Naozumi Hashimoto

Introduction: Although there is a remarkable increase in diagnostic flexible bronchoscopy (FB) in old patients, safety and efficacy of FB in very old patients remain to be elucidated. In this study, we aimed to evaluate the complications and diagnostic yield of FB in patients aged ≥ 80 years with lung cancer compared with those aged &lt  80 years. Materials and methods: We retrospectively analysed the medical records of 668 consecutive patients, which included 89 patients aged ≥ 80 years (older group) and 579 patients aged &lt  80 years (younger group) who underwent bronchoscopy for the diagnosis or staging of lung cancer between April 2011 and March 2016. Results: The median age of the patients was 82 and 69 years in the older and younger groups, respectively. Performance status and Charlson comorbidity index were comparable between the study groups. Diagnostic yield in the older and younger groups was equivalent, and stage distribution in both the groups was similar. Sixty-one patients (68.5%) received anticancer treatment including surgery, radiation and chemotherapy with cytotoxic or molecular-targeted agents in the older group. There were no statistical differences in the occurrence of overall complications between the two groups. Conclusions: Safety and efficacy of FB in the diagnosis of lung cancer in very old patients are comparable with those of younger patients. Accurate diagnosis established by bronchoscopy leads to appropriate treatment decision in very old patients.

Background: When epidermal growth factor receptor (EGFR) gene mutation-positive non-small cell lung cancer (NSCLC) acquires resistance to the initial tyrosine kinase inhibitor (TKI) treatment, reassessing the tumor DNA by re-biopsy is essential for further treatment selection. However, the process of TKI-sensitive tumor re-progression and whether re-biopsy is possible in all cases of acquired resistance to EGFR-TKI remain unclear. Methods: We retrospectively analyzed data from 69 consecutive patients with EGFR gene mutation-positive advanced NSCLC who had been treated with EGFR-TKI and exhibited disease relapse after initial disease remission. The relapsing lesions were identified at the time of RECIST-progressive disease (PD) and clinical-PD (when the attending physician judged the patient as clinically relapsing and stopped EGFR-TKI therapy). We determined the potential re-biopsy methods for each relapsing lesion and evaluated their feasibility according to difficulty and invasiveness criteria as follows: category A, accessible by conventional biopsy techniques; category B, difficult (but possible) to biopsy and accessible with invasive methods; and category C, extremely difficult to biopsy or inaccessible without using highly invasive methods, including surgical biopsy. Results: The total feasibility rate of re-biopsy (category A or B) was 68% at RECIST-PD and 84% at clinical-PD, and the most common accessible relapsing lesions were primary tumors at RECIST-PD and pleural effusion at clinicalPD. All relapsing lesions at primary sites (categories A and B) were assessed as having the potential for re-biopsy. However, re-biopsy for metastasis was assessed as difficult in a substantial proportion of the study population (42 and 20% category C at RECIST-PD and clinical-PD, respectively). Conclusions: Re-biopsy of relapsing disease is feasible in many cases, although it may present difficulties in cases with, e.g., metastatic relapsing lesions. To facilitate treatment strategies in NSCLC patients with relapse after EGFRTKI therapy, re-biopsy should be standardized with the use of simpler and more reliable methods.

Background: Bleomycin-induced lung injury, a major complication of chemotherapy for germ cell tumors, occasionally fails to respond to the standard treatment with corticosteroids and develops into severe respiratory insufficiency. Little is known about salvage treatment for refractory cases. Case presentation: A 63-year-old man who had been diagnosed with stage I seminoma and undergone a high orchiectomy 1 year previously developed swelling of his left iliac lymph node and was diagnosed with a recurrence of the seminoma. He was administered a standard chemotherapy regimen of cisplatin, etoposide, and bleomycin. At the end of second cycle, he developed a dry cough and fever that was accompanied by newly-identified bilateral infiltrates on chest X-ray. Despite initiation of oral prednisolone, his exertional dyspnea and decline in pulmonary functions continued to be aggravated. High-dose pulse treatment with methylprednisolone was introduced and improved his symptoms and radiologic findings. However, the maintenance dose of oral prednisolone allowed reactivation of the disease with evidence of newly-developed bilateral lung opacities on high-resolution CT scans. Considering his glucose intolerance and cataracts as complications of corticosteroid treatment, administration of pirfenidone was initiated with the patient's consent. Pirfenidone at 1800 mg/day was well tolerated, and resolved his symptoms and abnormal opacities on a chest CT scan. Subsequently, the dose of prednisolone was gradually tapered without worsening of the disease. At the most recent follow-up, he was still in complete remission of seminoma with a successfully tapered combination dose of prednisolone and pirfenidone. Conclusions: Pirfenidone, a novel oral agent with anti-inflammatory and -fibrotic properties, should be considered as a salvage drug for refractory cases of bleomycin-induced lung injury.

Diazinon is an organophosphorus (OP) insecticide and is widely used not only in agriculture but also homes and garden in Japan. Diazinon has been reported to increase TNF-alpha production in rat serum and brain, suggesting that it can modify the proinflammatory response. In this study, we investigated the effects of diazinon on macrophage functions, such as cytokine production, reactive oxygen species (ROS) generation, cyclooxygenase (COX)-2 and inducible nitric oxide synthase (iNOS) expressions, cell-surface molecule expressions, and phagocytosis in RAW264.7 cells. In RAW264.7 cells, diazinon induced the production of TNF-alpha and IL-6. Diazinon induced ROS generation and the expressions of COX-2, iNOS, and cell-surface molecules CD40, CD86, and MI-IC class II, but reduced phagocytic activity in RAW264.7 cells. ERIC and p38, but not JNK and p65 were involved in diazinon-induced IL-6 expression in RAW264.7 cells. We also examined these proinflammatory responses in bone marrow-derived macrophages (BMDM) and bronchoalveolar lavage fluid (BALF) cells. These results suggested that diazinon can activate macrophages and enhance inflammatory responses. (C) 2017 Elsevier B.V. All rights reserved.

Case Presentaion A 63-year-old woman visited our hospital for a further evaluation of progressive dyspnea. She had developed a progressive airflow obstruction after 3 years’ remission of non-Hodgkin's lymphoma (follicular mixed cell type), which had been treated with chemotherapy (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone). The patient's primary care physician had diagnosed her as having COPD and bronchial asthma and had treated her with medications including inhaled corticosteroids, tiotropium, and oral erythromycin. Her dyspnea had gradually worsened, however, and she had a score of 4 on the modified Medical Research Council dyspnea scale at the time of admission to our hospital.

Background: Non-small cell lung cancer (NSCLC) is the predominant cause of death in patients with COPD, and the severity of COPD in NSCLC patients is classified mainly as mild to moderate. Most advanced NSCLC patients with mild to moderate COPD are treated with chemotherapy; however, the feasibility for and prognosis after chemotherapy of these patients are not well understood. The aim of this study was to elucidate the impact of mild to moderate COPD on the feasibility for and prognosis after chemotherapy in NSCLC patients. Patients and methods: A retrospective review was performed on 268 NSCLC patients who received first-line chemotherapy from 2009 to 2014 in our institution. Finally, 85 evaluable patients were included in this study. The clinical characteristics, toxicity profile, objective response rate, and prognosis were analyzed and compared between patients with mild to moderate COPD and those without COPD (non-COPD). Results: Forty-three patients were classified as COPD (27 cases mild and 16 cases moderate) and 42 patients as non-COPD. The COPD group were older and had fewer never-smokers than the non-COPD group. The objective response rate did not differ between groups (p=0.14). There was no significant difference in overall survival between COPD and non-COPD groups (15.0 and 17.0 months, log-rank test p= 0.57). In the multivariate Cox's proportional hazard model, the adjusted hazard ratio (HRadj) was statistically significant for male sex (HRadj =5.382, 95% CI: 1.496-19.359; p=0.010), pathological diagnosis of adenocarcinoma (HRadj =0.460, 95% CI: 0.223-0.948; p=0.035), and epithelial growth factor receptor negative mutation (HRadj =6.040, 95% CI: 1.158-31.497; p=0.033), but not for the presence of COPD (HRadj =0.661, 95% CI: 0.330-1.325; p=0.24). Toxicity profile in COPD group was favorable, as in the non-COPD group. Conclusion: Mild to moderate COPD did not have a significant deleterious impact on toxicity and prognosis in NSCLC patients.

Background. There is only limited information on the clinical impact of combined pulmonary fibrosis and emphysema (CPFE) on postoperative and survival outcomes among patients with resected lung cancer. Methods. In a retrospective analysis, data were reviewed from 685 patients with resected lung cancer between 2006 and 2011. The clinical impact of thin-section computed tomography (TSCT)-determined emphysema, fibrosis, and CPFE on postoperative and survival outcomes was evaluated. Results. The emphysema group comprised 32.4% of the study population, the fibrosis group 2.8%, and the CPFE group 8.3%. The CPFE group had a more advanced pathologic stage and higher prevalence of squamous cell carcinoma as compared with the normal group without emphysema or fibrosis findings on TSCT. The incidence of postoperative complications was significantly higher in the CPFE group. Overall, the 30-day mortality in the CPFE group was 5.3%. Cancer recurrence at pathologic stage I and death due to either cancer or other causes were significantly higher in the CPFE group. Survival curves indicated that a finding of CPFE was associated with worse overall survival for patients with any stage disease. Multivariate analysis suggested that pathologic stage and CPFE were independent factors associated with worse overall survival. The adjusted hazard ratio of overall survival for the CPFE group versus the normal group was 2.990 (95% confidence interval: 1.801 to 4.962). Conclusions. Among patients with resected lung cancer, the presence of TSCT-determined CPFE might predict worse postoperative and survival outcomes. (C) 2016 by The Society of Thoracic Surgeons

Background: Persistent hypoxia stimulation, one of the most critical microenvironmental factors, accelerates the acquisition of epithelial-mesenchymal transition (EMT) phenotypes in lung cancer cells. Loss of phosphatase and tensin homologue deleted from chromosome 10 (PTEN) expression might accelerate the development of lung cancer in vivo. Recent studies suggest that tumor microenvironmental factors might modulate the PTEN activity though a decrease in total PTEN expression and an increase in phosphorylation of the PTEN C-terminus (p-PTEN), resulting in the acquisition of the EMT phenotypes. Nevertheless, it is not known whether persistent hypoxia can modulate PTEN phosphatase activity or whether hypoxia-induced EMT phenotypes are negatively regulated by the PTEN phosphatase activity. We aimed to investigate hypoxia-induced modulation of PTEN activity and EMT phenotypes in lung cancers. Methods: Western blotting was performed in five lung cancer cell lines to evaluate total PTEN expression levels and the PTEN activation. In a xenograft model of lung cancer cells with endogenous PTEN expression, the PTEN expression was evaluated by immunohistochemistry. To examine the effect of hypoxia on phenotypic alterations in lung cancer cells in vitro, the cells were cultured under hypoxia. The effect of unphosphorylated PTEN (PTEN4A) induction on hypoxia-induced EMT phenotypes was evaluated, by using a Dox-dependent gene expression system. Results: Lung cancer cells involving the EMT phenotypes showed a decrease in total PTEN expression and an increase in p-PTEN. In a xenograft model, loss of PTEN expression was observed in the tumor lesions showing tissue hypoxia. Persistent hypoxia yielded an approximately eight-fold increase in the p-PTEN/PTEN ratio in vitro. PTEN4A did not affect stabilization of hypoxia-inducible factor 1 alpha. PTEN4A blunted hypoxia-induced EMT via inhibition of beta-catenin translocation into the cytoplasm and nucleus. Conclusion: Our study strengthens the therapeutic possibility that compensatory induction of unphosphorylated PTEN may inhibit the acquisition of EMT phenotypes in lung cancer cells under persistent hypoxia.

Objective Endobronchial ultrasonography with a guide sheath (EBUS-GS) and virtual bronchoscopic navigation (VBN) improves the diagnostic yield in patients with peripheral pulmonary lesions (PPLs). Most previous reports on EBUS-GS-guided transbronchial biopsy (TBB) have included patients with benign and malignant diseases. We aimed to determine the factors that predicted a successful diagnosis by EBUS-GS-guided TBB diagnostic in patients with small peripheral lung cancer, with a focus on the high-resolution computed tomography (HRCT) findings before bronchoscopy. Methods We retrospectively reviewed the medical records of 173 consecutive patients with 175 small (<= 30 mm) PPLs who were diagnosed with primary lung cancer between June 2010 and October 2013 at Nagoya University Hospital. All patients underwent EBUS-GS-guided TBB with VBN using a ZioStation computer workstation (Ziosoft, Osaka, Japan). We analyzed the patient characteristics, HRCT findings, diagnostic yield, and the diagnostic factors in small peripheral lung carcinoma. Results The EBUS probe position was within the PPL in 83 of the 175 lesions (47%) and 112 (64.0%) cases were successfully diagnosed by EBUS-GS-guided TBB. A univariate analysis revealed that the following factors were associated with a significantly higher diagnostic yield: CT bronchus sign positivity, a lesion of >20 mm in diameter, a solid nodule, and a probe position that was within the lesion. The following factors were not significant: the lesion location, the number of biopsies, and the lung cancer histology. A multivariate analysis revealed that the following factors significantly affected the diagnostic yield: CT bronchus sign positivity [ odds ratio (OR) =2.479]; a probe position that was within the lesion (OR=2.542); and a solid nodule (OR=2.304). Conclusion The significant factors that were significantly associated with a successful diagnosis using EBUS-GS-guided TBB in small peripheral lung carcinoma were as follows: CT bronchus sign positivity, a solid nodule, and a probe position that was within the lesion.

A 73-year-old woman was diagnosed with pulmonary Mycobacterium avium complex (MAC) infection and received no treatment. Disease progression was evident one year later with the development of myeloperoxidase-antineutrophil cytoplasmic antibody (ANCA) titers and systemic symptoms of a fever, polyarthritis, purpura, and rapidly progressive glomerulonephritis. Her symptoms did not improve with antibiotic treatment. A renal biopsy revealed crescentic glomerulonephritis with immunodeposition. According to these findings, she was diagnosed with ANCA-associated vasculitis (AAV) superimposed on infection-related glomerulonephritis (IRGN). Although there was a risk of aggravating an underlying infection, the combination therapy of corticosteroid and antibiotics improved AAV, IRGN, and even the lung radiological findings. To the best of our knowledge, this is the first case of AAV and IRGN secondary to pulmonary MAC infection.

© 2014 by the authors; licensee MDPI, Basel, Switzerland. Zinc oxide (ZnO) nanoparticles are widely used in various products, and the safety evaluation of this manufactured material is important. The present study investigated the inflammatory and fibrotic effects of pulmonary exposure to ZnO nanoparticles in a mouse model of pulmonary fibrosis. Pulmonary fibrosis was induced by constant subcutaneous infusion of bleomycin (BLM). Female C57BL/6Jcl mice were divided into BLM-treated and non-treated groups. In each treatment group, 0, 10, 20 or 30 µg of ZnO nanoparticles were delivered into the lungs through pharyngeal aspiration. Bronchoalveolar lavage fluid (BALF) and the lungs were sampled at Day 10 or 14 after administration. Pulmonary exposure by a single bolus of ZnO nanoparticles resulted in severe, but transient inflammatory infiltration and thickening of the alveolar septa in the lungs, along with the increase of total and differential cell counts in BLAF. The BALF level of interleukin (IL)-1β and transforming growth factor (TGF)-β was increased at Day 10 and 14, respectively. At Day 10, the synergistic effect of BLM and ZnO exposure was detected on IL-1β and monocyte chemotactic protein (MCP)-1 in BALF. The present study demonstrated the synergistic effect of pulmonary exposure to ZnO nanoparticles and subcutaneous infusion of BLM on the secretion of pro-fibrotic cytokines in the lungs.

Transforming growth factor beta (TGF beta) causes the acquisition of epithelial-mesenchymal transition (EMT). Although the tumor suppressor gene PTEN (phosphatase and tensin homologue deleted from chromosome 10) can negatively regulate many signaling pathways activated by TGF beta, hyperactivation of these signaling pathways is observed in lung cancer cells. We recently showed that PTEN might be subject to TGF beta-induced phosphorylation of its C-terminus, resulting in a loss of its enzyme activities; PTEN with an unphosphorylated C-terminus (PTEN4A), but not PTEN wild, inhibits TGF beta-induced EMT. Nevertheless, whether or not the blockade of TGF beta-induced EMT by the PTEN phosphatase activity might be attributed to the unphosphorylated PTEN C-terminus itself has not been fully determined. Furthermore, the lipid phosphatase activity of PTEN is well characterized, whereas the protein phosphatase activity has not been determined. By using lung cancer cells carrying PTEN domain deletions or point mutants, we investigated the role of PTEN protein phosphatase activities on TGF beta-induced EMT in lung cancer cells. The unphosphorylated PTEN C-terminus might not directly retain the phosphatase activities and repress TGF beta-induced EMT; the modification that keeps the PTEN C-terminus not phosphorylated might enable PTEN to retain the phosphatase activity. PTEN4A with G129E mutation, which lacks lipid phosphatase activity but retains protein phosphatase activity, repressed TGF beta-induced EMT. Furthermore, the protein phosphatase activity of PTEN4A depended on an essential association between the C2 and phosphatase domains. These data suggest that the protein phosphatase activity of PTEN with an unphosphorylated C-terminus might be a therapeutic target to negatively regulate TGF beta-induced EMT in lung cancer cells.

Background: Recent advances in bronchoscopy, such as transbronchial biopsy (TBB) using endobronchial ultrasonography with a guide sheath (EBUS-GS), have improved the diagnostic yield of small-sized peripheral lung lesions. In some cases, however, it is difficult to obtain adequate biopsy samples for pathological diagnosis. Adequate prediction of the diagnostic accuracy of TBB with EBUS-GS is important before deciding whether bronchoscopy should be performed. Methods: We retrospectively reviewed 149 consecutive patients who underwent TBB with EBUS-GS for small-sized peripheral lung lesions (<= 30 mm in diameter) from April 2012 to March 2013. We conducted an exploratory analysis to identify clinical factors that can predict an accurate diagnosis by TBB with EBUS-GS. All patients underwent thin-section chest computed tomography (CT) scans (0.5-mm slices), and the CT bronchus sign was evaluated before bronchoscopy in a group discussion. The final diagnoses were pathologically or clinically confirmed in all studied patients (malignant lesions, 110 patients; benign lesions, 39 patients). Results: The total diagnostic yield in this study was 72.5 % (95 % confidence interval: 64.8-79.0 %). Lesion size, lesion visibility on chest X-ray, and classification of the CT bronchus sign were factors significantly associated with the definitive biopsy result in the univariate analysis. In the multivariate analysis, only the CT bronchus sign remained as a significant predictive factor for successful bronchoscopic diagnosis. The CT bronchus sign was also significantly associated with the EBUS findings of the lesions. Conclusion: Our results suggest that the CT bronchus sign is a powerful predictive factor for successful TBB with EBUS-GS.

Three-dimensional computed tomography (3D-CT) enables in vivo volumetry of total lung volume (TLV) and emphysematous low-attenuation volume (LAV) in patients with chronic obstructive pulmonary disease (COPD). We retrospectively investigated the correlation between preoperative 3D-CT volumetry and postoperative complications in lung cancer patients. We searched our institution's surgical records from December 2006 to December 2009 and selected patients who had undergone pulmonary lobectomy for primary lung cancer. From 3D-CT data, TLV and LAV <-950 HU of thresholds were retrospectively measured. The LAV% was calculated as follows: LAV% = LAV/TLV*100. The associations between the seven independent variables (LAV%, age, gender, body mass index, smoking history, forced expiratory volume in 1 second as percent forced vital capacity [FEV1%], and resected lobe) and the two outcomes (postoperative complications and prolonged postoperative stay [ PPS]) were compared using logistic regression analysis. A total of 309 patients (222 males, 87 females; mean age, 67 years; range, 40-87 years) were evaluated. On multivariate analysis, age and LAV% were significantly correlated with postoperative complications (p = 0.006 and p = 0.006, respectively), and LAV% was significantly correlated with PPS (p = 0.031). LAV% measured using 3D-CT is more sensitive for predicting complications after lobectomy for lung cancer than FEV1%.

Background: Acute respiratory distress syndrome (ARDS) can result in a life-threatening form of respiratory failure, and established, effective pharmacotherapies are therefore urgently required. Quercetin is one of the most common flavonoids found in fruits and vegetables, and has potent anti-inflammatory and anti-oxidant activities. Quercetin has been demonstrated to exhibit cytoprotective effects through the induction of heme oxygenase (HO)-1. Here, we investigated whether the intratracheal administration of quercetin could suppress lipopolysaccharide (LPS)-induced acute lung injury (ALI) in mice as well as the involvement of HO-1 in quercetin s suppressive effects. Methods: Mouse model of ALI were established by challenging intratracheally LPS. The wet lung-to-body weight ratio, matrix metalloproteinase (MMP)-9 activities, and pro-inflammatory cytokine productions, including tumor necrosis factor (TNF)-alpha, interleukin (IL)-1 beta, and IL-6 in bronchoalveolar lavage fluid (BALF) were examined in ALI mice with or without quercetin pretreatment. We also examined the effects of quercetin on LPS stimulation in the mouse alveolar macrophage cell line, AMJ2-C11 cells. Results: Intratracheal administration of quercetin decreased the wet lung-to-body weight ratio. Moreover, quercetin decreased MMP-9 activity and the production of pro-inflammatory cytokines in BALF cells activated by LPS in advance. We determined the expression of quercetin-induced HO-1 in mouse lung, e.g., alveolar macrophages (AMs), alveolar and bronchial epithelial cells. When AMJ2-C11 cells were cultured with quercetin, a marked suppression of LPS-induced pro-inflammatory cytokine production was observed. The cytoprotective effects were attenuated by the addition of the HO-1 inhibitor SnPP. These results indicated that quercetin suppressed LPS-induced lung inflammation, and that an HO-1-dependent pathway mediated these cytoprotective effects. Conclusions: Our findings indicated that quercetin suppressed LPS-induced lung inflammation, and that an HO-1-dependent pathway mediated these cytoprotective effects. Intratracheal administration of quercetin will lead to new supportive strategies for cytoprotection in these serious lung conditions.

Background: Recent studies suggest that coexistence of chronic obstructive pulmonary disease (COPD) might be independently related to a worse prognosis for lung cancer. However, because data on the substantial prevalence of COPD and its severity in Asian lung cancer patients remain limited, clinical impact of prevalence and severity of COPD among the population has not been fully evaluated. Furthermore, patients with COPD often have comorbidities. Thus, whether the decision-making process for therapeutic management of lung cancer patients might be independently affected by COPD remains elusive. Methods: Clinical impact of prevalence and severity of COPD were evaluated in 270 Japanese patients with newly diagnosed lung cancer who were sequentially registered and underwent bronchoscopy from August 2010 to July 2012 at Nagoya University hospital. Furthermore, to explore whether or not the severity of airflow obstruction might affect the decision to propose thoracic surgery with curative intent, we evaluated data from patients with lung cancer at stage 1A to 3A who underwent spirometry and bronchoscopy. Results: The prevalence rate of COPD was 54.4% among Japanese patients with lung cancer who underwent bronchoscopy. The incidence of Global Initiative for Chronic Obstructive Lung Disease (GOLD) grades 1 and 2 was significantly higher than that of GOLD grade 3. Although COPD-related comorbidities were not independent factors for proposing thoracic surgery, the number of thoracic surgeries performed was significantly less in the COPD group than the non-COPD group. Multivariate analysis showed that more severe airway obstruction, advanced clinical staging, and higher age, were independent factors associated with the decision on thoracic surgery. Conclusions: We demonstrated a high prevalence of COPD among Japanese lung cancer patients. Based on the knowledge that severity of COPD is one of the most important factors in the therapeutic decision, comprehensive assessment of COPD at bronchoscopy might allow us to implement the optimum management for lung cancer patients.

Background: Newer more advanced techniques in bronchoscopy may require longer procedure times, although a standard protocol for sedation during prolonged bronchoscopy has not yet been defined. Methods: We designed a prospective, non-randomized, single-arm study (UMIN trial number 000003971) using patient questionnaires and vital sign monitoring to assess the efficacy and safety of a standardized midazolam dosing protocol based on gender and age for use during bronchoscopy. The loading dose of midazolam was 0.075mg/kg for men ≤65 years old and women ≤70 and 0.05mg/kg for men ≥66 years and women ≥71 years, with subsequent doses of one-half the loading dose to be administered every 20min. The primary endpoint was tolerability and secondary endpoints included anxiety and recall of procedure, willingness to undergo repeat procedure, and complications. Safety was evaluated in terms of monitored changes in blood pressures, ECG, oxygen saturation, and CO2 content in expiration during the procedure. Results: A total of 204 patients were included in the study. Overall, 163 patients (79.9%) reported "no distress" during the procedure, 185 patients (90.7%) reported "no anxiety," and 175 (85.8%) replied that they would accept a repeat procedure, if necessary. The mean minimum oxygen saturation was 90.2% and the mean maximum expiratory CO2 level was 37.7mmHg. There were no serious complications related to the protocol. Conclusions: The midazolam dosing protocol examined in this study was safe and effective. It is simple, and it could easily be translated to routine clinical practice. © 2013 The Japanese Respiratory Society.

Background: We investigated correlations between lung volume collapsibility indices and pulmonary function test (PFT) results and assessed lobar differences in chronic obstructive pulmonary disease (COPD) patients, using paired inspiratory and expiratory three dimensional (3D) computed tomography (CT) images. Methods: We retrospectively assessed 28 COPD patients who underwent paired inspiratory and expiratory CT and PFT exams on the same day. A computer-aided diagnostic system calculated total lobar volume and emphysematous lobar volume (ELV). Normal lobar volume (NLV) was determined by subtracting ELV from total lobar volume, both for inspiratory phase (NLVI) and for expiratory phase (NLVE). We also determined lobar collapsibility indices: NLV collapsibility ratio (NLVCR) (%) = (1 - NLVE/NLVI) x 100%. Associations between lobar volumes and PFT results, and collapsibility indices and PFT results were determined by Pearson correlation analysis. Results: NLVCR values were significantly correlated with PFT results. Forced expiratory volume in 1 second, measured as percent of predicted results (FEV1%P) was significantly correlated with NLVCR values for the lower lobes (P < 0.01), whereas this correlation was not significant for the upper lobes (P=0.05). FEV1% P results were also moderately correlated with inspiratory, expiratory ELV (ELVI,E) for the lower lobes (P<0.05). In contrast, the ratio of the diffusion capacity for carbon monoxide to alveolar gas volume, measured as percent of predicted (DLCO/V-A%P) results were strongly correlated with ELVI for the upper lobes (P<0.001), whereas this correlation with NLVCR values was weaker for upper lobes (P, 0.01) and was not significant for the lower lobes (P=0.26). Conclusion: FEV1% P results were correlated with NLV collapsibility indices for lower lobes, whereas DLCO/V-A%P results were correlated with NLV collapsibility indices and ELV for upper lobes. Thus, evaluating lobar NLV collapsibility might be useful for estimating pulmonary function in COPD patients.

Transforming growth factor beta (TGF beta) derived from the tumor microenvironment induces malignant phenotypes such as epithelial-mesenchymal transition (EMT) and aberrant cell motility in lung cancers. TGF beta-induced translocation of beta-catenin from E-cadherin complexes into the cytoplasm is involved in the transcription of EMT target genes. PTEN (phosphatase and tensin homologue deleted from chromosome 10) is known to exert phosphatase activity by binding to E-cadherin complexes via beta-catenin, and recent studies suggest that phosphorylation of the PTEN C-terminus tail might cause loss of this PTEN phosphatase activity. However, whether TGF beta can modulate both beta-catenin translocation and PTEN phosphatase activity via phosphorylation of the PTEN C-terminus remains elusive. Furthermore, the role of phosphorylation of the PTEN C-terminus in TGF beta-induced malignant phenotypes has not been evaluated. To investigate whether modulation of phosphorylation of the PTEN C-terminus can regulate malignant phenotypes, here we established lung cancer cells expressing PTEN protein with mutation of phosphorylation sites in the PTEN C-terminus (PTEN4A). We found that TGF beta stimulation yielded a two-fold increase in the phosphorylated -PTEN/PTEN ratio. Expression of PTEN4A repressed TGF beta-induced EMT and cell motility even after snail expression. Our data showed that PTEN4A might repress EMT through complete blockade of beta-catenin translocation into the cytoplasm, besides the inhibitory effect of PTEN4A on TGF beta-induced activation of smad-independent signaling pathways. In a xenograft model, the tumor growth ratio was repressed in cells expressing PTEN4A. Taken together, these data suggest that phosphorylation sites in the PTEN C-terminus might be a therapeutic target for TGF beta-induced malignant phenotypes in lung cancer cells.

AimThe usefulness and safety of endobronchial ultrasound transbronchial needle aspiration (EBUS-TBNA) have been established recently, but no study has evaluated whether or not aging increases the risk of the procedure. In the present study, we aimed to assess the usefulness and safety of EBUS-TBNA in older patients. MethodsThe medical records and database of 109 patients who received EBUS-TBNA between 2008 and 2011 at Nagoya University Hospital, Nagoya, Japan were reviewed retrospectively. All patients underwent bronchoscopy under light sedation with midazolam. A total of 34 patients were aged 70 years or older (the older group) and 75 were aged 69 years or younger (the younger group). We analyzed patients' characteristics, changes of clinical parameters, usage doses of midazolam and lidocaine, procedure duration, geographic data of biopsied lymph nodes, diagnostic yield, and complications in both groups. ResultsThere were more comorbidities in the older group. Four patients (11.8%) in the older group had poor performance status (2-3). Systolic blood pressure at baseline was significantly higher in the older group. There were no statistical differences between the two groups in some clinical parameters (minimum oxygen saturation [SpO(2)], reduction in SpO(2), maximum oxygen supplementation, elevation of systolic blood pressure, increase of heart rate) during the procedure. Diagnostic performance in older patients was similar to that found in younger patients. There was no difference in the frequency of complications between both groups. ConclusionSafety and usefulness of EBUS-TBNA in older people were comparable with those in younger people. Geriatr Gerontol Int 2013; 13: 986-992.

Selective IgA deficiency (SIgAD) is the most common type of primary immunoglobulin deficiency. Most individuals with SIgAD are asymptomatic. However, some patients are associated with allergic and autoimmune disease. SIgAD is included in the list of differential diagnoses of eosinophilia. We experienced a patient who initially presented with abdominal pain and eosinophilia. A >1-year follow-up revealed SIgAD, and we had difficulty differentiating it from Churg-Strauss syndrome (CSS) or hypereosinophilic syndrome (HES). A 66-year-old Japanese male presented with a history of recurrent abdominal pain. A diagnostic work-up revealed eosinophilia, eosinophilic gastritis, eosinophilic pneumonia, and SIgAD over 1 year of clinical observation. He also suffered from asthma and sinusitis. Anti-neutrophil cytoplasmic antibody was negative and vasculitis was not detected in the obtained tissue specimens of stomach, lung, nose and skin. The patient showed no evidence of drug ingestion, parasitic infections, or malignant neoplasms. Although we cannot rule out prevasculitic CSS and idiopathic HES, the whole clinical picture in this patient can be explained most consistently by SIgAD.

Objective Endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) is a minimally invasive technique with a high diagnostic yield used in the investigation of mediastinal diseases including sarcoidosis. Although previous reports have discussed the echoic features of metastatic mediastinal lymph nodes in lung cancer, few have addressed those features of mediastinal lymph nodes with sarcoidosis. We therefore investigated whether the echoic features of lymph nodes with sarcoidosis are distinct when compared to those of metastatic lymph nodes in lung cancer.<br> Methods This retrospective analysis was held in one university hospital between April 2007 and June 2011. EBUS-guided biopsies were performed on 219 patients, and thus resulting in sarcoidosis diagnoses in 53 patients. We quantitatively analyzed the echoic morphologic features of 42 lymph nodes from 34 sarcoidosis patients and 59 lymph nodes from 44 patients with lung cancer using digital image analyzing software.<br> Results In patients with sarcoidosis, 64.3% of the lymph nodes had a round shape, 71.4% had a distinct margin, and 88.1% exhibited homogeneous echogenicity. A germinal center structure was observed in 71.4% of the cases. In the context of shape and margin, no significant difference could be observed between sarcoidosis and lung cancer metastasis. However, homogeneous low echogenicity and the presence of a germinal center structure were observed in sarcoidosis more frequently than in lung cancer.<br> Conclusion Homogeneous low echogenicity and the presence of a germinal central structure may be distinctive echoic features of lymph nodes with sarcoidosis. Analyzing the echogenicity of the mediastinal lymph nodes may help to distinguish sarcoidosis from lung cancer.<br>

Asthma is regarded as a multifactorial inflammatory disorder arising as a result of inappropriate immune responses in genetically susceptible individuals to common environmental antigens. However, the precise molecular basis is unknown. To identify genes for susceptibility to three asthma-related traits, airway hyperresponsiveness (AHR), eosinophil infiltration, and allergen-specific serum IgE levels, we conducted a genetic analysis using SMXA recombinant inbred (RI) strains of mice. Quantitative trait locus analysis detected a significant locus for AHR on chromosome 17. For eosinophil infiltration, significant loci were detected on chromosomes 9 and 16. Although we could not detect any significant loci for allergen-specific serum IgE, analysis of consomic strains showed that chromosomes 17 and 19 carried genes that affected this trait. We detected genetic susceptibility loci that separately regulated the three asthma-related phenotypes. Our results suggested that different genetic mechanisms regulate these asthma-related phenotypes. Genetic analyses using murine RI and consomic strains enhance understanding of the molecular mechanisms of asthma in human.

This study investigated the physiological effects of inhaled corticosteroids, which are used widely to treat asthma. The application of fluticasone propionate (FP, 100 mu M) induced sustained increases in the short-circuit current (ISC) in human airway Calu-3 epithelial cells. The FP-induced ISC was prevented by the presence of H89 (10 mu M, a protein kinase A inhibitor) and SQ22536 (100 mu M, an adenylate cyclase inhibitor). The FP-induced responses involved bumetanide (a Na+-K+-2Cl(-) cotransporter inhibitor)-sensitive and 4,4'-dinitrostilbene-2,2'-disulfonic acid (an inhibitor of HCO32- dependent anion transporters)-sensitive components, both of which reflect basolateral anion transport. Further, FP augmented apical membrane Cl- current (I-Cl), reflecting cystic fibrosis transmembrane conductance regulator (CFTR)-mediated conductance, in the nystatin-permeabilized monolayer. In ISC and ICl responses, FP failed to enhance the responses to forskolin (10 mu M, an adenylate cyclase activator). Nevertheless, we found that FP synergistically increased cytosolic cAMP concentrations in combination with forskolin. All these effects of FP were reproduced with the use of budesonide. Collectively, inhaled corticosteroids such as FP and budesonide stimulate CFTR-mediated anion transport through adenylate cyclase-mediated mechanisms in a nongenomic fashion, thus sharing elements of a common pathway with forskolin. However, the corticosteroids cooperate with forskolin for synergistic cAMP production, suggesting that the corticosteroids and forskolin do not compete with each other to exert their effects on adenylate cyclase. Considering that such synergism was also observed in the FP/salmeterol combination, these nongenomic aspects may play therapeutic roles in mucus congestive airway diseases, in addition to genomic aspects that are generally recognized.