巽 浩一郎

58歳男性。右腋窩潰瘍で救急外来を受診し、重度の皮膚軟部組織感染症にて入院となった。前縦隔腫瘍、口腔内カンジダ症の合併が判明し、加療中にニューモシスチス肺炎および細菌性肺炎を併発した。縦隔腫瘍は生検により胸腺腫WHO分類type Aと診断され、低γグロブリン血症の合併より、Good症候群と診断された。スルファメトキサゾール・トリメトプリム(sulfamethoxazole-trimethoprim:ST)合剤、ステロイド、免疫グロブリン補充療法などにより軽快退院した。前縦隔腫瘍に多様な感染症を合併した場合には、Good症候群を念頭に置き、早期診断治療に努める必要がある。(著者抄録)

Rationale: The effects of telemedicine on adherence in patients with obstructive sleep apnea with long-term continuous positive airway pressure (CPAP) use have never been investigated.Objectives: To examine effects of a telemedicine intervention on adherence in long-term CPAP users.Methods: In a prospective, randomized, multicenter noninferiority trial conducted in 17 sleep centers across Japan, patients who had used CPAP for >3 months and were receiving face-to-face follow-up by physicians every 1 or 2 months were randomized by a coordinating center in a blind manner to the following three groups: 1) follow-up every 3 months accompanied by a monthly telemedicine intervention (telemedicine group: TM-group), 2) follow-up every 3 months (3-month group: 3M-group), or 3) monthly follow-up (1-month group: 1M-group). Each group was followed up for 6 months. The change in percentage of days with ≥4 h/night of CPAP use from baseline to the end of the study period was evaluated. A decline of ≥5% from baseline was considered deterioration of adherence. Noninferiority of TM- and 3M-groups compared with the 1M-group according to the number of patients with deterioration of adherence was evaluated with the Farrington and Manning test (noninferiority margin 15%).Results: A total of 483 patients were analyzed (median duration of CPAP use, 29 [interquartile range, 12-71] mo), and deterioration of adherence was found in 41 of 161 (25.5%), 55 of 166 (33.1%), and 35 of 156 (22.4%) patients in the TM-, 3M-, and 1M-groups, respectively. The noninferiority of the TM-group compared with the 1M-group was verified (difference in percentage of patients with adherence deterioration, 3.0%; 95% confidence interval [CI], -4.8% to 10.9%; P < 0.01). Conversely, the 3M-group did not show noninferiority to the 1M-group (percentage difference, 10.7%; 95% CI, 2.6% to 18.8%; P = 0.19). In the stratified analysis, adherence in TM- and 1M-group patients with poor adherence at baseline improved (TM: 45.8% ± 18.2% to 57.3% ± 24.4%; P < 0.01; 1M: 43.1% ± 18.5% to 53.6% ± 24.3%; P < 0.01), whereas that of the 3M-group did not (39.3% ± 20.8% to 39.8% ± 24.8%; P = 0.84).Conclusions: Intensive telemedicine support could help to optimize CPAP adherence even after long-term CPAP use.Clinical trial registered with www.umin.ac.jp/ctr/index.htm (trial number: UMIN000023118).

Biomarkers are not available for monitoring the onset and progression of coronary artery disease (CAD) in patients with obstructive sleep apnea (OSA), a major risk factor for arteriosclerotic cardiovascular diseases. This study aimed to test for correlation between circulating anti-Sorting Nexins 16 antibody (SNX16-Ab) levels, CAD history and clinical parameters of patients with OSA. Sixty-four healthy donors, 82 adults with OSA, and 96 with acute coronary syndrome (ACS) were studied. Serum samples were collected at diagnostic polysomnography in the OSA group or at the disease onset in the ACS group. Serum SNX16-Ab levels were measured by amplified luminescence proximity homogeneous assay (AlphaLISA), and correlation between SNX16-Ab levels and clinical parameters was analyzed. SNX16-Ab levels and apnea-hypopnea index (AHI) were weakly correlated. Additionally, logistic regression analyses of OSA group identified that elevated SNX16-Ab level associated with the history of CAD. Circulating SNX16-Ab could increase during CAD pathogenesis in patients with OSA. Further prospective studies are required to prove the predictive potential of SNX16-Ab level in CAD onset of patients with OSA.

BACKGROUND: Pulmonary endothelial damage has a negative impact on the maintenance of normal pulmonary vascular function. Such damage results in delayed thrombus dissolution and vascular remodeling in chronic thromboembolic pulmonary hypertension (CTEPH). Although endothelial progenitor cells (EPCs) may be incorporated into neovasculature during vascular repair, their function in CTEPH remains unclarified, especially under the augmentation of soluble guanylate cyclase (sGC) activity. METHODS AND RESULTS: We evaluated the effect of EPCs on endothelial function and compared the effect of riociguat, a sGC stimulator, on the number and function of circulating EPCs in two groups of CTEPH patients. The two groups consisted 16 CTEPH patients who were treatment naïve (Naïve group), and 14 CTEPH patients who were being treated with riociguat, a sGC stimulator (Riociguat group). The number of circulating EPCs in the Riociguat group was significantly higher than that in the Naïve group. Gene expression levels associated with angiogenesis were significantly higher in EPCs of the Riociguat group. EPC-stimulated tube formation and migration of human pulmonary microvascular endothelial cell (hPMVEC) in the Riociguat group exceeded that in the Naïve group. The angiogenic ability of hPMVECs stimulated by EPCs in the Riociguat group was enhanced compared to that of the sGC stimulator, BAY 41-2272. CONCLUSION: These findings indicate that riociguat may induce EPCs to play a protective role via modulation of endothelial functions associated with CTEPH. TRANSLATION ASPECT OF THE WORK: Endothelial dysfunction exacerbates CTEPH. Riociguat enhanced the protective role of EPCs via neovascularization, which prevented vascular remodeling and alleviated CTEPH.

While the prognosis of idiopathic pulmonary arterial hypertension has improved significantly due to newer medications, lung transplantation remains a critical therapeutic option for severe pulmonary arterial hypertension. Hence, it is essential for patients awaiting lung transplantation to avoid complications, including thrombocytopenia, which may affect their surgical outcomes. Herein we present the case of a 21-year-old woman diagnosed with idiopathic pulmonary arterial hypertension at the age of 15. She developed thrombocytopenia while awaiting lung transplantation. Her medication was switched from epoprostenol to treprostinil, suspecting possible drug-induced thrombocytopenia. Furthermore, she was administered thrombopoietin receptor agonists in view of the possibility of idiopathic thrombocytopenic purpura, along with maximum support for right heart failure. Subsequently, her platelet count increased to >70,000/µL, enabling her to successfully undergo bilateral lung transplantation. Post-bilateral lung transplantation, pulmonary arterial hypertension as well as thrombocytopenia appeared to have resolved. In this case, we suspected that thrombocytopenia could have resulted owing to a combination of pulmonary arterial hypertension, right heart failure, drug interactions, and idiopathic thrombocytopenic purpura. Thrombocytopenia is a very critical condition in patients with pulmonary arterial hypertension, especially those awaiting lung transplantation. Several approaches are known to improve intractable thrombocytopenia in patients with pulmonary arterial hypertension.

<p>目的 : クリニカルクラークシップ (CC) における文献検索の現状と講義の効果を検証した. 方法 : 対象は2019年5〜12月に呼吸器内科CCに参加した医学生67名. CC中に文献検索に関するアンケートと講義を実施した. 結果 : 医学生はPubMedの使用頻度が多いが, 利用する文献は日本語教科書, ガイドラインが多く, 文献の吟味, 英語読解に困難を感じていた. また, 講義の前後で文献検索リテラシーの自己評価は有意に向上し, 課題への引用文献数が前年度から増加した. 結論 : 医学生は英語も含め文献検索は行うが文献の吟味や英語読解に困難を感じていた. また, 講義でも文献検索リテラシーの向上が得られる可能性が示唆された.</p>

The interventricular septum curvature, measured in images of electrocardiogram-gated 320-slice multidetector computed tomography, is reportedly useful and less invasive than right heart catheterization, as it could provide clues regarding pulmonary arterial pressure in patients with chronic thromboembolic pulmonary hypertension. Although pulmonary endarterectomy is an efficient treatment for chronic thromboembolic pulmonary hypertension, the interventricular septum curvature in patients who have received pulmonary endarterectomy has not been evaluated. We evaluated whether the interventricular septum curvature on electrocardiogram-gated 320-slice multidetector computed tomography can predict pulmonary hemodynamics in chronic thromboembolic pulmonary hypertension even after pulmonary endarterectomy. We studied 40 patients with chronic thromboembolic pulmonary hypertension (60.5 ± 9.7 years; 30 females), who underwent pulmonary endarterectomy at Chiba University Hospital between December 2010 and July 2018. To measure the interventricular septum curvature, we prepared left ventricular short-axis tomographic images from 4D images of electrocardiogram-gated 320-slice multidetector computed tomography. We calculated the radius of interventricular septum and determined the interventricular septum curvature in both the systolic and diastolic phases. We compared the interventricular septum curvature with pulmonary hemodynamics measured by right heart catheterization before and after pulmonary endarterectomy. After pulmonary endarterectomy, the correlations of the interventricular septum curvature with mean pulmonary arterial pressure, systolic pulmonary arterial pressure, and pulmonary vascular resistance disappeared, although the interventricular septum curvature was correlated with these pulmonary hemodynamic parameters before pulmonary endarterectomy. Changes in systolic interventricular septum curvature revealed significant correlations with changes in mean pulmonary arterial pressure, systolic pulmonary arterial pressure and pulmonary vascular resistance. Diastolic interventricular septum curvature also showed significant correlations with preoperative pulmonary hemodynamics, but not with postoperative pulmonary hemodynamics. Changes in the interventricular septum curvature after pulmonary endarterectomy could estimate the efficacy of pulmonary endarterectomy, although the interventricular septum curvature after pulmonary endarterectomy showed no significant correlations with pulmonary hemodynamics. Additionally, our findings confirmed that the interventricular septum curvature before pulmonary endarterectomy could be used to evaluate the severity of disease.

An asymptomatic 70-year-old woman presented with a nodular lesion overlapping the pulmonary artery at the right hilar region on a chest X-ray. Bronchial arteriography revealed an aneurysmal dilation of the long segment of the right bronchial artery and a shunt from the right bronchial artery to the right lower pulmonary artery. She was diagnosed with primary racemose hemangioma of the bronchial artery (RHBA). Considering the risk of hemoptysis, we performed a bronchial arterial embolization (BAE) using coils and N-butyl-2-cyanoacrylate. She had no complication after the BAE and no recurrences of hemoptysis at the 36-month follow-up. RHBA should be considered in case of aneurysmal dilation in the long segment of the bronchial artery, and BAE should be considered as a treatment strategy despite the absence of symptoms.

Objective Chronic thromboembolic pulmonary hypertension (CTEPH) is a form of pulmonary hypertension caused by persistent thromboemboli of the pulmonary arteries, and one of its etiological factors may be inflammation. Sleep disordered breathing (SDB) is reportedly an important complication of pulmonary hypertension. However, the association between SDB and inflammation in CTEPH has been undefined. This prospective observational study analyzed the association between the severity of SDB, pulmonary hemodynamic parameters and the systemic inflammation level in patients with CTEPH. Methods CTEPH patients admitted for a right heart catheter (RHC) examination were consecutively enrolled from November 2017 to June 2019 at the pulmonary hypertension center in Chiba University Hospital. Patients with idiopathic pulmonary arterial hypertension (IPAH) were also enrolled as a control group. All patients underwent a sleep study using a WatchPAT 200 during admission. Results The CTEPH patients showed worse nocturnal hypoxemia, oxygen desaturation index (ODI), and apnea-hypopnea index than the IPAH patients. Among these factors, only the nocturnal mean percutaneous oxygen saturation (SpO2) was negatively correlated with the pulmonary hemodynamic parameters. The circulating tumor necrosis factor-alpha (TNF-α) level was also high in the CTEPH group, and a multivariate analysis showed that the nocturnal mean SpO2 was the most important predictive factor for a high TNF-α level. Conclusion We showed that CTEPH patients had high serum TNF-α levels and that the nocturnal mean SpO2 was a predictive factor for serum TNF-α levels. Further investigations focused on nocturnal hypoxemia and the TNF-α level may provide novel insight into the etiology and new therapeutic strategies for CTEPH.

Idiopathic pulmonary fibrosis (IPF) is a fatal lung disease of unknown etiopathogenesis. The activation of extracellular matrix (ECM)-producing myofibroblasts plays a key role in fibrotic tissue remodeling. The dedifferentiation of myofibroblasts has attracted considerable attention as a promising target for the development of effective therapeutic interventions against IPF. Here, we screened a small library of epigenetics-related inhibitors using dedifferentiation assay of lung myofibroblasts prepared from a patient at the terminal stages of IPF and chose UNC0379. The inhibition of SET8, a histone H4 lysine 20 (H4K20) monomethyltransferase, by UNC0379 markedly suppressed the expression of α-smooth muscle actin (SMA) and ED-A-fibronectin in myofibroblasts. In IPF myofibroblasts, SET8 expression and H4K20 monomethylation (H4K20me1) levels, which were significantly higher than those in normal human lung fibroblasts, were reduced upon treatment with UNC0379. Hence, the changes in the expression of the two fibrotic markers clearly correlated with those in SET8 expression and H4K20me1 level. Furthermore, in a mouse model of bleomycin (BLM)-induced lung fibrosis, the intratracheal administration of UNC0379 at an early fibrotic stage markedly ameliorated the histopathological changes associated with collagen deposition in the lungs. However, treatment with UNC0379 did not significantly affect the number of proinflammatory cells or cytokine production in the bronchoalveolar lavage fluids from mice treated with BLM. In the BLM-injured lung, SET8 was predominantly localized to the nuclei of α-SMA-positive cells, which colocalized with H4K20me1. Taken together, our results indicate that the inhibition of SET8 resulting in myofibroblast dedifferentiation may partly mitigate lung fibrosis without affecting the inflammatory responses.

BACKGROUND: Combined pulmonary fibrosis with emphysema (CPFE) is a clinically meaningful syndrome characterized by coexisting upper-lobe emphysema and lower-lobe interstitial fibrosis. However, ambiguous diagnostic criteria and, particularly, the absence of objective methods to quantify emphysematous/fibrotic lesions in patients with CPFE confound the interpretation of the pathophysiology of this syndrome. We analyzed the relationship between objectively quantified computed tomography (CT) measurements and the results of pulmonary function testing (PFT) and clinical events in CPFE patients. MATERIALS AND METHODS: We enrolled 46 CPFE patients who underwent CT and PFT. The extent of emphysematous lesions was obtained by calculating the percent of low attenuation area (%LAA). The extent of fibrotic lesions was calculated as the percent of high attenuation area (%HAA). %LAA and %HAA values were combined to yield the percent of abnormal area (%AA). We assessed the relationships between CT parameters and other clinical indices, including PFT results. Multivariate analysis was performed to examine the association between the CT parameters and clinical events. RESULTS: A greater negative correlation with percent predicted diffusing capacity of the lung for carbon monoxide (DLCO %predicted) existed for %AA (r = -0.73, p < 0.001) than for %LAA or %HAA alone. The %HAA value was inversely correlated with percent predicted forced vital capacity (r = -0.48, p < 0.001), percent predicted total lung capacity (r = -0.48, p < 0.01), and DLCO %predicted (r = -0.47, p < 0.01). Multivariate logistic regression analysis found that %AA showed the strongest association with hospitalization events (odds ratio = 1.20, 95% confidence interval = 1.01-1.54, p = 0.029). CONCLUSION: Quantitative CT measurements reflected deterioration in pulmonary function and were associated with hospitalization in patients with CPFE. This approach could serve as a useful method to determine the extent of lung morphology, pathophysiology, and the clinical course of patients with CPFE.

INTRODUCTION: The Gender-Age-Physiology (GAP) system is a tool for predicting prognosis in patients with idiopathic pulmonary fibrosis (IPF). Yet, to date, the GAP system has not been evaluated in patients with IPF who received nintedanib. MATERIAL AND METHODS: This single-center retrospective study included 89 patients with IPF who received Nintedanib for at least 3 months. All-cause mortality was set as the end point. Clinical parameters, including the GAP stage, were statistically analyzed for risk factors leading to mortality using the Cox proportional hazard model. RESULTS: The median follow-up was 16.4 months (range 3.7-37.4 months), during which 23 patients died. Univariate analysis revealed that the GAP stage (hazard ratio [HR] 3.00, 95% confidence interval [CI] 1.52-5.92, p = 0.0014) and PaO2 (HR 0.95, 95% CI 0.92-0.98, p = 0.0063) were significant prognostic factors. Multivariate analysis revealed that the GAP stage was a significant prognostic factor (HR 2.26, 95% CI 1.07-4.78, p = 0.031). Log-rank analysis revealed that there were no significant differences in "Gender" (p = 0.47) and "Age" (p = 0.18) factors. However, there were significant differences in "Physiology" factors (% of forced vital capacity, p = 0.018; % of diffusing capacity of lung carbon monoxide, p < 0.001). The cumulative incidences of mortality at 1 and 2 years were as follows: GAP I: 5.1% and 6.8%; GAP II: 9.5% and 29.3%; and GAP III: 18.9% and 84.2%. CONCLUSIONS: The GAP system is useful as a prognostic tool in patients with IPF who have been treated with nintedanib.

<p>Idiopathic pulmonary fibrosis (IPF) is a fatal respiratory disease with an unknown cause and poor prognosis. To precisely know the pathophysiology of lung fibrotic disease, the appropriate animal model correlating to the pathology of IPF is required. Its establishment may contribute to develop a new strategy for the treatment of patients with IPF. From the transcriptome analysis using lung myofibroblasts derived from the patient with IPF, we found the possible correlation between ferroptosis and lung fibrosis. Then, to investigate whether the intracellular overload of ferrous ion in the lung parenchyma induces fibrotic formation, we subpleurally injected ferric chloride solution into the central part of left upper lobe. Within 1 h post-injection, the intracellular elevation of ferrous ion and ROS was detected by berlin blue and dihydrorhodamine, respectively. At 10 days post-injury, diffuse and severe fibrosis occurred in the whole lung lobe, which was well associated with an excessive collagen deposition, an increase in expression of myofibroblast markers and a decrease in static lung compliance. Likewise, the DNA array/gene set enrichment analysis clearly showed the accumulation of extracellular matrix including collagen in the ferric chloride-injured lung. In our model, it is noteworthy that a prominent hyperplasia of type2 alveolar epithelial cells was observed around the fibrotic lesion and that progressive and irreversible fibrogenesis was verified by a follow-up survey at least for 6 weeks. These features correlate to the pathology of IPF but are not observed in other existing mouse models. In conclusion, we established a new reliable lung fibrosis model.</p>

<p>Fibroblast-to-myofibroblast differentiation is recognized as critical process of developing irreversible pulmonary fibrosis through the excessive accumulation of extracellular matrix. To elucidate the factor that can induce dedifferentiation of myofibroblast phenotype will provide a new therapeutic target for pulmonary fibrosis. We have previously reported Lung mixed culture-derived epithelial cells (LMDECs) as the cell populations, collected from crude culture of the mouse whole lung, satisfied some characteristics of Type-2 alveolar epithelial cells, and ameliorated experimental pulmonary fibrosis. However, the mechanism as to how LMDECs exerts beneficial effects on the pulmonary fibrosis remains to be clarified. We showed the myofibroblasts dedifferentiation induced by the communication between LMDECs and myofibroblasts. The primary Myofibroblast-Like Cells (MyoLCs), exhibiting increased expression of myofibroblast marker proteins (α-smooth muscle actin and ED-A-fibronectin), were isolated from resected human fibrotic lung. Immunoblotting revealed reduced expression of myofibroblast marker proteins in LMDEC/MyoLC direct contact co-culture, while LMDEC did not change expression of them in non-contact co-culture. We will further investigate the association of LMDEC-derived membrane proteins with myofibroblast dedifferentiation.</p>

＜文献概要＞Point ◎気管支喘息は症状の変動性,症状を反復する病歴,悪化因子に注目することが重要である.◎喫煙歴のある40歳以上の成人で,労作時の呼吸困難や慢性の咳・痰がある場合にCOPDを疑う.◎無症状でも喫煙歴のある患者ではCOPDを疑うことが重要で,感冒時に症状が顕在化する場合がある.◎気管支喘息,COPD,オーバーラップの鑑別は,問診,併存疾患,検査所見から総合的に判断する.◎適切な診断のために画像検査や呼吸機能検査を医療圏で連携し,積極的に行うことが重要である.

Very recently, a modest but significant efficacy of granulocyte-macrophage colony-stimulating factor (GM-CSF) inhalation therapy for the treatment of mild to moderate autoimmune pulmonary alveolar proteinosis (aPAP) has been reported. As the ability to measure the level of GM-CSF autoantibody (GMAb) in the serum is required to decide the indication for this therapy, we developed a high-performance GMAb testing kit for clinical use. As the kit succeeded in reducing nonspecific IgG binding to the ELISA plate, the predictive performance shown in the training study to discriminate aPAP patients from healthy subjects was perfect, providing a cut-off value of 1.65 U·mL-1 in 78 patients with aPAP and 90 healthy subjects in an operator-blinded manner using logistic regression analysis. As in the validation study, serum samples from another 213 patients with aPAP were also blinded and evaluated in an operator-blinded manner against external 207 samples from patients with other types of PAP and patients exhibiting various ground-glass opacities on chest high-resolution computed tomography that require discrimination from PAP. The logistic regression analysis of these validation data sets revealed values of 97.6% and 100% for specificity and sensitivity, respectively. Thus, this new GMAb testing kit is reliable for the diagnosis of aPAP and differential diagnosis of other lung diseases.

BACKGROUND AND OBJECTIVE: The optimal oxygen supplementation needed to avoid tissue hypoxia in patients with pulmonary hypertension (PH) remains unclear. This study aimed to identify the arterial oxygen tension (PaO2 ) level needed to avoid tissue hypoxia which results in a poor prognosis in patients with PH. METHODS: We retrospectively analysed the data for 1571 right heart catheterizations in patients suspected of having PH between 1983 and 2017 at our institution. Examinations were classified according to mean pulmonary arterial pressure (mPAP), cardiac index (CI) and the presence of lung disease, pulmonary arterial hypertension (PAH) or chronic thromboembolic PH (CTEPH). The PaO2 levels needed to avoid tissue hypoxia were compared in each subgroup. RESULTS: The estimated PaO2 equivalent to a mixed venous oxygen tension (PvO2 ) of 35 mm Hg (tissue hypoxia) was 63.2 mm Hg in all patients, 77.0 mm Hg in those with decreased CI (<2.5 L/min/m2 ) and 57.0 mm Hg in those with preserved CI. Multivariate regression analysis identified mPAP, CI and PaO2 to be independent predictors of extremely low PvO2 . Similar results were observed regardless of the severity of PH or the presence of lung disease, PAH or CTEPH. The PaO2 level needed to avoid tissue hypoxia was higher in patients with mild PH and decreased CI than in those with severe PH and preserved CI (70.2 vs 61.5 mm Hg). CONCLUSION: These findings indicate that a decreased CI rather than increased mPAP induces tissue hypoxia in PH. Patients with PH and decreased CI may need adjustment of oxygen therapy at higher PaO2 levels compared with patients with preserved CI.

Background: Role-play (RP) and peer review (PR) are occasionally used in training and evaluating communication skills in clinical clerkship (CC). Thus, we evaluated the effect of combining RP and PR during student-oriented CC rounds.Methods: Clerkship students conducted medical interviews with and performed physical examinations on their patients, which were reviewed by five peer students who observed their performance while role-playing as senior physicians or patients' families. The peer reviewers then provided feedback to the students. The performance of the students was evaluated based on a mini-clinical evaluation exercise (Mini-CEX) and a professionalism mini-evaluation exercise (P-MEX) before and after the rounds by two attending physicians. After the CC, the students responded to questionnaires about the rounds.Results: Seventy-five students completed the rounds, and the duration of each round was 41.7 ± 7.1 min. Their communication skills and professionalism abilities on Mini-CEX and P-MEX showed significant improvement after the rounds. Improvements in medical interviewing and physical examinations were also noted. Additionally, the students recognized the importance of multiple viewpoints in patient care through experiences of the rounds.Conclusions: Combining RP and PR with CC rounds improves the students' clinical performance and professionalism and promotes their awareness of the importance of multiple viewpoints in patient care.

PURPOSE: Acute respiratory distress syndrome (ARDS) is an acute inflammatory lung injury that frequently shows fatal outcomes. As radiographic predictive factors, some reports have focused on the region of ill-aerated lung, but none have focused on well-aerated lung. Our objective was to evaluate the relationship between computed tomography (CT) volume of the well-aerated lung region and prognosis in patients with ARDS. METHOD: This retrospective observational study of a single intensive care unit (ICU) included patients with ARDS treated between April 2011 and May 2013. We identified 42 patients with ARDS for whom adequate helical CT scans were available. CT images were analyzed for 3-dimensional reconstruction, and lung region volumes were measured using automated volumetry methods. Lung regions were identified by CT attenuation in Hounsfield units (HU). RESULTS: Of the 42 patients, 35 (83.3 %) survived 28 days and 32 (76.2 %) survived to ICU discharge. CT lung volumetry was performed within 144.5 ± 76.6 s, and inter-rater reliability of CT lung volumetry for lung regions below -500 HU (well-aerated lung region) were near-perfect. Well-aerated lung region showed a positive correlation with 28-day survival (P = 0.020), and lung volumes below -900 HU correlated positively with 28-day survival and ICU survival, respectively (P = 0.028, 0.017). Survival outcome was better for percentage of well-aerated lung region/predicted total lung capacity ≥40 % than for <40 % (P = 0.039). CONCLUSIONS: CT lung volumetry of the well-aerated lung region using an automated method allows fast, reliable quantitative CT analysis and potentially prediction of the clinical course in patients with ARDS.

BACKGROUND AND OBJECTIVE: Analysis of the endobronchial ultrasound (EBUS) radiofrequency spectrum has been used for convex-probe EBUS technology. Quantitative imaging analysis is also warranted for guided bronchoscopy using radial-probe EBUS (RP-EBUS) targeting peripheral pulmonary lesions (PPL). This study aimed to determine the feasibility of radiofrequency spectrum analysis for distinguishing malignant and benign PPL during diagnostic bronchoscopy. METHODS: Raw RP-EBUS images with radiofrequency data, including backscatter signals, were prospectively recorded. The ultrasonic spectral parameters, such as intercept, midband-fit and slope within the region of interest, were retrospectively computed by linear regression analysis and compared with the final diagnosis. RESULTS: A total of 71 PPL, including 45 malignant and 26 benign lesions, were analysed. Malignant PPL showed a significantly lower intercept (P < 0.0001), lower midband-fit (P < 0.0001) and higher slope (P = 0.014) than benign PPL. Analyses of the area under the curve of receiver operating characteristic plots demonstrated that the intercept showed the best diagnostic performance among three parameters (0.87, 0.77 and 0.69 for intercept, midband-fit and slope, respectively). The sensitivity, specificity, accuracy, positive likelihood and negative likelihood were 75.6%, 96.2%, 83.1%, 19.6 and 0.25 for the intercept; 88.9%, 57.7%, 77.5%, 2.1 and 0.19 for the midband-fit; and 68.9%, 73.1%, 70.4%, 2.6 and 0.43 for the slope. CONCLUSION: Spectrum analysis of EBUS radiofrequency can be used as a novel non-invasive predictor of malignant or benign PPL. Analysis of the 'intercept' of the targeted lesion may provide useful supporting data for real-time sampling from PPL during diagnostic bronchoscopy.

BACKGROUND: Although indigo naturalis (IN) is effective for patients with active ulcerative colitis (UC), IN was associated with adverse events (AEs), including pulmonary arterial hypertension (PAH). Our aim was to evaluate the occurrence of IN-associated AEs and to evaluate any IN dose-effect on AEs. METHODS: A nationwide survey, using questionnaires, was conducted by conducted by the research group funded by the Ministry of Health, Labour and Welfare of Japan, between June 2017 and September 2018. A first questionnaire determined the occurrence of AEs associated with the therapeutic use of IN or herbal medicines containing IN in patients with UC. A second survey identified the clinical characteristics of patients who developed IN-associated critical AEs, namely, liver dysfunction, PAH, and intussusception. RESULTS: Across 337 participating institutions, 49,320 patients with UC were identified, with IN used in 877 (1.8%). AEs were reported in 91 patients (107 events), including liver dysfunction (n = 40), gastrointestinal symptoms (n = 21), headache (n = 13), and PAH (n = 11). No dose-effect relationship between IN and AEs was identified. Liver dysfunction tended to be mild and reversible. Ten cases of intussusception were reported, with 40% of these patients requiring surgical resection. IN-induced PAH was recovered in patients who discontinued to use IN. No IN-associated deaths were reported. CONCLUSIONS: IN-associated AEs were identified among patients with UC, with liver dysfunction often being reversible, while surgical resection was required in a high proportion of patients who developed intussusception. Both healthcare workers and patients should adequately recognize the potential for AEs with the use of IN.

Background: Although radial probe endobronchial ultrasonography (EBUS) with a guide sheath (GS; EBUS-GS) is widely used for sampling peripheral pulmonary lesions (PPLs), a standard training model for EBUS-GS remains to be developed. The purpose of this study was to evaluate the feasibility of a novel pulmonary biosimulator for hands-on training in peripheral tissue sampling using EBUS-GS. Methods: We established a novel biosimulator for EBUS-GS using porcine lungs. The simulator was equipped with multiple pseudo PPLs that were created using blue agar solution injected through GS inserted in a bronchoscope. A total of 12 voluntary trainees participated in a hands-on training course using the biosimulator. The size of samples acquired using biopsy forceps were compared between initial and post-training biopsies, and trainee satisfaction with the biosimulator and training program were evaluated using a questionnaire. Results: Under the guidance of a trainer, all trainees successfully detected pseudo PPLs using radial probe EBUS before the initial biopsy, and 11 trainees acquired samples from the target lesions during the initial biopsy. Post-training biopsy samples were larger than the initial samples for eight trainees. The results of the questionnaire revealed that all trainees were satisfied with the biosimulator. Moreover, eight trainees who had previously participated in another hands-on EBUS-GS training program involving a synthetic phantom model showed greater satisfaction for the biosimulator. Conclusions: A hands-on training program using the novel biosimulator assessed in this study could aid clinicians in improving their skills for EBUS-GS and acquiring larger peripheral tissue samples using biopsy forceps inserted through GS.

Pulmonary capillary hemangiomatosis (PCH) is a very rare and refractory disease characterized by capillary angioproliferation. The updated classification of pulmonary hypertension categorizes PCH into a subgroup of pulmonary arterial hypertension (PAH) alongside pulmonary veno-occlusive disease (PVOD). However, the definitive diagnosis of PCH only with noninvasive tools remains difficult. The aim of this study was to elucidate the radiological and physiological characteristics of PCH. We searched for cases of pathologically confirmed PCH in the English literature published between 2000 and 2018. We identified 26 cases among 39 studies. Then, we extracted and evaluated the relevant clinical information in all cases with available data. On chest computed tomography (CT), ground-glass opacities (GGOs) were observed in 92% of the cases, in which poorly defined nodular pattern was the most common (88%). GGOs in a bat-wing distribution were observed in one case. Septal lines and lymph node enlargement were observed less frequently (each 19%, 12%). Seven cases (27%) had overlapping abnormalities. Diffusing capacity of the lung for carbon monoxide (DLCO) was remarkably decreased. Alveolar hemorrhage by histological findings or bronchoalveolar lavage (BAL) was observed in seven cases. The present study showed that the most characteristic findings of CT in PCH was centrilobular GGOs with a poorly defined nodular pattern, and septal lines and lymph node enlargement were seen less frequently. Alveolar hemorrhage detected by BAL and decreased DLCO may also be helpful to recognize the possibility of PCH like PVOD.

BACKGROUND: Pulmonary alveolar proteinosis is a disease characterized by abnormal accumulation of surfactant in the alveoli. Most cases are autoimmune and are associated with an autoantibody against granulocyte-macrophage colony-stimulating factor (GM-CSF) that prevents clearing of pulmonary surfactant by alveolar macrophages. An open-label, phase 2 study showed some therapeutic efficacy of inhaled recombinant human GM-CSF in patients with severe pulmonary alveolar proteinosis; however, the efficacy in patients with mild-to-moderate disease remains unclear. METHODS: We conducted a double-blind, placebo-controlled trial of daily inhaled recombinant human GM-CSF (sargramostim), at a dose of 125 μg twice daily for 7 days, every other week for 24 weeks, or placebo in 64 patients with autoimmune pulmonary alveolar proteinosis who had a partial pressure of arterial oxygen (Pao2) while breathing ambient air of less than 70 mm Hg (or <75 mm Hg in symptomatic patients). Patients with severe pulmonary alveolar proteinosis (Pao2 <50 mm Hg) were excluded to avoid possible exacerbation of the disease in patients who were assigned to receive placebo. The primary end point was the change in the alveolar-arterial oxygen gradient between baseline and week 25. RESULTS: The change in the mean (±SD) alveolar-arterial oxygen gradient was significantly better in the GM-CSF group (33 patients) than in the placebo group (30 patients) (mean change from baseline, -4.50±9.03 mm Hg vs. 0.17±10.50 mm Hg; P = 0.02). The change between baseline and week 25 in the density of the lung field on computed tomography was also better in the GM-CSF group (between-group difference, -36.08 Hounsfield units; 95% confidence interval, -61.58 to -6.99, calculated with the use of the Mann-Whitney U test and the Hodges-Lehmann estimate of confidence intervals for pseudo-medians). Serious adverse events developed in 6 patients in the GM-CSF group and in 3 patients in the placebo group. CONCLUSIONS: In this randomized, controlled trial, inhaled recombinant human GM-CSF was associated with a modest salutary effect on the laboratory outcome of arterial oxygen tension, and no clinical benefits were noted. (Funded by the Japan Agency for Medical Research and Development and the Ministry of Health, Labor, and Welfare of Japan; PAGE ClinicalTrials.gov number, NCT02835742; Japan Medical Association Center for Clinical Trials number, JMA-IIA00205.).

Pleuroparenchymal fibroelastosis (PPFE) is characterized by upper lobe-predominant subpleural fibroelastosis. Despite its characteristic uneven distribution, detailed whole-lung pathological features of PPFE have rarely been studied. We investigated PPFE in the explanted lungs from a 19-year-old male patient with a history of chemotherapy. Grossly, the explanted lungs showed upper lobe-predominant shrinkage with subpleural and central consolidation. Histologically, fibroelastosis was prominent in the perilobular areas and along the bronchovascular bundles. The other areas of the lung showed diffuse, non-specific interstitial pneumonia (NSIP)-like change with a characteristic increase of septal elastic fibers. In the digital image analysis, the ratio of elastic fibers to whole fibrosis (EF score) was lower in the subpleural areas than in the NSIP-like lesions, but the EF scores of the latter showed no significant difference between upper and middle/lower lobes. In the present case, the diffusely distributed elastic fiber-rich NSIP-like change, probably caused by the earlier chemotherapy, may have been conducive to the development of PPFE. This suggests that some unknown vulnerability of the upper lobe may exist, various primary lesions converging to the upper lobe predominance of PPFE.

The migration of lung fibroblasts plays a pivotal role in wound repair and fibrotic processes in the lung. Although the receptor for advanced glycation end products (RAGE) has been implicated in the pathogenesis of lung diseases, its role in lung fibroblast migration is unclear. The current study examined the effect of three different RAGE ligands, namely, high mobility group box 1 (HMGB1), S100A12, and N-epsilon-(carboxymethyl) lysine (CML), on human fibronectin-directed human fetal lung fibroblast (HFL-1) migration. HMGB1 augmented, whereas S100A12 inhibited, HFL-1 migration in a concentration-dependent manner. CML did not affect HFL-1 migration. The effect of HMGB1 was not through RAGE. However, the effect of S100A12 was mediated by RAGE, but not Toll-like receptor 4. S100A12 did not exert a chemoattractant effect, but inhibited HFL-1 chemotaxis and/or chemokinesis. Moreover, S100A12 mediated HFL-1 migration through p38 mitogen-activated protein kinase (MAPK) but not through nuclear factor-kappa B, protein kinase A, phosphatase and tensin homolog deleted on chromosome 10, or cyclooxygenase. In addition, western blot analysis showed that S100A12 augmented p38 MAPK activity in the presence of human fibronectin. In conclusion, S100A12 inhibits lung fibroblast migration via RAGE-p38 MAPK signaling. This pathway could represent a therapeutic target for pulmonary conditions characterized by abnormal tissue repair and remodeling.

Hepatopulmonary syndrome (HPS) and pulmonary arteriovenous malformation (PAVM) are hypoxemic diseases caused by right-to-left shunting but are rarely concomitant with pulmonary hypertension (PH). A 66-year-old woman with chronic hepatitis C was scheduled to undergo liver transplantation. She was referred to our department for hypoxia and an abnormal shadow in the right lung found on a preoperative examination. She was diagnosed with HPS and a PAVM in the right middle lobe. After liver transplantation, PH temporarily developed, but the pulmonary arterial pressure normalized after coil embolization. Combined HPS and PAVM may cause unique changes in pulmonary hemodynamics during treatment.

Recurrence of an embolized pulmonary arteriovenous malformation (PAVM) is common after coil embolization. A 23-year-old woman who had undergone multiple instances of transcatheter coil embolization was admitted with hypoxia and hemoptysis. A PAVM in the left S6 was found to be recanalized by reperfusion through the pulmonary and bronchial arteries. The left S6 was partially resected; the specimen contained necrotic granulomas and non-tuberculous mycobacteria (NTM) around the PAVM. Clinicians should consider possible recurrence of PAVM after reperfusion of the pulmonary and bronchial arteries, as well as the risk of NTM infection during follow-up of patients who have undergone repeated coil embolization.

KRAS is one of the most frequently mutated oncogenes in human non-small cell lung cancer (NSCLC). Mutations in KRAS are detected in 30% of NSCLC cases, with most of them occurring in codons 12 and 13 and less commonly in others. Despite intense efforts to develop drugs targeting mutant KRAS, no effective therapeutic strategies have been successfully tested in clinical trials. Here, we investigated molecular targets for KRAS-activated lung cancer cells using a drug library. A total of 1271 small molecules were screened in KRAS-mutant and wild-type lung cancer cell lines. The screening identified the cytotoxic effects of benzimidazole derivatives on KRAS-mutant lung cancer cells. Treatments with two benzimidazole derivatives, methiazole and fenbendazole-both of which are structurally specific-yielded significant suppression of the RAS-related signaling pathways in KRAS-mutated cells. Moreover, combinatorial therapy with methiazole and trametinib, a MEK inhibitor, induced synergistic effects in KRAS-mutant lung cancer cells. Our study demonstrates that these benzimidazole derivatives play an important role in suppressing KRAS-mutant lung cancer cells, thus offering a novel combinatorial therapeutic approach against such cancer cells.

Polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, and skin changes (POEMS) syndrome is a rare plasma cell disease. Patients with POEMS syndrome are considered to be at a high risk of developing pulmonary hypertension (PH). We report a 51-year-old woman diagnosed with PH associated with POEMS syndrome. She was started on dexamethasone and thalidomide. Although, the plasma vascular endothelial growth factor (VEGF) level decreased, systolic pulmonary artery pressure (sPAP) remained high. Auto-peripheral blood stem cell transplantation improved the plasma VEGF and sPAP levels. Four years later, she presented with dyspnoea on exertion, and elevated plasma VEGF and sPAP levels. Subsequently, on administering sildenafil and macitentan, the plasma VEGF and PH levels improved. Pulmonary vasodilators can be considered when PH remains after treatment of POEMS syndrome.

Objective Since pulmonary complications are a major cause of mortality in patients with hematologic diseases, their rapid detection and treatment are essential. Bronchoalveolar lavage (BAL) is widely performed to diagnose pulmonary infiltrates not evident with non-invasive investigations; however, reports on its clinical benefits for patients with hematologic diseases are limited. The aim of our study was to investigate the utility of diagnostic bronchoscopy with BAL for those patients. Methods We retrospectively reviewed the clinical records of 37 consecutive BAL procedures in 33 adult patients with hematological diseases and pulmonary infiltrates with at least 6 months of follow-up between August 2013 and September 2017 (total 747 BAL procedures). The BAL results, ensuing treatment modifications, treatment outcomes, survival times, and adverse events were evaluated. Results Microbiological findings were detected in 11 (29.7%), even though wide-spectrum antibiotics and antifungal drugs had been empirically administered to most patients (>70%) prior to the bronchoscopy procedure. Overall, 25 of the 37 BAL procedures (67.6%) had some impact on the diagnosis of pulmonary diseases. Patients without specific diagnostic findings from BAL had a significantly poorer survival than those with diagnostic findings via BAL (30-day survival: 33.3% vs. 92.0%; 180-day survival: 8.3% vs. 64.0%). Four patients (12.1%) experienced complications associated with bronchoscopy; there were no procedure-related deaths. Conclusion BAL seems still important for diagnosing pulmonary infiltrates and/or excluding some of the important respiratory tract pathogens in patients with hematological diseases; furthermore, negative specific diagnostic findings from BAL may be associated with poor prognoses.

慢性閉塞性肺疾患(COPD)はタバコ煙を主とする有害物質を長期に吸入することにより生じる肺疾患で、呼吸機能検査で気流閉塞を示す。一方、画像診断技術の発達に伴い、形態学的な観点からも多くの検討がなされている。本稿では画像診断に必要なCOPDの臨床知識、画像解析との関連について概説する。(著者抄録)

Drug-induced lung injury is an adverse effect of drug treatment that can result in respiratory failure. Because lipid profiling could provide cutting-edge understanding of the pathophysiology of toxicological responses, we performed lipidomic analyses of drug-induced lung injury. We used a mouse model of bleomycin-induced lung injury and followed the physiological responses at the acute inflammatory (day 2), inflammatory-to-fibrosis (day 7) and fibrosis (day 21) phases. The overall lipid profiles of plasma, lung and bronchoalveolar lavage fluid (BALF) revealed that drastic changes in lipids occurred in the lung and BALF, but not in the plasma, after 7 and 21 days of bleomycin treatment. In the lung, the levels of ether-type phosphatidylethanolamines decreased, while those of phosphatidylcholines, bismonophosphatidic acids and cholesterol esters increased on days 7 and 21. In BALF, the global lipid levels increased on days 7 and 21, but only those of some lipids, such as phosphatidylglycerols/bismonophosphatidic acids and phosphatidylinositols, increased from day 2. The lung levels of prostaglandins, such as prostaglandin D2 , were elevated on day 2, and those of 5- and 15-lipoxygenase metabolites of docosahexaenoic acid were elevated on day 7. In BALF, the levels of 12-lipoxygenase metabolites of polyunsaturated fatty acids were elevated on day 7. Our comprehensive lipidomics approach suggested anti-inflammatory responses in the inflammatory phase, phospholipidosis and anti-inflammatory responses in the inflammatory-to-fibrosis phase, and increased oxidative stress and/or cell phenotypic transitions in the fibrosis phase. Understanding these molecular changes and potential mechanisms will help develop novel drugs to prevent or treat drug-induced lung injury.

The patient was a 71-year-old man with severe idiopathic pulmonary fibrosis (IPF) and who demonstrated a slow deterioration of his respiratory condition. After nintedanib administration, his forced vital capacity and chest high-resolution computed tomography (HRCT) findings were stable, but his dyspnea on exertion were worsened. He was diagnosed with pulmonary hypertension (PH) by right heart catheterization (mean pulmonary arterial pressure: 30 mmHg). In this case, we suspected that nintedanib caused his PH, as his IPF had not progressed.