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Background The response rate for osimertinib is high among patients with untreated epidermal growth factor receptor (EGFR) mutation-positive non-small cell lung cancer (NSCLC). However, there exist no biomarkers to predict the efficacy of the same. This study investigated whether BIM-γ mRNA expression in circulating tumor cells (CTCs) predicts poor outcomes for osimertinib treatment in patients with EGFR mutation-positive NSCLC. Methods Patients with advanced EGFR-tyrosine kinase inhibitor-untreated NSCLC or post-operative recurrence with EGFR-sensitive mutations (exon 19 deletion or L858R mutation) were included. Informed consent was obtained from all participants. The candidate biomarker BIM-γ was measured in CTCs after blood collection (10 mL of whole blood) at baseline. CTCs were collected with the ClearCell FX system, and quantitative real-time PCR was performed. Relative expression of BIM-γ mRNA from CTCs, as normalized to the reference gene (GAPDH mRNA), was calculated using the KCL22 cell line for calibration. Results We enrolled 30 EGFR mutation-positive NSCLC patients treated with osimertinib during the period from April 2018 through December 2019. All the patients had an EGFR mutation at the primary site: exon 19 deletion in 15 cases and L858R in 15 cases. Median CTC count at baseline was 12 (range 3–127)/7.5 mL, and median BIM-γ mRNA expression was 0.073 (range 0–1.37). Furthermore, the response rate to osimertinib was worse in patients with high than in those with low BIM-γ mRNA expression (n = 15 each) (26.6% vs. 73.3%, respectively; p = 0.011). Progression-free survival did not significantly differ between groups (p = 0.13). Conclusions BIM-γ mRNA overexpression in CTCs from EGFR mutation-positive NSCLC patients is a potential a biomarker for poor response to osimertinib. Clinical trial registration number UMIN:00032055.

The distress experienced by patients during bronchoscopy is often more severe than bronchoscopists anticipate. We examined the accuracy of bronchoscopist evaluation of predicted patient discomfort during bronchoscopy under intravenous sedation. This study retrospectively reviewed 186 consecutive patients who underwent bronchoscopy between December 2018 and April 2019. Ultimately, 113 patients who underwent bronchoscopy with pethidine and 64 patients who underwent bronchoscopy with pethidine and midazolam were assigned to the pethidine group and pethidine with midazolam combination group, respectively. We compared the patient discomfort score obtained by self-assessment with the patient discomfort score predictively evaluated by bronchoscopists using a 5-point rating scale in each sedation group. Any discrepancy was then evaluated. The pethidine group had significantly higher self-assessed patient discomfort scores than the predictive assessment by bronchoscopists [mean score 3.4±1.3 vs. 2.9±1.2; P < 0.0001]. Conversely, the pethidine with midazolam group had significantly lower self-assessed patient discomfort score than the bronchoscopists’ predictive assessment [mean score 2.4±1.5 vs. 3.3±1.4; P = 0.0004]. Multivariate analysis identified the use of midazolam as a significant factor affecting patient discomfort (odds ratio: 0.176, P < 0.001). Bronchoscopists may underestimate patient discomfort during bronchoscopy under intravenous sedation. The use of midazolam in combination with pethidine relieved patient discomfort.

Yellow nail syndrome (YNS) is a rare disorder characterized by the triad of yellow nails, lymphedema and chronic respiratory manifestations. Lymphatic abnormalities are a characteristic finding of YNS. Nevertheless, proof of lymphatic vessel abnormality by direct needle puncture for contrast agent injection is technically challenging because the lymphatic vessels in YNS are dysplastic. Thus, we opted for contrast-enhanced magnetic resonance (MR) lymphangiography with subcutaneous injection in patients suspected of YNS to facilitate easier comprehensive lymphatic vessel visualization. The lymphatic vessels of the thighs were few and barely recognizable, indicating weak flow cranially and lymphatic vessel hypoplasia. These findings were suggestive of dysplasia of the lymphatic vessels. Therefore, MR lymphangiography may be a useful novel diagnostic modality for YNS.

Background: The ATS/JRS/ALAT Guidelines for the Diagnosis of Hypersensitivity Pneumonitis (GL for HP) were published in 2020. Humidifier lung and summer-type HP are forms of HP, but it is unclear whether they can be diagnosed using the GL for HP. This study examined the level of confidence with which humidifier lung and summer-type HP can be diagnosed with the GL for HP.Methods: Data from 23 patients with humidifier lung and 20 patients with summer-type HP (mean age, 67.3 and 57.4 years, respectively) diagnosed between October 2012 and January 2022 were retrospectively reviewed. We evaluated high resolution computed tomography (HRCT) patterns, bronchoalveolar lavage fluid (BALF) findings, exposures, and histopathological findings to determine the level of confidence with which a diagnosis of HP could be made using the GL for HP. Results: HRCT pattern was classified as typical HP in 5 (22%) and compatible with HP in 18 (78%) patients with humidifier lung and judged as typical HP in 17 (85%) and compatible with HP in 3 (15%) summer-type-HP patients. The confidence level for diagnosis of HP was definite in 2 (8.7%), moderate in 14 (60.9%), and low in 7 (30.4%) patients with humidifier lung. It was definite in 12 (60%), high in 3 (15%), and moderate in 5 (25%) patients with summer-type HP.Conclusions: The GL for HP showed utility in the diagnosis of humidifier lung in many patients with a moderate to low confidence. There was, however, a definite to high confidence for patients with summer-type HP.

Background: The ATS/JRS/ALAT Guidelines for the Diagnosis of Hypersensitivity Pneumonitis (GL for HP) were published in 2020. Humidifier lung and summer-type HP are forms of HP, but it is unclear whether they can be diagnosed using the GL for HP. This study examined the level of confidence with which humidifier lung and summer-type HP can be diagnosed with the GL for HP.Methods: Data from 23 patients with humidifier lung and 20 patients with summer-type HP (mean age, 67.3 and 57.4 years, respectively) diagnosed between October 2012 and January 2022 were retrospectively reviewed. We evaluated high resolution computed tomography (HRCT) patterns, bronchoalveolar lavage fluid (BALF) findings, exposures, and histopathological findings to determine the level of confidence with which a diagnosis of HP could be made using the GL for HP. Results: HRCT pattern was classified as typical HP in 5 (22%) and compatible with HP in 18 (78%) patients with humidifier lung and judged as typical HP in 17 (85%) and compatible with HP in 3 (15%) summer-type-HP patients. The confidence level for diagnosis of HP was definite in 2 (8.7%), moderate in 14 (60.9%), and low in 7 (30.4%) patients with humidifier lung. It was definite in 12 (60%), high in 3 (15%), and moderate in 5 (25%) patients with summer-type HP.Conclusions: The GL for HP showed utility in the diagnosis of humidifier lung in many patients with a moderate to low confidence. There was, however, a definite to high confidence for patients with summer-type HP.

TOLLIP polymorphism has been implicated in the development and prognosis of idiopathic pulmonary fibrosis (IPF), mainly in whites. However, ethnic differences in the characteristics of other interstitial pneumonia (non-IPF) subtypes are unclear. We evaluated the association between the rs3750920 genotype and the clinical characteristics of Japanese patients with fibrosing interstitial lung diseases (ILD). We genotyped 102 patients with fibrosing ILD (75 IPF and 27 non-IPF patients) and analyzed the interaction between the rs3750920 genotype distribution and their clinical characteristics. The overall frequencies of the C/C, C/T, and T/T genotypes were 69%, 25%, and 6%, respectively. The proportion of minor T allele carriers was larger in IPF patients than in non-IPF patients (37% vs. 15%, P = 0.031). In addition, survival at 3 years was significantly better for carriers than for non-carriers of the T allele. There was no significant association between genotype distribution and change in pulmonary function after introduction of antifibrotic agents. The frequency of the minor T allele of rs3750920 was low in Japanese patients with fibrosing ILD, particularly in non-IPF patients. Carriers of the minor T allele had better survival than non-carriers. Presence of the T allele might thus be an indicator of better outcomes for fibrosing ILD.

Key message Spigot dropping is a rare but an intractable complication, because it is difficult to salvage a dropped spigot from the thoracic cavity. If the pneumothorax with a large fistula is recurrent, replacement with a larger size spigot may be recommended., Spigot dropping is a rare but an intractable complication of bronchial occlusion because it is difficult to salvage a dropped spigot from the thoracic cavity. If the pneumothorax with a large fistula is recurrent, replacement with a larger size spigot may be recommended.

Background Acute exacerbation of idiopathic pulmonary fibrosis (AE-IPF) is a fatal event that can occur during the clinical course of idiopathic pulmonary fibrosis (IPF). Although data from clinical trials suggest that the antifibrotic agents pirfenidone and nintedanib might reduce the risk of AE-IPF, the incidence of AE-IPF in patients receiving antifibrotic agents in clinical settings is unclear. Objectives To determine the incidence of AE-IPF in patients receiving antifibrotic agents and compare AE-IPF frequency in patients receiving pirfenidone and nintedanib. Methods We retrospectively reviewed the clinical records of 199 patients with IPF who were started on pirfenidone or nintedanib at our institution during the period from 2009 through 2018. Baseline characteristics, incidence of AE-IPF, and outcome after AE-IPF onset were analyzed. Results During the observation period, the 1-, 2-, and 3-year cumulative incidences of AE-IPF were 9.3 %, 22.1 %, and 25.0 %, respectively. The 1-, 2-, and 3-year cumulative incidence rates for AE-IPF in the pirfenidone group and nintedanib group were 5.1 % vs. 18.6 %, 20.4 % vs. 25.2 %, and 22.6 % vs. 29.6 %, respectively. AE-IPF incidence was significantly lower in patients treated with pirfenidone than in those treated with nintedanib (log rank test, P = 0.035). The 3-month survival rate after AE-IPF onset was 61.1 % in the pirfenidone group and 61.5 % in the nintedanib group; thus, outcomes after AE-IPF onset were similar in the 2 groups. Conclusion The reduction in AE-IPF risk might be greater for pirfenidone than for nintedanib.

A 65-year-old man with coronavirus disease 2019 (COVID-19) was admitted to our hospital. Computed tomography detected bilateral pneumonia with a lung nodule suspicious for lung cancer. Lobectomy was performed 3 months after the treatment for COVID-19 without any complications. The surgical specimen revealed fibrosis below the pleura with a small collection of lymphocytes and intravascular hemorrhagic thrombosis, and no residual RNA was detected. This is the first report describing a surgical specimen after recovery from COVID-19 pneumonia, and suggests that elective thoracic surgery can be performed safely, depending on the patient's respiratory function, without infectious risk.

Ultrasonic humidifier lung is a rare form of hypersensitivity pneumonitis (HP), and its clinical and radiological features are unclear. This study examined the clinical and radiological characteristics of humidifier lung.Data from 18 patients with humidifier lung (mean age, 67.3 years) diagnosed during October 2012 through April 2018 were retrospectively reviewed. We compared clinical, laboratory, and CT findings and bronchoalveolar lavage fluid (BALF) characteristics of these patients with those of 19 patients with summer-type HP (mean age, 57.4 years).Cough and dyspnea were the most common symptoms. White blood cell count and serum C-reactive protein titers were higher for humidifier lung than for summer-type HP. Serum levels of Krebs von den Lungen-6 and surfactant protein D were significantly lower for humidifier lung than for summer-type HP. The most common chest CT findings in humidifier lung were ground-glass opacities (88.9%) and mosaic attenuation (50.0%). Centrilobular ground glass nodules were less common in humidifier lung than in summer-type HP (27.8% vs 63.1%; P = 0.043). Peribronchovascular or subpleural nonsegmental consolidation was more frequent in humidifier lung than in summer-type HP (44.4% vs 5.3%; P = 0.013). Lymphocyte fractions in BALF specimens were significantly lower for humidifier lung than for summer-type HP (37.3% vs 69.0%; P 0.001). Neutrophil fractions were higher for humidifier lung, but the difference was not significant (22.1% vs 8.1%; P = 0.153). The CD4/8 ratio was higher for humidifier lung than for summer-type HP (1.7 vs 0.8; P = 0.003).The clinical and radiological characteristics of humidifier lung differ from those of summer-type HP.

Background: Recent clinical trials demonstrated the benefits of several guided-bronchoscopy technologies for the diagnosis of peripheral pulmonary lesions (PPLs). However, introduction of these technologies is expensive. Therefore, in clinical practice, these are unavailable in many hospitals. In contrast, virtual bronchoscopy (VB) using the computed tomography (CT) workstation can be made available immediately without additional cost as many hospitals already have the CT scan facility. However, the effectiveness of VB alone remains to be shown. Objectives: The aim of this study was to investigate the effect of VB using the CT workstation in hospitals performing conventional bronchoscopy. Methods: Results from consecutive patients who underwent bronchoscopy for small PPLs (major diameter ≤30 mm) were retrospectively reviewed. Sixty-nine patients who underwent bronchoscopy without VB from April 2014 to March 2015 and 56 patients who underwent bronchoscopy with VB from April 2015 to December 2015 were assigned to non-VB and VB groups, respectively. We compared the two groups and analyzed the factors affecting the diagnostic yield. Results: The VB group had a significantly higher diagnostic yield than the non-VB group (57.1 vs. 33.3%; p = 0.008). In the multivariate analysis, VB was identified as a significant factor affecting the diagnostic yield (odds ratio: 3.30, p = 0.011). Conclusions: In the conventional bronchoscopy settings, VB using the CT workstation is efficient for the diagnosis of PPLs when other guided-bronchoscopy techniques are unavailable.

Anti-tumor necrosis factor α (anti-TNFα) agents increase the risk of tuberculosis (TB), but cases are rarely fatal. This report concerns a patient who was undergoing treatment with infliximab and presented with acute respiratory distress syndrome due to miliary TB without a miliary shadow. The findings of a pathological autopsy revealed innumerable granulomas in the organs, and the miliary nodules in the lung consisted of more unstructured granulomas. Anti-TNFα agents are unusual in the presentation of TB. It is important, particularly for patients receiving anti-TNFα agents, to constantly consider the possibility of TB and to prepare for appropriate management.

Background Pathological findings of interstitial pneumonia (IP) reveal the accumulation of inflammatory cells and proliferation of fibroblasts in lung tissue. Although a treatment has not yet been established for IP, particularly for IP with collagen diseases, chemokines may play a role in the pathogenesis of IP for inflammatory cell infiltration. We previously reported that chemokine (C-X3-C motif) ligand 1 (CX3CL1, also known as fractalkine) has potential as a therapeutic target for rheumatoid arthritis (RA).1,2,3Humanized anti-human CX3CL1 monoclonal antibody (mAb) is currently undergoing clinical trials for RA.4 Objectives In the present study, we examined the therapeutic effects of CX3CL1 blockade in a murine model of IP. Methods Bleomycin (BLM)-induced IP was developed by the intratracheal administration of BLM to C57BL/6 mice. The murine lung was stained with hematoxylin and eosin, and the expression of CX3CL1 and CX3CR1, a receptor for CX3CL1, was analyzed by immunohistochemistry. Mice were treated with anti-CX3CL1 mAb for 2 weeks. Collagen eluted from the lung was quantified using the SircolTM Collagen Assay. The expression of CX3CL1 and CX3CR1 by mouse lung fibroblasts (MLFs) was examined with quantitative RT-PCR and Western blotting, respectively. Cell movement was investigated using the scrape motility assay. Results The expression of CX3CL1 and CX3CR1 was upregulated in BLM-induced IP. The treatment with anti-CX3CL1 mAb did not significantly alter inflammatory cell infiltration. However, collagen in the lung was decreased by the treatment with anti-CX3CL1 mAb. Stimulation with CX3CL1 did not alter the in vitro production of collagen by MLFs, but significantly enhanced cell movement. Conclusion CX3CL1 may be involved in increasing collagen in IP and the cell movement of MLFs. The present results suggest that CX3CL1 plays an important role in fibrosis in IP. References [1] Nanki T, et al. Inhibition of fractalkine ameliorates murine collagen-induced arthritis. J Immunol. 2004;173(11):7010-6. [2] Nanki T, et al. Migration of CX3CR1-positive T cells producing type 1 cytokines and cytotoxic molecules into the synovium of patients with rheumatoid arthritis. Arthritis Rheum. 2002;46(11):2878-83. [3] Nanki T, et al. Fractalkine/CX3CL1 in rheumatoid arthritis. Mod Rheumatol. 2017 May;27(3):392-397. [4] Tanaka Y, et al. Safety, pharmacokinetics, and efficacy of E6011, an antifractalkine monoclonal antibody, in a first-in-patient phase 1/2 study on rheumatoid arthritis. Modern rheumatology. 2018;28(1):58-65. Disclosure of Interests Soichi Yamada: None declared, Shion Miyoshi: None declared, Natsuko Kusunoki: None declared, Hiroshi Sato: None declared, Yoshikazu Kuboi Shareholder of: Eisai Co., Ltd., Employee of: KAN Research Institute, Inc. (subsidiary of Eisai Co., Ltd.), Kana Hoshino-Negishi Shareholder of: Eisai Co., Ltd., Employee of: KAN Research Institute, Inc. (subsidiary of Eisai Co., Ltd.), NAOTO ISHII Shareholder of: Eisai Co., Ltd., Employee of: KAN Research Institute, Inc. (subsidiary of Eisai Co., Ltd.), Toshio Imai Shareholder of: Eisai Co., Ltd., Employee of: KAN Research Institute, Inc. (subsidiary of Eisai Co., Ltd.), Tetsuo Mikami Speakers bureau: EA Pharma, Hiroyasu Nakano: None declared, Shinichi Kawai Grant/research support from: Nippon Zoki, Chugai, Ono, Ayumi, Hisamitu, Eisai, Japan Tobacco, Nippon Kayaku, Daiichi Sankyo, Astellas, Yutoku, and Mitsubishi Tanabe, Consultant for: Santen, Japan Tobacco, Speakers bureau: Ayumi, Chugai, Ono, Astellas, Pfizer, Celltrion, Toshihiro Nanki Grant/research support from: Chugai, Eisai, Takeda, Teijin, Eli Lilly, Bristol-Myers, AbbVie, Ono, Novartis, Asahikasei, Mitsubishi-Tanabe, Astellas, Ayumi, Pfizer, Daiichi Sankyo, Shionogi, Sanofi, Nippon Kayaku, Yutoku, Actelion, UCB, Bayer, Nihon Pharmaceutical., Consultant for: UCB, Eisai, Chugai, Ono, Gilead., Speakers bureau: Mitsubishi-Tanabe, Chugai, Eisai, Takeda, Astellas, Janssen, Eli Lilly, Ayumi, Pfizer, Asahikasei, Sanofi, Daiichi Sankyo, Otsuka, AbbVie, Ono, Teijin, Nippon Kayaku, UCB.

An 80-year-old woman with rheumatoid arthritis and a past history of tuberculosis presented with exertional dyspnea and edema of both legs. Chest X-ray performed on admission showed bilateral pleural effusion. Thoracoscopy under local anesthesia was performed, and vasodilation and non-specific yellowish inflammatory changes were noted in the pleura. A pathological examination showed chronic fibrosing pleuritis in addition to chronic pleural inflammatory changes with lymphoid aggregates. The nails on all fingers and toes were thickened and displayed yellow discoloration, and the edema was resistant to diuretics. Lymphoscintigraphy was conducted, which showed lymphatic drainage abnormalities. The patient was ultimately diagnosed as having yellow nail syndrome.

Invasive pulmonary aspergillosis (IPA) usually occurs in patients with severe immunodeficiencies involving neutropenia. Underlying lung disease is a well-known risk factor of IPA; however, interstitial lung disease has not been recognized as a risk factor of IPA. We herein report a patient with fibrotic nonspecific interstitial pneumonia who experienced IPA without neutropenia. His IPA was fatal and showed unusually slow disease progression over one month. The computed tomography findings showed only nonspecific consolidation and no typical lesions suggestive of IPA. Finally, the autoptic findings revealed numerous Aspergillus fungi, neutrophilic pulmonary necrosis, and vessels invaded by Aspergillus fungi.

Type II alveolar epithelial cells (AEC2s) play a crucial role in the regeneration of type I AECs after acute lung injury. The mechanisms underlying the regeneration of AEC2s are not fully understood. To address this issue, here, we investigated a murine model of acute lung injury using mice expressing human Diphtheria Toxin Receptor (DTR) under the control of Lysozyme M promoter (LysM-DTR). DT injection induced the depletion of AEC2s, alveolar macrophages, and bone marrow (BM)-derived myeloid cells in LysM-DTR mice, and the mice died within 6 days after DT injection. Apoptotic AEC2s and bronchiolar epithelial cells appeared at 24 hr, whereas Ki67-positive proliferating cells appeared in the alveoli and bronchioles in the lung of LysM-DTR mice at 72-96 hr after DT injection. Transfer of wild-type BM cells into LysM-DTR mice accelerated the regeneration of AEC2s along with the up-regulation of several growth factors. Moreover, several metabolites were significantly decreased in the sera of LysM-DTR mice compared with WT mice after DT injection, suggesting that these metabolites might be biomarkers to predict AEC2s injury. Together, LysM-DTR mice might be useful to identify growth factors to promote lung repair and the metabolites to predict the severity of lung injury.

Takotsubo cardiomyopathy is a transient left-ventricular dysfunction that typically occurs in elderly women due to emotional or physical stress. An 85-y-old woman underwent flexible bronchoscopy to evaluate her malignant lymphoma. After flexible bronchoscopy, she experienced takotsubo cardiomyopathy diagnosed by left ventriculography and subsequent generalized tonic-clonic seizure diagnosed by electroencephalography. Magnetic resonance imaging of her brain after 1 d showed post-convulsive encephalopathy. We believe that these 2 consecutive incidents were caused by the physical stress of the flexible bronchoscopy.

Background Some trials recently demonstrated the benefit of targeted treatment for malignant disease; therefore, adequate tissues are needed to detect the targeted gene. Pleural biopsy using flex-rigid pleuroscopy and pleural effusion cell block analysis are both useful for diagnosis of malignancy and obtaining adequate samples. The purpose of our study was to compare the diagnostic utility between the two methods among patients with malignant pleural disease with effusion. Methods Data from patients who underwent flex-rigid pleuroscopy for diagnosis of pleural effusion suspicious for malignancy at the National Cancer Center Hospital, Japan between April 2011 and June 2014 were retrospectively reviewed. All procedures were performed under local anesthesia. At least 150 mL of pleural fluid was collected by pleuroscopy, followed by pleural biopsies from the abnormal site. Results Thirty-five patients who were finally diagnosed as malignant pleural disease were included in this study. Final diagnoses of malignancy were 24 adenocarcinoma, 1 combined adeno-small cell carcinoma, and 7 malignant pleural mesothelioma (MPM), and 3 metastatic breast cancer. The diagnostic yield was significantly higher by pleural biopsy than by cell block [94.2% (33/35) vs. 71.4% (25/35); p = 0.008]. All patients with positive results on cell block also had positive results on pleural biopsy. Eight patients with negative results on cell block had positive results on pleural biopsy (lung adenocarcinoma in 4, sarcomatoid MPM in 3, and metastatic breast cancer in 1). Two patients with negative results on both cell block and pleural biopsy were diagnosed was sarcomatoid MPM by computed tomography-guided needle biopsy and epithelioid MPM by autopsy. Conclusion Pleural biopsy using flex-rigid pleuroscopy was efficient in the diagnosis of malignant pleural diseases. Flex-rigid pleuroscopy with pleural biopsy and pleural effusion cell block analysis should be considered as the initial diagnostic approach for malignant pleural diseases presenting with effusion.