Continuous positive airway pressure versus high-flow nasal cannula oxygen therapy for acute hypoxemic respiratory failure: A randomized controlled trial.

BACKGROUND AND OBJECTIVE: The relative effectiveness of initial non-invasive respiratory strategies for acute respiratory failure using continuous positive airway pressure (CPAP) or high-flow nasal cannula (HFNC) is unclear. METHODS: We conducted a multicenter, open-label, parallel-group randomized controlled trial to compare the efficacy of CPAP and HFNC on reducing the risk of meeting the prespecified criteria for intubation and improving clinical outcomes of acute hypoxemic respiratory failure. The primary endpoint was the time taken to meet the prespecified criteria for intubation within 28 days. RESULTS: Eighty-five patients were randomly assigned to the CPAP or HFNC group. Eleven (28.9%) in the CPAP group and twenty (42.6%) in the HFNC group met the criteria for intubation within 28 days. Compared with HFNC, CPAP reduced the risk of meeting the intubation criteria (hazard ratio [HR], 0.327; 95% CI, 0.148-0.724; p = 0.006). There were no significant between-group differences in the intubation rates, in-hospital and 28-day mortality rates, ventilator-free days, duration of the need for respiratory support, or duration of hospitalization for respiratory illness. Pulmonary oxygenation was significantly better in the CPAP group, with significantly lower pH and higher partial pressure of carbon dioxide, but there were no differences in the respiratory rate between groups. CPAP and HFNC were associated with few possibly causal adverse events. CONCLUSION: CPAP is more effective than HFNC at reducing the risk of meeting the intubation criteria in patients with acute hypoxemic respiratory failure.

Guide sheath versus non-guide sheath method for endobronchial ultrasound-guided biopsy of peripheral pulmonary lesions: a multicentre randomised trial.

BACKGROUND: Guide sheaths (GSs) have been widely used during radial probe endobronchial ultrasound-guided transbronchial biopsy (rEBUS-TBB) of peripheral pulmonary lesions. However, it remains unknown whether a GS enhances the diagnostic yield. We compared the diagnostic yields of small peripheral pulmonary lesions between rEBUS-TBB with and without a GS. METHODS: In eight institutions, patients with peripheral pulmonary lesions ≤30 mm in diameter were enrolled and randomised to undergo rEBUS-TBB with a GS (GS group) or without a GS (non-GS group) using a 4.0-mm thin bronchoscope, virtual bronchoscopic navigation and fluoroscopy. The primary end-point was the diagnostic yield of the histology specimens. RESULTS: A total of 605 patients were enrolled; ultimately, data on 596 (300 in the GS group and 296 in the non-GS group) with peripheral pulmonary lesions having a longest median diameter of 19.6 mm were analysed. The diagnostic yield of histological specimens from the GS group was significantly higher than that from the non-GS group (55.3% versus 46.6%; p=0.033). Interactions were evident between the diagnostic yields, procedures, lobar locations (upper lobe versus other regions; p=0.003) and lesion texture (solid versus part-solid nodules; p=0.072). CONCLUSIONS: The diagnostic yield for small peripheral pulmonary lesions afforded by rEBUS-TBB using a GS was higher than that without a GS.

Effects of Oral Morphine on Dyspnea in Patients with Cancer: Response Rate, Predictive Factors, and Clinically Meaningful Change (CJLSG1101).

BACKGROUND: Although the efficacy of parenteral morphine for alleviating dyspnea has been previously demonstrated in several studies, little is known regarding the efficacy of oral morphine for dyspnea among patients with cancer, including its response rate and predictive factors of effectiveness. Therefore, the aim of this study was to clarify the effectiveness of oral morphine on dyspnea in patients with cancer and elucidate the predictive factors of its effectiveness. SUBJECTS, MATERIALS, AND METHODS: In this multicenter prospective observational study, we investigated the change in dyspnea intensity in patients with cancer before and after the administration of oral morphine by using a visual analog scale (VAS). We also administered a self-assessment questionnaire to determine whether the patients believed oral morphine was effective. RESULTS: Eighty patients were enrolled in the study, and 71 of these patients were eligible. The least square mean of the VAS scores for dyspnea intensity was 53.5 at baseline, which decreased significantly to 44.7, 40.8, and 35.0 at 30, 60, and 120 minutes after morphine administration, respectively. Fifty-four patients (76.1%) reported that oral morphine was effective on the self-assessment questionnaire. Among the background factors, a high score for "sense of discomfort" on the Cancer Dyspnea Scale (CDS) and a smoking history of fewer pack-years were associated with greater effectiveness. CONCLUSION: Oral morphine was effective and feasible for treating cancer-related dyspnea. A higher score for "sense of discomfort" on the CDS and a smaller cumulative amount of smoking may be predictive factors of the effectiveness of oral morphine. IMPLICATIONS FOR PRACTICE: This study demonstrated that oral morphine was effective in alleviating cancer-related dyspnea due to multiple factors including primary lung lesions, airway narrowing, and pleural effusion. Approximately 76% of patients reported that oral morphine was effective. A higher score for "sense of discomfort" on the Cancer Dyspnea Scale and a lower cumulative amount of smoking may be predictive factors for the effectiveness of oral morphine. Interestingly, respiratory rates in patients who reported the morphine to be effective decreased significantly after oral morphine administration, unlike the respiratory rates in "morphine-ineffective" patients.

How Many Passes Are Needed for Endobronchial Ultrasound-Guided Transbronchial Needle Aspiration for Sarcoidosis? A Prospective Multicenter Study.

BACKGROUND: While endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) is widely used as an initial diagnostic procedure for pathological confirmation of sarcoidosis, it is unclear how many passes are required to obtain diagnostic materials. OBJECTIVES: The aim of this study was to determine the number of needle passes needed for the diagnosis of stage I/II sarcoidosis using EBUS-TBNA. METHODS: At three institutions, 109 patients with suspected stage I/II sarcoidosis were recruited and underwent 6 passes of EBUS-TBNA for the main target lesion. Additional EBUS-TBNA for other lesions was permitted. The cumulative yields of needle passes for detecting noncaseating epithelioid cell granulomas were analyzed. RESULTS: A total of 109 patients underwent EBUS-TBNA for 184 lesions. EBUS-TBNA identified specimens containing granulomas in 81 of 92 patients (88%) with a final diagnosis of sarcoidosis. The cumulative yields through the first, second, third, fourth, fifth, and sixth passes for the main target lesion were 63, 75, 82, 85, 86 and 88%, respectively. In the 55 patients that underwent EBUS-TBNA for multiple lesions, the cumulative yields of 2 passes per lesion for 2 lesions (total of 4 passes) and of 4 passes for single lesions were 86 and 84%, respectively (p = 1.00). CONCLUSIONS: If rapid on-site cytological evaluation is not available, we recommend at least 4 passes per patient for either single or multiple lesions with EBUS-TBNA for pathological diagnosis of stage I/II sarcoidosis.

Utility of serum immunoglobulin A antibody against glycopeptidolipid core antigen in the diagnosis and management of hypersensitivity pneumonitis associated with Mycobacterium avium complex: A case report.

Measurement of the levels of serum immunoglobulin A antibody against glycopeptidolipid (GPL) core antigen, a cell surface antigen found in Mycobacterium avium complex (MAC), has been reported to be useful in the diagnosis and management of pulmonary MAC infection. However, evidence on its utility in hypersensitivity pneumonitis (HP) associated with MAC (i.e., "hot-tub lung") is limited. We herein report a case of HP associated with MAC in which the GPL core antibody levels were serially measured from diagnosis to treatment and thereafter. A 61-year-old man was suspected to have non-fibrotic HP based on the clinical course, laboratory findings, imaging pattern, bronchoalveolar lavage (BAL) lymphocytosis, and histopathological findings. Based on the history of whirlpool bath use, inhalation of aerosolized MAC was suspected as the cause of HP. The GPL core antibody level, measured using an enzyme-linked immunosorbent assay kit, was elevated, suggesting an immunological sensitization to MAC. A provocation test using the patient's whirlpool bath was positive. An identical MAC strain was isolated from the BAL fluid and bathtub. Accordingly, the patient was diagnosed with HP caused by the inhalation of aerosolized MAC from the whirlpool bath. The patient recovered after steroid treatment and discontinuation of the whirlpool bath. The GPL core antibody levels decreased with disease improvement. In conclusion, GPL core antibody levels could be elevated in HP associated with MAC and decrease with disease improvement. Thus, measurement of the GPL core antibody level may be useful for the diagnosis and management of HP associated with MAC.

Involvement of the transcription factor twist in phenotype alteration through epithelial-mesenchymal transition in lung cancer cells.

Epithelial-mesenchymal transition (EMT), which involves the persistent loss of epithelial markers and expression of mesenchymal markers, is assumed to have a critical role in not only tissue development during embryogenesis but also central mechanisms that enhance the invasive and metastatic ability of cancer cells. Twist has been identified to play an essential role in EMT-mediated tumor invasion and metastasis. Although recent studies suggest that twist expression levels in tissue specimens of lung cancer might be associated with prognosis, the expression of twist in lung cancer cells itself and its effect have not been fully evaluated. Here, we evaluated twist expression and its effect on phenotype alteration in lung cancer cell lines. Twist expression varied among human lung cancer cell lines. The lung cancer cell lines with high twist expression also tended to show a high vimentin/E-cadherin ratio, which was supported by a migration assay, in which high twist expression gave rise to high cell motility. Furthermore, in comparison to control cells, the lung cancer cells with ectopic expression of twist showed a significant phenotype alteration through EMT and an increasing ability to migrate in vitro, in part, due to a tenfold increase in matrix metalloproteinases activity and almost a 60% increase in modulation of focal adhesion kinase activity, although a contribution of microRNA appeared unlikely in our study. Our present analysis of twist expression in lung cancer provide clues to comprehensive understanding of the mechanisms, by which metastasis often develops in lung cancer.

[A case of irinotecan or panitumumab-induced interstitial pneumonia successfully treated by steroid pulse therapy].

We report a case of a 58-year-old man suffering from advanced colon cancer with liver metastases. After the sigmoidectomy and left lateral segmentectomy, mFOLFOX6+bevacizumab was initiated. The mFOLFOX6+bevacizumab therapy was performed for 15 courses, but it was stopped because of an increase in serum levels of tumor markers(CEA and CA19-9). For the next treatment, FOLFIRI+panitumumab therapy was performed. At the beginning of the second course, he suffered from dyspnea. Computed tomography showed ground-glass opacities and traction bronchiectasis in both lung fields. He was diagnosed with interstitial pneumonitis induced by irinotecan or panitumumab. Corticosteroid therapy consisting of methyl- prednisolone(1 g/day)administered for three days was significantly effective for treating respiratory failure. Two courses of the therapy were performed, and he was discharged without aftereffects. As with other EGFR tyrosine kinase inhibitors, the frequency of interstitial pneumonitis induced by irinotecan in Japan may increase to European and American levels.

Hemodiafiltration combined with polymyxin B-immobilized fiber column direct hemoperfusion is effective for acute postoperative exacerbation of interstitial pneumonia: a case report.

BACKGROUND: Postoperative acute exacerbation of interstitial pneumonia has a high mortality rate; however, its treatment methods have not been standardized. CASE PRESENTATION: A 72-year-old man with rheumatoid arthritis developed acute respiratory failure about 3 weeks after lung cancer surgery. There were increased diffuse frosted shadows in both lung fields. His condition was diagnosed as an acute exacerbation of interstitial pneumonia associated with rheumatoid arthritis, and he was started on steroid pulse therapy; however, his respiratory condition deteriorated. He was urgently intubated and started on veno-venous extracorporeal membrane oxygenation. Further, intensive care, including blood purification therapy, was initiated. The blood purification therapy comprised a combination of hemodiafiltration and 6-h polymyxin B-immobilized fiber column direct hemoperfusion. The patient was weaned off veno-venous extracorporeal membrane oxygenation, extubated, and discharged from the intensive care unit on the ninth day. CONCLUSIONS: Blood purification therapy was effective for acute exacerbation of interstitial pneumonia.

Endothelial-mesenchymal transition in bleomycin-induced pulmonary fibrosis.

The pathological hallmark lesions in idiopathic pulmonary fibrosis are the fibroblastic foci, in which fibroblasts are thought to be involved in the tissue remodeling, matrix deposition, and cross-talk with alveolar epithelium. Recent evidence indicates that some fibroblasts in fibrosis may be derived from bone marrow progenitors as well as from epithelial cells through epithelial-mesenchymal transition. To evaluate whether endothelial cells could represent an additional source for fibroblasts, bleomycin-induced lung fibrosis was established in Tie2-Cre/CAG-CAT-LacZ double-transgenic mice, in which LacZ was stably expressed in pan-endothelial cells. Combined X-gal staining and immunocytochemical staining for type I collagen and alpha-smooth muscle actin revealed the presence of X-gal-positive cells in lung fibroblast cultures from bleomycin-treated mice. To explore the underlying mechanisms, by which loss of endothelial-specific markers and gain of mesenchymal phenotypes could be involved in microvascular endothelial cells, the effects of activated Ras and TGF-beta on the microvascular endothelial cell line MS1 were analyzed. Combined treatment with activated Ras and TGF-beta caused a significant loss of endothelial-specific markers, while inducing de novo mesenchymal phenotypes. The altered expression of these markers in MS1 cells with activated Ras persisted after withdrawal of TGF-beta in vitro and in vivo. These findings are the first to show that lung capillary endothelial cells could give rise to significant numbers of fibroblasts through an endothelial-mesenchymal transition in bleomycin-induced lung fibrosis model.

Erythromycin-induced CXCR4 expression on microvascular endothelial cells.

Although stromal-derived factor-1 (SDF-1) via its cognate receptor CXCR4 is assumed to play a critical role in migration of endothelial cells during new vessel formation after tissue injury, CXCR4 expression on endothelial cells is strictly regulated. Erythromycin (EM), a 14-membered ring macrolide, has an anti-inflammatory effect that may account for its clinical benefit in the treatment of chronic inflammatory diseases. However, the effects of EM on endothelial cells and especially their expression of CXCR4 have not been fully evaluated. In this study, we demonstrated that EM markedly induced CXCR4 surface expression on microvascular endothelial cells in vitro and lung capillary endothelial cells in vivo. This ability to induce CXCR4 surface expression on endothelial cells was restricted to 14-membered ring macrolides and was not observed in other antibiotics including a 16-membered ring macrolide, josamycin. Furthermore, this EM-induced expression of CXCR4 on endothelial cells was functionally significant as demonstrated by chemotaxis assays in vitro. These findings suggest that EM-induced CXCR4 surface expression on endothelial cells may promote migration of CXCR4-expressing endothelial cells into sites of tissue injury, which may be associated with the known anti-inflammatory activity of this macrolide.

[Prevalence of myeloperoxidase-anti-neutrophil cytoplasmic antibody (MPO-ANCA) in patients with interstitial pneumonia].

Myeloperoxidase-anti-neutrophil cytoplasmic antibody (MPO-ANCA) is an autoantibody that is frequently found in patients with vasculitides. We encountered some MPO-ANCA positive patients with interstitial pneumonia who lacked vasculitides, but its meaning remains unclear. We measured MPO-ANCA titers in 69 patients with interstitial pneumonia (IP) who did not have collagen vascular diseases and observed their outcome. MPO-ANCA was positive in 5 patients and its prevalence was 7.2%. Patients with MPO-ANCA positive showed higher positivity in rheumatoid factor (RF) than patients with MPO-ANCA negative. The sensitivity and specificity of a combination of anti-nuclear antibody-negative and RF-positive were 80.0% and 87.7%, respectively. Two patients were accompanied by microscopic polyangiitis and the 3-year survival rate was 40% in all patients with MPO-ANCA. Measurement of MPO-ANCA titers in patients with IPs is meaningful for determining therapeutic strategy.

[A case of primary pulmonary MALT lymphoma with diffuse micronodules and anemia].

A 52-year-old woman presented with low grade fever and fatigue. She had diffuse micronodules in both lung fields on chest X-ray. Chest CT showed diffuse multiple small nodules. Laboratory examination revealed high values for C-reactive protein, together with anemia and polyclonal hyper-immunoglobulinemia and an elevated interleukin-6 level. Although we suspected multicentric Castleman's disease, thoracoscopic lung biopsy revealed primary pulmonary MALT lymphoma by immunohistochemical analysis of tissue specimens. After COP and rituximab therapy, partial remission was obtained.

Knockdown of ZEB1, a master epithelial-to-mesenchymal transition (EMT) gene, suppresses anchorage-independent cell growth of lung cancer cells.

We found that among four master epithelial-to-mesenchymal transition (EMT)-inducing genes (ZEB1, SIP1, Snail, and Slug) ZEB1expression was most significantly correlated with the mesenchymal phenotype (high Vimentin and low E-cadherin expression) in non-small cell lung cancer (NSCLC) cell lines and tumors. Furthermore, ZEB1 knockdown with RNA interference in three NSCLC cell lines with high ZEB1 expression suppressed to varying degrees mass culture growth and liquid colony formation but in all cases dramatically suppressed soft agar colony formation. In addition, ZEB1 knockdown induced apoptosis in one of the three lines, indicating that the growth inhibitory effects of ZEB1 knockdown occurs in part through the activation of the apoptosis pathway. These results suggest that inhibiting ZEB1 function may be an attractive target for NSCLC therapeutic development.