Ryo Tachikawa

Rebiopsy of non-small cell lung cancer patients with acquired resistance to epidermal growth factor receptor-tyrosine kinase inhibitor: Comparison between T790M mutation-positive and mutation-negative populations.

The secondary epidermal growth factor receptor (EGFR) mutation Thr790Met (T790M) accounts for approximately half of acquired resistances to EGFR‐tyrosine kinase inhibitor (TKI). Recent reports have demonstrated that the emergence of T790M predicts a favorable prognosis and indolent progression. However, rebiopsy to confirm T790M status can be challenging due to limited tissue availability and procedural feasibility, and little is known regarding the differences among patients with or without T790M mutation.

Clinical Features and Outcome of Acute Exacerbation of Interstitial Pneumonia: Collagen Vascular Diseases-Related versus Idiopathic

Background: Relatively little is known about acute exacerbation (AE) of interstitial pneumonia associated with collagen vascular diseases (CVD-IPs). Objectives: This study was aimed at clarifying clinical characteristics and outcome in AE of CVD-IPs, compared with those of idiopathic interstitial pneumonias (IIPs). Methods: We retrospectively reviewed 112 admission cases with suspected AE of CVD-IPs or IIPs during 2003–2009. IIPs were diagnosed with idiopathic pulmonary fibrosis (IPF) or non-IPF, mostly based on radiologic findings. Of these, 15 AEs of CVD-IPs (6 rheumatoid arthritis, 6 dermatomyositis and 3 systemic sclerosis) and 47 AEs of IIPs (13 IPF and 34 non-IPF) were included. Results: The clinical characteristics in AE of CVD-IPs were similar to those of IIPs, except for younger age (63.3 ± 6.8 vs. 73.8 ± 9.1 years; p = 0.0001) and higher PaO2/FiO2 at the onset of AE (205 ± 81.2 vs. 145 ± 53.8 mm Hg; p = 0.002) in the former. Dermatomyositis-related interstitial pneumonia (IP) showed a relatively indolent onset and was often associated with worsening control of the underlying disease, whereas AE of other CVD-IPs resembled that of IIPs. 90-day mortality of 33% in AE of CVD-IPs was similar to that of IIPs (44%; p = 0.44) or non-IPF (34%; p = 0.94), but was significantly better than that of IPF (69%; p = 0.04). Conclusion: Clinical features and outcome in AE of CVD-IPs were similar, if not identical, to those of IIPs, having a significant impact on the clinical course. AE of advanced IPF with typical radiologic features seems to have higher mortality compared with other forms of IP.

How Sensitive Are Epidermal Growth Factor Receptor–Tyrosine Kinase Inhibitors for Squamous Cell Carcinoma of the Lung Harboring EGFR Gene–Sensitive Mutations?

Introduction: Epidermal growth factor receptor (EGFR) mutations are found mostly in adenocarcinoma, and rarely in squamous cell carcinoma (SQC). Little is known about SQC harboring EGFR mutations. Methods: Between April 2006 and October 2010, we investigated the incidence of EGFR activating mutations in SQC of the lung using the peptide nucleic acid-locked nucleic acid polymerase chain reaction clamp method. The efficacy of EGFR-tyrosine kinase inhibitors (TKIs) was retrospectively evaluated in patients with EGFR-mutated SQC. Further pathologic analyses were performed using immunohistochemistry. Results: Thirty-three of 249 patients with SQC (13.3%) had EGFR mutations, including exon 19 deletion (19 of 33 patients, 58%), L858R point mutation in exon 21 (12 of 33, 36%), and G719S point mutation in exon 18 (2 of 33, 6%). Twenty of these 33 patients received EGFR-TKI therapy, and five of these 20 responded to EGFR-TKIs with a response rate of 25.0% (95% confidence interval [CI], 8.7%–49.1%). The patients’ median progression-free survival and median overall survival were 1.4 months (95% CI, 0.7–5.8 months) and 14.6 months (95% CI, 2.9–undeterminable months), respectively. Approximately one third of the EGFR-mutated SQC patients achieved progression-free survival for longer than 6 months. Some of these patients had high carcinoembryonic antigen levels or a history of never smoking, or were positive for thyroid transcription factor-1. Conclusions: Although EGFR-TKIs seem to be generally less effective in EGFR-mutated SQC than in EGFR-mutated adenocarcinoma, some EGFR-mutated SQC patients can obtain clinical benefit from EGFR-TKIs. To better identify these patients, not only EGFR mutation status, but also clinical factors and pathologic findings should be taken into consideration.

Changes in Energy Metabolism after Continuous Positive Airway Pressure for Obstructive Sleep Apnea

RATIONALE Disrupted energy homeostasis in obstructive sleep apnea (OSA) may lead to weight gain. Paradoxically, treating OSA with continuous positive airway pressure (CPAP) may also promote weight gain, although the underlying mechanism remains unclear. OBJECTIVES To explore the underlying mechanism by which patients with OSA gain weight after CPAP. METHODS A comprehensive assessment of energy metabolism was performed in 63 newly diagnosed OSA study participants (51 men; 60.8 ± 10.1 yr; apnea-hypopnea index >20 h(-1)) at baseline, CPAP initiation, and at a 3-month follow-up. Measurements included polysomnography, body weight, body composition, basal metabolic rate (BMR), hormones (norepinephrine, cortisol, leptin, ghrelin, insulin-like growth factor-1), dietary intake, eating behavior, and physical activity. MEASUREMENTS AND MAIN RESULTS BMR significantly decreased after CPAP (1,584 kcal/d at baseline, 1,561 kcal/d at CPAP initiation, and 1,508 kcal/d at follow-up; P < 0.001), whereas physical activity and total caloric intake did not significantly change. In multivariate regression, baseline apnea-hypopnea index, Δurine norepinephrine, and CPAP adherence were significant predictors of ΔBMR. The weight gainers had higher leptin levels, lower ghrelin levels, and higher eating behavior scores than the non-weight gainers, indicating a positive energy balance and disordered eating behavior among the weight gainers. Among the parameters related to energy metabolism, increased caloric intake was a particularly significant predictor of weight gain. CONCLUSIONS Although a reduction in BMR after CPAP predisposes to a positive energy balance, dietary intake and eating behavior had greater impacts on weight change. These findings highlight the importance of lifestyle modifications combined with CPAP. Clinical trial registered with http://www.umin.ac.jp/english/ (UMIN000012639).

The use of non-invasive ventilation for life-threatening asthma attacks: Changes in the need for intubation.

Background and objective:  Although non‐invasive ventilation (NIV) has been shown to be effective in a wide variety of respiratory diseases, its role in severe asthma attacks remains uncertain. The aim of this study was to clarify the effectiveness of NIV in patients experiencing severe attacks of asthma.

Cytokeratin 19 fragment predicts the efficacy of epidermal growth factor receptor-tyrosine kinase inhibitor in non-small-cell lung cancer harboring EGFR mutation.

Background: EGFR gene mutation is independently associated with a favorable response in non–small-cell lung cancer (NSCLC) patients receiving epidermal growth factor receptor -tyrosine kinase inhibitors (EGFR-TKIs), regardless of sex or smoking history. Squamous cell carcinoma patients harboring EGFR mutations show a significantly worse response to EGFR-TKIs compared with adenocarcinoma patients. We hypothesized that the serum cytokeratin 19 fragment (CYFRA 21-1) is associated with the efficacy of EGFR-TKIs in EGFR-mutated NSCLC patients. Methods: We retrospectively screened 160 NSCLC patients harboring EGFR mutations, who had received either gefitinib, or erlotinib between 1992 and 2011. Patients were screened for clinical characteristics, the efficacy of EGFR-TKI, and tumor markers (carcinoembryonic antigen [CEA]/CYFRA 21-1) at the initial diagnosis. Results: Of 160 eligible patients treated with EGFR-TKIs, 77 patients with high CYFRA 21-1 level (>2 ng/ml) showed significantly shorter progression-free survival (PFS) than the 83 patients with normal CYFRA 21-1 level (median PFS, 7.5 versus 13.3 months; p < 0.001). No significant difference in PFS was observed between the high-CEA group (>5 ng/ml) and the normal-CEA group (median PFS, 8.6 versus 11.2 months; p = 0.242). A multivariate analysis revealed that high CYFRA 21-1 level is independently associated with PFS (hazard ratio, 1.27; p = 0.002). No significant difference in overall survival was observed between the high- and the normal-CYFRA 21-1 groups (median overall survival, 24.8 versus 39.1 months; p = 0.104). Conclusions: Patients with a high CYFRA 21-1 level have significantly shorter PFS. CYFRA 21-1 is not a prognostic but a predictive marker of EGFR-TKI treatment in EGFR-mutated NSCLC patients.

Evaluation of the chronic obstructive pulmonary disease assessment test for measurement of health-related quality of life in patients with interstitial lung disease

Background and objective:  A well‐validated instrument that is simple to use is needed to assess health‐related quality of life in patients with interstitial lung disease (ILD). The COPD assessment test (CAT) is a recently introduced, short and simple questionnaire for COPD patients, which shows good and valid measurement properties. This study was conducted to evaluate the validity of the CAT in patients with ILD.

Preexisting interstitial lung disease is inversely correlated to tumor epidermal growth factor receptor mutation in patients with lung adenocarcinoma

INTRODUCTION Interstitial lung disease (ILD), especially idiopathic pulmonary fibrosis, has been shown to be associated with lung carcinogenesis. However, an association between epidermal growth factor receptor (EGFR) mutation status and preexisting ILD in patients with lung adenocarcinoma is unknown. METHODS Between January 2008 and April 2012, we analyzed 602 patients with lung adenocarcinoma. EGFR mutation status was analyzed using the peptide nucleic acid-locked nucleic acid polymerase chain reaction clamp method, and preexisting ILD was diagnosed based on clinical features, chest high-resolution computed tomography (HRCT) findings, and histological findings. RESULTS There were 555 patients with pulmonary adenocarcinoma with tumor EGFR mutation data available for analysis. Of them, 31 patients (6%) had preexisting ILD, and EGFR mutations were detected in 246 of the 555 patients (46%). In the comparison between patients with EGFR mutations and those with wild-type EGFR, there was a significant inverse association between occurrence of tumors with EGFR mutations and ILD (1/246 vs. 30/309, P<0.001). Based on the multivariate analysis of age, gender, smoking status, Eastern Cooperative Oncology Group Performance Status, stage, and ILD, EGFR mutations were found to be independently associated with females (OR, 1.58; 95% CI, 1.01-2.46; P=0.048), never-smokers (OR, 3.31; 95% CI, 2.12-5.20; P<0.001), and the absence of ILD (OR, 17.41; 95% CI, 3.54-315.34; P<0.001). CONCLUSIONS This study showed that patients with pulmonary adenocarcinoma and ILD had a lower probability of carrying tumor EGFR mutations.

Detection of Herpes Viruses by Multiplex and Real-Time Polymerase Chain Reaction in Bronchoalveolar Lavage Fluid of Patients with Acute Lung Injury or Acute Respiratory Distress Syndrome

Background: Human herpes viruses (HHVs) are important pathogens in acute lung injury (ALI) and acute respiratory distress syndrome (ARDS). Rapid and efficient diagnostic tools are needed to detect HHVs in the lung in ALI/ARDS patients. Objectives: This study aimed to evaluate the usefulness of multiplex and real-time polymerase chain reaction (PCR) analysis of bronchoalveolar lavage fluid (BALF) for detecting HHV reactivation in ALI/ARDS patients. Methods: Between August 2008 and July 2012, eighty-seven BALF samples were obtained from ALI/ARDS patients with unknown etiology and analyzed for HHVs. The types of HHVs in the BALF samples were determined using qualitative multiplex PCR followed by quantitative real-time PCR. Results: Multiplex PCR identified herpes simplex virus type 1 (HSV-1) (n = 11), Epstein-Barr virus (EBV) (n = 16), cytomegalovirus (CMV) (n = 21), HHV type 6 (HHV-6) (n = 2), and HHV-7 (n = 1) genomic DNA in 35 (40%) of the BALF samples, including 14 (16%) samples containing 2 or 3 HHV types. CMV and EBV reactivation was rare in immunocompetent patients, whereas reactivation of HSV-1 was predominantly observed in intubated patients regardless of their immune status. Overall, HHVs were almost exclusively found in patients with immunosuppression or endotracheal intubation. Real-time PCR detected 0.95-1.59 × 106 copies of viral DNA/μg human genome DNA, and HSV-1 (n = 4), CMV (n = 9), and HHV-6 (n = 1) were identified as potentially pathogenic agents. Conclusions: The implementation of multiplex and real-time PCR of BALF was feasible in ALI/ARDS patients, which allowed efficient detection and quantification of HHV DNA.

Plasma Incretin Levels and Dipeptidyl Peptidase-4 Activity in Patients with Obstructive Sleep Apnea

RATIONALE Incretin hormones, namely glucagon-like peptide-1 (GLP-1) and gastric inhibitory polypeptide/glucose-dependent insulinotropic polypeptide (GIP), and dipeptidyl peptidase-4 (DPP-4) activity are important factors in glucose metabolism and have not been investigated in patients with obstructive sleep apnea (OSA). OBJECTIVES The objective of this study was to investigate the association between OSA and incretin and DPP-4 activity. METHODS This study included 96 consecutive patients without diabetes who were suspected of having OSA. We investigated the fasting and post-prandial incremental area under the curve (IAUC) of GLP-1, GIP serum levels, and serum DPP-4 activity levels, as well as their association with OSA. Changes in clinical variables were evaluated in the 43 patients who continued continuous positive airway pressure therapy for 3 months. MEASUREMENTS AND MAIN RESULTS Apnea-hypopnea index was an independent determining factor for fasting GLP-1 (β = 0.31; P = 0.0019) and IAUC GIP (β = -0.21; P = 0.037) after adjusting for known confounding factors. In those with very severe OSA (apnea-hypopnea index ≥50), the IAUCs for GLP-1 and GIP were significantly decreased, while fasting GLP-1 and fasting GIP were significantly increased. DPP-4 activity had no relation to OSA parameters or severity, while body mass index was significantly higher in those with severe OSA. Although significant changes in incretin secretion were not seen for 3 months after onset of continuous positive airway pressure therapy, the fasting GLP-1 level in the treated patients with severe OSA decreased to the same level as in untreated patients with normal to moderately severe OSA. CONCLUSIONS OSA is associated with elevated serum levels of the incretin hormones GLP-1 (fasting) and GIP (post-prandial) in patients without diabetes. A significant association between body mass index and DPP-4, which is said to exist in healthy persons, was not found in the patients with OSA. Fasting GLP-1 in patients without diabetes with OSA may influence fasting glucose levels.