Kentaro Ito

Indacaterol improves daily physical activity in patients with chronic obstructive pulmonary disease

Background The current mainstay of therapy for chronic obstructive pulmonary disease (COPD) is long-acting bronchodilators. To date, the effect of indacaterol, a β2-agonist, on activities of daily living in COPD patients is not well understood. The aim of this study was to evaluate the efficacy of indacaterol with regard to activities of daily living in patients with COPD. Methods In this nonrandomized open-label study, 23 patients with COPD were instructed to carry an accelerometer for 4 weeks without indacaterol therapy and then for another period of 4 weeks while receiving indacaterol therapy. Results The number of steps, duration of moderate or greater physical activity, and energy expenditure were significantly increased after treatment with indacaterol compared with baseline data in all patients with COPD; the metabolic equivalent of task was also significantly enhanced after treatment with indacaterol. Conclusion This study provides early evidence that indacaterol improves daily physical activity in patients with COPD.

Sequential Therapy with Crizotinib and Alectinib in ALK-Rearranged Non–Small Cell Lung Cancer—A Multicenter Retrospective Study

Introduction: Alectinib and crizotinib have been approved for the therapy of NSCLC caused by anaplastic lymphoma kinase gene (ALK) rearrangement. The effect of alectinib or crizotinib on overall survival (OS) in patients with ALK‐rearranged NSCLC remains unknown. Methods: A multicenter retrospective study was conducted to compare OS between patients receiving alectinib and crizotinib and between patients treated with alectinib and those treated sequentially with crizotinib and then alectinib after crizotinib failure. The time to treatment failure (TTF), progression‐free survival (PFS), and OS were compared. Results: Sixty‐one patients with ALK‐rearranged NSCLC were enrolled. Forty‐six patients were treated with anaplastic lymphoma kinase (ALK) inhibitors (31 with crizotinib, 28 with alectinib, and 13 with both ALK inhibitors). The response rate was 66.7% for the crizotinib‐treated group and 80.8% for the alectinib‐treated group. Among all patients, TTF and PFS were significantly prolonged in the alectinib‐treated group compared with in the crizotinib‐treated group. Subgroup analyses revealed significantly prolonged TTF for alectinib compared with crizotinib therapy in the ALK inhibitor–naive population. OS was significantly longer in the alectinib‐treated group than in the crizotinib‐treated group. The TTF and OS of patients treated sequentially with crizotinib and then with alectinib after crizotinib failure tended to be longer than those of patients treated with alectinib alone. Conclusions: Therapy with alectinib alone was significantly superior to therapy with crizotinib alone in terms of TTF, PFS, and OS, and sequential therapy with crizotinib and alectinib after crizotinib failure tended to provide a better OS benefit than did therapy with alectinib alone in patients with ALK‐positive NSCLC. However, large‐scale prospective studies are needed to confirm these observations.

“Pseudoprogression” of Pulmonary Pleomorphic Carcinoma during Nivolumab Therapy

“Pseudoprogression” of Pulmonary Pleomorphic Carcinoma during Nivolumab Therapy Kentaro Ito, MD, Osamu Hataji, MD, Koji Katsuta, MD, Tetsu Kobayashi, MD, Esteban C. Gabazza, MD,* Yasushi Yatabe, MD, Osamu Taguchi, MD, Nobuyuki Yamamoto, MD Respiratory Center, Matsusaka Municipal Hospital, Matsusaka, Japan Department of Pathology, Matsusaka Municipal Hospital, Matsusaka, Japan Department of Pulmonary and Critical Care Medicine, Mie University Graduate School of Medicine, Tsu, Japan Department of Immunology, Mie University Graduate School of Medicine, Tsu, Japan Department of Pathology and Molecular Diagnostics, Aichi Cancer Center Hospital, Nagoya, Japan Mie University Center for Physical and Mental Health, Mie University Graduate School of Medicine, Tsu, Japan Third Department of Internal Medicine, Wakayama Medical University, Wakayama, Japan

Smart watch‑based coaching with tiotropium and olodaterol ameliorates physical activity in patients with chronic obstructive pulmonary disease

Combined therapy with tiotropium and olodaterol notably improves parameters of lung function and quality of life in patients with chronic obstructive pulmonary disease (COPD) compared to mono-components; however, its effect on physical activity is unknown. The present study evaluated whether combination therapy affects daily physical performance in patients with COPD under a smart watch-based encouragement program. This was a non-blinded clinical trial with no randomization or placebo control. A total of 20 patients with COPD were enrolled in the present study. The patients carried an accelerometer for 4 weeks; they received no therapy during the first 2 weeks but they were treated with combined tiotropium and olodaterol under a smart watch-based encouragement program for the last 2 weeks. The pulmonary function test, COPD assessment test, 6-min walk distance and parameters of physical activity were significantly improved (P<0.05) by combination therapy under smart watch-based coaching compared with values prior to treatment. To the best of our knowledge, the present study for the first time provides evidence that smart watch-based coaching in combination with tiotropium and olodaterol may improve daily physical activity in chronic obstructive pulmonary disease.

Three-dimensional computed tomography angiography for the preoperative evaluation of coronary artery disease in lung cancer patients

BackgroundThe number of elderly patients undergoing surgery for lung cancer is increasing. In this study, we assessed the usefulness of three-dimensional computed tomographicangiography (3D-CTA) for the detection of coronary disease in the elderly before surgical intervention for lung cancer.MethodsOne hundred twenty patients admitted to our institution for lung cancer resection were enrolled in the study. 3D-CTA was performed in all 120 patients.ResultsSeventy-one patients had normal findings, and forty-nine patients showed coronary stenosis on 3D-CTA examination. Among the latter 49 patients, 24 with slight stenosis underwent lung tumor resection, 23 had coronary angiography for severe stenosis before lung surgery and 2 were not eligible for lung resection because of very severe coronary stenosis. The diagnostic value of 3D-CTA was better than conventional CT.ConclusionsThis study suggests the usefulness of 3D-CTA for the preoperative diagnosis of coronary ischemic disease in elderly lung cancer patients.

Utility of Liquid Biopsy by Improved PNA-LNA PCR Clamp Method for Detecting EGFR Mutation at Initial Diagnosis of Non–Small-Cell Lung Cancer: Observational Study of 190 Consecutive Cases in Clinical Practice

Micro‐Abstract We reviewed 190 consecutive unselected patients who underwent liquid biopsy for detecting an EGFR mutation. The results indicated that not all patients should be candidates for liquid biopsy at initial diagnosis, while some patients gain benefit from initial liquid biopsy in clinical practice. These real‐world data supply useful information in choosing patients appropriate for liquid biopsy. Background: The clinical benefit of liquid biopsy for unselected patients at initial diagnosis has thus far been unclear. We aimed to evaluate the utility of liquid biopsy at initial diagnosis, as well as the efficacy of epidermal growth factor receptor–tyrosine kinase inhibitor (EGFR‐TKI) based on liquid biopsy results in clinical practice, using the improved peptide nucleic acid–locked nucleic acid (PNA‐LNA) PCR clamp method. Patients and Methods: We routinely performed liquid biopsy using the improved PNA‐LNA PCR clamp method for all patients diagnosed with non–small‐cell lung cancer (NSCLC) between June 2015 and October 2016. We retrospectively evaluated the reliability of liquid biopsy based either on clinical stage or between sensitizing EGFR mutation and T790M mutation, and the clinical benefit of EGFR‐TKI based on the liquid biopsy results in practice. Results: A total of 244 patients underwent liquid biopsies, with 168 patients tested at diagnosis and 22 tested for T790M after pretreatment of EGFR‐TKI. For detecting a sensitizing EGFR mutation, the sensitivity, specificity, positive predictive value, and negative predictive value were 72.7%, 100%, 100%, and 93.7% in the group with advanced‐stage NSCLC and 0, 100%, not evaluable, and 70.5% in the group with early‐stage NSCLC. The positive predictive value and negative predictive value for T790M were 33.3% and 55.6%, respectively. Fourteen patients in the liquid‐positive group and 16 patients in the tissue‐positive group received EGFR‐TKI. The objective response rates of first‐ and second‐generation EGFR‐TKI for the liquid‐positive and tissue‐positive groups were 90.0% and 90.9%, respectively. There was no significant difference in median progression‐free survival between the liquid‐positive and tissue‐positive groups (P = .839). Conclusion: Patients with early‐stage NSCLC should not be candidates for this liquid biopsy method. We recommend tissue biopsy as the preferred initial method of molecular analysis, with the exception of patients who are T790M positive or patients who are unable to tolerate invasive biopsy. Graphical abstract: Figure. No Caption available.

Comparable immunoreactivity rates of PD-L1 in archival and recent specimens from non-small cell lung cancer: PD-L1 in archival and recent samples

Molecular targeted therapy including the use of monoclonal antibodies directed against the immune checkpoints PD‐L1 and PD‐1 receptor have remarkably improved the therapeutic response and survival of cancer patients. The tumor expression level of PD‐L1 can predict the response rate to checkpoint inhibitors. We evaluated whether the time interval between tumor tissue sampling/paraffinization and immunohistochemistry affects the staining level of PD‐L1 in non‐small cell lung cancer (NSCLC).

Osimertinib therapy as first-line treatment before acquiring T790M mutation: from AURA1 trial

First- or second-generation EGFR tyrosine kinase inhibitors (EGFR-TKI) have been the first-line treatment for NSCLC harboring EGFR mutation (1-6), however almost all patients inevitably acquire resistance during EGFR-TKI therapy.

Renal Injury during Long-Term Crizotinib Therapy

Crizotinib is highly effective against anaplastic lymphoma kinase-positive and c-ros oncogen1-positive non-small cell lung cancer. Renal dysfunction is associated with crizotinib therapy but the mechanism is unknown. Here, we report a case of anaplastic lymphoma kinase positive non-small cell lung cancer showing multiple cysts and dysfunction of the kidneys during crizotinib administration. We also present results demonstrating that long-term crizotinib treatment induces fibrosis and dysfunction of the kidneys by activating the tumor necrosis factor-α/nuclear factor-κB signaling pathway. In conclusion, this study shows the renal detrimental effects of crizotinib, suggesting the need of careful monitoring of renal function during crizotinib therapy.

Efficacy of osimertinib in a patient with non‑small cell lung cancer harboring epithelial growth factor receptor exon 19 deletion/T790M mutation, with poor performance status

Osimertinib, a third-generation epithelial growth factor receptor (EGFR) tyrosine kinase inhibitor, has been demonstrated to be effective for treating patients with T790M-positive advanced non-small cell lung cancer (NSCLC) with a relatively good performance status (grade 0–1). Reports of therapeutic response to osimertinib in advanced NSCLC patients with poor performance status are infrequent. The present case report discusses a patient with advanced lung adenocarcinoma harboring EGFR exon 19 deletion and T790M mutation with central nervous system involvement and poor performance status. The patient had a past history of partial lung resection due to lung adenocarcinoma, positive genetic test for EGFR exon 19 deletion in post-surgical tumor specimens, and therapy with erlotinib and onartuzumab for the appearance of a lung metastatic tumor during the post-surgical follow-up. The combined therapy was continued until the discovery of metastatic tumors in bones and the central nervous system. The Cobas test performed using tissue from bone metastatic tumor was positive for exon 19 deletion and for T790M mutation. The patient was treated with osimertinib and adverse effects or hematological toxicity were not observed. Performance status of the patient improved from grade 4 to 2. Subsequent studies revealed remission of bone metastasis and reduced central nervous system lesions. This report provides evidence on the safety and efficacy of osimertinib for treating NSCLC patients with progressive disease, central nervous system lesion and poor performance status.