Naoki Furuya

Cell therapy with adipose tissue-derived stem/stromal cells for elastase-induced pulmonary emphysema in rats

AIMS The purpose of this study was to elucidate the mechanism underlying the effects of adipose tissue-derived stem/stromal cell (ASC) transplantation on porcine pancreatic elastase-induced emphysema. MATERIALS & METHODS ASCs (2.5 × 10(6)) were transplanted into pancreatic elastase (250 U/kg)-treated rats, after which gas exchange and growth factor/cytokine levels in lung tissue were determined. RESULTS ASC transplantation restored pulmonary function (arterial oxygen tension and alveolar-arterial oxygen tension difference) almost to that of normal animals. Enlargement of the alveolar airspaces was inhibited. HGF and CINC-1 levels were significantly higher in the ASC group even at 2 weeks after transplantation. Sponge implantation with CINC-1 induced neovascular formation with increased HGF. In vitro secretion of HGF and CINC-1 from ASCs was promoted in the presence of IL-1β. CONCLUSION Not only HGF, but also CINC-1, secreted from transplanted and viable ASCs presumably contributed to lung repair through angiogenesis.

IgG4-related pleural disease presenting as a massive bilateral effusion.

A 74-year-old woman with massive bilateral pleural effusion, which was exudative in nature, and with mononuclear cell predominance underwent a pleuroscopy. Parietal pleura were thickened and partly reddish in color. Biopsy specimens taken from the parietal pleura revealed lymphoplasmacytic inflammation with fibrosis. As her performance status rapidly worsened with thoracentesis, we performed bilateral pleurodesis using talc. Pathologic evaluation of the pleural biopsy specimen with immunohistochemical staining revealed 91 IgG4-positive plasma cells per high-power field and an IgG4/IgG ratio of 91%. Thus, the diagnosis of pleuritis from IgG4-related disease was established. Our case suggests that IgG4-related disease is one of the causes of pleural effusion, and it should be included in the differential diagnosis of unexplained pleuritis.

New technique for endobronchial ultrasound-guided transbronchial needle aspiration to improve diagnostic yield.

Background:Although the pooled sensitivity of endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) using a convex scanning ultrasound bronchoscope is equivalent to the gold standard of mediastinoscopy, diagnosis cannot be obtained in a small number of patients with poor cellularity. The method described was investigated with the aim of avoiding puncturing the cartilage and enabling reliable tissue harvesting, as this can be expected to improve diagnostic yield. Methods:Outer sheath method (OSM): While pressing the outer sheath (OS) of the puncture needle gently against the bronchial wall, the hyperechoic line appeared on surface of the bronchial wall on EBUS image. Then pulling and pushing the entire bronchoscope, the tip of OS moved to the epithelium above the bronchial cartilage while detecting the best position for puncturing on the EBUS images simultaneously. The bronchoscopist could visualize the cartilage moving longitudinally on EBUS image. The movement of the cartilage was stopped when the tip of the OS was caught in a concavity between 2 rings of cartilage. Group A consisted of 169 patients who underwent EBUS-TBNA before the introduction of OSM, and group B consisted of 169 patients who underwent EBUS-TBNA after the introduction of OSM. These 2 groups were compared with to investigate the usefulness of OSM. Results:Adding this operation enabled a suitable puncture site to be identified, significantly improving diagnostic yield from 92.7% (group A) to 98.2% (group B). Conclusions:This method was regarded as useful for improving diagnostic yield by enabling the selection of a puncture site between rings of cartilage during EBUS-TBNA.

Vibration response imaging in healthy Japanesesubjects

BACKGROUND Vibration response imaging (VRI) records the intensity and distribution of lung sounds during the respiration cycle. Our objective was to analyze VRI findings in healthy Japanese adults. METHODS VRI images of 106 healthy subjects (33.7±9.6 years, 52 male and 54 female), including 67 nonsmokers and 39 asymptomatic smokers, were recorded. The regional intensity of vibrations was assessed using quantitative lung data (QLD), and VRI dynamic images by rater assessment, left and right lung asynchrony (gap index), and regional lung asynchrony (asynchrony score). RESULTS A dominance of total left lung QLD was observed in all subjects, and this phenomenon was more prominent in female subjects. However, there was no significant difference between the total left and total right lung QLD in smokers. Rater assessments showed that 81.1% of all subjects had a normal final assessment. Male subjects had a significantly higher percentage of good or normal assessments for all image scores, except dynamic image scoring. The asynchrony score was significantly higher in female subjects. There were no significant differences in these qualitative assessments between non-smokers and smokers. CONCLUSIONS Although our QLD results were similar to those of a previous report, there were discrepancies between sexes for the qualitative assessments. A significantly higher number of female subjects had abnormal images as assessed by the raters. Furthermore, significantly higher asynchrony scores were observed in female subjects. The VRI variability in sex may be considered normal among the Japanese population. This study is registered with UMIN-CTR under registration number UMIN000002355.

The Correlation between Lung Sound Distribution and Pulmonary Function in COPD Patients

Background Regional lung sound intensity in chronic obstructive pulmonary disease (COPD) patients is influenced by the severity and distribution of emphysema, obstructed peripheral airways, and altered ribcage and diaphragm configurations and movements due to hyperinflation. Changes in the lung sound distribution accompanied by pulmonary function improvements in COPD patients were observed after bronchodilator inhalation. We investigated the association of lung sound distribution with pulmonary functions, and the effects of emphysematous lesions on this association. These studies were designed to acquire the basic knowledge necessary for the application of lung sound analysis in the physiological evaluation of COPD patients. Methods Pulmonary function tests and the percentage of upper- and lower-lung sound intensity (quantitative lung data [QLD]) were evaluated in 47 stable male COPD patients (54 - 82 years of age). In 39 patients, computed tomography taken within 6 months of the study was available and analyzed. Results The ratio of lower QLD to upper QLD showed significant positive correlations with FEV1 %predicted (%FEV1; ρ = 0.45, p<0.005) and MEF50 %predicted (%MEF50; ρ = 0.46, p<0.005). These correlations were not observed in COPD patients with dominant emphysema (% low attenuation area >40%, n = 20) and were stronger in less emphysematous patients (n = 19, %FEV1; ρ = 0.64, p<0.005, %MEF50; ρ = 0.71, p<0.001). Conclusions In COPD patients, the ratio of lower- to upper-lung sound intensities decreased according to the severity of obstructive changes, although emphysematous lesions considerably affected lung sound distribution.

Differences in skeletal muscle loss caused by cytotoxic chemotherapy and molecular targeted therapy in patients with advanced non‐small cell lung cancer

Recent studies have revealed a reduction in the skeletal muscle area in patients with advanced non‐small cell lung cancer (NSCLC) after chemotherapy. EGFR and ALK tyrosine kinase inhibitor (TKI)‐based therapies are less cytotoxic than chemotherapy, but differences in skeletal muscle mass between patients receiving EGFR and ALK TKI therapies and patients receiving cytotoxic chemotherapy have not yet been reported.

Assessment of Bronchial Obstruction Using Lateral Pressure Measurement during Bronchoscopy

Background: In patients with bronchial obstruction estimating the location of the maximal obstruction is crucial for guiding interventional bronchoscopy. However, flow-volume curves cannot discriminate between the right and left lungs. Objectives: The aim of this study was to physiologically evaluate bronchial obstruction during interventional bronchoscopy. Methods: We prospectively measured lateral airway pressure (Plat) at either side of the obstruction using a double-lumen catheter (pressure-pressure [P-P] curve) simultaneously to assess the degree of bronchial obstruction in 22 patients. The shape of the P-P curve was assessed to confirm the site of maximal obstruction. Results: In the experimental study, Plat was uniform between both bronchi in the normal model. For the unilateral and bilateral obstruction models, a phase shift was only seen for the more obstructed side. In healthy subjects, the angle of the P-P curve was close to 45° and linear in shape. In patients with bronchial obstruction, the angle was much smaller but approached 45° after the bronchoscopic procedure. The degree of bronchial obstruction was significantly correlated with the angle of the P-P curve (r = –0.51, p < 0.01). Dyspnea significantly increased when the airway lumen was obstructed by more than 60% (p < 0.0001), and when the P-P curve appeared loop-shaped (p < 0.01). Conclusions: The shape of the P-P curve could be used to detect the site of maximal obstruction for the optimal positioning of the stent and assess the need for additional procedures in real time in patients with bronchial obstruction.

Regional Lung Sound Asynchrony in Chronic Obstructive Pulmonary Disease Patients

Background: Regional lung sound distribution in chronic obstructive pulmonary disease (COPD) is reported to be asynchronous. Mathematical analyses using vibration response imaging (VRI), such as left and right lung asynchrony (gap index; GI) and regional lung asynchrony (asynchrony score; AS), are useful measures to evaluate lung sound asynchrony. Objectives: The aim of this study was to investigate the association of lung sound asynchrony with pulmonary functions and emphysematous lesions in COPD patients. Methods: VRI recordings and pulmonary function tests were performed in 46 stable male COPD patients and in 40 healthy male smokers. Lung sound asynchrony was evaluated using GI, AS of the left and right lung (AS L-R), and AS of the upper and lower lung (AS U-L). In 38 patients, computed tomography taken within 6 months was available and analyzed. Results: AS L-R and AS U-L were significantly higher in COPD patients than in healthy smokers, with no significant difference in GI. There were no significant correlations with either AS and pulmonary functions, excluding a negative correlation between AS U-L and diffusion capacity. Although there were no significant correlations between both AS and severity of emphysema, significant positive correlations were observed between heterogeneity of emphysematous lesions and AS L-R (ρ = 0.38, p < 0.05) or AS U-L (ρ = 0.51, p < 0.005). Conclusions: Regional lung sounds are distributed more asynchronously in COPD patients than in healthy smokers, which correlates with the heterogeneous distribution of emphysematous lesions.

Narrow-band imaging thoracoscopy in pleural amyloidosis: NBI thoracoscopy in pleural amyloidosis

We report the case of a 68‐year‐old male non‐smoker suffering from shortness of breath for 1 year. He was referred to our institution for a definitive diagnosis. Both chest X‐ray and computed tomography scans showed bilateral hydrothorax with no pleural thickening. We performed flexi‐rigid thoracoscopic pleural biopsy on the right side with a single port under local anaesthesia. Multiple white nodules were seen in parietal and visceral pleura, and these nodules were small and flat under white light. Narrow‐band imaging demonstrated pathognostic findings on parietal pleura. Irregular dilative vessels were seen around these nodules. Subsequently, we performed parietal pleural biopsy for these nodules. Pathological examination with haematoxylin and eosin staining revealed eosinophilic matrix material depositions present in the pleural parenchyma and the vessel wall. These depositions were positive for Congo red stain and showed apple‐green birefringence under polarized light. These findings were compatible with pleural amyloidosis.

Disseminated erythema with intense and selective inflammation of sweat gland and lichenoid drug eruption during nivolumab therapy

Dear Editor, Nivolumab, a monoclonal antibody against programmed cell death 1 (PD-1), induces antitumor immune reactions and is increasingly used for treating malignant melanoma, lung cancer and other malignancies. With increasing frequency of nivolumab use, the incidences of immune-related adverse events (irAE) are also increasing. The reported cutaneous irAE include vitiligo, maculopapular rash, lichenoid dermatitis, erythematous, psoriasiform eruption, bullous reaction, pruritus, perivascular dermatitis and eczema. Here, we report a rare and distinctive cutaneous irAE seen in a patient receiving nivolumab therapy. A 70-year old Japanese man with lung cancer was treated with nivolumab (3 mg/kg per dose) every 2 weeks. After 18 courses, the patient developed disseminated faint erythema with pruritus on his trunk and upper extremities (Fig. 1a) and erythematous-to-violaceous papules with peripheral desquamative scales on the dorsa of his hands (Fig. 1b). He had no history of skin disease prior to nivolumab therapy, and there were no other suspicious medications. At the time of developing skin eruptions, his complete blood cell count revealed hemoglobin content of 8.7 g/dL; moreover, his serum chemistry was within normal limits except for creatinine level, which was 1.66 mg/mL. Biopsies were performed for both skin eruptions. The histopathology of disseminated erythema showed scattered lymphocytes mostly in the upper dermis (Fig. 1c). Strikingly, dense lymphocytic infiltration was noted, particularly around the sweat gland (Fig. 1c,d). The infiltrated lymphocytes mostly consisted of CD4 and CD8 lymphocytes, and a few CD20 lymphocytes were also seen. Erythematous-toviolaceous papules revealed histopathological characteristics of lichen planus, including hyperkeratosis, thickening of the granular layer, liquefaction degeneration of the basal layer and dense band-like lymphocytic infiltration in the upper dermis (Fig. 1e). We treated the disseminated erythema and erythematous-to-violaceous papules with a topical steroid. The disseminated erythema gradually disappeared and the erythematous-to-violaceous papules was flattened within a few months. The present case was characterized by two kinds of skin rashes: faint erythema and lichenoid drug eruption caused by nivolumab therapy. Surprisingly, the histopathology of faint erythema revealed selective lymphocytic infiltration around the sweat gland. It is well known that nivolumab causes lichenoid drug eruption. Hwang et al. reported that 17% of patients