Osamu Hataji

Percutaneous Radiofrequency Ablation of Lung Neoplasms: Initial Therapeutic Response

PURPOSE To evaluate the feasibility, safety, and initial therapeutic effect of radiofrequency (RF) ablation in the treatment of unresectable malignant lung tumors. MATERIALS AND METHODS Fifty-four lung neoplasms in 31 patients were treated with RF ablation. Thirteen tumors were primary lung cancers and 41 were pulmonary metastases. Tumor sizes ranged from 0.7 to 6.0 cm, with a mean size of 2.7 +/- 1.3 cm. After the RF electrode was placed in the tumor with computed tomographic (CT) fluoroscopic guidance, RF energy was applied. Initial therapeutic response was evaluated by (18) F fluorodeoxyglucose positron emission tomography (FDG-PET) and contrast-enhanced CT. The disappearance of FDG uptake on PET images and tumor enhancement on CT images were considered to indicate complete tumor necrosis. Complete necrosis rates were evaluated according to tumor size and type (primary or secondary lung neoplasm). RESULTS RF ablation was technically successful in all lesions. Complete necrosis was achieved in 32 of the 54 tumors (59%) after initial RF session. There was a significant difference in the rate of complete tumor necrosis between tumors 3 cm or less and tumors larger than 3 cm (69% vs. 39%; P <.05). Tumor type did not influence complete necrosis rates. Lung abscesses developed in two patients with large tumors. CONCLUSION Lung RF ablation is a feasible, relatively safe, and promising treatment for unresectable lung neoplasms. Tumor size is an important factor in achieving complete tumor necrosis.

Thrombin in the airways of asthmatic patients.

Abstract. The mechanism of airway remodeling in asthmatic patients is poorly understood. Thrombin is a multifunctional protease that, in addition to its critical role in thrombotic processes, has also been described as inducing cellular and molecular events relevant to tissue remodeling. The present investigation was undertaken to evaluate the activity of thrombin in the sputum of asthmatic patients and its potential role in airway remodeling. The study population comprised 8 healthy subjects and 14 stable patients with bronchial asthma. The concentrations of thrombin, thrombin-antithrombin complex (TAT), and tissue factor were measured in the sputum of all subjects. The concentrations of thrombin (p= 0.007), TAT (p= 0.01), and tissue factor (p= 0.02) in sputum were significantly higher in asthmatic patients than in healthy controls. The proliferative effects that sputum from asthmatic patients (p= 0.01) and thrombin (p= 0.03) have on cultured human smooth muscle cells was inhibited significantly in the presence of recombinant hirudin, a specific thrombin inhibitor. Significant statistical correlation was observed between the degree of bronchial responsiveness and the sputum concentrations of thrombin (r=−0.8; p= 0.02) and TAT (r=−0.9; p= 0.01). The results of this study showed that increased thrombin generation occurs in the airway of patients with asthma and that it may play a role in the pathogenesis of airway remodeling. Further studies should be carried out to assess whether these findings are also observed in other airway diseases.

Activation of protein C pathway in the airways.

The protein C (PC) pathway plays important roles in the regulation of the coagulation system and inflammatory response. This study evaluated the degree of PC activation in the airway of patients with bronchial asthma (BA), and the expression and regulation of PC and its receptor in airway epithelial cell lines. Thirteen BA patients and 8 healthy volunteers were enrolled in the study. BEAS-2B and A549 epithelial cell lines were used in experimental assays. Expression of anticoagulant factors was evaluated by RT-PCR and Western blotting. The activated protein C (APC)/thrombin (1.65 +/- 0.35 vs 3.34 +/- 0.59) and APC/PC (8.30 +/- 2.26 vs 24.41 +/- 9.88) ratios were significantly decreased and the concentrations of soluble thrombomodulin (TM) were significantly increased in induced sputum from BA patients compared with healthy subjects. Airway epithelial cells express PC, its receptor, and TM. PC antigen prepared from epithelial cells was significantly activated in the presence of thrombin. Thrombin increased the expression of PC antigen from lung epithelial cells. However, tumor necrosis factor-alpha, eotaxin, and RANTES (regulated on activation, normal T-cell expressed and secreted) decreased the expression of PC and its receptor in bronchial epithelial cells. Overall, these results showed for the first time that reduced activation of PC pathway occurs in the airway of BA patients and that TM, PC, and its receptor, are expressed by human airway epithelial cells. The expression of these PC pathway components was found to be downregulated by inflammatory cytokines. The decrease in PC activation may contribute to exacerbation of the inflammatory response in the airway of asthmatic patients.

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.

Role of nitric oxide in airway remodelling

Airway remodelling, which is manifested by thickening of bronchial wall, is an important causative factor of bronchial hyper-responsiveness in asthma. The pathophysiological mechanism of airway remodelling is not clear. In the present study we evaluated the relationship between nitric oxide (NO) generation and airway wall thickening in patients with chronic asthma. As a marker of NO production, the levels of nitrite/nitrate were measured in induced sputum, and bronchial wall thickening was measured by high-resolution computed tomography. Sputum concentrations of nitrite/nitrate were significantly increased in asthmatic patients compared with controls. The ratio of airway wall thickness to lumen diameter was significantly correlated with the sputum concentration of nitrite/nitrate. Although statistical correlation does not prove causation, this finding suggests that NO may play a key role in the pathogenesis of airway remodelling.

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.

Dose-dependent differential effects of thrombin in allergic bronchial asthma

Apart from its role in the coagulation system, thrombin plays an important role in the inflammatory response through its protease‐activated receptors (PARs). However, the role of thrombin in the immune response is not clear.

Thrombin-Activatable Fibrinolysis Inhibitor Protects against Acute Lung Injury by Inhibiting the Complement System

Acute lung injury (ALI) is a devastating disease with an overall mortality rate of 30 to 40%. The coagulation/fibrinolysis system is implicated in the pathogenesis of ALI. Thrombin-activatable fibronolysis inhibitor (TAFI) is an important component of the fibrinolysis system. Recent studies have shown that the active form of TAFI can also regulate inflammatory responses by its ability to inhibit complement C3a, C5a, and osteopontin. We hypothesized that TAFI might have a protective role in ALI. To demonstrate this hypothesis, the development of ALI was compared between wild-type (WT) and TAFI-deficient mice. ALI was induced by intratracheal instillation of LPS. Control mice were treated with saline. Animals were killed 24 hours after LPS. The number of inflammatory cells and the concentration of total protein and inflammatory cytokines were significantly increased in bronchoalveolar lavage fluid from LPS-treated, TAFI-deficient mice compared with their WT counterparts. Significantly higher concentrations of C5a were found in bronchoalveolar lavage fluid and plasma in LPS-treated TAFI knockout mice compared with WT mice. Pretreatment with inhaled C5a receptor antagonist blocked the detrimental effects of TAFI deficiency to levels found in WT mice. Our results show that TAFI protects against ALI, at least in part, by inhibiting the complement system.

Ct Scores of Emphysema and Oxygen Desaturation During Low-Grade Exercise in Patients with Emphysema

PURPOSE We evaluated the usefulness of CT for assessing oxygen desaturation during walking in patients with emphysema. MATERIAL AND METHODS The study comprised 32 patients with emphysema (mean age 67+/-6 years). Serial CT images of 5 mm were obtained from the apex to the basal regions of the lung during deep inspiration. The severity of emphysema was scored by four physicians according to a visual method. A six-minute walking test and oxygen desaturation (pSO2) measurements were performed. RESULTS AND CONCLUSION The mean CT score of the four observers was significantly correlated with the nadir pSO2 and deltapSO2, but did not correlate with the total distance walked. These results suggest that CT may be used for the assessment of oxygen desaturation during low-grade exercise in patients with emphysema.

“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