。複数の組織学的パターンの重複が認められ、特異的組織病理型が決定できなかったことから、肺症状はnTFHLに伴う続発性間質性肺炎であると考えられた。診断後に胸水が悪化したため、リンパ腫の節外浸潤の可能性を考慮してプレドニゾロン治療を開始すると、間質性肺炎が改善し、リンパ節サイズが縮小し、胸水量が減少した。

Language：Japanese   Publishing type：Research paper (scientific journal)  

Language：English   Publisher：BMC Pulmonary Medicine  

Background: We conducted a prospective observational study to elucidate the long-term prognosis and management of chronic obstructive pulmonary disease (COPD) in clinical practice in Japan in the mid-2010s. Methods: This prospective cohort study included 29 facilities. Data from 427 patients clinically diagnosed with COPD, enrolled between September 2013 and April 2016, were analyzed. Interstitial pneumonia was excluded through a central multidisciplinary discussion. Follow-up data were collected for up to 5 years after patient registration. Results: At the time of registration, 53 patients clinically diagnosed with COPD did not have airflow limitation (AFL). In the cohort with AFL (n = 374), 232 patients completed a 5-year follow-up, while 49 patients died during the 1576.6 person-years of observation. The mean age was 71.7 years with an overall 5-year survival rate of 85.4%. Stratified by % forced expiratory volume in one second (FEV1), survival rates were 93.6% in the mild and moderate AFL group, 82.5% in the severe AFL group, and 66.1% in the very severe AFL group. The prognosis of the subpopulation without AFL was poor with a 5-year survival of 81.6%. This subpopulation exhibited respiratory symptoms, low vital capacity and total lung capacity, and emphysematous changes. Conclusions: Our study presents the 5-year survival and real-world clinical practice scenario of a prospective cohort of patients clinically diagnosed with COPD in Japan in the mid-2010s. The survival rates of our cohort were numerically better than the Japanese cohort in the 1990s, regardless of the high median age of this cohort. Overall, 12.4% of the patients in this cohort with no AFL at registration exhibited respiratory symptoms and distinct spirometric patterns, and had a poor prognosis.

DOI： 10.1186/s12890-024-03347-5

Web of Science

Scopus

PubMed

Language：Japanese   Publishing type：Research paper (scientific journal)  

Language：English   Publisher：Scandinavian Journal of Rheumatology  

Objective: This study aimed to analyse whether initiating nintedanib treatment at a reduced dose could improve the treatment continuation rate while maintaining efficacy in patients with connective tissue disease (CTD)-associated interstitial lung disease. Method: In total, 51 patients (age 61.6 ± 13.2 years; 38 women, 13 men) were retrospectively analysed. The primary endpoint was the cumulative discontinuation rate due to adverse events. Secondary endpoints included changes in drug dosage, efficacy evaluated based on annual changes in forced vital capacity (FVC), and safety assessed based on the frequency of adverse events. Results: Eighteen patients who started treatment at the standard dose of 300 mg (standard dosage group) were compared with 33 patients who started treatment at a reduced dose (reduced dosage group). Systemic sclerosis was the most common CTD (n = 32), followed by idiopathic inflammatory myopathies and, rarely, rheumatoid arthritis. Both groups exhibited comparable cumulative discontinuation rates due to adverse events and similar frequencies of adverse events. No significant differences were observed in maintenance doses between the two groups; however, patients in the reduced dosage group had a lower cumulative dose for up to 52 weeks than those in the standard dosage group. No significant differences were observed in changes in FVC between the two groups. Conclusion: There was no evidence for a difference between the two groups in terms of discontinuation rates, efficacy, and safety. To provide further evidence, future studies using more precise dose-escalation protocols are warranted.

DOI： 10.1080/03009742.2024.2327159

Web of Science

Scopus

PubMed

Language：English  

DOI： 10.7759/cureus.61470

Web of Science

PubMed

Language：English   Publisher：Respirology Case Reports  

We report the first case of drug-induced interstitial lung disease attributed to lemborexant. A 66-year-old man reported to our hospital with the acute onset of cough and breathlessness with ground-glass opacity on radiological examination. Symptoms were identified after taking lemborexant for 2 consecutive days. The patient had undergone lemborexant treatment 2 years prior and had exhibited no symptoms at that time. The drug-induced lymphocyte stimulation test for lemborexant was positive. He showed rapid improvement upon treatment with steroid. With the rise in prescriptions of lemborexant for insomnia, lemborexant should be considered as a possible cause of drug-induced interstitial lung disease.

DOI： 10.1002/rcr2.1334

Web of Science

Scopus

PubMed

Language：English   Publisher：eLife  

Anticancer treatments can result in various adverse effects, including infections due to immune suppression/dysregulation and drug-induced toxicity in the lung. One of the major opportunistic infections is Pneumocystis jirovecii pneumonia (PCP), which can cause severe respiratory complications and high mortality rates. Cytotoxic drugs and immune-checkpoint inhibitors (ICIs) can induce interstitial lung diseases (ILDs). Nonetheless, the differentiation of these diseases can be difficult, and the pathogenic mechanisms of such diseases are not yet fully understood. To better comprehend the immunophenotypes, we conducted an exploratory mass cytometry analysis of immune cell subsets in bronchoalveolar lavage fluid from patients with PCP, cytotoxic drug-induced ILD (DI-ILD), and ICI-associated ILD (ICI-ILD) using two panels containing 64 markers. In PCP, we observed an expansion of the CD16+ T cell population, with the highest CD16+ T proportion in a fatal case. In ICI-ILD, we found an increase in CD57+ CD8+ T cells expressing immune checkpoints (TIGIT+ LAG3+ TIM-3+ PD-1+), FCRL5+ B cells, and CCR2+ CCR5+ CD14+ monocytes. These findings uncover the diverse immunophenotypes and possible pathomechanisms of cancer treatment-related pneumonitis.

DOI： 10.7554/eLife.87288

Web of Science

Scopus

PubMed

Language：Japanese   Publishing type：Research paper (scientific journal)  

Language：Japanese   Publishing type：Research paper (scientific journal)  

Language：English   Publisher：American Journal of Respiratory and Critical Care Medicine  

DOI： 10.1164/rccm.202309-1562LE

Web of Science

Scopus

PubMed

Web of Science

Web of Science

Language：Japanese   Publishing type：Research paper (scientific journal)  

Language：Japanese   Publishing type：Research paper (scientific journal)  

DOI： 10.1183/13993003.congress-2023.PA1232

Web of Science

DOI： 10.1183/13993003.congress-2023.PA2887

Web of Science

Language：English  

DOI： 10.1093/jjco/hyad053

Web of Science

PubMed

Language：Japanese   Publishing type：Research paper (scientific journal)  

DOI： 10.1111/1759-7714.15005.

Language：Japanese   Publishing type：Research paper (scientific journal)  

Language：Japanese   Publishing type：Research paper (scientific journal)  

Language：Japanese   Publishing type：Research paper (scientific journal)  

Language：English   Publisher：Respiratory Medicine Case Reports  

Pleuroparenchymal fibroelastosis (PPFE) is a rare form of interstitial pneumonitis. Although most cases of PPFE are idiopathic, some cases of PPFE occur secondary to stem cell transplantation. We report a 41-year-old woman developed pneumonia after autologous peripheral blood system cell transplantation (PBSCT). Eleven years after PBSCT, she presented with dyspnea. A computed tomographic scan showed pleuroparenchymal thickening and predominantly in the upper lobes. She was diagnosed with PPFE secondary to PBSCT. She was started nintedanib and administered oxygen therapy. Most cases of PPFE secondary to stem cell transplantation have been reported. However, we experienced the case of PPFE post-autologous PBSCT.

DOI： 10.1016/j.rmcr.2023.101845

Scopus

PubMed

Language：Japanese   Publishing type：Research paper (scientific journal)  

Language：English   Publisher：Chest  

Case Presentation: An 85-year-old Japanese man, who was taking aspirin and edoxaban for previous myocardial infarction and atrial fibrillation, came to our hospital with a chief complaint of dyspnea for 3 weeks. Chest radiography showed a massive left pleural effusion (Fig 1A). Analysis of pleural fluid showed an elevated hematocrit level at 32.8% (blood hematocrit level, 32.0%), and he was diagnosed with hemothorax. However, he had neither coagulation disorder nor thrombocytopenia, and the pleural effusion was negative for atypical cells. These findings suggested that the antithrombotic and anticoagulant medications might have induced the hemothorax.

DOI： 10.1016/j.chest.2021.09.012

Web of Science

Scopus

PubMed

Event date： 2023.4

Language：Japanese   Presentation type：Oral presentation (general)  

Venue：東京   Country：Japan  

Event date： 2023.4

Language：Japanese  

Venue：東京   Country：Japan  

researchmap

Event date： 2022.10

Language：Japanese   Presentation type：Symposium, workshop panel (public)  

Venue：オンライン   Country：Japan  

Event date： 2022.10

Language：Japanese   Presentation type：Oral presentation (general)  

Venue：東京   Country：Japan  

Language：English  

Language：Japanese  

Language：Japanese  

Language：Japanese  

Language：Japanese  

Language：Japanese  

Language：Japanese  

Language：Japanese  

Language：Japanese  

Language：Japanese  

Language：English  

Language：English  

Language：Japanese  

Language：Japanese  

Language：Japanese