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BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is associated with a poor prognosis with variable clinical course. Early identification of patients at high risk for disease progression and death would lead to early therapeutic intervention and thereby improvement of outcomes. Cold-inducible RNA-binding protein (CIRBP) is produced in response to cellular stresses, which is implicated in multiple biological processes, including cell survival and proliferation.RESEARCH QUESTION: Is CIRBP a useful biomarker for predicting the outcomes of patients with IPF?STUDY DESIGN AND METHODS: This study included 95 and 93 patients with IPF from two independent hospitals (derivation and validation cohorts, respectively). The association s of serum CIRBP level upon IPF diagnosis with disease progression within 1 year after diagnosis (i.e. ≥10% relative decline in percent predicted forced vital capacity or death) and all-cause mortality were retrospectively analysed. Discrimination performances for predicting these outcomes were evaluated using the c-index. RESULTS: Serum and lung tissue CIRBP levels were higher in patients with IPF than in control subjects. In the derivation cohort, the CIRBP high sub-group had significantly higher 1-year disease progression rates and lower cumulative survival rates than the CIRBP low sub-group, and the results were replicated in the validation cohort. In multivariate analyses, high serum CIRBP level was independently associated with higher 1-year disease progression and all-cause mortality rates in both cohorts. Combining the Gender-Age-Physiology and serum CIRBP models improved the c-indices for predicting 1-year disease progression and all-cause mortality compared with that of each model alone. The c-indices of serum CIRBP were particularly high in patients with Gender-Age-Physiology stage I.INTERPRETATION: This study successfully validated that serum CIRBP level was an independent predictor of 1-year disease progression and all-cause mortality in IPF. CIRBP is a promising biomarker that can help identify high-risk patients with IPF, especially in the early stage.

Background Lipids have immunomodulatory functions and the potential to affect cancer immunity. Methods The associations of pretreatment serum cholesterol and long-chain fatty acids with the objective response rate (ORR), progression-free survival (PFS), and overall survival (OS) were evaluated in 148 patients with non-small cell lung cancer who received nivolumab. Results When each lipid was separately evaluated, increased low-density lipoprotein (LDL)-cholesterol (P P = 0.014), total cholesterol (P = 0.007), lauric acid (P = 0.015), myristic acid (P = 0.022), myristoleic acid (P = 0.035), stearic acid (P = 0.028), linoleic acid (P = 0.005), arachidic acid (P = 0.027), eicosadienoic acid (P = 0.017), dihomo-γ-linolenic acid (P = 0.036), and behenic acid levels (P = 0.032) were associated with longer PFS independent of programmed death ligand 1 (PD-L1) expression. Meanwhile, increased LDL-cholesterol (P P = 0.009), total cholesterol (P = 0.036), linoleic acid (P = 0.014), and lignoceric acid levels (P = 0.028) were associated with longer OS independent of PD-L1 expression. When multiple lipids were evaluated simultaneously, LDL-cholesterol (P = 0.003), HDL-cholesterol (P = 0.036), and lauric acid (P = 0.036) were independently predictive of PFS, and LDL-cholesterol (P = 0.008) and HDL-cholesterol (P = 0.031) were predictive of OS. ORR was not associated with any serum lipid. Conclusions Based on the association of prolonged survival in patients with increased serum cholesterol and long-chain fatty acid levels, serum lipid levels may be useful for predicting the efficacy of immune checkpoint inhibitor therapy.

Antifibrotic therapy (AFT) slows disease progression in patients with idiopathic pulmonary fibrosis (IPF). The Gender-Age-Physiology (GAP) index, was developed based on data at IPF diagnosis before the introduction of AFT and has not been evaluated in the AFT context. Further, recent advances have revealed the importance of body-composition factors in prognosis of IPF treated with AFT. This multi-centre, retrospective study aimed to evaluate the GAP index and body mass index (BMI) at the time of AFT initiation for predicting prognosis in patients with IPF. This study included two patient cohorts of IPF receiving AFT, Hamamatsu cohort (n = 110) and Seirei cohort (n = 119). The distribution of GAP stages I, II, and III was 38.2%, 43.6%, and 18.2%, respectively, in Hamamatsu cohort; in Seirei cohort, it was 41.2%, 50.4%, and 8.4%, respectively. In both cohorts, the GAP index distinctly classified prognosis into three groups (log-rank test). Interestingly, a lower BMI showed prognostic value independent of the GAP index in multivariate analyses. Subsequently, combining the GAP index with BMI at AFT initiation successfully divided the patients with IPF into four distinct prognoses. Assessment of the GAP index and BMI measurement at AFT initiation are important for predicting prognosis in patients with IPF.

Background Currently, there are two antifibrotics used to treat idiopathic pulmonary fibrosis (IPF): pirfenidone and nintedanib. Antifibrotics slow disease progression by reducing the annual decline of forced vital capacity (FVC), which possibly improves outcomes in IPF patients. During treatment, patients occasionally switch antifibrotic treatments. However, prognostic implication of changing antifibrotics has not yet been evaluated. Methods This multi-center retrospective cohort study examined 262 consecutive IPF patients who received antifibrotic therapy. Antifibrotic agents were switched in 37 patients (14.1%). The prognoses were compared between the patient cohort that switched antifibrotics (Switch-IPF) and those without (Non-Switch-IPF) using propensity-score matched analyses. Results The median period between the initiation of antifibrotic therapy and the drug switch was 25.8 (12.7–35.3) months. The most common reasons for the switch were disease progression (n = 17) followed by gastrointestinal disorders (n = 12). Of the 37 patients that switched antifibrotics, only eight patients disrupted switched antifibrotics by their adverse reactions. The overall prognosis of the Switch-IPF cohort was significantly better than the Non-Switch-IPF cohort (median periods: 67.2 vs. 27.1 months, p p = 0.0219). The second-line antifibrotic therapy showed similar survival probabilities than those in first-line antifibrotic therapy in multistate model analyses. Conclusion Switching antifibrotics is feasible and may improve prognosis in patients with IPF. A further prospective study will be required to confirm clinical implication of switching the antifibrotics.

Background The precise classification of idiopathic interstitial pneumonia (IIP) is essential for selecting treatment as well as estimating clinical outcomes; however, this is sometimes difficult in clinical practice. Therefore, cluster analysis was used to identify the clinical phenotypes of IIPs, and its usefulness for predicting clinical outcomes was evaluated. Methods Cluster analysis was performed using clinical features including patients’ demographics; histories; pulmonary function test data; and laboratory, physical and radiological findings. Results In 337 patients with IIPs, four clusters were identified: Cluster I, in which > 80% of the patients had autoimmune features; Cluster II, which had the lowest rate of smoking, the lowest percent predicted forced vital capacity (%FVC) and the lowest body mass index (BMI); Cluster III, which had the highest rate of smoking, the highest rate of dust exposure, the second lowest %FVC and normal BMI; and Cluster IV, which exhibited maintenance of %FVC and normal BMI. Cluster IV had significantly longer overall survival than Clusters II and III. Clusters I and III had significantly longer overall survival than Cluster II. Clusters II and III had a significantly higher cumulative incidence of acute exacerbation than Cluster IV. Conclusion Cluster analysis using clinical features identified four clinical phenotypes of IIPs, which may be useful for predicting the risk of acute exacerbation and overall survival.

Fraction of exhaled nitric oxide (FeNO) provides information about chronic inflammation in asthma. However, its relationship with structural changes in the airways is unknown. We aimed to evaluate the correlation between computer-based airway changes and FeNO in patients with asthma. The wall area (WA) and airway inner luminal area (Ai) of the third- to sixth-generation bronchi were measured using three-dimensional computed tomography in asthmatic patients. Each value was corrected by body surface area (BSA). Relationships between FeNO and WA/BSA and Ai/BSA were evaluated. Forty-one clinically stable patients with asthma were evaluated. FeNO was significantly correlated with WA/BSA of the third-, fourth-, fifth- and sixth-generation bronchi (Spearman correlation coefficient (ρ) = 0.326, p = 0.041; ρ = 0.356, p = 0.025; ρ = 0.496, p = 0.002; and ρ = 0.529, p p = 0.047). Partial rank correlation analysis indicated FeNO was significantly correlated with WA/BSA of the sixth-generation bronchi, independent from confounding factors of Ai/BSA, age, duration of asthma, dose of inhaled corticosteroid, blood eosinophil percentage, and blood IgE (ρ = 0.360, p = 0.034). In contrast, there was no correlation between FeNO and Ai/BSA. FeNO correlates with bronchial wall thickening in asthma patients. Measurement of FeNO may be useful to detect airway remodeling in asthma.

Objectives Conventional evaluation of anti-tumor activity on the basis of tumor size is inadequate for immune checkpoint inhibitors (ICIs). We therefore aimed to assess the usefulness of intravoxel incoherent motion magnetic resonance imaging (IVIM-MRI) for evaluation of the therapeutic efficacy of ICIs. Materials and methods A chest IVIM-MRI was performed before and 2, 4, and 8 weeks after administration of ICIs in patients with advanced non-small-cell lung cancer. Apparent diffusion coefficient (ADC), skewness of ADC (ADCskew), kurtosis of ADC (ADCkurt), true diffusion coefficient (D), pseudodiffusion coefficient (D*), and perfusion fraction (f) were evaluated at each evaluation point and changes from the baseline (Δ). Results Twenty patients were enrolled in this study. An increased ADC 8 weeks and decreased ADCkurt and ΔADCkurt 4 weeks after ICIs was associated with objective responses and longer progression-free survival (PFS). A decreased ΔADCskew at 4 weeks was associated with objective responses, disease control, and longer PFS and overall survival. There was no correlation between the efficacy of ICIs and D, D* and f. All of three patients who had pseudoprogression had decreased ΔADCskew at 4 weeks and two of them had decreased ΔADCkurt at 4 weeks. Inversely, all five patients who had progressive disease (PD) did not have increased ΔADCskew at 4 weeks and only one of them had decreased ΔADCkurt at 4 weeks. Conclusions Changes in histograms of ADC may be useful for predicting long-term efficacy and distinguishing between pseudoprogression and actual PD after ICIs.

Objectives Most patients with non-small cell lung cancer (NSCLC) are diagnosed at advanced stages where small biopsy specimens obtained through endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) are sometimes the only available samples for diagnosis. We aimed to determine whether EBUS-TBNA specimens are suitable for the evaluation of PD-L1 protein expression and copy number alterations (CNAs). Materials and methods PD-L1 protein expression and CNAs in 71 EBUS-TBNA specimens of NSCLC were assessed. Sixty-eight corresponding transbronchial biopsy (TBB) specimens from primary sites, thirteen resected primary tumors, and six resected metastases were comparatively analyzed. PD-L1 expression in tumor cells was assessed by immunohistochemistry (E1L3N). Positivity of ≥1% was used as the cutoff. PD-L1 CNAs were assessed with fluorescent in situ hybridization and were classified into three categories: amplification, polysomy, and disomy. Concordance between EBUS-TBNA and other specimens was calculated. Results The cohort comprised 48 men (67.6%), 15 never-smokers (21.1%), and 39 adenocarcinomas (54.9%). The concordance of PD-L1 positivity between EBUS-TBNA and other specimens was moderate; κ = 0.63 for EBUS-TBNA vs. TBB, κ = 0.68 for EBUS-TBNA vs. resected primary tumors, and κ = 1.0 for EBUS-TBNA vs. resected metastases. The concordance of PD-L1 CNA status was comparable with that of PD-L1 expression: κ = 0.60 for EBUS-TBNA vs. TBB and κ = 0.74 for EBUS-TBNA vs. resected primary tumors. When PD-L1 copy number was assessed as a continuous variable, the correlation of PD-L1 CNAs was superior to that of PD-L1 expression. Intratumorally, PD-L1 copy number was less heterogeneous than protein expression in whole sections of resected tumors. Conclusion EBUS-TBNA specimens can be used to assess PD-L1 CNAs and protein expression. Although spatial heterogeneity should be considered for accurate interpretation, the evaluation of PD-L1 CNAs provides more reproducible results than that of protein expression levels especially with regard to intratumoral heterogeneity.

Background The stepping down of asthma treatment can be considered when asthma symptoms have been well controlled with inhaled corticosteroids (ICSs)/long-acting β2 adrenergic agonists (LABAs). However, few data are available comparing the efficacy between two step-down strategies, to reduce ICS/LABA dose or to withdraw LABA continuing ICS, in well-controlled asthmatics. Methods This was a prospective multicentre randomized, two-arm, controlled study. Ninety-one asthmatic patients controlled by budesonide/formoterol combination (BFC) 320/9 μg twice daily were assigned to 2 stepping-down treatments as follows: the BFC group; BUD/FM 160/4.5 μg twice daily, and the ICS group; ICS (budesonide 400 μg twice daily or equivalent dose of ICS) without LABA, and followed for 12 weeks. The primary outcome was the incidence of asthma exacerbations. Asthma control, pulmonary function tests, and fraction of exhaled nitric oxide (FeNO) were evaluated at the beginning and end of the period. Results The incidence of exacerbations was 16.3% in the BFC groups and 12.5% in the ICS group, which were not different between the groups (p = 0.766). No significant differences were found in QOL score and FeNO between 0 week and 12 week in the both group. FEV1 and FEV1 percentage of the predicted value were lower at week 12 than at week 0 in the ICS group, but not in the BFC group. Conclusions The two step-down strategies for 12 weeks have equal acceptability in well-controlled asthmatics treated with medium-dose of BFC, however, withdrawal of LABA may have potential risk to deteriorate FEV1. Clinical trial registration This study was registered to UMIN-CTR ( http://www.umin.ac.jp/ctr/ ), UMIN000010333.

New reliable biomarkers are needed to predict the response to immune checkpoint inhibitors against programmed death-1 (PD-1) and its ligand (PD-L1), because PD-L1 expression on tumor cells has limited power for selecting patients who may benefit from such therapy. Here we investigated the significance of PD-L1 and PD-L2 gene copy number gains using fluorescence in situ hybridization as well as PD-L1 and PD-L2 expression in 654 patients with resected non-small-cell lung cancer. The prevalence of PD-L1 amplification and polysomy was 3.1% and 13.2%, respectively. The PD-L1 gene copy number status was in agreement with both the PD-L2 and Janus kinase 2 gene copy number statuses. PD-L1 and PD-L2 expression was observed in 30.7% and 13.1%, respectively. Both PD-L1 copy number gains and expression were associated with smoking-related tumors. Tumor cells with PD-L1 genomic gains exhibited significantly higher levels of PD-L1 expression than those without, but PD-L2 copy number gains were not related to PD-L2 augmentation. PD-L1 gene amplification and polysomy were independently associated with PD-L1 expression, with high immune infiltrates and EGFR expression in a multivariate logistic regression model. Comparative analysis between primary tumors and synchronous regional lymph node metastases revealed that the PD-L1 gene copy number alterations were highly consistent and reproducible compared with the PD-L1 expression. Both PD-L1 amplification and level of protein expression were predictors of poor survival using Cox univariate analyses. Therefore, we conclude that an increase in PD-L1 gene copy number can be a feasible alternative biomarker for predicting response to anti-PD-1/PD-L1 therapy.

Background Dyspnea is a common symptom in chronic obstructive pulmonary disease (COPD). The modified Medical Research Council (mMRC) dyspnea scale is a widely used questionnaire to assess dyspnea. However, the relationship of the mMRC dyspnea scale with morphological airway structures in COPD remains unclear. We evaluated the correlation between the mMRC dyspnea scale and imaging-based airway structures in patients with COPD. Methods The wall area (WA) and airway inner luminal area (Ai) of third-to sixth-generation bronchi and the percentage of low attenuation area with less than −950 HU (%LAA) of the lungs were measured using three-dimensional computed tomography in patients with COPD. WA and Ai were corrected by body surface area (BSA). Results Forty-two clinically stable patients with COPD were enrolled. The median (range) mMRC dyspnea scale was 2 (0–3). The mMRC dyspnea scale score was significantly correlated with WA/BSA of fifth- and sixth-generation bronchi (Spearman correlation coefficient ρ = 0.386, p = 0.012; ρ = 0.484, p = 0.001, respectively). Partial rank correlation analysis showed that the mMRC dyspnea scale score was significantly correlated with WA/BSA of sixth-generation bronchi, independent of the confounding factors of age, body mass index, %predicted forced expiratory volume in 1 s, %LAA, and Ai/BSA (ρ = 0.481, p = 0.003). However, the %LAA and Ai/BSA were not correlated with this dyspnea scale. Conclusion Bronchial WA assessed by three-dimensional computed tomography may be used as an assessment tool for dyspnea in patients with COPD.

Expiratory flow limitation (EFL) during tidal breathing is common in patients with severe COPD, and a major determinant of dynamic hyperinflation and exercise limitation. The negative expiratory pressure (NEP) technique has been the gold standard to detect EFL, while the forced oscillation technique (FOT) has also been reported to detect it. However, the association of FOT with NEP is not fully understood. We assessed whether broadband frequency FOT would predict the presence of EFL measured by NEP. FOT, NEP, and spirometry were performed in 51 patients with COPD. The extent of emphysema was measured by high-resolution computed tomography and scored. Fifteen patients were classified into the EFL-positive group and 36 into the EFL-negative group. In multivariate logistic regression analysis, EFL was independently predicted by emphysema score, forced vital capacity, and whole-breath respiratory system reactance at 5Hz (X5). The receiver operator characteristic curve analysis revealed that inspiratory X5 best predicted EFL-positivity. X5-related forced oscillatory parameters are useful for detecting EFL in the management of COPD.

Background Recent studies have shown that the microbiome, namely Aspergillus species, play a previously unrecognized role in both stable and exacerbated chronic obstructive pulmonary disease (COPD). Galactomannan is a major component of the Aspergillus cell wall that has been widely used as a diagnostic marker. Objectives To explore whether serum levels of Aspergillus-galactomannan antigen could be used to evaluate the risk of severe acute exacerbation of COPD (AE-COPD). Methods We measured the Aspergillus-galactomannan antigen levels of 191 patients with stable COPD, and examined its clinical relevance including AE-COPD. Results There were 77 (40.3%) patients who were positive for serum Aspergillus-galactomannan antigen (≥0.5). High Aspergillus-galactomannan antigen level (≥0.7) was associated with older age and presence of bronchiectasis and cysts on computed tomography images. Compared to patients with low Aspergillus-galactomannan antigen level (

Background Respiratory impedance comprises the resistance and reactance of the respiratory system and can provide detailed information on respiratory function. However, details of the relationship between impedance and morphological airway changes in asthma are unknown. Objective We aimed to evaluate the correlation between imaging-based airway changes and respiratory impedance in patients with asthma. Methods Respiratory impedance and spirometric data were evaluated in 72 patients with asthma and 29 reference subjects. We measured the intraluminal area (Ai) and wall thickness (WT) of third- to sixth-generation bronchi using three-dimensional computed tomographic analyses, and values were adjusted by body surface area (BSA, Ai/BSA, and WT/the square root (√) of BSA). Results Asthma patients had significantly increased respiratory impedance, decreased Ai/BSA, and increased WT/√BSA, as was the case in those without airflow limitation as assessed by spirometry. Ai/BSA was inversely correlated with respiratory resistance at 5 Hz (R5) and 20 Hz (R20). R20 had a stronger correlation with Ai/BSA than did R5. Ai/BSA was positively correlated with forced expiratory volume in 1 second/forced vital capacity ratio, percentage predicted forced expiratory volume in 1 second, and percentage predicted mid-expiratory flow. WT/√BSA had no significant correlation with spirometry or respiratory impedance. Conclusions & clinical relevance Respiratory resistance is associated with airway narrowing.

Chronic eosinophilic pneumonia (CEP) is characterized by the accumulation of eosinophils in the lung with unknown etiology. Although systemic corticosteroid administration leads to dramatic improvement, nearly half the patients with CEP experience relapse and some develop persistent impairment of pulmonary function. However, predictive factors for this persistent impairment have not been determined.To investigate the occurrence of persistent impairment of pulmonary function in CEP and determine its predictive factors.This observational study consisted of 133 consecutive patients with CEP who were followed for longer than 1 year. Spirometry was performed at the time of diagnosis and at follow-up.During the observational period (6.1 ± 4.1 years), relapse occurred in 75 patients (56.4%). Remarkably, 42 patients (31.6%) had a persistent pulmonary function defect (27 obstructive, 10 restrictive, and 4 obstructive and restrictive cases) at the last evaluation. Logistic analyses showed that the relapse was associated with neither persistent obstructive nor restrictive defects. Persistent obstructive defect was significantly associated with the comorbidity of asthma and obstructive defect at the initial CEP diagnosis, whereas persistent restrictive defect was significantly related to reticulation at high-resolution computer tomography and restrictive defect at diagnosis.Persistent impairment of pulmonary function is common in CEP. Concurrent asthma and obstructive defects at diagnosis were predictors for persistent obstructive impairments, whereas reticulation at high-resolution computer tomography and restrictive defect at diagnosis predicted persistent restrictive impairment. Attention should be paid to these persistent impairments in the management of CEP.http://www.umin.ac.jp/ctr/index-j.htm Identifier: UMIN000019092 (principal investigator, Takafumi Suda, MD, PhD).

The forced oscillation technique provides information concerning respiratory impedance, which comprises resistance and reactance of the respiratory system. However, its relationship with morphological changes of the lungs in chronic obstructive pulmonary disease (COPD) remains unclear. Respiratory impedance and spirometric data were evaluated in 98 patients with COPD and 49 reference subjects. Wall thickness (WT) and airway intraluminal area (Ai) of third- to sixth-generation bronchi, and percentage low-attenuation area with less than −950 HU (%LAA) of lungs were measured using three-dimensional computed tomography. COPD patients had higher respiratory impedance, decreased Ai, and increased %LAA compared with reference subjects. Indices of respiratory resistance and reactance and forced expiratory volume in 1 second (FEV1) were correlated with Ai, and the association between percent predicted FEV1 and Ai was predominant in distal bronchi. The difference in respiratory resistance between 5 Hz and 20 Hz (R5–R20) and FEV1/forced vital capacity ratio (FEV1/FVC) were correlated with WT. The %LAA was correlated with the FEV1/FVC ratio and respiratory reactance. Airway function measurements with the forced oscillation technique provide complementary information to spirometry in COPD.

Multidisciplinary discussion (MDD) requiring close communication between specialists (clinicians, radiologists and pathologists) is the gold standard for the diagnosis of idiopathic interstitial pneumonias (IIPs). However, MDD by specialists is not always feasible because they are often separated by time and location. An online database would facilitate data sharing and MDD. Our aims were to develop a nationwide cloud-based integrated database containing clinical, radiological and pathological data of patients with IIPs along with a web-based MDD system, and to validate the diagnostic utility of web-based MDD in IIPs. Clinical data, high-resolution computed tomography images and lung biopsy slides from patients with IIPs were digitised and uploaded to separate servers to develop a cloud-based integrated database. Web-based MDD was performed using the database and video-conferencing to reach a diagnosis. Clinical, radiological and pathological data of 524 patients in 39 institutions were collected, uploaded and incorporated into the cloud-based integrated database. Subsequently, web-based MDDs with a pulmonologist, radiologist and pathologist using the database and video-conferencing were successfully performed for the 465 cases with adequate data. Overall, the web-based MDD changed the institutional diagnosis in 219 cases (47%). Notably, the MDD diagnosis yielded better prognostic separation among the IIPs than did the institutional diagnosis. This is the first study of developing a nationwide cloud-based integrated database containing clinical, radiological and pathological data for web-based MDD in patients with IIPs. The database and the web-based MDD system that we built made MDD more feasible in practice, potentially increasing accurate diagnosis of IIPs., A cloud-based integrated database of idiopathic interstitial pneumonias containing clinical, radiological and pathological data along with a web-based multidisciplinary discussion system can make discussions more feasible and improve disease management http://ow.ly/NqqD30nYenb

SummaryBackground Clinical application of the forced oscillation technique (FOT) has progressed with the spread of commercially available FOT devices. The correlation between respiratory impedance and spirometry has been reported; however, the association with airway inflammation and pulmonary function, in the lung periphery in particular, is unclear. Objective To assess whether respiratory impedance is associated with peripheral airway inflammation and dysfunction in asthma. Methods Subjects included 78 patients with overall controlled asthma. We measured whole-breath or within-breath respiratory system resistance (Rrs) and reactance (Xrs) using a commercially available multi-frequency FOT device (MostGraph-01), and assessed the correlation with the fraction of exhaled nitric oxide (FeNO), alveolar nitric oxide concentration (CANO), maximal NO flux in the conductive airways (J'awNO), and the N2 phase III slope of single breath N2 washout (delta N2). Results The differences between inspiratory and expiratory phases of Xrs at 5 Hz (X5), resonant frequency (Fres), and a low-frequency reactance area (ALX) were significantly correlated with CANO; however, there was no correlation between respiratory impedance and FeNO or J'awNO. The delta N2 values were significantly correlated with whole-breath, inspiratory, and expiratory Rrs and Xrs, except for R20. Conclusions and Clinical Relevance We conclude that respiratory impedance reflects peripheral airway inflammation and ventilation inhomogeneity.

Background Macrophage activation is involved in the pathogenesis of polymyositis (PM)/dermatomyositis (DM). CD163, a scavenger receptor expressed on the surface of activated macrophages, mediates anti-inflammatory functions. This study aimed to evaluate the clinical significance of soluble CD163 (sCD163) in PM/DM-related interstitial lung disease (ILD). Methods The main subjects were 48 patients with PM/DM-related ILD. As controls, 10 patients with PM/DM without ILD and 20 healthy volunteers were enrolled. In patients with PM/DM-related ILD, the baseline characteristics and clinical course were obtained through a review of patient medical records. Serum sCD163 levels at ILD diagnosis were quantified by enzyme-linked immunosorbent assay, which were compared with the other baseline clinical factors and evaluated for potential as a prognostic biomarker. In addition, immunohistochemistry analysis using anti-human CD163 antibody was performed on the lung sections of two patients with DM-related ILD (a survivor and non-survivor, respectively) and one patient with early-stage lung cancer as a normal control. Results The median value of serum sCD163 in patients with PM/DM-related ILD was 818 ng/mL, which was higher than that of PM/DM patients without ILD and healthy volunteers (716 ng/mL and 340 ng/mL, respectively). Significant but mild correlations with serum sCD163 levels were observed for serum C-reactive protein levels (r = 0.322) and % predicted forced vital capacity (r = −0.301) in patients with PM/DM-related ILD. A Cox proportional hazard model demonstrated that patients with PM/DM-related ILD and higher sCD163 levels had worse prognosis (age-adjusted and gender-adjusted hazard ratio per 100 ng/mL increase 1.27, 95% confidence interval 1.11–1.45, P

Thyroid transcription factor 1 (TTF1) located on chromosome band 14q13.3 is an oncogene and a suppressor gene in non-small cell lung cancer (NSCLC). The prognostic relevance of TTF1 copy number alterations (CNAs) and their association with TTF1 protein expression are poorly understood. Here, we assessed TTF1 CNAs and protein expression using microarrays in a cohort of 636 NSCLC, including 423 adenocarcinoma (ADC) and 171 squamous cell carcinoma (SCC). In addition, fluorescent in situ hybridization and immunohistochemistry were performed. TTF1 CNAs were detected in 23% of NSCLC (23% of ADC and 20% of SCC). Specifically, TTF1 amplification and polysomy were observed in 5% and 18% of NSCLC, and in 7% and 16% of ADC, respectively. TTF1 expression was detected in 85% of ADC. TTF1 CNAs were significantly associated with advanced tumor stage, EGFR mutations, and TTF1 expression. A multivariate Cox hazards model analysis of overall survival and recurrence-free survival demonstrated that both TTF1 amplification and polysomy were independent indicators of an unfavorable prognosis in patients with NSCLC. Survival was inversely correlated with TTF1 copy number. In contrast, TTF1 protein expression was an independent favorable prognostic factor. Intratumoral and intertumoral heterogeneities of TTF1 CNAs and TTF1 protein expression were assessed using primary cores from 138 pairs of primary tumors and corresponding nodal metastases. The concordance rate for TTF1 CNAs and TTF1 protein expression was high within tumors and between primary and metastatic tumors. Altogether, these results suggest that TTF1 CNAs are correlated with TTF1 protein expression, but have opposing effects on survival.

Previous studies have reported that patients with idiopathic pulmonary fibrosis occasionally develop lung cancer (LC). However, in connective tissue disease (CTD)-related interstitial lung disease (ILD), there are few data regarding the LC development. The aim of the present study was to evaluate the clinical significance of LC development in patients with CTD-ILD. A retrospective review of our database of 562 patients with ILD between 2000 and 2014 identified 127 patients diagnosed with CTD-ILD. The overall and cumulative incidences of LC were calculated. In addition, the risk factors and prognostic impact of LC development were evaluated. The median age at the ILD diagnosis was 63 years (range 37–84 years), and 73 patients (57.5%) were female. The median follow-up period from the ILD diagnosis was 67.4 months (range 10.4–322.1 months). During the period, 7 out of the 127 patients developed LC (overall incidence 5.5%). The cumulative incidences at 1, 3, and 5 years were 0.0%, 1.8%, and 2.9%, respectively. The risk of LC development was significantly higher in patients with higher smoking pack-year (odds ratio [OR] 1.028; 95% confidence interval [CI] 1.008–1.049; P = 0.007) and emphysema on chest high-resolution computed tomography (OR 14.667; 95% CI 2.871–74.926; P = 0.001). The median overall survival time after developing LC was 7.0 months (95% CI 4.9–9.1 months), and the most common cause of death was LC, not ILD. According to the Cox proportional hazard model analysis with time-dependent covariates, patients who developed LC showed significantly poorer prognosis than those who did not (hazard ratio 87.86; 95% CI 19.56–394.67; P

The forced oscillation technique (FOT) is a noninvasive method with which to measure respiratory system resistance (Rrs) and reactance (Xrs) at a wide range of frequencies during breathing at rest in a short time. The purpose of this study was to assess the differences in Rrs and Xrs between patients with chronic obstructive pulmonary disease (COPD) and asthma using a new method of FOT with colored 3-dimensional visualization.Fifty-one patients with stable COPD and 49 patients with controlled or partly controlled asthma were enrolled. Whole-breath or within-breath changes of Rrs and Xrs were measured and compared between the diseases.The colored 3-dimensional images clarified the complex oscillatory properties of the respiratory system. Whole-breath resistance (the difference in Rrs at 5 and 20 Hz) and reactance (Xrs at 5 Hz and resonant frequency), and within-breath changes in reactance (Xrs at 5 Hz and resonant frequency) discriminated between patients with COPD and asthma. In multivariate regression analyses, inspiratory-expiratory differences in Xrs at 5 Hz contributed significantly to the differentiation between COPD and asthma, independent of age, gender, body weight, and pulmonary function.This new method of FOT is useful in the differential diagnosis of COPD and asthma.

Background Asthma–chronic obstructive pulmonary disease (COPD) overlap (ACO) is a clinical phenotype sharing features of asthma and COPD. Multidetector row computed tomography (MDCT) can be used to evaluate the airway structure; however, differences between asthma and ACO seen on MDCT are poorly understood. Objective To investigate the difference in airway structural between asthma and ACO, using MDCT in patients with clinical asthma. Methods Sixty-four patients with asthma were allocated to an asthma group (never smokers and ex-smokers with a smoking history of Results Forty-three patients were included in the asthma group (20 with AL, 23 without AL) and 16 in the ACO group. Patients with asthma and ACO had significantly greater WT than the healthy controls. WT in the third-generation bronchi was significantly greater in the ACO group than in the asthma group. The ACO group and the asthma with AL group were matched for age, disease duration, and FEV1/FVC. The WT in the third-generation bronchi was still greater in the ACO group than in the asthma with AL group. Conclusion Patients with ACO have a thicker airway wall than those with asthma, suggesting that airway remodeling is more prominent in ACO than in asthma. UMIN Clinical Trials Registry (UMIN-CTR) system ( http://www.umin.ac.jp/ctr/UMIN000028913 ).

A 70-year old man was admitted to our hospital because of nonproductive cough, fever and increasing dyspnea associated with alveolar opacities on chest roentgenogram, which later migrated to previously unaffected areas. The diagnosis of Chlamydial pneumonitis was made on serological grounds. Organizing pneumonia was documented by transbronchial lung biopsies and the subsequent course was satisfactory under minocycline therapy. Chlamydial infection should be considered in the differential diagnosis of migratory pulmonary infiltrates.

The nitrogen (N₂) single-breath washout (SBW) test is a measure of ventilation distribution inhomogeneity and also a small airway function that offers complementary information to spirometry; however, the relevance to the forced oscillation technique (FOT) and pulmonary emphysema in COPD is not fully understood. We hypothesized that pulmonary functions, forced oscillatory parameters, and emphysema extent would contribute independently to the results of the SBW test. In this cross-sectional study we assessed the relationship between the phase III slope (delta N₂) derived from N₂ SBW and these parameters. Spirometry, lung volumes, N₂ SBW, and the broadband frequency FOT were performed in 56 patients with COPD. Emphysema extent was measured by high-resolution computed tomography and scored. In multiple regression analyses, the delta N₂ was independently predicted by forced vital capacity, resonant frequency, and emphysema score (R(2)=0.57, p

The coexistence of emphysema and pulmonary fibrosis is known as combined pulmonary fibrosis and emphysema (CPFE). The aim of this study was to compare the lung mechanics measured by multi-frequency forced oscillation technique (FOT) among patients with CPFE, interstitial pneumonia (IP), and chronic obstructive pulmonary disease (COPD). FOT and pulmonary function tests were performed in 41 patients with CPFE, 47 with IP, and 86 with COPD. Whole-breath resistance at 20 Hz was significantly lower in patients with CPFE than in those with IP or COPD, irrespective of the severity of airflow limitation. Within-breath analyses of resistance revealed no difference among the 3 groups; however, the difference between inspiratory and expiratory phases of reactance at 5 Hz, which reflects expiratory flow limitation, in patients with CPFE was significantly higher than in those with IP and lower than in those with COPD. In conclusion, both emphysema and fibrosis affect lung mechanics in CPFE, leading to different findings from IP or COPD alone.

Coronary artery spasm has an important function in the etiology of variant angina and other acute coronary syndromes. Abnormal activation of Rho-family GTPases has been observed in cardiovascular disorders, but the function of genetic variability in Rho-family GTPases remains to be evaluated in cardiovascular disorders. We examined the genetic variability of Rho-family GTPases and their regulators in coronary artery spasm. We performed a comprehensive candidate gene analysis of 67 single nucleotide polymorphisms with amino-acid substitution in Rho-family GTPases and their regulators in 103 unrelated Japanese patients with acetylcholine-induced coronary artery spasm and 102 control Japanese subjects without acetylcholine-induced coronary artery spasm. We noted an association of the single nucleotide polymorphism of ARHGAP9 (rs11544238, Ala370Ser) with coronary artery spasm (odds ratio =2.67). We found that ARHGAP9 inactivated Rac as RacGAP and that the mRNA level of ARHGAP9 was strongly detected in hematopoietic cells. ARHGAP9 negatively regulated cell migration. The Ala370Ser polymorphism counteracted ARHGAP9-reduced cell migration, spreading and adhesion. The Ala370Ser polymorphism in the ARHGAP9 gene is associated with coronary artery spasm. These data suggest that the polymorphism of ARHGAP9 has a critical function in the infiltration of hematopoietic cells into the endothelium and inflammation leading to endothelial dysfunction.

A 22-year-old man was admitted to our hospital with fever, cough and dyspnea. His chest radiograph showed diffuse ground-glass attenuation in both lung fields. Arterial blood gas analysis showed hypoxemia (PaO2 28.7 Torr breathing room air) and he required mechanical ventilation within 6 hours after admission. Gomori methenamine silver (GMS) stain of the bronchoalveolar lavage (BAL) fluid smear showed round and indented organisms, and polymerase chain reaction revealed pneumocystis jirovecii in the BAL fluid. The HIV antibody was positive and peripheral blood CD4-positive lymphocytes decreased to 4.0%. Pneumocystis pneumonia complicated with acquired immunodeficiency syndrome (AIDS) was diagnosed. There was no four-fold rise in screen viral titers. We treated him with antibiotics, trimethoprim-sulfamethoxazole, ganciclovir, fos-fluconazole, steroid pulse therapy and sivelestat sodium hydrate. Respiratory failure was relieved within 5 days following treatment. The percentage of neutrophils in the BAL fluid was elevated (44.6%). Neutrophil elastase on admission was increased and improved to the normal range after treatment. Sivelestat sodium hydrate is an anti-neutrophil elastase inhibitor and may be one of the treatment options for acute respiratory failure due to pneumocystis pneumonia in AIDS patients.

Background Expiratory flow limitation (EFL) during tidal breathing is common in patients with severe COPD, and a major determinant of dynamic hyperinflation and exercise limitation. EFL can be measured by the forced oscillation technique (FOT); however, the relevance to clinical parameters is not fully understood. We hypothesized that emphysema extent and pulmonary function would contribute independently to the degree of EFL. Methods Broadband frequency FOT and pulmonary function tests were performed in 74 patients with COPD to derive respiratory system resistance (Rrs) and reactance (Xrs), and the EFL index as expressed by the differences between inspiratory and expiratory phases of Xrs at 5 Hz (ΔX5). Emphysema extent was measured by high-resolution computed tomography and scored. Results On the basis of the median value of ΔX5 (0.55 cmH2O/L/s), patients were classified into a high or low EFL index group. In multivariate regression analyses, a high EFL index was independently predicted by emphysema score, peripheral airway obstruction (forced expiratory flow between 25% and 75% of forced vital capacity), hyperinflation (functional residual capacity), and airway caliber (whole-breath Rrs at 5 Hz). Conclusions EFL measured by FOT is a global measure of COPD that has separable etiologies and is useful for evaluating the disease condition.