巽 浩一郎

BACKGROUND: Everolimus (ERL), a mammalian target of rapamycin (mTOR) inhibitor, has been used for the management of several advanced cancers. ERL frequently causes lung injury, although the clinical and radiographic features have not been clarified. The aim of this study was to assess the clinical features of ERL-induced lung injury and determine the associated risk factors. METHODS: This single-center, retrospective study included 45 patients (29 men, 16 women; age, 12-78 years) who had received ERL at our hospital between August 2010 and March 2016. Drug-induced lung injury (DILI) was diagnosed using the Japanese Respiratory Society criteria. We obtained information regarding the clinical course, symptoms, clinical findings, blood test findings, and chest computed tomography findings from the patients' medical records. Risk factors for DILI onset were investigated using the Wilcoxon rank sum test. RESULTS: Fifteen patients (33%) were diagnosed with DILI. The median time from ERL administration to DILI onset was 64 days. High Serum Krebs von den Lungen-6 (KL-6) levels and a low estimated glomerular filtration rate (eGFR) before ERL administration were found to be significant risk factors for DILI. KL-6 and lactate dehydrogenase (LDH) were significantly elevated at the onset of DILI. All 15 patients recovered; 11 were without steroids. CONCLUSIONS: Our results suggest that patients with high KL-6 levels and a low eGFR at baseline are at increased risk of ERL-induced lung injury. In addition, KL-6 and LDH may be useful biomarkers of ERL-induced lung injury.

OBJECTIVE: Although severe obstructive sleep apnea (OSA) is an important risk factor for atherosclerosis-related diseases including coronary artery disease (CAD), there is no reliable biomarker of CAD risks in patients with OSA. This study aimed to test our hypothesis that circulating autoantibodies against neuroblastoma suppressor of tumorigenicity 1 (NBL1-Abs) are associated with the prevalence of CAD in patients with OSA. METHODS: Eighty-two adults diagnosed with OSA by polysomnography, 96 patients with a diagnosis of acute coronary syndrome (ACS) and 64 healthy volunteers (HVs) were consecutively enrolled. Serum samples were collected from patients with OSA at diagnostic polysomnography and from patients with ACS at disease onset. Serum NBL1-Ab level was measured by amplified luminescence proximity homogeneous assay and its association with clinical variables related to atherosclerosis was evaluated. RESULTS: NBL1-Ab level was significantly elevated in patients with both OSA and ACS compared with HVs. Subgroup analyses showed that NBL1-Ab level was markedly higher in patients with severe OSA and OSA patients with a history of CAD. Weak associations were observed between NBL1-Ab level and apnea-hypopnea index, age, mean SpO2 and arousal index, whereas significantly higher NBL1-Ab levels were observed in OSA patients with a history of CAD than in those without a history of CAD. Sensitivity analysis using a logistic regression model also demonstrated that increased NBL1-Ab levels were associated with the previous history of CAD in patients with OSA. CONCLUSIONS: Elevated NBL1-Ab levels may be associated with the prevalence of CAD in patients with OSA, which needs to be confirmed further.

Transcriptional repressor B-cell lymphoma 6 (Bcl6) appears to regulate TH2 immune responses in allergies, but its precise role is unclear. We previously reported that Bcl6 suppressed IL-4 production in naïve CD4+ T cell-derived memory TH2 cells. To investigate Bcl6 function in allergic responses in naturally occurring memory phenotype CD4+ T (MPT) cells and their derived TH2 (MPTH2) cells, Bcl6-manipulated mice, highly conserved intron enhancer (hcIE)-deficient mice, and reporter mice for conserved noncoding sequence 2 (CNS2) 3' distal enhancer region were used to elucidate Bcl6 function in MPT cells. The molecular mechanisms of Bcl6-mediated TH2 cytokine gene regulation were elucidated using cellular and molecular approaches. Bcl6 function in MPT cells was determined using adoptive transfer to naïve mice, which were assessed for allergic airway inflammation. Bcl6 suppressed IL-4 production in MPT and MPTH2 cells by suppressing CNS2 enhancer activity. Bcl6 downregulated Il4 expression in MPTH2 cells, but not MPT cells, by suppressing hcIE activity. The inhibitory functions of Bcl6 in MPT and MPTH2 cells attenuated allergic responses. Bcl6 is a critical regulator of IL-4 production by MPT and MPTH2 cells in TH2 immune responses related to the pathogenesis of allergies.

Background: Although appropriate sedation is recommended during flexible bronchoscopy (FB), patients are at risk for hypoventilation due to inadvertent oversedation. End-tidal capnography is expected as an additional useful monitor for these patients during FB. Objectives: The aim of this study was to evaluate the benefit of additional end-tidal capnography monitoring in reducing the incidence of hypoxemia during FB in patients under sedation. Methods: Patients undergoing FB under moderate sedation without tracheal intubation were randomly assigned to receive standard monitoring including pulse oximetry or additional capnography monitoring. Bronchoscopy examiners for the only capnography group were informed of apnea events by alarms and display of the capnography monitor. Results: A total of 185 patients were enrolled. Patient characteristics were well balanced between the two groups. Hypoxemia (at least one episode of pulse oximeter oxygen saturation [SpO(2)] <90%) was observed in 27 out of 94 patients in the capnography group (29%) and in 42 out of 91 patients in the control group (46%; p = 0.014), resulting in an absolute risk difference of -17.4% (95% confidence interval, -31.1 to -3.7). In the capnography group, hypoxemia duration was shorter (20.4 vs. 41.7 s, p = 0.029), severe hypoxemic events (SpO(2) <85%) were observed less frequently (16 [17%] vs. 29 [32%], p= 0.019), and the mean lowest SpO(2) value was higher (90.5 vs. 87.6%, p = 0.002). Conclusion: End-tidal capnography monitoring can reduce the incidence and duration of hypoxemia during FB in nonintubated patients under sedation. (C) 2018 S. Karger AG, Basel

A 67-year-old woman with fever and cough was diagnosed with eosinophilic pneumonia because of eosinophilia and increased eosinophil levels in the bronchoalveolar lavage fluid and transbronchial biopsy lung specimens. However, prednisolone therapy at a previous hospital was ineffective. Histological findings from thoracoscopic lung and lymph node biopsies were consistent with multicentric Castleman's disease (MCD). Since specimens also showed prominent eosinophil and IgG4-positive plasma cell infiltration, it was difficult to distinguish IgG4-related disease (IgG4-RD) from MCD. Administration of prednisolone plus tocilizumab improved the symptoms and lung lesions, and prednisolone administration was successfully reduced and then terminated. The present case highlights the difficulty in diagnosing MCD and IgG4-RD, and suggests that combined administration of tocilizumab and prednisolone might be effective in such a case.

Partial anomalous pulmonary venous return (PAPVR) is a rare congenital cardiovascular anomaly. A 68-year-old woman was referred to our hospital for detailed examination for pulmonary hypertension (PH). She had been diagnosed as having pulmonary artery dilation and suspected to have PH during a health check seven years prior. A contrast computed tomography showed that the right upper pulmonary vein (RUPV) returned to the superior vena cava (SVC) with a preserved normal connection to the left atrium (LA). Surgical repair was performed. We reported an extremely rare case of isolated PAPVR with PH showing dual drainage into the SVC and LA.

Introduction: The INPULSIS-ON trial demonstrated that nintedanib reduced decline in forced vital capacity (FVC) and low pulmonary function (%FVC < 50%) of patients with idiopathic pulmonary fibrosis (IPF). However, there is no sufficient evidence in real world. Objectives: Reveal the utility and adverse events of nintedanib for severe IPF patients. Methods: This was a single-center retrospective study. Patients who met the eligibility criteria of the INPULSIS trial (%FVC ≥ 50%; %DLCO [diffusing capacity of the lung carbon monoxide % predicted] ≥ 30%) were classified as Mild to Moderate Group (n = 34); patients who did not meet the criteria were classified as Severe Group (n=17). Results: The body mass index (24.7 ± 3.4 vs 22.4 ± 3.6 kg/m2; P = 0.021) were significantly low in Severe Group. Main adverse events (diarrhea, nausea, liver disorder, and acute exacerbation) tended to be more in Severe Group than in Mild to Moderate Group; however, the difference was not significant (P = 0.76, 0.14, 0.18, and 0.67, respectively). The continuation rates over 12 months tended to be higher in Mild to Moderate Group than in Severe Group (77% vs 44%; P = 0.027). Log-rank test revealed that the prognosis was significantly better in Mild to Moderate Group than in Severe Group (P = 0.014). In the Severe Group, patients who were able to continue nintedanib for more than 3 months had significantly better prognosis compared to those who could not (P = 0.007). Conclusion: The benefit from nintedanib was reduced in patients in Severe Group when compared to those in Mild to Moderate Group; however, the prognosis is expected to improve with control of side effects and long-term administration. It is more important to control the side effects in Severe Group.

BACKGROUND: Re-biopsy by bronchoscopy is an important part of treatment for patients with relapsed lung cancer; however, some patients refuse to undergo a re-examination due to discomfort during their first bronchoscopy. The aim of the present study was to determine factors causing discomfort during bronchoscopy and to identify the factors that affect patients' reluctance to undergo repeat examinations via a questionnaire administered immediately after the initial bronchoscopy. METHODS AND FINDINGS: We evaluated 283 patients who underwent bronchoscopy at Chiba University Hospital between September 2015 and March 2017. Following bronchoscopy, the patients answered a questionnaire regarding the procedure. We identified patient characteristics and factors related to bronchoscopy that were associated with patients' reluctance to undergo re-examination. Two hundred nine patients were ultimately enrolled in the study. The factors affecting patient tolerance for re-examination were female sex (odds ratio [OR], 2.81; 95% confidence interval [CI], 1.43-5.53), discomfort during the examination (OR, 1.70; 95% CI, 1.13-2.56), and unexpectedness of discomfort during the examination (OR, 1.83; 95% CI, 1.19-2.81). Patients experienced discomfort most frequently owing to throat anesthesia (n = 50 [24%]). CONCLUSIONS: Comfort during bronchoscopy is an important factor influencing patient tolerance for re-examination. Expectations of discomfort during bronchoscopy, as indicated by instructions provided before examination, and throat anesthesia are also important factors. Detailed explanations about bronchoscopy and improvement of the methods of throat anesthesia could decrease patient discomfort and may help decrease patients' reluctance to undergo re-examinations.

BACKGROUND: The trend of the initial treatment strategy for pulmonary arterial hypertension (PAH) has changed from monotherapies to upfront combination therapies. This study analyzed treatments and outcomes in Japanese patients with PAH, using data from the Japan PH Registry (JAPHR), which is the first organized multicenter registry for PAH in Japan.Methods and Results:We studied 189 consecutive patients (108 treatment-naïve and 81 background therapy patients) with PAH in 8 pulmonary hypertension (PH) centers enrolled from April 2008 to March 2013. We performed retrospective survival analyses and analyzed the association between upfront combination and hemodynamic improvement, adjusting for baseline NYHA classification status. Among the 189 patients, 1-, 2-, and 3-year survival rates were 97.0% (95% CI: 92.1-98.4), 92.6% (95% CI: 87.0-95.9), and 88.2% (95% CI: 81.3-92.7), respectively. In the treatment-naïve cohort, 33% of the patients received upfront combination therapy. In this cohort, 1-, 2-, and 3-year survival rates were 97.6% (95% CI: 90.6-99.4), 97.6% (95% CI: 90.6-99.4), and 95.7% (95% CI: 86.9-98.6), respectively. Patients on upfront combination therapy were 5.27-fold more likely to show hemodynamic improvement at the first follow-up compared with monotherapy (95% CI: 2.68-10.36). CONCLUSIONS: According to JAPHR data, initial upfront combination therapy is associated with improvement in hemodynamic status.

AIM: Medical comorbidities are a major cause of death among patients with mental illness. The purpose of this study was to clarify the risk factors for mortality among psychiatric patients with medical comorbidities. METHODS: We retrospectively reviewed the clinical files of patients transferred to Tokyo Metropolitan Matsuzawa Hospital from a psychiatric hospital to treat medical comorbidities during the 3-year period from January 2014 to December 2016. We analyzed the clinical differences between the expired and alive patients. RESULTS: Of the 287 patients included, 29 (10.1%) had expired at the time of hospital discharge, while 258 (89.9%) were living. A multivariable analysis to determine the prognostic factors related to mortality from medical comorbidities showed that body mass index <18.5 had the highest odds ratio among the predictive factors (5.1; 95% confidence interval, 1.5-17.1; P < 0.05), followed by a serum albumin level < 3.0 mg/dL (3.0; 95% confidence interval, 1.1-8.1; P < 0.05). CONCLUSION: We found that underweight and hypoalbuminemia were risk factors for mortality among psychiatric patients with medical comorbidities. Physicians at psychiatric hospitals should consider transferring patients with medical comorbidities to a general medical hospital in the presence of underweight and/or hypoalbuminemia.

BACKGROUND: Genetically modified adenoviruses (Ad) with preferential replications in tumor cells have been examined for a possible clinical applicability as an anti-cancer agent. A simple method to detect viral and cellular proteins is valuable to monitor the viral infections and to predict the Ad-mediated cytotoxicity. METHODS: We used type 5 Ad in which the expression of E1A gene was activated by 5'-regulatory sequences of genes that were augmented in the expression in human tumors. The Ad were further modified to have the fiber-knob region replaced with that derived from type 35 Ad. We infected human mesothelioma cells with the fiber-replaced Ad, and sequentially examined cytotoxic processes together with an expression level of the viral E1A, hexon, and cellular cleaved caspase-3 with image cytometric and Western blot analyses. RESULTS: The replication-competent Ad produced cytotoxicity on mesothelioma cells. The infected cells expressed E1A and hexon 24 h after the infection and then showed cleavage of caspase-3, all of which were detected with image cytometry and Western blot analysis. Image cytometry furthermore demonstrated that increased Ad doses did not enhance an expression level of E1A and hexon in an individual cell and that caspase-3-cleaved cells were found more frequently in hexon-positive cells than in E1A-positive cells. Image cytometry thus detected these molecular changes in a sensitive manner and at a single cell level. We also showed that an image cytometric technique detected expression changes of other host cell proteins, cyclin-E and phosphorylated histone H3 at a single cell level. CONCLUSIONS: Image cytometry is a concise procedure to detect expression changes of Ad and host cell proteins at a single cell level, and is useful to analyze molecular events after the infection.

Pulmonary arterial hypertension (PAH) is characterized by progressive obstructive remodeling of pulmonary arteries. However, no reports have described the causative role of the autophagic pathway in pulmonary vascular endothelial cell (EC) alterations associated with PAH. This study investigated the time-dependent role of the autophagic pathway in pulmonary vascular ECs and pulmonary vascular EC kinesis in a severe PAH rat model (Sugen/hypoxia rat) and evaluated whether timely induction of the autophagic pathway by rapamycin improves PAH. Hemodynamic and histological examinations as well as flow cytometry of pulmonary vascular EC-related autophagic pathways and pulmonary vascular EC kinetics in lung cell suspensions were performed. The time-dependent and therapeutic effects of rapamycin on the autophagic pathway were also assessed. Sugen/hypoxia rats treated with the vascular endothelial growth factor receptor blocker SU5416 showed increased right ventricular systolic pressure (RVSP) and numbers of obstructive vessels due to increased pulmonary vascular remodeling. The expression of the autophagic marker LC3 in ECs also changed in a time-dependent manner, in parallel with proliferation and apoptotic markers as assessed by flow cytometry. These results suggest the presence of cross talk between pulmonary vascular remodeling and the autophagic pathway, especially in small vascular lesions. Moreover, treatment of Sugen/hypoxia rats with rapamycin after SU5416 injection activated the autophagic pathway and improved the balance between cell proliferation and apoptosis in pulmonary vascular ECs to reduce RVSP and pulmonary vascular remodeling. These results suggested that the autophagic pathway can suppress PAH progression and that rapamycin-dependent activation of the autophagic pathway could ameliorate PAH.

BACKGROUND: Pulmonary fibrosis is a late manifestation of acute respiratory distress syndrome (ARDS). Sepsis is a major cause of ARDS, and its pathogenesis includes endotoxin-induced vascular injury. Recently, endothelial-to-mesenchymal transition (EndMT) was shown to play an important role in pulmonary fibrosis. On the other hand, dipeptidyl peptidase (DPP)-4 was reported to improve vascular dysfunction in an experimental sepsis model, although whether DPP-4 affects EndMT and fibrosis initiation during lipopolysaccharide (LPS)-induced lung injury is unclear. The aim of this study was to investigate the anti-EndMT effects of the DPP-4 inhibitor vildagliptin in pulmonary fibrosis after systemic endotoxemic injury. METHODS: A septic lung injury model was established by intraperitoneal injection of lipopolysaccharide (LPS) in eight-week-old male mice (5 mg/kg for five consecutive days). The mice were then treated with vehicle or vildagliptin (intraperitoneally, 10 mg/kg, once daily for 14 consecutive days from 1 day before the first administration of LPS.). Flow cytometry, immunohistochemical staining, and quantitative polymerase chain reaction (qPCR) analysis was used to assess cell dynamics and EndMT function in lung samples from the mice. RESULTS: Lung tissue samples from treated mice revealed obvious inflammatory reactions and typical interstitial fibrosis 2 days and 28 days after LPS challenge. Quantitative flow cytometric analysis showed that the number of pulmonary vascular endothelial cells (PVECs) expressing alpha-smooth muscle actin (α-SMA) or S100 calcium-binding protein A4 (S100A4) increased 28 days after LPS challenge. Similar increases in expression were also confirmed by qPCR of mRNA from isolated PVECs. EndMT cells had higher proliferative activity and migration activity than mesenchymal cells. All of these changes were alleviated by intraperitoneal injection of vildagliptin. Interestingly, vildagliptin and linagliptin significantly attenuated EndMT in the absence of immune cells or GLP-1. CONCLUSIONS: Inhibiting DPP-4 signaling by vildagliptin could ameliorate pulmonary fibrosis by downregulating EndMT in systemic LPS-induced lung injury.

Background: Pulmonary fibrosis is a late manifestation of acute respiratory distress syndrome (ARDS). Sepsis is a major cause of ARDS, and its pathogenesis includes endotoxin-induced vascular injury. Recently, endothelial-to-mesenchymal transition (EndMT) was shown to play an important role in pulmonary fibrosis. On the other hand, dipeptidyl peptidase (DPP)-4 was reported to improve vascular dysfunction in an experimental sepsis model, although whether DPP-4 affects EndMT and fibrosis initiation during lipopolysaccharide (LPS)-induced lung injury is unclear. The aim of this study was to investigate the anti-EndMT effects of the DPP-4 inhibitor vildagliptin in pulmonary fibrosis after systemic endotoxemic injury. Methods: A septic lung injury model was established by intraperitoneal injection of lipopolysaccharide (LPS) in eight-week-old male mice (5 mg/kg for five consecutive days). The mice were then treated with vehicle or vildagliptin (intraperitoneally, 10 mg/kg, once daily for 14 consecutive days from 1 day before the first administration of LPS.). Flow cytometry, immunohistochemical staining, and quantitative polymerase chain reaction (qPCR) analysis was used to assess cell dynamics and EndMT function in lung samples from the mice. Results: Lung tissue samples from treated mice revealed obvious inflammatory reactions and typical interstitial fibrosis 2 days and 28 days after LPS challenge. Quantitative flow cytometric analysis showed that the number of pulmonary vascular endothelial cells (PVECs) expressing alpha-smooth muscle actin (a-SMA) or S100 calcium-binding protein A4 (S100A4) increased 28 days after LPS challenge. Similar increases in expression were also confirmed by qPCR of mRNA from isolated PVECs. EndMT cells had higher proliferative activity and migration activity than mesenchymal cells. All of these changes were alleviated by intraperitoneal injection of vildagliptin. Interestingly, vildagliptin and linagliptin significantly attenuated EndMT in the absence of immune cells or GLP-1. Conclusions: Inhibiting DPP-4 signaling by vildagliptin could ameliorate pulmonary fibrosis by downregulating EndMT in systemic LPS-induced lung injury.

Pulmonary arterial hypertension (PAH) is a lethal disease that often affects the young. Although Bone Morphogenetic Protein Receptor Type 2 gene (BMPR2) mutations are related with idiopathic and heritable PAH, the low penetrance and variable expressivity in PAH suggest the existence of other genetic and/or environmental factors. In this study, we aimed to identify novel genetic factors associated with PAH, irrespective of BMPR2 mutation. We performed genome-wide association study (GWAS) in a Japanese population comprising 44 individuals with idiopathic and heritable PAH, and 2,993 controls. Seven loci identified in the genome-wide study were submitted to the validation study, and a novel susceptibility locus, PDE1A|DNAJC10, was identified that maps to 2q32.1 (rs71427857, P = 7.9 × 10-9, odds ratio in the validation study = 5.18; 95% CI 1.86 - 14.42). We also found the augmentation of PDE1A protein in distal remodeled pulmonary artery walls in idiopathic PAH patients. Given that phosphodiesterase 5 inhibitors are effective for the treatment of idiopathic and heritable PAH, our findings suggest that PDE1A could be a novel therapeutic target of PAH.

BACKGROUND: Replication-competent adenoviruses (Ad) produced cytotoxic effects on infected tumors and have been examined for the clinical applicability. A biomarkers to predict the cytotoxicity is valuable in a clinical setting. METHODS: We constructed type 5 Ad (Ad5) of which the expression of E1A gene was activated by a 5' regulatory sequences of survivin, midkine or cyclooxygenase-2, which were highly expressed in human tumors. We also produced the same replication-competent Ad of which the fiber-knob region was replaced by that of Ad35 (AdF35). The cytotoxicity was examined by a colorimetric assay with human tumor cell lines, 4 kinds of pancreatic, 9 esophageal carcinoma and 5 mesothelioma. Ad infectivity and Ad-mediated gene expression were examined with replication-incompetent Ad5 and AdF35 which expressed the green fluorescence protein gene. Expression of cellular receptors for Ad5 and AdF35 was also examined with flow cytometry. A transcriptional activity of the regulatory sequences was investigated with a luciferase assay in the tumor cells. We then investigated a possible correlation between Ad-mediated cytotoxicity and the infectivity/gene expression, the transcriptional activity or the p53 genotype. RESULTS: We found that the cytotoxicity was greater with AdF35 than with Ad5 vectors, but was not correlated with the Ad infectivity/gene expression irrespective of the fiber-knob region or the E1A-activating transcriptional activity. In contrast, replication-competent Ad produced greater cytotoxicity in p53 mutated than in wild-type esophageal carcinoma cells, suggesting a possible association between the cytotoxicity and the p53 genotype. CONCLUSIONS: Sensitivity to Ad-mediated cytotoxic activity was linked with the p53 genotype but was not lineally correlated with the infectivity/gene expression or the E1A expression.

Rationale: A useful semiquantitative method of using computed tomographic (CT) images to evaluate therapeutic response in pulmonary alveolar proteinosis (PAP) has not been established, although the extent score or grading score of ground-glass opacities has been used. Objectives: The purpose of this study was to establish a semiquantitative method for evaluating therapeutic response in PAP. Methods: CT scans were obtained within 1 month before and after therapy from 32 patients with PAP who participated in a multicenter phase II trial of granulocyte-macrophage colony-stimulating factor inhalation therapy. The scans were evaluated by two chest radiologists independently. Increased parenchymal opacity was evaluated on the basis of its intensity and extent (CT grade), and the severity scores were compared with CT scores based on the extent alone (CT extent), as well as on the basis of physiological and serological results. Results: CT grade score and CT extent score had significant correlationwith diffusing capacity of the lung for carbon monoxide percent predicted (%DLCO), PaO2, VC percent predicted (%VC), Krebs von den Lungen (KL)-6, and surfactant protein D. The change in CT grade score between pre- and post-treatment examinations (ΔCT grade) correlated better with difference of PaO2 between pre- and post-treatment examinations (ΔPaO2) than DCT extent (difference of CT extent score between pre- and post-treatment examinations). In univariate analysis, ΔCT grade, ΔCT extent, ΔKL-6, Δ%DLCO, Δ%VC, and change in surfactant protein D correlated significantly with ΔPaO2. Inmultivariate analysis, ΔCT grade and ΔKL-6 correlated more closely with ΔPaO2.

Rationale: A useful semiquantitative method of using computed tomographic (CT) images to evaluate therapeutic response in pulmonary alveolar proteinosis (PAP) has not been established, although the extent score or grading score of ground-glass opacities has been used. Objectives: The purpose of this study was to establish a semiquantitative method for evaluating therapeutic response in PAP. Methods: CT scans were obtained within 1 month before and after therapy from 32 patients with PAP who participated in a multicenter phase II trial of granulocyte-macrophage colony-stimulating factor inhalation therapy. The scans were evaluated by two chest radiologists independently. Increased parenchymal opacity was evaluated on the basis of its intensity and extent (CT grade), and the severity scores were compared with CT scores based on the extent alone (CT extent), as well as on the basis of physiological and serological results. Results: CT grade score and CT extent score had significant correlationwith diffusing capacity of the lung for carbon monoxide percent predicted (% DLCO), Pa-O2, VC percent predicted (% VC), Krebs von den Lungen (KL)-6, and surfactant protein D. The change in CT grade score between pre-and post-treatment examinations (Delta CT grade) correlated better with difference of Pa-O2 between pre-and post-treatment examinations (Delta Pa-O2) than Delta CT extent (difference of CT extent score between pre-and post-treatment examinations). In univariate analysis, Delta CT grade, Delta CT extent, Delta KL-6, Delta%DLCO, Delta%VC, and change in surfactant protein D correlated significantly with Delta Pa-O2. Inmultivariate analysis, Delta CT grade and DKL-6 correlated more closely with Delta Pa-O2. Conclusions: Although a number of CT variables were collected, the currently proposed grading system that correlates well with Pa-O2 should be viewed as a retrospective scoring system that needs future validation with another PAP cohort.

RATIONALE: A useful semiquantitative method of using computed tomographic (CT) images to evaluate therapeutic response in pulmonary alveolar proteinosis (PAP) has not been established, although the extent score or grading score of ground-glass opacities has been used. OBJECTIVES: The purpose of this study was to establish a semiquantitative method for evaluating therapeutic response in PAP. METHODS: CT scans were obtained within 1 month before and after therapy from 32 patients with PAP who participated in a multicenter phase II trial of granulocyte-macrophage colony-stimulating factor inhalation therapy. The scans were evaluated by two chest radiologists independently. Increased parenchymal opacity was evaluated on the basis of its intensity and extent (CT grade), and the severity scores were compared with CT scores based on the extent alone (CT extent), as well as on the basis of physiological and serological results. RESULTS: CT grade score and CT extent score had significant correlation with diffusing capacity of the lung for carbon monoxide percent predicted (%DlCO), PaO2, VC percent predicted (%VC), Krebs von den Lungen (KL)-6, and surfactant protein D. The change in CT grade score between pre- and post-treatment examinations (ΔCT grade) correlated better with difference of PaO2 between pre- and post-treatment examinations (ΔPaO2) than ΔCT extent (difference of CT extent score between pre- and post-treatment examinations). In univariate analysis, ΔCT grade, ΔCT extent, ΔKL-6, Δ%DlCO, Δ%VC, and change in surfactant protein D correlated significantly with ΔPaO2. In multivariate analysis, ΔCT grade and ΔKL-6 correlated more closely with ΔPaO2. CONCLUSIONS: Although a number of CT variables were collected, the currently proposed grading system that correlates well with PaO2 should be viewed as a retrospective scoring system that needs future validation with another PAP cohort.

BACKGROUND: Dilatation of the pulmonary artery and right ventricle on chest computed tomography images is often observed in patients with pulmonary hypertension. The clinical significance of these image findings has not been defined in chronic thromboembolic pulmonary hypertension. We investigated whether the pulmonary arterial and right ventricle dilatation was associated with poor outcome in chronic thromboembolic pulmonary hypertension. METHODS: This was a retrospective cohort investigation in 60 subjects with inoperable chronic thromboembolic pulmonary hypertension diagnosed consecutively between 1997 and 2010 at Chiba University Hospital. Digital scout multi-detector chest computed tomography images were obtained. The main pulmonary arterial to ascending aortic diameter ratio and the right ventricular to left ventricular diameter ratio were calculated. RESULTS: Main pulmonary arterial to ascending aortic diameter ratio ranged from 0.85 to 1.84, and right ventricular to left ventricular diameter ratio ranged from 0.71 to 2.88. During the observation period of 1284.5days (range, 21-4550days), 13 patients required hospitalization due to worsening; 6 of them died. Kaplan-Meier analysis showed significant differences in hospitalization between the patients with main pulmonary arterial to ascending aortic diameter ratio of ≥1.1 and <1.1 (log-rank test, p=0.014) and between the patients with right ventricular to left ventricular diameter ratio of ≥1.2 and <1.2 (log-rank test, p=0.013). There was a significant difference in the prognosis between the patients with RV/LV ratio≥1.2 and those with RV/LV ratio<1.2 (log-rank test, p=0.033). CONCLUSIONS: Main pulmonary arterial to ascending aortic diameter ratio measured using enhanced CT images was associated with the risk for first clinical exacerbation, and right ventricular to left ventricular diameter ratio was associated with the risk for poor prognosis in inoperable chronic thromboembolic pulmonary hypertension.

Pulmonary arteriovenous malformation (PAVM) is an abnormal blood vessel connecting a pulmonary artery and a vein, and is accompanied by paradoxical embolism to other organs due to a right-to-left shunt. We report the case of a 66-year-old woman with PAVM complicated by splenic infarction and abscess. Although the PAVM had been detected on a chest image 2 years previously, and she had been advised to have further investigations, she decided not to follow this further at the time. She then visited our hospital complaining of worsening dyspnoea on exertion. Detailed examinations revealed splenic infarction and abscessation due to PAVM. PAVM embolization was performed after antibiotic treatment. It is very rare for PAVM to be complicated by splenic infarction and abscess. Regardless of its size, embolization of a PAVM as soon as possible can reduce not only the risk of central nervous system complications, but also the risk of splenic infarction and abscess.

Although nivolumab is known to cause immune-related interstitial lung diseases (ILD), the detailed characteristics of ILD are still not fully understood. A 68-year-old man was treated with nivolumab because of unresectable sinonasal melanoma, he achieved a complete response soon after the initiation of the therapy and a complete response was thereafter maintained for 30 weeks until the patient experienced dyspnea of subacute onset. CT images revealed patchy infiltrates and ground-glass opacifications. The bronchoalveolar lavage fluid (BALF) contained elevated percentages of lymphocytes (53%) and neutrophils (30%). A transbronchial lung biopsy revealed intraalveolar fibrin balls without hyaline membranes, which was considered to be consistent with the pattern of acute fibrinous and organizing pneumonia (AFOP). This is the first report of AFOP induced by nivolumab.

BACKGROUND: Chronic thromboembolic pulmonary hypertension (CTEPH) is difficult to diagnose as patients rarely present with specific symptoms. However, a mosaic attenuation pattern (MAP) in chest computed tomography (CT) suggests CTEPH. Areas of increased attenuation are not always visible using default CT settings for the lung. Thus, we examined the utility of non-contrast CT imaging with new settings focusing on MAP (CTMosaic) for the assessment of pulmonary perfusion in patients with CTEPH. The regional perfusion defects visualized using CTMosaic and single-photon-emission CT with fusion of CT images (SPECT/CT) were compared. METHODS: Twenty-seven patients with CTEPH (20 women; aged 62.8±7.9 years) underwent imaging with non-contrast CT and SPECT/CT. We converted non-contrast mediastinal CT images into various CT window settings to identify the MAP, and the CT window setting that could most easily identify the MAP was defined as CTMosaic. We then scored and compared lung segments depending on the degree of perfusion on CTMosaic and SPECT/CT. RESULTS: CTMosaic was identified as the CT window setting in which the window level was -800 Hounsfield units (HU), and the window width was 200 HU. Using CTMosaic, MAP was detected in 366 of 486 segments (75.3%). The agreement between CTMosaic and perfusion defects on SPECT/CT was 84.9%. Weighted kappa statistics demonstrated a good agreement between the two examinations (κ=0.605, 95% confidence interval, 0.502-0.707). CONCLUSIONS: The CTMosaic setting can easily identify an MAP in CTEPH patients. Therefore, this may be useful as a simple and cost-effective evaluation method for blood distribution in patients with CTEPH.

Patients undergoing chemotherapy usually undergo placement of a totally implantable venous access port (TIVAP), but TIVAP catheter fracture is rare. We encountered a case where flushing the TIVAP catheter became impossible because of resistance. A 61-year-old-woman underwent TIVAP placement. Although a chest X-ray revealed the fractured catheter had migrated into the right hilar area, the timing of the fracture was unclear. Four-dimensional computed tomography (4D-CT) showed that the tip of the fractured catheter was located at the anterior segmental artery of the right upper lobe and was immobile, with the remaining portion flapping with the blood flow. Transcatheter removal of the migrated catheter was judged to be possible and was performed successfully. 4D-CT may be useful as an appropriate approach in transcatheter removal of a migrated fractured catheter.

Patients with chronic thromboembolic pulmonary hypertension (CTEPH) require lifelong anticoagulation therapy. However, the bleeding risk and recurrence of venous thromboembolism (VTE) in CTEPH patients who are administered warfarin have not been adequately evaluated. The purpose of this study was to evaluate the risk of clinically relevant bleeding, recurrent VTE, and clinical worsening in patients with CTEPH who were administered warfarin. The clinical records of 72 patients with CTEPH who regularly visited our institution and were administered warfarin were retrospectively reviewed between 1 January 2011 and 31 December 2015. We investigated the incidence of clinically relevant bleeding events, recurrent VTE, and hospitalization for the deterioration of pulmonary hypertension or right heart failure (RHF) during the observation period. The mean observation period for the 72 patients was 3.601.60 person-years. Clinically relevant bleeding, RHF, and recurrent VTE occurred in 21 (29.2%), eight (11.1%), and three (4.2%) of 72 patients, respectively, and the incidence rates for these events were 8.1%/person-year, 3.1%/person-year, and 1.2%/person-year, respectively. The incidence rates for the major and non-major bleeding events were 5.0%/person-year and 3.9%/person-year, respectively. The incidence of clinically relevant bleeding events was 20.8%/person-year during medical treatment with a soluble guanylate cyclase stimulator. One of 35 patients (2.9%) during the post-pulmonary endarterectomy period experienced hemoptysis during observation period (&gt; 6 months after pulmonary endarterectomy). No bleeding events occurred during the post-balloon pulmonary angioplasty period. In conclusion, warfarin effectively prevents VTE recurrence in CTEPH patients, but its effects may be associated with a considerable bleeding risk.

The epithelial-to-mesenchymal transition (EMT) in cancer is associated with invasion, metastasis and chemoresistance. Recent studies have revealed the increased expression of programmed death-ligand 1 (PD-L1) in cells undergoing EMT. The underlying mechanism of EMT involves transforming growth factor-β (TGF-β) and fibroblast growth factor-2 (FGF-2). Pirfenidone and the known EMT-suppressor nintedanib suppress pulmonary fibrosis partially through suppression of TGF-β. The present study aimed to determine whether pirfenidone has the potential to induce EMT-reversion, using nintedanib as a reference. The human lung adenocarcinoma cell lines A-549, HCC-827, and PC-9 were treated with TGF-β and FGF-2 to induce EMT. The EMT-induced cells were further treated with pirfenidone or nintedanib. Phenotypic alterations associated with EMT were assessed by examining the following: i) The expression levels of E-cadherin, vimentin, fibronectin and slug, using reverse transcription-quantitative polymerase chain reaction (RT-qPCR) and fluorescent immunohistochemistry; ii) cell motility via wound-healing assays; and iii) the expression of PD-L1 using RT-qPCR. The combination of TGF-β and FGF-2 successfully induced EMT in all three cell lines, characterized by a significant reduction in E-cadherin expression in the A-549 and HCC-827 cells, increased expression levels of vimentin, fibronectin, slug and PD-L1, and increased cell motility in all three cell lines. Pirfenidone and nintedanib reverted all of these phenotypes, with the exception of unaltered E-cadherin expression in all three cell lines, and inconsistent expression of vimentin in the HCC-827 and PC-9 cells. Thus, pirfenidone and nintedanib have the ability to induce EMT-reversion in human lung adenocarcinoma.

BACKGROUND: There has been limited information about epidemiology and clinical practice of acute respiratory distress syndrome (ARDS) in Japan. METHODS: An invitation letter to the web-based survey was mailed to all 871 board certified hospitals of the Japanese Respiratory Society. The questionnaires were designed to collect data on epidemiology and clinical practice of ARDS, including diagnostic measures and therapeutics. RESULTS: Within 4 months of the survey period, valid responses were obtained from 296 (34%) hospitals. The incidence of ARDS was estimated to be 3.13 cases/100 hospital beds or 1.91 cases/ICU bed per year. The most frequent underlying disease was pneumonia (34%), followed by sepsis (29%). In hospitals with fewer ICU beds, pulmonologists tended to be in charge of management of ARDS patients. Routine diagnostic measures included computed tomography of the chest (69.6% of the hospitals) and Swan-Ganz catheterization was rarely performed for diagnosis. In 87.4% of the hospitals, non-invasive ventilation was applied to management of ARDS patients, especially those with mild disease. Prone positioning and extracorporeal membrane oxygenation (ECMO) for ARDS patients was more widely adopted in hospitals with larger numbers of ICU beds and intensivists. In 58.2% of the responding hospitals, corticosteroid was considered as a treatment option for ARDS, among which pulse therapy was routinely introduced to ARDS patients in 35.4%. CONCLUSIONS: The incidence of ARDS in Japan was estimated to be lower than that in the recent international study. The scale and equipment of hospitals and the number of intensivists might influence clinical practice of ARDS.

BACKGROUND: Riociguat, the first approved drug for patients with chronic thromboembolic pulmonary hypertension (CTEPH), is a soluble guanylate cyclase (sGC) Stimulator. It directly stimulates sGC independently of nitric oxide (NO) and increases sGC sensitivity for NO. The safety and efficacy of transitioning from a phosphodiesterase 5 inhibitor (PDE5i) to riociguat is unknown. METHODS AND RESULTS: Twenty-three patients were prospectively enrolled: 8 symptomatic patients with inadequate clinical responses to PDE5i were changed to riociguat (transitioned group); 15 started riociguat anew (new or add-on group). We analyzed the change from baseline to 6-12 months of riociguat treatment for the 6-minute walk distance (6MWD), mean pulmonary arterial pressure (mPAP), pulmonary vascular resistance (PVR), cardiac index (CI), partial pressure of oxygen in arterial blood (PaO2), brain natriuretic peptide (BNP), World Health Organization (WHO) functional class, safety and adverse events. The mPAP, BNP and WHO functional class significantly improved in total. In the transitioned group, BNP significantly decreased by -116.5±188.6pg/ml (P=0.0156). The 6MWD, mPAP, PVR, CI, and PaO2 improved but not significantly. The baseline condition was significantly more severe in the transitioned than in the new or add-on group. No patients discontinued riociguat. Relatively rapid transitioning from PDE5i to riociguat was safe under careful observation. CONCLUSIONS: Transitioning to riociguat may be safe and effective in CTEPH patients with inadequate clinical responses to PDE5i.

BACKGROUND: Mesothelioma is resistant to conventional treatments and is often defective in p53 pathways. We then examined anti-tumor effects of metformin, an agent for type 2 diabetes, and combinatory effects of metformin and nutlin-3a, an inhibitor for ubiquitin-mediated p53 degradation, on human mesothelioma. METHODS: We examined the effects with a colorimetric assay and cell cycle analyses, and investigated molecular events in cells treated with metformin and/or nutlin-3a with Western blot analyses. An involvement of p53 was tested with siRNA for p53. RESULTS: Metformin suppressed cell growth of 9 kinds of mesothelioma including immortalized cells of mesothelium origin irrespective of the p53 functional status, whereas susceptibility to nutlin-3a was partly dependent on the p53 genotype. We investigated combinatory effects of metformin and nutlin-3a on, nutlin-3a sensitive MSTO-211H and NCI-H28 cells and insensitive EHMES-10 cells, all of which had the wild-type p53 gene. Knockdown of p53 expression with the siRNA demonstrated that susceptibility of MSTO-211H and NCI-H28 cells to nutlin-3a was p53-dependent, whereas that of EHMES-10 cells was not. Nevertheless, all the cells treated with both agents produced additive or synergistic growth inhibitory effects. Cell cycle analyses also showed that the combination increased sub-G1 fractions greater than metformin or nutlin-3a alone in MSTO-211H and EHMES-10 cells. Western blot analyses showed that metformin inhibited downstream pathways of the mammalian target of rapamycin (mTOR) but did not activate the p53 pathways, whereas nutlin-3a phosphorylated p53 and suppressed mTOR pathways. Cleaved caspase-3 and conversion of LC3A/B were also detected but it was dependent on cells and treatments. The combination of both agents in MSTO-211H cells rather suppressed the p53 pathways that were activated by nutrin-3a treatments, whereas the combination rather augmented the p53 actions in NCI-H28 and EHMES-10 cells. CONCLUSION: These data collectively indicated a possible interactions between mTOR and p53 pathways, and the combinatory effects were attributable to differential mechanisms induced by a cross-talk between the pathways.

STUDY OBJECTIVES: Although moderate to severe obstructive sleep apnea (OSA) is an independent risk factor for severe arteriosclerotic diseases such as cardiovascular disease (CVD) and stroke, the development of atherosclerosis-related diseases cannot yet be predicted in patients with OSA. In a pilot study, we identified autoantibodies against the coatomer protein complex, subunit epsilon [circulating anti-coatomer protein complex subunit epsilon autoantibody (COPE-Ab)], a cytosolic complex that mediates protein transport in the Golgi compartment, as a potential novel biomarker of atherosclerosis. This study aimed to evaluate whether COPE-Ab levels had an association with cardiovascular and cerebrovascular events in patients with OSA. METHODS: Eighty-two adult patients with a diagnosis of OSA via polysomnography and 64 healthy donors were studied. Serum COPE-Ab levels were measured using an amplified luminescence proximity homogeneous assay. Then, clinical factors related to atherosclerosis were evaluated with respect to COPE-Ab levels. RESULTS: Significant differences in COPE-Ab levels were observed in terms of OSA severity. COPE-Ab levels were significantly higher in patients with OSA and also CVD and/or stroke, hypertension, and a high body mass index. Univariate and multivariate logistic regression analyses of patients with OSA identified elevated COPE-Ab level as a significant predictor of CVD and/or stroke. CONCLUSIONS: An elevated COPE-Ab level may be a potential predictor of the risks of cardiovascular and cerebrovascular events in patients with OSA. Therefore, patients with higher COPE-Ab levels may require more careful and intensive treatment. COMMENTARY: A commentary on this article appears in this issue on page 361.

PURPOSE: Right ventricular myocardial (RVM) fibrosis may be a significant indicator of prognosis in pulmonary hypertension (PH). To detect the presence of RVM fibrosis in PH subjects, we employed ECG gated 320-slice CT. METHODS: 62 confirmed PH subjects (16 males; 55±16years; 45 chronic thromboembolic PH (CTEPH) who underwent conventional non-surgical medical therapy; and 17 pulmonary arterial hypertension (PAH)) underwent ECG-gated 320-slice CT. On CT, RV fibrosis was defined as contrast defect in the early phase and conversely abnormal enhancement in the late phase. RESULTS: RVM fibrosis was observed in 14 subjects (23%) on CT (CTEPH 22%; PAH 29%; P=0.91). CT attenuation of RVM in the late phase was significantly greater in subjects with RVM fibrosis than in those without (P=0.025). ROC curves of CT attenuation of RVM in the early and late phase, and ratio of CT attenuation of RVM in the early phase/late phase showed AUCs of 0.55, 0.70, and 0.65, respectively. The best cutoff points of 79.5 HU (sensitivity of 50% and specificity of 69% for CT attenuation of RVM in the early phase, P=0.59), 99.5 HU (sensitivity of 50% and specificity of 88% for CT attenuation of RVM in the late phase, P=0.025), and 1.416 (sensitivity of 29% and specificity of 94% for ratio of CT attenuation of RVM in the early phase/late phase, P=0.092) were used to distinguish subjects±RVM fibrosis. CONCLUSION: Quantitative-measurement of CT attenuation of RVM in the late phase may be able to detect presence of RVM fibrosis in PH subjects.

Mice deficient in the transcriptional repressor B-cell CLL/lymphoma 6 (Bcl6) exhibit similar T helper 2 (TH2) immune responses as patients with allergic diseases. However, the molecularmechanisms underlying Bcl6-directed regulation of TH2 cytokine genes remain unclear. We identified multiple Bcl6/STAT binding sites (BSs) in TH2 cytokine gene loci. We found that Bcl6 is modestly associated with the BSs, and it had no significant effect on cytokine production in newly differentiated TH2 cells. Contrarily, in memory TH2 (mTH2) cells derived from adaptively transferred TH2 effectors, Bcl6 outcompeted STAT5 for binding to TH2 cytokine gene loci, particularly Interleukin4 (Il4) loci, and attenuated GATA binding protein 3 (GATA3) binding to highly conserved intron enhancer regions in mTH2 cells. Bcl6 suppressed cytokine production epigenetically in mTH2 cells to negatively tune histone acetylation at TH2 cytokine gene loci, including Il4 loci. In addition, IL-33, a pro-TH2 cytokine, diminished Bcl6's association with loci to which GATA3 recruitment was inversely augmented, resulting in altered IL-4, but not IL-5 and IL-13, production in mTH2 cells but no altered production in newly differentiated TH2 cells. Use of a murine asthma model that generates high levels of pro-TH2 cytokines, such as IL-33, suggested that the suppressive function of Bcl6 in mTH2 cells is abolished in severe asthma. These findings indicate a role of the interaction between TH2-promoting factors and Bcl6 in promoting appropriate IL-4 production in mTH2 cells and suggest that chronic allergic diseases involve the TH2-promoting factor-mediated functional breakdown of Bcl6, resulting in allergy exacerbation.

Mice deficient in the transcriptional repressor B-cell CLL/lymphoma 6 (Bcl6) exhibit similar T helper 2 (TH2) immune responses as patients with allergic diseases. However, the molecular mechanisms underlying Bcl6-directed regulation of TH2 cytokine genes remain unclear. We identified multiple Bcl6/STAT binding sites (BSs) in TH2 cytokine gene loci. We found that Bcl6 is modestly associated with the BSs, and it had no significant effect on cytokine production in newly differentiated TH2 cells. Contrarily, in memory TH2 (mTH2) cells derived from adaptively transferred TH2 effectors, Bcl6 outcompeted STAT5 for binding to TH2 cytokine gene loci, particularly Interleukin4 (Il4) loci, and attenuated GATA binding protein 3 (GATA3) binding to highly conserved intron enhancer regions in mTH2 cells. Bcl6 suppressed cytokine production epigenetically in mTH2 cells to negatively tune histone acetylation at TH2 cytokine gene loci, including Il4 loci. In addition, IL-33, a pro-TH2 cytokine, diminished Bcl6's association with loci to which GATA3 recruitment was inversely augmented, resulting in altered IL-4, but not IL-5 and IL-13, production in mTH2 cells but no altered production in newly differentiated TH2 cells. Use of a murine asthma model that generates high levels of pro-TH2 cytokines, such as IL-33, suggested that the suppressive function of Bcl6 in mTH2 cells is abolished in severe asthma. These findings indicate a role of the interaction between TH2-promoting factors and Bcl6 in promoting appropriate IL-4 production in mTH2 cells and suggest that chronic allergic diseases involve the TH2-promoting factor-mediated functional breakdown of Bcl6, resulting in allergy exacerbation.

BACKGROUND: Apnea developing as a result of oversedation is a potential clinical problem in patients undergoing flexible bronchoscopy (FB) under sedation. However, there are no reports of evaluation using a standardized method of the frequency of occurrence of apnea episodes during FB under sedation. The aim of this study was to investigate the frequency of apnea episodes during FB under sedation in the clinical setting by end-tidal capnography. METHODS: This study was a single-institution retrospective review of a prospectively maintained database and medical records, including capnographic data, from April 2015 to March 2016. We enrolled patients who were sedated with midazolam and underwent diagnostic FB under end-tidal capnographic monitoring. Apnea was defined as cessation of airflow for more than 10 s. RESULTS: Data from a total of 121 eligible patients were analyzed. A total of 131 apnea episodes (median duration 33 s) were recorded in 59 patients (48.8%). Prolonged apnea episodes lasting for more than 30 s occurred in 24 patients (19.8%). Furthermore, 55 apnea episodes (42.0%) were followed by a decline of the SpO2 by ≥4% from the baseline. CONCLUSIONS: In this study, end-tidal capnography revealed the occurrence of apnea episodes at a high frequency in patients undergoing FB under sedation in the clinical setting.

AIM: Radiographic testing has an important role in the diagnosis and evaluation of pneumonia. The aim of the present study was to evaluate the usefulness of computed tomography (CT), in comparison with chest roentography (CR), in the diagnosis and evaluation of nursing- and healthcare-associated pneumonia (NHCAP) . METHODS: The utility of CT in the diagnosis of NHCAP was compared with that of CR in a prospective study of patients who visited the emergency room in Nissan Tamagawa Hospital, Tokyo, Japan, with clinical symptoms that were indicative of NHCAP. We also evaluated whether particular CT findings were risk factors for NHCAP-associated mortality. RESULTS: A total of 162 patients with suspected NHCAP were included in the study. The 162 patients included 147 (90.6%) patients who were diagnosed with NHCAP based on the detection of pneumonic infiltration on CT. In contrast, CR was not capable of recognizing pneumonic infiltration in 15 of the 147 (10.2%) patients. A multivariable analysis which was carried out to determine the risk factors for NHCAP-associated mortality, showed that oxygen desaturation had the greatest odds ratio, followed by a blood urea nitrogen level of ≥21 mg/dL and the detection of bilateral pneumonic infiltration by CT. CONCLUSIONS: We herein show that CT is superior to CR for the diagnosis and evaluation of NHCAP. The present study will provide a foundation for further studies to clarify whether the use of CT in the diagnosis and evaluation of NHCAP can improve the clinical outcome of patients with NHCAP. Geriatr Gerontol Int 2017; 17: 41-47.

Background: Recent advances in multidetector computed tomography (MDCT) facilitate acquiring important clinical information for managing patients with COPD. MDCT can detect the loss of lung tissue associated with emphysema as a low-attenuation area (LAA) and the thickness of airways as the wall area percentage (WA%). The percentage of small pulmonary vessels &lt;5 mm(2) (% cross-sectional area [CSA]&lt;5) has been recently recognized as a parameter for expressing pulmonary perfusion. We aimed to analyze the longitudinal changes in structural abnormalities using these CT parameters and analyze the effect of exacerbation and smoking cessation on structural changes in COPD patients. Methods: We performed pulmonary function tests (PFTs), an MDCT, and a COPD assessment test (CAT) in 58 patients with COPD at the time of their enrollment at the hospital and 2 years later. We analyzed the change in clinical parameters including CT indices and examined the effect of exacerbations and smoking cessation on the structural changes. Results: The CAT score and forced expiratory volume in 1 second (FEV1) did not significantly change during the follow-up period. The parameters of emphysematous changes significantly increased. On the other hand, the WA% at the distal airways significantly decreased or tended to decrease, and the % CSA &lt;5 slightly but significantly increased over the same period, especially in ex-smokers. The parameters of emphysematous change were greater in patients with exacerbations and continued to progress even after smoking cessation. In contrast, the WA% and % CSA &lt;5 did not change in proportion to emphysema progression. Conclusion: The WA% at the distal bronchi and the % CSA &lt;5 did not change in parallel with parameters of LAA over the same period. We propose that airway disease and vascular remodeling may be reversible to some extent by smoking cessation and appropriate treatment. Optimal management may have a greater effect on pulmonary vascularity and airway disease than parenchymal deconstruction in the early stage of COPD.

Objective Osteoporosis, which is now recognized as a major comorbidity of chronic obstructive pulmonary disease (COPD), must be diagnosed by appropriate methods. The aims of this study were to clarify the relationships between bone mineral density (BMD) and COPD-related clinical variables and to explore the association of BMD with the updated Global Initiative for Chronic Obstructive Lung Disease (GOLD) classification in men. Methods We enrolled 50 Japanese men with clinically stable COPD who underwent dual-energy X-ray absorptiometry (DEXA), pulmonary function testing, and computerized tomography (CT) and who had completed a questionnaire (COPD assessment test [CAT]). We determined the association between the T-score and other tested parameters and compared the BMD of patients in each GOLD category. Results Twenty-three of the 50 patients (46.0%) were diagnosed with osteopenia, and 7 (14.0%) were diagnosed with osteoporosis. The BMD findings were significantly correlated with the CAT score, forced expiratory volume in 1 second percentage predicted (FEV1% predicted), low attenuation volume percentage (LAV%), and percentage of cross-sectional area of small pulmonary vessels (%CSA) on CT images. Notably, the median T-score of the GOLD category D participants was significantly lower than that of the participants in each of the other categories (A [-0.98], B [-1.06], C [-1.05], and D [-2.19], p<0.05). Conclusion Reduced BMD was associated with airflow limitation, extent of radiographic findings, and a poor quality of life (QOL) in patients with COPD. The BMD of GOLD category D patients was the lowest of all of the patients evaluated, and category D patients may benefit from active intervention for osteoporosis.

BACKGROUND AND OBJECTIVE: Chronic thromboembolic pulmonary hypertension (CTEPH) is a progressive disease in some patients, despite improved treatments. Microvasculopathy has been implicated in the poor outcomes of patients with CTEPH. A reduction in the diffusing capacity for carbon monoxide (DLCO ) was previously suggested to indicate microvasculopathy in CTEPH patients; therefore, we assessed DLCO /alveolar ventilation (DLCO /VA ) as a prognostic and pathophysiological marker in CTEPH. METHODS: We performed a retrospective cohort study of 214 CTEPH patients consecutively diagnosed between 1986 and 2011. After exclusion of 24 patients because of missing DLCO data or severe obstructive impairment, the mortality rates of medically treated patients classified with normal or decreased DLCO values were compared, and prognostic factors were determined. The relationship between long-term surgical outcomes and DLCO /VA was also investigated. RESULTS: Ninety-one inoperable patients were treated medically, two of whom underwent balloon pulmonary angioplasty. Ninety-nine underwent pulmonary endarterectomy. The 5-year survival rate of medically treated patients was significantly lower in patients with decreased DLCO /VA than in those with normal values (61.4% vs 90.4%, P = 0.017). Decreased preoperative DLCO /VA was associated with a smaller percent decrease in post-operative pulmonary vascular resistance, but not with the extent of proximal thrombi; these results may support our hypothesis that DLCO reflects microvascular involvement. CONCLUSION: Decreased DLCO /VA was associated with poor outcomes of medically treated CTEPH patients; and may be useful for identifying high-risk patients, potentially leading to earlier and more appropriate interventions.