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The newly developed portable oxygen concentrator with an auto-demand oxygen delivery system (auto-DODS) automatically switches between 3 sensitivities according to the negative pressure gradient of inhalation and supplies oxygen only during inhalation. The aim of this study was to verify the effectiveness and safety of auto-demand devices compared with a continuous flow oxygen concentrator, during sleep, in a randomized crossover noninferiority trial. We alternatively used an auto-DODS or a continuous-flow oxygen concentrator, all night on separate days for HOT (Home Oxygen Therapy) patients with nocturnal hypoxemic symptoms. The primary endpoints were the mean value of oxygen saturation (SpO 2 ) over the total sleep time. The secondary endpoints included the efficacy endpoints and the safety endpoints. Regarding the primary endpoint, the difference in SpO 2 between the auto-DODS and continuous flow was 0.835%. Since the upper limit of this difference did not exceed 2.8, which was set as the noninferiority margin, it was shown that the auto-DODS did not reduce SpO 2 by at least 2.8% on average compared to continuous flow. No equipment failure or exacerbation of disease was observed, confirming the safety of the auto-DODS during the night., (© 2024. The Author(s).)

Epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKIs) are key drugs for patients with EGFR mutation-positive non-small-cell lung cancer, and osimertinib is the standard treatment. Although drug-induced interstitial lung disease (ILD) is a remarkable adverse event of EGFR-TKIs, evidence regarding the continuation and re-challenge of EGFR-TKIs after drug-induced severe ILD is lacking. This is the first report of successful switching to ramucirumab plus erlotinib after osimertinib-induced severe ILD in an 81-year-old woman with stage IV lung adenocarcinoma harboring the EGFR L858R mutation in exon 21. These findings suggest that ramucirumab plus erlotinib may be a viable treatment option for osimertinib-induced severe ILD.

The respiratory rate is an important factor for assessing patient status and detecting changes in the severity of illness. Real-time determination of the respiratory rate will enable early responses to changes in the patient condition. Several methods of wearable devices have enabled remote respiratory rate monitoring. However, gaps persist in large-scale validation, patient-specific calibration, standardization and their usefulness in clinical practice has not been fully elucidated. The aim of this study was to evaluate the accuracy of 2 wearable stretch sensors, C-STRECH® which is used in clinical practice and a novel stretchable capacitor in measuring the respiratory rate. The respiratory rate of 20 healthy subjects was measured by a spirometer with the stretch sensor applied to 1 of 5 locations (umbilicus, lateral abdomen, epigastrium, lateral chest, or chest) of their body at rest while they were in a sitting or supine position before or after exercise. The sensors detected the largest amplitudes at the epigastrium and umbilicus compared to other sites of measurement for the sitting and supine positions, respectively. At rest, the respiratory rate of the sensors had an error of 0.06 to 2.39 breaths/minute, whereas after exercise, an error of 1.57 to 3.72 breaths/minute was observed compared to the spirometer. The sensors were able to detect the respiratory rate of healthy volunteers in the sitting and supine positions, but there was a need for improvement in detection after exercise., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2024 the Author(s). Published by Wolters Kluwer Health, Inc.)

Background: There have been reports on the impact of concurrent drugs on the outcome of immunotherapy for non-small cell lung carcinoma (NSCLC). However, the effect of some drugs, such as antibiotics and nonsteroidal anti-inflammatory drugs (NSAIDs), has not been clarified in patients with NSCLC. In the present study, we aimed to assess the association between concurrent drugs and the outcomes of immune checkpoint inhibitors (ICIs) alone or in combination with chemotherapy for patients with advanced NSCLC., Methods: We retrospectively assessed patients with advanced NSCLC who underwent ICI treatment between September 2017 and December 2021 at Kobe University Hospital. We evaluated the data regarding the use of antibiotics within 30 days before ICI initiation, as well as the use of proton pump inhibitors (PPIs) and NSAIDs during ICI initiation., Results: A total of 127 patients were assessed, among whom 28 (22.0%) patients received antibiotics, 39 (30.7%) PPIs, and 36 (28.3%) NSAIDs. No significant differences were observed between the patients with and without antibiotic use. However, patients using NSAIDs had significantly worse objective response rates (ORR) and progression-free survival (PFS) with ICI alone or in combination with chemotherapy compared to those who did not (ORR, 47.2% vs. 67.0%; p = 0.045. PFS, 6.3 months vs. 10.8 months; p = 0.02). Patients using PPIs demonstrated a worse ORR of ICI in combination with chemotherapy compared to those who did not (ORR, 45.2% vs. 72.6%; p = 0.013)., Conclusions: The unnecessary use of NSAIDs along with immunotherapy should be discouraged., (© 2024 The Authors. Thoracic Cancer published by John Wiley & Sons Australia, Ltd.)

Background: Next-generation sequencing (NGS) is essential for lung cancer treatment. It is important to collect sufficient tissue specimens, but sometimes we cannot obtain large enough samples for NGS analysis. We investigated the yield of NGS analysis by frozen cytology pellets using an Oncomine Comprehensive Assay or Oncomine Precision Assay., Methods: We retrospectively enrolled patients with lung cancer who underwent bronchoscopy at Kobe University Hospital and were enrolled in the Lung Cancer Genomic Screening Project for Individualized Medicine. We investigated the amount of extracted DNA and RNA and determined the NGS success rates. We also compared the amount of DNA and RNA by bronchoscopy methods. To create the frozen cytology pellets, we first effectively collected the cells and then quickly centrifuged and cryopreserved them., Results: A total of 132 patients were enrolled in this study between May 2016 and December 2022; of them, 75 were subjected to frozen cytology pellet examinations and 57 were subjected to frozen tissue examinations. The amount of DNA and RNA obtained by frozen cytology pellets was nearly equivalent to frozen tissues. Frozen cytology pellets collected by endobronchial ultrasound-guided transbronchial needle aspiration yielded significantly more DNA than those collected by transbronchial biopsy methods. (P < 0.01) In RNA content, cytology pellets were not inferior to frozen tissue. The success rate of NGS analysis with frozen cytology pellet specimens was comparable to the success rate of NGS analysis with frozen tissue specimens., Conclusions: Our study showed that frozen cytology pellets may have equivalent diagnostic value to frozen tissue for NGS analyses. Bronchial cytology specimens are usually used only for cytology, but NGS analysis is possible if enough cells are collected to create pellet specimens. In particular, the frozen cytology pellets obtained by endobronchial ultrasound-guided transbronchial needle aspiration yielded sufficient amounts of DNA., Trial Registration: This was registered with the University Medical Hospital Information Network in Japan (UMINCTR registration no. UMIN000052050)., (© 2024. The Author(s).)

Objectives: : Several studies have reported that oropharyngeal myofunctional therapy (OMT) reduces the severity of obstructive sleep apnea (OSA). However, because OMT protocols are often complicated, they take time and effort to implement. The aim of this study was to determine the therapeutic effect of 8 weeks of simple tongue strength training with a training device., Methods: : Twenty patients with mild to moderate sleep-disordered breathing were randomized to the control group (n=10) or intervention group (n=10). The patients in the intervention group completed 8 weeks of daily tongue strength training using a training device. After 8 weeks, we evaluated each patient for sleep-disordered breathing by portable monitoring. We also evaluated each patient's body mass index (BMI), neck circumference, Epworth Sleepiness Scale (ESS) score, and tongue pressure., Results: No significant difference was found in the change in apnea hypopnea index (AHI) from baseline to 8 weeks between the control and intervention groups (P=0.44). However, the changes in neck circumference (P=0.02) and maximum tongue pressure (P=0.03) from baseline to 8 weeks were significantly different between the two groups. No significant difference was found for changes in BMI and ESS scores from baseline to 8 weeks between the two groups., Conclusions: : Tongue strength training in patients with sleep-disordered breathing did not significantly improve AHI as measured by portable monitoring, although significant changes were observed for increased tongue pressure and reduced neck circumference., Competing Interests: CONFLICTS OF INTEREST: The authors declare no conflict of interest., (2024 The Japanese Association of Rehabilitation Medicine.)

Background: Skin disorders are the most common side effect associated with epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) therapy. It is important to manage skin lesions. Adapalene has been used to treat skin lesions caused by EGFR-TKIs in some cases. The aim of this study was to investigate the functional mechanism of adapalene in erlotinib-induced skin disorder., Methods: To analyze the effect of adapalene on skin rash, afatinib and adapalene were administered to mice. The relationship between the concentration of adapalene and skin disorders was also examined by analyzing AQP3 expression. A skin lesion model was experimentally established in human skin keratinocytes (HaCaT) by using erlotinib with TNF-α and IL-1β. We used qRT-PCR to analyze chemokine-induced inflammation and western blotting to analyze the effects of adapalene on the NF-κB signaling pathway. Antimicrobial peptides and adhesion factors were also examined using qRT-PCR., Results: Mice administered 0.01% adapalene had less skin inflammation than mice treated with afatinib alone. The expression level of AQP3 decreased in an adapalene concentration-dependent manner. The mRNA levels of proinflammatory cytokines such as CCL2 and CCL27 in HaCaT cells were significantly reduced by adapalene. The expression of an antimicrobial peptide, hBD3, was upregulated after adapalene treatment. Adhesion factors, such as E-cadherin, were significantly downregulated by EGFR-TKI and significantly upregulated by adapalene treatment. Western blot analysis suggested that erlotinib-induced phosphorylation of p65 was decreased by adapalene., Conclusion: We suggest that adapalene may be a possible treatment option for skin disorders induced by EGFR-TKIs., (© 2024 The Authors. Thoracic Cancer published by John Wiley & Sons Australia, Ltd.)

Tumor-associated macrophages (TAMs) are abundant in the tumor microenvironment and are considered potential targets for cancer immunotherapy. To examine the antitumor effects of agents targeting human TAMs in vivo , we here established preclinical tumor xenograft models based on immunodeficient mice that express multiple human cytokines and have been reconstituted with a human immune system by transplantation of human CD34 + hematopoietic stem and progenitor cells (HIS-MITRG mice). HIS-MITRG mice supported the growth of both human cell line (Raji)- and patient-derived B cell lymphoma as well as the infiltration of human macrophages into their tumors. We examined the potential antitumor action of an antibody to human SIRPα (SE12C3) that inhibits the interaction of CD47 on tumor cells with SIRPα on human macrophages and thereby promotes Fcγ receptor-mediated phagocytosis of the former cells by the latter. Treatment with the combination of rituximab (antibody to human CD20) and SE12C3 inhibited Raji tumor growth in HIS-MITRG mice to a markedly greater extent than did rituximab monotherapy. This enhanced antitumor effect was dependent on human macrophages and attributable to enhanced rituximab-dependent phagocytosis of lymphoma cells by human macrophages. Treatment with rituximab and SE12C3 also induced reprogramming of human TAMs toward a proinflammatory phenotype. Furthermore, the combination treatment essentially prevented the growth of patient-derived diffuse large B cell lymphoma in HIS-MITRG mice. Our findings thus support the study of HIS-MITRG mice as a model for the preclinical evaluation in vivo of potential therapeutics, such as antibodies to human SIRPα, that target human TAMs., Competing Interests: TM and YM hold a patent on the antitumor drug “anti-SIRPα Ab” Japan patent number P6923942. TM has received royalties from Daiichi Sankyo. He also has received a research grant from JCR Pharmaceuticals Co. Ltd. The remaining 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. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (Copyright © 2023 Saito, Iida-Norita, Afroj, Refaat, Hazama, Komori, Ohata, Takai, Oduori, Kotani, Funakoshi, Koma, Murata, Yakushijin, Matsuoka, Minami, Yokozaki, Manz and Matozaki.)

Background: Actionable tumor genomic alterations, primarily EGFR mutations, occur in nearly 70% of Japanese advanced nonsquamous non-small cell lung cancer (NSCLC) patients. Standard assessment of tumor tissue includes rapid testing for EGFR mutations, ALK fusions and ROS1 fusions. We conducted a prospective observational study (WJOG13620L) of follow-on next-generation sequencing of circulating tumor DNA (ctDNA) in patients without driver alterations after EGFR testing., Methods: Patients with untreated advanced (Stage IIIB-IV or relapsed) nonsquamous NSCLC without EGFR mutations according to single-plex testing of tumor tissue, were enrolled into this study. Patients with other known driver mutations or who underwent comprehensive genomic profiling were excluded. Plasma was analyzed by Guardant360, and the primary endpoint was the proportion of patients with pathogenic gene alterations in at least one of nine genes., Results: Among the 72 patients enrolled, ALK and ROS1 fusions were tested in 86.1% and 65.2%, respectively. Alterations in pre-defined genes were detected in 21 patients (29.2%; 95% confidence interval: 19.0-41.1, p < 0.001 [one-sided null hypothesis proportion of 10%]), including RET fusion (n = 1) and mutations in KRAS (n = 11), EGFR (n = 5), ERBB2 (n = 3), and BRAF (n = 1). Median time from sample submission to results was 8 days (range, 5-17 days)., Conclusion: Rapid follow-on comprehensive testing of ctDNA should be considered prior to first-line treatment for patients with advanced nonsquamous NSCLC when no alterations are detected after single-plex tissue testing., (© 2023 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

Introduction: Pulmonary sarcomatoid carcinoma (PSC) is a rare subtype of lung cancer associated with poor prognosis and resistance to conventional chemotherapy. Immune checkpoint inhibitors (ICIs), alone or in combination with chemotherapy, were found to have clinical benefits in PSC in recent studies. Nevertheless, because these studies included a small number of patients owing to disease rarity, larger studies are needed to evaluate the effectiveness and safety of ICI-based therapy for PSC., Methods: This multicenter retrospective study evaluated patients with ICI-naive advanced or metastatic PSC who were treated with ICI-based therapy at 25 hospitals in Japan., Results: A total of 124 patients were evaluated. The overall response rate, median progression-free survival (PFS), and median overall survival (OS) were 59.0%, 10.5 months, and 32.8 months, respectively. The PFS and OS rates at 24 months were 35.3% and 51.5%, respectively. Programmed death-ligand 1 expression, concomitant chemotherapy, and the treatment line were not significantly associated with PFS or OS. Immune-related adverse events (irAEs) were observed in 70 patients (56.5%), including 30 (24.2%) with grade 3 to 5 events. Patients with mild irAEs (grades 1-2) had longer PFS and OS than did those with severe (grades 3-5) or no irAEs. In a multivariate analysis, any-grade irAEs and the absence of liver metastases were independently associated with PFS, whereas any-grade irAEs and Eastern Cooperative Oncology Group performance status less than or equal to 1 were independently associated with OS., Conclusions: ICI-based therapy was found to have promising effectiveness in patients with advanced or metastatic PSC, regardless of programmed death-ligand 1 expression, concomitant chemotherapy, or treatment line., (© 2023 The Authors.)

The molecular etiology of idiopathic pulmonary fibrosis (IPF) has been extensively investigated to identify new therapeutic targets. Although anti-inflammatory treatments are not effective for patients with IPF, damaged alveolar epithelial cells play a critical role in lung fibrogenesis. Here, we establish an organoid-based lung fibrosis model using mouse and human lung tissues to assess the direct communication between damaged alveolar type II (AT2)-lineage cells and lung fibroblasts by excluding immune cells. Using this in vitro model and mouse genetics, we demonstrate that bleomycin causes DNA damage and activates p53 signaling in AT2-lineage cells, leading to AT2-to-AT1 transition-like state with a senescence-associated secretory phenotype (SASP). Among SASP-related factors, TGF-β plays an exclusive role in promoting lung fibroblast-to-myofibroblast differentiation. Moreover, the autocrine TGF-β-positive feedback loop in AT2-lineage cells is a critical cellular system in non-inflammatory lung fibrogenesis. These findings provide insights into the mechanism of IPF and potential therapeutic targets., (© 2023. Springer Nature Limited.)

Ultrathin bronchoscopy has been reported to have a higher diagnostic yield than thin bronchoscopy for small peripheral lung lesions in transbronchial biopsy under radial endobronchial ultrasonography (EBUS). However, data comparing the number of tumor cells in non-small cell lung cancer (NSCLC) are limited. We retrospectively compared the number of NSCLC tumor cells in peripheral lung lesions obtained using an ultrathin bronchoscope and a thin bronchoscope with radial EBUS between April 2020 and October 2021. In all patients, we used virtual bronchoscopic navigation (VBN) software, and guide sheaths were used in thin bronchoscopy cases. A total of 175 patients were enrolled in this study. Ultrathin bronchoscopy cases (n = 69) had lesions with a smaller diameter that are more peripherally located compared to thin bronchoscopy cases (n = 106) (median, 25.0 vs. 26.5 mm, mean bronchial generations accessed by bronchoscopy; 4.4±1.2 vs. 3.8±1.0, respectively; p<0.010). There were no significant differences in the overall diagnostic yield (ultrathin vs. thin bronchoscopy cases, 68.1% vs. 72.6%, p = 0.610) or diagnostic yield in only lung cancer cases (78.6% vs. 78.5%, p = 1.000). In histologically NSCLC cases (n = 102), the maximum number of tumor cells per slide as the primary endpoint was similar (average, 307.6±246.7 vs. 328.7±314.9, p = 0.710). The success rate of the Oncomine™ analysis did not differ significantly (80.0% vs. 55.6%, p = 0.247). The yield of NSCLC tumor cells was not different between the samples obtained by the ultrathin bronchoscope and those obtained by the thin bronchoscope., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2023 Yatani et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

High-flow nasal cannulas (HFNCs) have become common devices for patients with respiratory failure who are treated in general wards. Few reports have been published on in-hospital mortality associated with the ratio of oxygen saturation (ROX) index, measured by pulse oximetry/fraction of inspired oxygen to respiratory rate, in patients treated with HFNCs. We aimed to examine in-hospital mortality and associated factors in patients who initiated HFNC use in a general ward. Sixty patients who initiated HFNC use in general wards at Kobe University Hospital between December 2016 and October 2020 were retrospectively enrolled. We assessed in-hospital mortality, comorbidities, and ROX index. The in-hospital mortality was 48.3%, and ROX index values were significantly lower in patients who died than in those who did not (at HFNC oxygen therapy initiation; 6.93 [2.73-18.5] vs. 9.01 [4.62-18.1], p = 0.00861). Although the difference was not statistically significant, the change in ROX index values between HFNC initiation and 12 hours after initiation tended to be greater in the patients who died in the hospital (0.732 [-2.84-3.5] vs. -0.35[-4.3-2.6], p = 0.0536). Lower ROX index values may be associated with the in-hospital death of patients who are treated with HFNCs in general wards.

Langerhans cell histiocytosis (LCH) is a rare neoplastic disorder characterized by inflammatory lesions arising from the anomalous accumulation of pathogenic CD1a + CD207 + dendritic cells (DCs). SIRPα is a transmembrane protein highly expressed in myeloid cells such as DCs and macrophages. Here we show that SIRPα is a potential therapeutic target for LCH. We found that SIRPα is expressed in CD1a + cells of human LCH lesions as well as in CD11c + DCs in the spleen, liver, and lung of a mouse model of LCH (BRAFV600E CD11c mouse), in which an LCH-associated active form of human BRAF is expressed in a manner dependent on the mouse Cd11c promoter. BRAFV600E CD11c mice manifested markedly increased numbers of CD4 + T cells, regulatory T cells, and macrophages as well as of CD11c + MHCII + DCs in the spleen. Monotherapy with a mAb to SIRPα greatly reduced the percentage of CD11c + MHCII + DCs in peripheral blood, LCH-like lesion size in the liver, and the number of CD11c + MHCII + DCs in the spleen of the mutant mice. Moreover, this mAb promoted macrophage-mediated phagocytosis of CD11c + DCs from BRAFV600E CD11c mice, whereas it had no effects on the viability or CCL19-dependent migration of such CD11c + DCs or on their expression of the chemokine genes Ccl5, Ccl20, Cxcl11, and Cxcl12. Our results thus suggest that anti-SIRPα monotherapy is a promising approach to the treatment of LCH that is dependent in part on the promotion of the macrophage-mediated killing of LCH cells., (© 2023 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.)

Background: The desired depth of sedation during flexible bronchoscopy is one in which verbal contact is possible whenever necessary. Although it is common that the depth of sedation is assessed by validated instruments such as the modified observer's assessment of alertness and sedation (MOAA/S) score, the repeated stimulation associated with the assessment can affect the sedation. The bispectral index (BIS) has been widely used for general anesthesia due to its objective and noninvasive nature. However, the utility of BIS monitoring and a target BIS value for use during bronchoscopy have not been fully elucidated., Methods: We performed a retrospective observational study to assess the utility of the BIS value for monitoring conscious sedation during bronchoscopy at Kobe University Hospital from August 2020 to April 2021., Results: Eighteen patients underwent bronchoscopy with BIS monitoring. The BIS value significantly correlated with the MOAA/S score (r = 0.2, p < 0.01), and the correlation was stronger in sufficiently sedated patients (r = 0.486, p < 0.01). The lowest MOAA/S score during the procedure was highly correlated with the BIS value (r = 0.625, p < 0.01). The BIS monitoring seemed to be more sensitive to changes in the sedation level than the MOAA/S score, heart rate and mean arterial pressure. The median BIS value at an MOAA/S score of 3-4, the desired depth of sedation, was 82.0., Conclusions: BIS value is useful for monitoring sedation during bronchoscopy. This study suggests that a BIS value of 82 reflects an adequate level of sedation., (© 2022 The Authors. Thoracic Cancer published by China Lung Oncology Group and John Wiley & Sons Australia, Ltd.)

Background: Chronic obstructive pulmonary disease (COPD) is a health problem that results in death, commonly due to the development of pulmonary hypertension (PH). Here, by utilizing a mouse model of intratracheal elastase-induced emphysema that presents three different phases of COPD, we sought to observe whether budesonide/glycopyrronium/formoterol fumarate (BGF) triple therapy could prevent COPD-PH in addition to ameliorating COPD progression., Methods: We utilized intratracheal elastase-induced emphysema mouse model and performed experiments in three phases illustrating COPD progression: inflammatory (1 day post-elastase), emphysema (3 weeks post-elastase) and PH (4 weeks post-elastase), while treatments of BGF and controls (vehicle, one-drug, and two-drug combinations) were started in prior to elastase instillation (inflammatory phase), at day 7 (emphysema), or at day 14 (PH phase). Phenotype analyses were performed in each phase. In vitro, A549 cells or isolated mouse lung endothelial cells (MLEC) were treated with TNFα with/without BGF treatment to analyze NFκB signaling and cytokine expression changes., Results: We observed significant reductions in the proinflammatory phenotype observed in the lungs and bronchoalveolar lavage fluid (BALF) 1 day after elastase administration in mice treated with BGF compared with that in mice administered elastase alone (BALF neutrophil percentage, p = 0.0011 for PBS/Vehicle vs. PBS/Elastase, p = 0.0161 for PBS/Elastase vs. BGF). In contrast, only BGF treatment significantly ameliorated the elastase-induced emphysematous lung structure and desaturation after three weeks of elastase instillation (mean linear intercept, p = 0.0156 for PBS/Vehicle vs. PBS/Elastase, p = 0.0274 for PBS/Elastase vs. BGF). Furthermore, BGF treatment prevented COPD-PH development, as shown by improvements in the hemodynamic and histological phenotypes four weeks after elastase treatment (right ventricular systolic pressure, p = 0.0062 for PBS/Vehicle vs. PBS/Elastase, p = 0.027 for PBS/Elastase vs. BGF). Molecularly, BGF acts by inhibiting NFκB-p65 phosphorylation and subsequently decreasing the mRNA expression of proinflammatory cytokines in both alveolar epithelial and pulmonary endothelial cells., Conclusion: Our results collectively showed that BGF treatment could prevent PH in addition to ameliorating COPD progression via the inhibition of inflammatory NFκB signaling., (© 2022. The Author(s).)

Background: Bronchoscopy can be a distress for the patient. There have been few studies on the combination of sedatives and opioids. The aim of this study was to demonstrate the usefulness and safety of administration of the combination of midazolam and pethidine during bronchoscopy., Methods: In this prospective randomized single (patient)-blind study, we randomly assigned 100 patients who were scheduled to undergo bronchoscopy biopsy to receive treatment with either the midazolam/pethidine combination (combination group) or midazolam alone (midazolam group) during examinations. After the end of bronchoscopy, patients completed a questionnaire and the visual analogue scale was measured. The primary outcome was the patients' acceptance of re-examination assessed by visual analogue scale. We also assessed pain levels, vital signs, midazolam use, xylocaine use, and adverse events. Univariate analyses were performed using Fisher's exact test for categorical data, and the t-test or Mann-Whitney test was carried out for analysis of numeric data. All P-values were two-sided, and values < 0.05 were considered statistically significant., Results: We analyzed 47 patients in the combination group and 49 patients in the midazolam group. The primary outcome was a good trend in the combination group, but not significantly different (3.82 ± 2.3 in combination group versus 4.17 ± 2.75 in midazolam alone, P = 0.400). In the combination group, the visual analog scale score for pain during bronchoscopy was significantly lower (1.10 ± 1.88 versus 2.13 ± 2.42, P = 0.022), and the sedation level score per the modified observer's assessment of alertness/sedation scale was significantly deeper (3.49 ± 0.98 versus 3.94 ± 1.03, P = 0.031). Maximal systolic blood pressure during testing was significantly lower (162.39 ± 23.45 mmHg versus 178.24 ± 30.24 mmHg, P = 0.005), and the number of additional administrations of midazolam was significantly lower (2.06 ± 1.45 versus 2.63 ± 1.35, P = 0.049). There were also significantly fewer adverse events (30 versus 41, P = 0.036)., Conclusions: The combination uses of midazolam and pethidine for sedation resulted in significant improvements in the pain, blood pressure, additional use of midazolam, and safety during bronchoscopy among patients., Trial Registration: This study was registered in the University Medical Hospital Information Network in Japan (UMINCTR Registration number: UMIN000032230 , Registered: 13/April/2018)., (© 2022. The Author(s).)

The interaction of signal regulatory protein α (SIRPα) on macrophages with CD47 on cancer cells is thought to prevent antibody (Ab)-dependent cellular phagocytosis (ADCP) of the latter cells by the former. Blockade of the CD47-SIRPα interaction by Abs to CD47 or to SIRPα, in combination with tumor-targeting Abs such as rituximab, thus inhibits tumor formation by promoting macrophage-mediated ADCP of cancer cells. Here we show that monotherapy with a monoclonal Ab (mAb) to SIRPα that also recognizes SIRPβ1 inhibited tumor formation by bladder and mammary cancer cells in mice, with this inhibitory effect being largely dependent on macrophages. The mAb to SIRPα promoted polarization of tumor-infiltrating macrophages toward an antitumorigenic phenotype, resulting in the killing and phagocytosis of cancer cells by the macrophages. Ablation of SIRPα in mice did not prevent the inhibitory effect of the anti-SIRPα mAb on tumor formation or its promotion of the cancer cell-killing activity of macrophages, however. Moreover, knockdown of SIRPβ1 in macrophages attenuated the stimulatory effect of the anti-SIRPα mAb on the killing of cancer cells, whereas an mAb specific for SIRPβ1 mimicked the effect of the anti-SIRPα mAb. Our results thus suggest that monotherapy with Abs to SIRPα/SIRPβ1 induces antitumorigenic macrophages and thereby inhibits tumor growth and that SIRPβ1 is a potential target for cancer immunotherapy., Competing Interests: The authors declare no competing interest., (Copyright © 2021 the Author(s). Published by PNAS.)

Background/aim: Chloride intracellular channel 1 (CLIC1) is a member of the chloride channel protein family. The aim of this study was to clarify the role of CLIC1 in lung adenocarcinoma., Patients and Methods: The expression levels of CLIC1 in 74 patients with completely resected lung adenocarcinoma were analyzed by immunohistochemistry. Overall survival was assessed in relation to the expression level of CLIC1. Moreover, in the lung cancer cell lines A549 and PC9, CLIC1 expression was inhibited by small interfering RNA. The function of CLIC1 was analyzed in these cell lines., Results: High expression of CLIC1 was associated with short overall survival compared to low expression (p=0.0327). Multivariate analysis revealed that CLIC1 expression was an independent prognostic factor. Knockdown of CLIC1 inhibited cell proliferation and migration through suppression of the p38 MAPK signaling pathway in A549 and PC9 cells., Conclusion: CLIC1 may be a useful prognostic factor in lung adenocarcinoma., (Copyright © 2022 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Background: Nocturnal desaturation is common in patients with chronic obstructive pulmonary disease (COPD) and impacts disease exacerbation and prognosis. In our previous study, we developed a diagnostic algorithm to classify nocturnal desaturation from SpO 2 waveform patterns based on data from patients receiving home oxygen therapy. In this study, we aimed to investigate nocturnal desaturation in patients with COPD based on SpO 2 waveform patterns and the associations between the waveforms and clinical data., Methods: We investigated patients diagnosed with COPD and measured SpO 2 and nasal airflow with a type 4 portable long-term recordable pulse oximeter. Then, we classified the SpO 2 waveforms with the algorithm and compared the clinical data., Results: One hundred fifty-three patients (136 male and 17 female) were analysed. One hundred twenty-eight of the 153 (83.7%) patients had nocturnal desaturation, with an intermittent pattern (70.6%), sustained pattern (13.1%) and periodic pattern (68.0%). Intriguingly, desaturation with an intermittent pattern was associated with the apnoea-hypopnea index obtained with the portable monitor, and desaturation with a sustained pattern was associated with the cumulative percentage of time at a SpO 2 below 90%., Conclusions: We found that nocturnal desaturation was frequently observed in patients with COPD and could be classified into 3 types of waveform patterns., (© 2021. The Author(s).)

Introduction: : When using portable oxygen, a demand oxygen delivery system (DODS), which senses the beginning of inhalation and delivers a bolus of oxygen, is often used. However, conventional DODS may not supply sufficient oxygen when reduced tidal flow fails to trigger the flow sensor. Recently, "auto-DODS," which detects the negative pressure of inhalation and switches among 3 trigger sensitivity levels (standard, high, and extra high), has been developed to improve the efficacy of oxygenation. An auto-DODS can also supply pulsed-flow oxygen when it detects apnea, whereas a conventional DODS has only standard sensitivity. This randomized, open-label, crossover pilot study compared the performance of an auto-DODS with that of a conventional DODS., Methods: : We recruited patients with chronic obstructive pulmonary disease (COPD) or interstitial pneumonia receiving long-term oxygen therapy. Interventions were performed on 2 different days for each participant. On each day, an auto-DODS or a conventional DODS were tested at rest for 30 minutes and during the 6-minute walk test. The primary outcome was mean oxygen saturation (SpO2). Secondary outcomes were the ratios of time for each sensitivity level and pulsed-flow oxygen when using the auto-DODS, total time desaturated below SpO2 90%, percentage of time desaturated below SpO2 90%, minimum SpO2, mean and maximum pulse rate, six-minute walk distance, recovery time after 6-minute walk test, modified Borg scale, comfort, and discomfort index., Results: : When using the auto-DODS at rest, a high or extra high sensitivity level was observed in addition to standard sensitivity in 6 of 8 participants. During the 6-minute walk test, only standard sensitivity was observed in 6 participants. Mean SpO2 differences between the auto-DODS and conventional DODS at rest and during the 6-minute walk test were -0.6 [-4.5, 3.4] and 0.0 [-2.5, 2.5] ([95% confidence interval]), respectively, neither of which were significant (P = .73 and P = .99). There were no significant differences in secondary outcomes. There were no adverse events when using the auto-DODS., Conclusions: : This study showed that the auto-DODS did not show superiority in oxygenation either at rest or during exercise compared to a conventional DODS. The auto-DODS was shown to supply oxygen safely and detect inhalations with various trigger sensitivities., (Copyright © 2021 the Author(s). Published by Wolters Kluwer Health, Inc.)

Objective evaluations of cough frequency are considered important for assessing the clinical state of patients with respiratory diseases. However, cough monitors with audio recordings are rarely used in clinical settings. Issues regarding privacy and background noise with audio recordings are barriers to the wide use of these monitors; to solve these problems, we developed a novel automatic cough frequency monitoring system combining a triaxial accelerator and a stretchable strain sensor. Eleven healthy adult volunteers and 10 adult patients with cough were enrolled. The participants wore two devices for 30 min for the cough measurements. An accelerator was attached to the epigastric region, and a stretchable strain sensor was worn around their neck. When the subjects coughed, these devices displayed specific waveforms. The data from all the participants were categorized into a training dataset and a test dataset. Using a variational autoencoder, a machine learning algorithm with deep learning, the components of the test dataset were automatically judged as being a "cough unit" or "non-cough unit". The sensitivity and specificity in detecting coughs were 92% and 96%, respectively. Our cough monitoring system has the potential to be widely used in clinical settings without any concerns regarding privacy or background noise.

Medium-sized macrocyclic peptides are an alternative to small compounds and large biomolecules as a class of pharmaceutics. The CD47-SIRPα signaling axis functions as an innate immune checkpoint that inhibits phagocytosis in phagocytes and has been implicated as a promising target for cancer immunotherapy. The potential of macrocyclic peptides that target this signaling axis as immunotherapeutic agents has remained unknown, however. Here we have developed a macrocyclic peptide consisting of 15 amino acids that binds to the ectodomain of mouse SIRPα and efficiently blocks its interaction with CD47 in an allosteric manner. The peptide markedly promoted the phagocytosis of antibody-opsonized tumor cells by macrophages in vitro as well as enhanced the inhibitory effect of anti-CD20 or anti-gp75 antibodies on tumor formation or metastasis in vivo. Our results suggest that allosteric inhibition of the CD47-SIRPα interaction by macrocyclic peptides is a potential approach to cancer immunotherapy., Competing Interests: Declaration of Interests The authors declare no competing interests., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Purpose: Pseudo-progression (PsPD) is a rare phenomenon observed in <5% of cases of non-small cell lung cancer (NSCLC). This event is challenging for both clinicians and patients. Viable biomarkers to distinguish between PsPD and true progressive disease (TPD) are lacking. The aim of our study was to determine the correlation between PsPD and the neutrophil-to-lymphocyte ratio (NLR) in patients with NSCLC treated with immune checkpoint inhibitors (ICIs)., Patients and Methods: We retrospectively reviewed the clinical records of NSCLC patients treated with ICI monotherapy from December 2015 to October 2018 at Kobe University Hospital, Japan. Twenty-five patients were determined to have either PsPD (n =4) or TPD (n =21). We focused on longitudinal radiological images and NLRs., Results: Here, we report four patients with PsPD. The pre- and post-treatment NLRs were significantly lower in patients with PsPD than in patients with TPD (p = 0.019 and p = 0.007, respectively). The receiver operating characteristic curve according to the pre- and post-treatment NLR showed areas under the curve of 0.82 and 0.94, respectively. The optimal cut-off values for pre- and post-treatment NLR were 4.1 and 3.2, respectively. The pre- and post-treatment NLRs were useful in distinguishing between PsPD and TPD. Both a pre-treatment NLR <4.1 and a post-treatment NLR <3.2 were significantly associated with longer overall survival compared to a pre-treatment NLR ≥4.1 (p < 0.001) and post-treatment NLR ≥3.2 (p = 0.004), respectively., Conclusion: The NLR could be a viable clue for distinguishing between PsPD and TPD. Patients with a high post-treatment NLR in this study all had TPD, suggesting that these subjects should be considered for an early transition to the next drug treatment regimen., Competing Interests: The authors report no conflicts of interest in this work., (© 2019 Kiriu et al.)

Extracellular vesicles (EVs) are circulating vesicles secreted by various cell types. EVs are classified into three groups according to size, structural components, and generation process of vesicles: exosomes, microvesicles, and apoptotic bodies. Recently, EVs have been considered to be crucial for cell-to-cell communications and homeostasis because they contain intracellular proteins and nucleic acids. Epithelial cells from mice suffering from bronchial asthma (BA) secrete more EVs and suppress inflammation-induced EV production. Moreover, microarray analyses of bronchoalveolar lavage fluid have revealed that several microRNAs are useful novel biomarkers of BA. Mesenchymal stromal cell-derived EVs are possible candidates of novel BA therapy. In this review, we highlight the biologic roles of EVs in BA and review novel EV-targeted therapy to help understanding by clinicians and biologists.

In the human intestinal tract, there are more than 100 trillion symbiotic bacteria, which form the gut microbiota. Approximately 70% of the human immune system is in the intestinal tract, which prevents infection by pathogenic bacteria. When the intestinal microbiota is disturbed, causing dysbiosis, it can lead to obesity, diabetes mellitus, inflammatory bowel disease, rheumatoid arthritis, multiple sclerosis, autism spectrum disorder and cancer. Recent metabolomics analyses have also made the association between the microbiota and carcinogenesis clear. Here, we review the current evidence on the association between the microbiota and gastric, bladder, hepatobiliary, pancreatic, lung and colorectal cancer. Moreover, several animal studies have revealed that probiotics seem to be effective for the prevention of carcinogenesis to some extent. In this review, we focused on this relationship between the microbiota and cancer, and considered how to prevent cancer using strategies involving the gut microbiota., Competing Interests: Dr Yoshihiro Nishimura reports grants from Eli Lilly Japan K.K. and personal fees from AstraZeneca K.K. outside the submitted work. The authors report no other conflicts of interest in this work.

Background/aim: Immune checkpoint inhibitors (ICI) are a novel medication for non-small cell lung cancer (NSCLC). Recent reports indicated that baseline tumor size (BTS) relates to the efficacy of ICI therapy for melanoma, but no study exists for NSCLC. This study aimed to evaluate the utility of BTS for ICI therapy., Patients and Methods: Data from 58 patients diagnosed with NSCLC who underwent ICI monotherapy, were retrospectively analyzed. Patients were divided into two groups according to BTS (below 101 mm, above 101 mm). The primary endpoint was progression-free survival (PFS) and the secondary endpoint was overall survival (OS)., Results: PFS of patients with a large BTS was significantly shorter than that of those with a small BTS (median; 2.07 [95% confidence interval [CI]=0.99-6.77] months versus 6.39 [95%CI=4.17-11.50] months) (p=0.044). OS of patients with large BTS was also significantly shorter (p<0.01)., Conclusion: BTS is a predictive and prognostic negative factor of ICI therapy for NSCLC., (Copyright© 2019, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Interaction of signal regulatory protein α (SIRPα) expressed on the surface of macrophages with its ligand CD47 expressed on target cells negatively regulates phagocytosis of the latter cells by the former. We recently showed that blocking Abs to mouse SIRPα enhanced both the Ab-dependent cellular phagocytosis (ADCP) activity of mouse macrophages for Burkitt's lymphoma Raji cells opsonized with an Ab to CD20 (rituximab) in vitro as well as the inhibitory effect of rituximab on the growth of tumors formed by Raji cells in nonobese diabetic (NOD)/SCID mice. However, the effects of blocking Abs to human SIRPα in preclinical cancer models have remained unclear given that such Abs have failed to interact with endogenous SIRPα expressed on macrophages of immunodeficient mice. With the use of Rag2 -/- γ c -/- mice harboring a transgene for human SIRPα under the control of human regulatory elements (hSIRPα-DKO mice), we here show that a blocking Ab to human SIRPα significantly enhanced the ADCP activity of macrophages derived from these mice for human cancer cells. The anti-human SIRPα Ab also markedly enhanced the inhibitory effect of rituximab on the growth of tumors formed by Raji cells in hSIRPα-DKO mice. Our results thus suggest that the combination of Abs to human SIRPα with therapeutic Abs specific for tumor antigens warrants further investigation for potential application to cancer immunotherapy. In addition, humanized mice, such as hSIRPα-DKO mice, should prove useful for validation of the antitumor effects of checkpoint inhibitors before testing in clinical trials., (© 2018 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.)

Background: Nivolumab improves the survival of advanced non-small cell lung cancer (NSCLC), but a significant number of patients still fail to benefit from this treatment. In this study, we evaluated the efficacy of the time-series behavior of neutrophil-to-lymphocyte ratio (NLR) in a complete blood count from advanced NSCLC patients as a predictive marker of the anticancer effect of nivolumab., Methods: We performed a retrospective review of medical records and collected data on patients with advanced NSCLC treated with nivolumab as second- and further-line treatments from December 2015 to March 2017. The NLRs were calculated before each treatment cycle for four cycles. These parameters were tested for its association with the overall survival (OS), progression-free survival (PFS) and time to treatment failure (TTF)., Results: Nineteen patients were treated with nivolumab. Stratified by the response to nivolumab, the median OS was 2.8 months in progressive disease (PD) and 14.0 months in non-PD (p = 0.002). Before discontinuation of PD or toxicity, an NLR is rising from baseline in 5 out of 7 patients with PD and all of 4 patients with discontinuation due to toxicity. Patients with an >30% increase in NLR were associated with a significantly shorter TTF compared with those with stable or decrease in NLR both after first cycle (p = 0.014) and second cycle (p < 0.001)., Conclusions: The NLR is suggested to be useful not only as a prognostic marker but also as a predictive marker for treatment with nivolumab. Further prospective study is warranted to develop a predictive algorithm to detect PD cases as early as possible by focusing the time-series behavior of NLR.

A 62-year-old male with lung adenocarcinoma harboring an exon 19 deletion in the Epidermal growth factor receptor (EGFR) was treated with EGFR-tyrosine kinase inhibitors (TKIs) and several cytotoxic agents. After administering a fifth-line chemotherapy regimen, a liver biopsy revealed a diagnosis of recurrence with a T790M mutation. After an 82-day course of osimertinib therapy, the patient developed osimertinib-induced interstitial lung disease (ILD). Osimertinib was discontinued, and oral prednisolone was started. The ILD quickly improved, but liver metastases progressed and osimertinib was restarted concurrently with prednisolone. The patient showed neither disease progression nor a recurrence of ILD at 5 months. In situations in which no alternative treatment is available, osimertinib rechallenge should thus be considered as an alternative treatment.

Tumor cells are thought to evade immune surveillance through interaction with immune cells. Much recent attention has focused on the modification of immune responses as a basis for new cancer treatments. SIRPα is an Ig superfamily protein that inhibits phagocytosis in macrophages upon interaction with its ligand CD47 expressed on the surface of target cells. Here, we show that SIRPα is highly expressed in human renal cell carcinoma and melanoma. Furthermore, an anti-SIRPα Ab that blocks the interaction with CD47 markedly suppressed tumor formation by renal cell carcinoma or melanoma cells in immunocompetent syngeneic mice. This inhibitory effect of the Ab appeared to be mediated by dual mechanisms: direct induction of Ab-dependent cellular phagocytosis of tumor cells by macrophages and blockade of CD47-SIRPα signaling that negatively regulates such phagocytosis. The antitumor effect of the Ab was greatly attenuated by selective depletion not only of macrophages but also of NK cells or CD8 + T cells. In addition, the anti-SIRPα Ab also enhances the inhibitory effects of Abs against CD20 and programmed cell death 1 (PD-1) on tumor formation in mice injected with SIRPα-nonexpressing tumor cells. Anti-SIRPα Abs thus warrant further study as a potential new therapy for a broad range of cancers., Competing Interests: The authors have declared that no conflict of interest exists.

Platypnea-orthodeoxia syndrome (POS) is a rare condition characterized by interatrial right-to-left shunting that is exacerbated in the upright position. We herein report a 78-year-old woman with POS that remained undiagnosed for 2 years, despite repetitive transthoracic echocardiography (TTE). POS was ultimately diagnosed using contrast transesophageal echocardiography (TEE), which revealed a marked increase in right-to-left shunting in the sitting position, associated with simultaneous desaturation. Therefore, we propose that POS should be considered according to the clinical symptoms, regardless of the repetitive TTE results, and contrast TEE should be performed in both the supine and sitting positions to exclude a diagnosis of POS.