Kazuyoshi Imaizumi

Central sleep apnoea and inflammation are independently associated with arrhythmia in patients with heart failure.

We examined whether the severity of central sleep apnoea (CSA) and the level of C‐reactive protein are associated with the prevalence and complexity of arrhythmias, and whether these factors contribute to increased risk of nocturnal sudden death.

Clinical impact of prevalence and severity of COPD on the decision-making process for therapeutic management of lung cancer patients

BackgroundRecent 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.MethodsClinical 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.ResultsThe 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.ConclusionsWe 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.

Prospective analysis of efficacy and safety of an individualized-midazolam-dosing protocol for sedation during prolonged bronchoscopy.

BACKGROUNDnNewer more advanced techniques in bronchoscopy may require longer procedure times, although a standard protocol for sedation during prolonged bronchoscopy has not yet been defined.nnnMETHODSnWe 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.nnnRESULTSnA 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.nnnCONCLUSIONSnThe midazolam dosing protocol examined in this study was safe and effective. It is simple, and it could easily be translated to routine clinical practice.

Bronchus sign on thin-section computed tomography is a powerful predictive factor for successful transbronchial biopsy using endobronchial ultrasound with a guide sheath for small peripheral lung lesions: a retrospective observational study

BackgroundRecent 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.MethodsWe retrospectively reviewed 149 consecutive patients who underwent TBB with EBUS-GS for small-sized peripheral lung lesions (≤30xa0mm 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).ResultsThe total diagnostic yield in this study was 72.5xa0% (95xa0% confidence interval: 64.8–79.0xa0%). 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.ConclusionOur results suggest that the CT bronchus sign is a powerful predictive factor for successful TBB with EBUS-GS.

Involvement of TGFβ-Induced Phosphorylation of the PTEN C-Terminus on TGFβ-Induced Acquisition of Malignant Phenotypes in Lung Cancer Cells

Transforming growth factor β (TGFβ) derived from the tumor microenvironment induces malignant phenotypes such as epithelial-mesenchymal transition (EMT) and aberrant cell motility in lung cancers. TGFβ-induced translocation of β-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 β-catenin, and recent studies suggest that phosphorylation of the PTEN C-terminus tail might cause loss of this PTEN phosphatase activity. However, whether TGFβ can modulate both β-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 TGFβ-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 TGFβ stimulation yielded a two-fold increase in the phosphorylated -PTEN/PTEN ratio. Expression of PTEN4A repressed TGFβ-induced EMT and cell motility even after snail expression. Our data showed that PTEN4A might repress EMT through complete blockade of β-catenin translocation into the cytoplasm, besides the inhibitory effect of PTEN4A on TGFβ-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 TGFβ-induced malignant phenotypes in lung cancer cells.

Febrile complications after endobronchial ultrasound-guided transbronchial needle aspiration for intra-pulmonary mass lesions of lung cancer—a series of 3 cases

Recent case reports have shown that endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) for mediastinal lesions is sometimes accompanied by severe infectious complications. Here, we report 3 cases with refractory febrile complications following EBUS-TBNA for intra-pulmonary large mass lesion of lung cancer (squamous cell carcinoma, n=2; adenocarcinoma, n=1). After the EBUS-TBNA, all cases showed prolonged fever and systemic inflammation despite receiving a sufficient dose of broad-spectrum antibiotics. The presence of a low-density area inside the masses upon CT examination, suggesting necrosis, may be a predictive sign of febrile complications associated with EBUS-TBNA.

Hypoxia-induced modulation of PTEN activity and EMT phenotypes in lung cancers

BackgroundPersistent 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.MethodsWestern 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.ResultsLung 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 1α. PTEN4A blunted hypoxia-induced EMT via inhibition of β-catenin translocation into the cytoplasm and nucleus.ConclusionOur 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.

Post-Progression Survival after EGFR-TKI for Advanced Non-Small Cell Lung Cancer Harboring EGFR Mutations

Background Non-small cell lung cancer (NSCLC) patients that harbor epidermal growth factor receptor (EGFR) mutations benefit from receiving an EGFR-tyrosine kinase inhibitor (TKI); however, post-progression survival (PPS) after EGFR-TKI treatment has not been sufficiently studied. Methods We retrospectively reviewed the clinical data from stage IV or recurrent NSCLC patients who harbored EGFR mutations and who received EGFR-TKI as their first-line treatment in our institute between 2009 and 2011. Results In total, 36 patients received EGFR-TKI treatment as their first-line therapy. Of those 36 patients, 30 experienced recurrence and were enrolled in this study. The median progression-free survival (PFS) of these patients was 8.2 months. Twelve patients received EGFR-TKI treatment beyond the diagnosis of progressive disease (PD), and 8 received second-line therapy. The PPS after EGFR-TKI treatment was 9.1 months, and survival after the termination of EGFR-TKI treatment in those patients treated with second-line chemotherapy was 13.9 months. The site of relapse was investigated and PFS in EGFR-TKI-treated patients with relapse in the brain (11.6 months) showed a trend toward a longer PFS compared with patients with relapse at other sites (8.2 months). The median PPS after EGFR-TKI treatment also showed the same trend in each group (12.9 and 9.2 months, respectively). Conclusions The PPS after EGFR-TKI treatment failure was 9.1 months, while the survival of patients who underwent second-line chemotherapy after the termination of EGFR-TKI treatment was 13.9 months, comparable with the overall survival of EGFR mutation-negative patients, as previously reported. The prognosis of these NSCLC patients with EGFR mutations varied according to the sites of recurrence after first-line EGFR-TKI treatment. Of particular note was the prognosis of patients with brain metastases, which tended to be better than that of patients with metastases to other sites.

Endobronchial ultrasound transbronchial needle aspiration in older people

The 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.

Aqueous fraction of Sauropus androgynus might be responsible for bronchiolitis obliterans

Background and objective:u2003 Bronchiolitis obliterans (BO) has been reported to develop following ingestion of Sauropus androgynus (SA), a leafy shrub distributed in Southeast Asia. Little is known about direct effects of SA on airway resident cells or haematopoietic cells in vitro. Identification of the SA component responsible for the development of BO would be an important key to elucidate its mechanism. We sought to elucidate the direct effects of SA on airway resident cells or haematopoietic cells and identify the SA element responsible for the pathogenesis of BO.