Language：Japanese   Publisher：(NPO)日本肺癌学会  

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Language：English   Publisher：(一社)日本癌治療学会  

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Language：Japanese   Publisher：(NPO)日本肺癌学会  

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BACKGROUND: The epidermal growth factor receptor (EGFR) mutation is a risk factor associated with brain metastases (BMs) in patients with non-small cell lung cancer (NSCLC). This study aimed to evaluate the impact of osimertinib early dose reduction on BM worsening. METHODS: We retrospectively analyzed EGFR-mutant NSCLC patients treated with osimertinib as first-line treatment between August 2018 and October 2021. To evaluate the impact of osimertinib early dose reduction, we performed a landmark analysis of patients who achieved disease control at 4 months. Patients were divided into two groups according to whether the osimertinib dose was reduced or not, within 4 months after the start of treatment. We evaluated the time to BMs onset or progression, progression-free survival, and overall survival. RESULTS: In total, 62 NSCLC patients with EGFR mutations were analyzed. Thirteen patients experienced early dose reduction of osimertinib treatment. Seven patients received osimertinib 40 mg daily, and six received 80 mg every other day. The most common reason for dose reduction was gastrointestinal toxicity (n = 4), followed by skin rashes (n = 3). The time to BMs onset or progression was significantly shorter in patients who experienced early dose reduction than in those who continued regular treatment (Hazard ratio 4.47, 95% confidence interval, 1.52-13.11). The 1-year cumulative incidence of BM onset or progression was 23.1% in the reduced-dose group and 5.0% in the standard dose group. The risk of worsening BMs with early dose reduction of osimertinib treatment was higher in patients who had BMs before treatment and in younger patients. CONCLUSION: Early dose reduction of osimertinib was a risk factor for the worsening of BMs. A higher risk was associated with younger patients and those presenting BMs before treatment.

DOI： 10.1002/cam4.6393

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Language：Japanese   Publisher：(NPO)日本肺癌学会  

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Language：Japanese   Publisher：(NPO)日本肺癌学会  

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Language：Japanese   Publisher：日本内科学会-関東地方会  

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Language：Japanese   Publisher：日本内科学会-関東地方会  

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Language：Japanese   Publisher：(NPO)日本肺癌学会  

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Language：Japanese   Publisher：(NPO)日本肺癌学会  

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Language：Japanese   Publisher：(NPO)日本呼吸器内視鏡学会  

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Language：Japanese   Publisher：(一社)日本呼吸器学会  

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Language：Japanese   Publisher：(一社)日本呼吸器学会  

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Language：Japanese   Publisher：(一社)日本呼吸器学会  

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Language：Japanese   Publisher：(一社)日本呼吸器学会  

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Language：Japanese   Publisher：(一社)日本呼吸器学会  

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Language：Japanese   Publisher：(一社)日本呼吸器学会  

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Language：Japanese   Publisher：(一社)日本呼吸器学会  

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Language：Japanese   Publisher：(一社)日本呼吸器学会  

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Language：Japanese   Publisher：(一社)日本呼吸器学会  

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Language：Japanese   Publisher：(一社)日本呼吸器学会  

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Language：Japanese   Publisher：日本結核・非結核性抗酸菌症学会関東支部学会・日本呼吸器学会関東地方会  

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Despite the relatively short follow-up period in our previous study, we had reported that increased cough reflex sensitivity (CRS) may predict the efficacy of bronchial thermoplasty (BT) for treating asthma. Herein, we examined whether CRS predicts the efficacy of BT 2 years after the final BT treatment. We also investigated the influence of BT on CRS. We reviewed 10 patients 2 years after their final BT treatment. CRS, asthma-related symptoms, asthma exacerbations, and cough-related quality of life were assessed at baseline and 2 years after BT. Five patients responded positively to BT (BT responders) and their asthma control improved. No significant difference in CRS at baseline was detected between the BT responders and nonresponders. In contrast, BT responders exhibited significant improvements in CRS 2 years after BT. CRS at baseline could not predict the BT efficacy after 2 years. This is the first report demonstrating BT desensitized CRS in consecutive case series. J. Med. Invest. 70 : 271-275, February, 2023.

DOI： 10.2152/jmi.70.271

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Language：Japanese   Publisher：(NPO)日本肺癌学会  

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Language：Japanese   Publisher：(NPO)日本呼吸器内視鏡学会  

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Language：Japanese   Publisher：(一社)日本呼吸器内視鏡学会  

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Language：English  

Primary ciliary dyskinesia (PCD) is a genetic disease with chronic airway infection and inflammation caused by ciliary ultrastructural defects and impairment in ciliary function. We present an adult case of PCD with compound heterozygous nonsense variants in CCDC39. The ciliary ultrastructure findings using electron microscopy and ciliary movement using high-speed video analysis matched the genotype. This is the first case report of PCD with CCDC39 variants in Japan demonstrating specific ciliary ultrastructure and movement related to the genotype.

DOI： 10.1016/j.resinv.2022.05.005

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BACKGROUND: Immune checkpoint inhibitor (ICI) monotherapy is more effective than cytotoxic chemotherapy in improving overall survival (OS) among patients with advanced-stage non-small cell lung cancer (NSCLC). Recently, chemotherapy combined with ICI has been found to yield good outcomes. However, ICI monotherapy is still considered an important treatment option. Data on long-term progression-free survival (PFS) and OS in real-world settings are limited. PATIENTS AND METHODS: This was a multicenter retrospective observational study. A total of 435 consecutive patients histologically diagnosed with advanced, metastatic, or recurrent NSCLC treated with ICI monotherapy were enrolled in this study from December 2015 to December 2018. Clinical data were collected from electronic medical records and pharmacy databases. RESULTS: The PFS and OS of the patients were 3.4 and 13.0 months, respectively. The objective response and disease control rates were 22.8% and 54.9%, respectively, and the 4-year survival rate was 17.9%. Multivariate analyses revealed that elder patients (>70 years), good Eastern Cooperative Oncology Group Performance Status (ECOG PS) score, programmed death-ligand 1 tumor proportion score (PD-L1 TPS) of ≥ 50%, absence of bone metastasis, and presence of immune-related skin toxicity, which is an immune-related adverse event, were correlated with good PFS. Moreover, good ECOG PS score, PD-L1 TPS of ≥ 50%, absence of bone metastasis, and presence of skin toxicity were correlated with good OS. CONCLUSIONS: The 4-year survival rate was 17.9%. Good ECOG PS score, PD-L1 TPS of ≥ 50%, absence of bone metastasis, and presence of skin toxicity were correlated with good PFS and OS.

DOI： 10.1016/j.cllc.2022.03.008

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Language：Japanese   Publisher：日本結核・非結核性抗酸菌症学会関東支部学会・日本呼吸器学会関東地方会  

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Language：Japanese   Publisher：日本結核・非結核性抗酸菌症学会関東支部学会・日本呼吸器学会関東地方会  

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This study compared the bioavailability of two pimitespib formulations (Formulations A and B), evaluated the food effect on Formulation A, and evaluated the safety and efficacy of multiple pimitespib doses in patients with solid tumors. This clinical, pharmacological multicenter study had two cohorts and periods. A single dose of Formulation A or B was administered in a crossover design to compare the pharmacokinetics in Cohort 1. In Cohort 2, the effects of fed vs fasting conditions were evaluated among those receiving Formulation A. Subsequently, multiple Formulation A doses were administered to all patients for safety and efficacy assessments. In Cohorts 1 and 2, 12 and 16 patients, respectively, were analyzed for pharmacokinetics. Thirty patients were analyzed for safety and efficacy. Maximum concentration (Cmax), area under the curve (AUC)last, and AUCinf geometric mean ratios for Formulations A and B (90% confidence interval [CI]) were 0.8078 (0.6569-0.9933), 0.7973 (0.6672-0.9529), and 0.8094 (0.6697-0.9782), respectively; 90% CIs were not within the bioequivalence range (0.80-1.25). In Cohort 2, mean Cmax, AUClast, and AUCinf were higher in fed vs fasting conditions. No safety concerns emerged with single or multiple administration. Overall response rate, disease control rate, and median progression-free survival were 0%, 33%, and 1.5 months, respectively. Four patients had stable disease ≥ 5 months. Bioequivalence of the two formulations was unconfirmed. Systemic exposure of Formulation A was approximately 20% less than Formulation B. A high-fat/calorie meal increased the relative pharmacokinetics and bioavailability of a single 160-mg dose. Trial Registration: JapicCTI-184191 (Japan Pharmaceutical Information Center) registered on November 5, 2018.

DOI： 10.1007/s10637-022-01285-9

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Language：Japanese   Publisher：(NPO)日本肺癌学会  

背景.胸腺癌は年間10万人あたり0.02人に発症する希少癌であり,診断時点で30%の患者が進行期である.診断時の状態から治療導入に難渋するケースが存在する.症例.44歳,女性.20XX年12月末より上腹部膨満感を自覚し前医を受診した.胸部単純CT検査でびまん性肝腫瘍と高度の肝腫大,及び胸腺腫瘍を指摘され当院紹介となった.PET-CTでは胸腺,肝及び骨にFDGの異常集積を認めた.肝生検は困難であり胸腺よりCTガイド下生検が施行され,胸腺癌が検出された.cT1bN2M1b,stage IVb期(OSS,HEP)と診断された.急速な肝機能の増悪,黄疸や高アンモニア血症の出現及び増悪も認めた.当科転科第4病日よりcarboplatin(AUC=6)とpaclitaxel(100mg/m2)による併用療法を開始した.1サイクル終了時には肝機能は改善し,原発巣及びびまん性肝腫瘍の急速な縮小を認めた.結論.胸腺癌は予後不良な希少疾患である.進行例に対するエビデンスは乏しく,高度な肝機能障害を伴う症例に対する化学療法の報告も少ない.貴重な症例と考え報告した.(著者抄録)

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Language：Japanese   Publisher：(NPO)日本肺癌学会  

背景.胸腺癌は年間10万人あたり0.02人に発症する希少癌であり,診断時点で30%の患者が進行期である.診断時の状態から治療導入に難渋するケースが存在する.症例.44歳,女性.20XX年12月末より上腹部膨満感を自覚し前医を受診した.胸部単純CT検査でびまん性肝腫瘍と高度の肝腫大,及び胸腺腫瘍を指摘され当院紹介となった.PET-CTでは胸腺,肝及び骨にFDGの異常集積を認めた.肝生検は困難であり胸腺よりCTガイド下生検が施行され,胸腺癌が検出された.cT1bN2M1b,stage IVb期(OSS,HEP)と診断された.急速な肝機能の増悪,黄疸や高アンモニア血症の出現及び増悪も認めた.当科転科第4病日よりcarboplatin(AUC=6)とpaclitaxel(100mg/m2)による併用療法を開始した.1サイクル終了時には肝機能は改善し,原発巣及びびまん性肝腫瘍の急速な縮小を認めた.結論.胸腺癌は予後不良な希少疾患である.進行例に対するエビデンスは乏しく,高度な肝機能障害を伴う症例に対する化学療法の報告も少ない.貴重な症例と考え報告した.(著者抄録)

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Other Link： https://search.jamas.or.jp/default/link?pub_year=2022&ichushi_jid=J01244&link_issn=&doc_id=20220914290010&doc_link_id=%2Fec7jaluc%2F2022%2F006204%2F010%2F0335-0340%26dl%3D0&url=https%3A%2F%2Fwww.medicalonline.jp%2Fjamas.php%3FGoodsID%3D%2Fec7jaluc%2F2022%2F006204%2F010%2F0335-0340%26dl%3D0&type=MedicalOnline&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00004_2.gif

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Objectives: Investigate the activity of rhythmic masseter muscles activity (RMMA) during sleep in patients with dentofacial deformities. Materials and methods: Fifty patients with dentofacial deformities (16 male, 34 female) who required orthognathic surgery. An electrode was attached to the masseter muscle bilaterally, and preoperative polysomnography was performed. The frequency of RMMA onset per hour was measured on the left and the right sides. Values were classified as phasic (grinding: P-RMMA) and tonic (clenching: T-RMMA) to examine the onset of RMMA. Correlation between the RMMA index and various morphological and physical factors were determined including sleep or awake, rapid eye movement (REM), non-rapid eye movement (NREM) phases (NR1-NR4) in the sleep stage, phasic and tonic, gender, and mandibular asymmetry. Results: The RMMA index values at the time of sleep were significantly small than during awake. The values were significantly higher during the NREM sleep than during the REM sleep and were the highest in the NR1 phase. P-RMMA index was significantly higher than the T-RMMA index. The P-RMMA index was also significantly higher than the T-RMMA index for men. In patients with greater asymmetry in the RMMA index values between the left and the right side (more than 30% difference), deviation between the midpoint of the maxillary and the mandibular incisal edges (U1-L1 deviation) was significantly higher. Conclusion: RMMA in patients with dentofacial deformity was statistically higher in awake than sleep, higher in NREM sleep than REM sleep, higher in male than female on grinding, and higher in upper and lower incisor high deviation.

DOI： 10.1007/s12663-020-01467-z

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Language：Japanese   Publisher：(NPO)日本呼吸器内視鏡学会  

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Language：Japanese   Publisher：(NPO)日本呼吸器内視鏡学会  

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Language：Japanese   Publisher：(NPO)日本呼吸器内視鏡学会  

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Language：Japanese   Publisher：(NPO)日本呼吸器内視鏡学会  

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Language：Japanese   Publisher：(一社)日本呼吸器学会  

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Language：Japanese   Publisher：(一社)日本呼吸器学会  

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Language：Japanese   Publisher：(一社)日本呼吸器学会  

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Language：Japanese   Publisher：(一社)日本呼吸器学会  

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Language：Japanese   Publisher：(一社)日本呼吸器学会  

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Publishing type：Research paper (scientific journal)   Publisher：Springer Science and Business Media LLC  

Abstract

Background

CheckMate 9LA, a phase 3, randomized, open-label study in first-line advanced non-small cell lung cancer (NSCLC), showed significantly improved overall survival (OS) with nivolumab plus ipilimumab combined with 2 cycles of chemotherapy versus chemotherapy alone (4 cycles). We present results for the Asian subpopulation enrolled in Japan and China.

Methods

Patients aged ≥ 18 years with treatment-naive, histologically confirmed stage IV or recurrent NSCLC, Eastern Cooperative Oncology Group performance status 0–1 and no sensitizing EGFR/ALK mutations were randomized 1:1 to nivolumab [360 mg every 3 weeks (Q3W)] plus ipilimumab (1 mg/kg Q6W) combined with chemotherapy (Q3W for 2 cycles), or chemotherapy alone (Q3W for 4 cycles). Primary endpoint was OS; secondary endpoints included progression-free survival (PFS) and objective response rate (ORR).

Results

Twenty-eight patients received nivolumab plus ipilimumab combined with chemotherapy and 30 received chemotherapy. At a minimum follow-up of 12.7 months, median OS was not reached with nivolumab plus ipilimumab combined with chemotherapy versus 13.3 months with chemotherapy [hazard ratio (HR) 0.33; 95% confidence interval (CI) 0.14–0.80]. Median PFS was 8.4 versus 5.4 months (HR 0.47; 95% CI 0.24–0.92) and ORR was 57% versus 23%, respectively. Grade 3–4 treatment-related adverse events were observed in 57% versus 60% of patients, respectively.

Conclusion

Consistent with results in the all randomized population, nivolumab plus ipilimumab combined with chemotherapy improved efficacy in the Asian subpopulation versus chemotherapy alone and had a manageable safety profile, supporting its use as first-line treatment for advanced NSCLC in Asian patients.

DOI： 10.1007/s10147-022-02120-0

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Other Link： https://link.springer.com/article/10.1007/s10147-022-02120-0/fulltext.html

Publishing type：Research paper (scientific journal)   Publisher：Springer Science and Business Media LLC  

DOI： 10.1007/s12194-021-00648-w

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Other Link： https://link.springer.com/article/10.1007/s12194-021-00648-w/fulltext.html

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OBJECTIVES: Interstitial lung disease (ILD) associated with the antimelanoma differentiation-associated protein 5 (anti-MDA5) antibody is a rapidly progressive disease that requires timely, aggressive treatment. However, prompt diagnosis is difficult due to the longer time required for antibody detection. This study described the computed tomography (CT) findings of anti-MDA5 antibody-positive ILD (anti-MDA5-ILD). METHODS: CT findings of 20 patients (7 men, 13 women; mean age, 53.6 ± 13.5 years) with anti-MDA5-ILD were retrospectively reviewed. All patients had clinical diagnoses of dermatomyositis, and 14 patients presented with amyopathic findings. RESULTS: Bilateral ground-glass attenuation, air-space consolidation, and reticular shadows were observed in 20 (100%), 15 (75%), and 3 (15%) patients, respectively. The spread of air-space consolidation was 6.0 ± 5.6% (mean ± standard deviation). Univariate analysis revealed that high Krebs von den Lungen-6, high spread of consolidation, low partial pressure of oxygen, and low forced vital capacity were significant predictors for poor survival. The final radiological diagnoses were nonspecific interstitial pneumonia and organising pneumonia (OP) in 2 (10%) and 16 (80%) patients, respectively. Further, 30% of OP patients showed fibrosis. CONCLUSION: The characteristic CT findings of patients with anti-MDA5-ILD were ground-glass attenuation, air-space consolidation, and less reticulation. These CT findings were compatible with those of OP.

DOI： 10.1093/mr/roab006

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A 38-year-old man with renal cell carcinoma was referred to our hospital because of a productive cough. He had received radiotherapy for lung metastasis and been treated with axitinib. Bronchoscopy revealed necrosis in the bronchi of the right middle and lower lobes. Culture of the necrotic bronchial specimen revealed methicillin-resistant Staphylococcus aureus (MRSA). Although radiotherapy in combination with axitinib carries a risk of causing airway toxicity, MRSA necrotizing bronchitis has not been reported. Physicians should consider the possibility of infectious necrotizing bronchitis if irradiated patients show prolonged respiratory symptoms.

DOI： 10.2169/internalmedicine.9143-21

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Language：Japanese   Publisher：(一社)日本アレルギー学会  

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Introduction: In advanced non-small-cell lung cancer (NSCLC), immune checkpoint inhibitors (ICIs) have been reported a better treatment outcome on primary lesions, however, the therapeutic effect on bone metastases has not been clarified. This study investigates the therapeutic effect of ICIs on bone metastases in advanced NSCLC. Methods: The data of patients with advanced NSCLC, treated with ICIs from 2016 to 2019 at our hospital, were analyzed. The therapeutic effects of ICIs on primary lung and metastatic bone lesions, concomitant use of bone modifying agents (BMA), treatment outcomes, and frequency of immune-related adverse events (irAEs) and skeletal-related events (SREs) were investigated. Results: A total of 29 patients were included (19 men and 10 women; mean age, 64.2 years). Among the ICIs, pembrolizumab was the most used (55.2%), and concomitant use of BMA was prevalent in 21 patients (zoledronic acid=1, denosumab=20). The therapeutic effect was partial response (PR) in 10.3% (n=3) on primary lung lesions by RECIST 1.1, complete response (CR) in 6.9% (n=2) and PR in 17.2% (n=5) on bone metastatic lesions by MDA criteria. ICIs suppressed the progression of bone metastasis in 21 cases (72.4%). All patients in CR and PR were treated with pembrolizumab and denosumab. SREs and irAEs were developed in 3.4% (n=1) and 20.7% (n=6), respectively. The median survival time after treatment with ICIs was 11.0 months. Concomitant therapy with ICIs and denosumab significantly prolonged the overall survival compared to ICI-only therapy (16.0 months vs. 2.5 months, p<0.01). Conclusions: This study showed that treatment with ICIs may successfully suppress the progression of bone metastasis in advanced NSCLC. Pembrolizumab with denosumab had the highest therapeutic effect on both primary lung lesions and bone metastases. Systemic treatment with this combination and conservative treatment of bone metastasis could be one of the options in the treatment of advanced NSCLC.

DOI： 10.3389/fonc.2022.871675

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DOI： 10.1164/rccm.202105-1306IM

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Language：Japanese   Publisher：(NPO)日本肺癌学会  

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Language：Japanese   Publisher：(NPO)日本肺癌学会  

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BACKGROUND: The clinical course of patients with systemic sclerosis-associated interstitial lung disease (SSc-ILD) is highly variable. The Krebs von den Lungen-6 (KL-6) glycoprotein is a promising biomarker for reflecting epithelial injury. However, serum KL-6 and its association with the progression of SSc-ILD have been understudied. METHODS: We reviewed 77 consecutive patients with SSc-ILD seen from 2004 to 2016. A longitudinal study of forced vital capacity (FVC), serum KL-6 levels, and changes in KL-6 levels from baseline (ΔKL-6) was conducted. The progression of ILD was defined as ≥10% relative decline in FVC predicted or 5%-10% decline in FVC predicted along with radiological progression on chest computed tomography. The risk factors for ILD progression were assessed by univariate and multivariate regression. RESULTS: During a 5-year follow-up period, 10 (13%) patients showed rapid progression of ILD within 2 years, 39 (51%) showed overall progression during the 5 years, and 28 (36%) had stable disease. Most patients with progressive ILD showed elevations in serum KL-6 levels over the initial 1-year follow-up period. The best cut-off value for ΔKL-6 that predicted progression of ILD was 193 U/mL (sensitivity 81.6%, specificity 92.9%). Multivariate analysis adjusted by age, sex, smoking status, and immunosuppressant use found that diffuse cutaneous SSc (hazard ratio [HR] 4.51; 95% confidence interval [CI] 1.56-13.04) and ΔKL-6 > 193 U/mL from baseline (HR 7.19; 95% CI 3.30-15.69) were independent predictors for progression of SSc-ILD. CONCLUSION: Changes in the KL-6 level can be useful for predicting disease progression in patients with SSc-ILD.

DOI： 10.1016/j.rmed.2021.106689

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DOI： 10.1164/rccm.202107-1780LE

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DOI： 10.1016/j.alit.2021.10.003

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Language：Japanese   Publisher：(一社)日本呼吸器学会  

症例は76歳男性。限局型小細胞肺癌(cT1aN2M0、Stage IIIA)に対して、シスプラチン(cisplatin)とエトポシド(etoposide)の化学療法と胸部放射線照射の同時併用治療が開始されたが、化学療法中に嘔気と食欲不振が出現した。頭部造影MRIで下垂体腫瘍を、三者負荷試験で下垂体前葉機能の低下を認め、小細胞肺癌の下垂体転移による下垂体前葉機能低下症と診断された。経過で尿崩症も発症した。下垂体転移に対する全脳照射後も内分泌機能は改善しなかったが、ホルモン補充療法により嘔気と食欲不振は改善した。(著者抄録)

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Background: Molecular targeted therapy has been developed as an innovative treatment for metastatic cancer. Epidermal growth factor receptor (EGFR) mutation is one of the most important and frequent oncogenic drivers in non-small-cell lung cancer, and EGFR-tyrosine kinase inhibitors are indispensable drugs for mutation-positive patients. Currently, the acquired resistance to epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) is a problem, the mechanism of which has not been elucidated. The histological transformation from original adenocarcinoma to small-cell carcinoma is rare; however, it has been detected in many cases after EGFR-TKI treatment. This study aimed to evaluate mutational status in two different histological types and further elucidate the molecular pathogenesis. Methods: Three patients with EGFR-mutant lung cancer who underwent a histological transformation to small-cell carcinoma after growth factor receptor-TKI treatment were enrolled in this study. Two samples per patient were collected from histologically different lesions, and DNA samples were extracted from formalin-fixed, paraffin-embedded tumor tissues. The paired samples were subjected to next-generation sequencing of 160 cancer-related genes. Based on the sequencing results, the expression levels of related proteins were validated using reverse-transferase polymerase chain reaction and immunohistochemical staining. Results: The following five variants were common among the three cases: MTOR, JAK1, NOTCH2, CSF1R, and MAP2K2. The former four variants were additive to small-cell carcinoma, and the last variant was lost. Both TP53 and Rb1 alterations were detected in adenocarcinoma. Notch2 expression was negative in small-cell carcinoma in both reverse-transcriptase polymerase chain reaction analysis and immunohistochemical staining. ASCL1 expression increased after histological transformation detected using both methods in one case, only these samples were evaluable. Conclusions: Notch and ASCL1 signaling are the master regulators of neuroendocrine differentiation in small-cell lung carcinoma. Our results suggest that the Notch-ASCL1 axis may also play an essential role in the transformation of small-cell carcinoma under TP53 and RB1 inactivation.

DOI： 10.21037/tlcr-21-536

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Language：Japanese   Publisher：(公社)日本放射線技術学会  

フラットパネルディテクター(FPD)を用いて呼吸状態を連続撮影する胸部X線動態撮影(DCR)は、高い時間分解能と広い撮像視野、さらに動画解析技術により動的画像所見に基づく肺機能診断を可能にする。DCRの撮影システム、撮影方法について述べ、以下の動的画像所見、解析方法などを紹介した。1)横隔膜運動、2)肺面積変化、3)肋骨動態、4)肺野濃度の変化、5)V/Q study(換気血流比)、6)気管径変化、7)肺癌の動き、について述べた。

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Language：Japanese   Publisher：(NPO)日本肺癌学会  

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Language：Japanese   Publisher：(NPO)日本肺癌学会  

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Language：Japanese   Publisher：(NPO)日本肺癌学会  

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Language：Japanese   Publisher：(一社)日本アレルギー学会  

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Background: Dynamic chest radiography (DCR) is a type of non-contrast-enhanced functional lung imaging with a dynamic flat-panel detector (FPD). This study aimed to assess the clinical significance of ventilation and perfusion metrics derived from changes in radiographic lung density on DCR in comparison to nuclear medicine imaging-derived metrics. Methods: DCR images of 42 lung cancer patients were sequentially obtained during respiration using a dynamic FPD imaging system. For each subdivided lung region, the maximum change in the averaged pixel value (Δmax), i.e., lung density, due to respiration and cardiac function was calculated, and the percentage of Δmax relative to the total of all lung regions (Δmax%) was computed for ventilation and perfusion, respectively. The Δmax% was compared to the accumulation of radioactive agents such as Tc-99m gas and Tc-99m macro-aggregated albumin (radioactive agents%) on ventilation and perfusion scans in the subdivided lung regions, by Spearman's correlation coefficient (r) and the Dice similarity coefficients (DSC). To facilitate visual evaluation, Δmax% was visualized as a color scaling, where larger Δmax values were indicated by higher color intensities. Results: We found a moderate correlation between Δmax% and radioactive agents% on ventilation and perfusion scans, with perfusion metrics (r=0.57, P<0.001) showing a higher correlation than ventilation metrics (r=0.53, P<0.001). We also found a good or strong correlation (r≥0.5) in 80.9% (34/42) of patients for perfusion metrics (r=0.60±0.16) and in 52.4% (22/42) of patients for ventilation metrics (r=0.53±0.16). DSC indicated a moderate correlation for both metrics. Decreased pulmonary function was observed in the form of reduced color intensities on color-mapping images. Conclusions: DCR-derived ventilation and perfusion metrics correlated reasonably well with nuclear medicine imaging findings in lung subdivisions, suggesting that DCR could provide useful information on pulmonary function without the use of radioactive contrast agents.

DOI： 10.21037/qims-20-1217

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Language：Japanese   Publisher：(一社)日本アレルギー学会  

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Spirometry is a crucial test used in the diagnosis and monitoring of patients with chronic obstructive pulmonary disease (COPD). Severe acute respiratory syndrome coronavirus 2 pandemic has posed numerous challenges in performing spirometry. Dynamic-ventilatory digital radiography (DR) provides sequential chest radiography images during respiration with lower doses of radiation than conventional X-ray fluoroscopy and computed tomography. Recent studies revealed that parameters obtained from dynamic DR are promising for evaluating pulmonary function of COPD patients. We report two cases of COPD evaluated by dynamic-ventilatory DR for pulmonary function and treatment efficacy and discuss the potential of dynamic DR for evaluating COPD therapy.

DOI： 10.1016/j.resinv.2021.07.005

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Language：Japanese   Publisher：(一社)日本アレルギー学会  

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Pembrolizumab plus pemetrexed-platinum significantly improved overall survival (OS) and progression-free survival (PFS) with manageable safety compared with placebo plus pemetrexed-platinum in patients with previously untreated metastatic nonsquamous non-small-cell lung cancer (NSCLC) without EGFR/ALK alterations in the global, randomized, double-blind, phase 3 KEYNOTE-189 study. We present results of Japanese patients enrolled in the KEYNOTE-189 global and Japan extension studies. Patients were randomized 2:1 to intravenous pembrolizumab 200 mg or placebo every 3 weeks (Q3W) for up to 35 cycles. All patients received pemetrexed 500 mg/m2 plus the investigator's choice of cisplatin or carboplatin Q3W for four cycles, followed by maintenance pemetrexed 500 mg/m2 Q3W (all intravenous). Co-primary endpoints were OS and PFS. Forty Japanese patients enrolled (pembrolizumab, n = 25; placebo, n = 15). At data cutoff (20 May 2019; median time from randomization to data cutoff, 18.5 [range, 14.7-38.2] months), the median OS was not reached in the pembrolizumab plus pemetrexed-platinum arm; the median OS was 25.9 (95% confidence interval [CI], 11.9-29.0) months in the placebo plus pemetrexed-platinum arm (hazard ratio [HR] .29; 95% CI, .07-1.15). The median (95% CI) PFS was 16.5 (8.8-21.1) compared with 7.1 (4.7-21.4) months (HR, .62; 95% CI, .27-1.42), respectively. There were no grade 5 adverse events (AE). Grade 3/4 AE occurred in 72% vs 60% of patients in the pembrolizumab vs placebo arms; 40% vs 20% had immune-mediated AE, and 4% vs 0% had infusion reactions. Efficacy and safety outcomes were similar to those from the global study and support first-line therapy with pembrolizumab plus pemetrexed-platinum in Japanese patients with nonsquamous NSCLC without EGFR/ALK alterations.

DOI： 10.1111/cas.14980

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Language：Japanese   Publisher：(一社)日本アレルギー学会  

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Background: The utility of bronchoalveolar lavage (BAL) in the evaluation of systemic sclerosis-associated interstitial lung disease (SSc-ILD) remains controversial. Fractional analysis of BAL (FBAL) is a technique that can analyze small airways and alveolar compartments separately and has proven informative in other ILDs. The aim of this study was to explore FBAL characteristics across the spectrum of SSc-ILD severity. Methods: We retrospectively reviewed patients with SSc-ILD who underwent bronchoscopy with FBAL using three 50 mL aliquots of saline solution. These aliquots were analyzed separately for differential cell composition (FBAL-1, -2, and -3). We compared the FBAL cell composition to the progression of ILD and end-stages of ILD using Cox proportional hazards models. Results: Sixty-eight patients with SSc-ILD were enrolled in this study. The percentage of neutrophils and eosinophils was lower in FBAL-3 compared to FBAL-1. In contrast, the percentage of macrophages and lymphocytes was higher in FBAL-3. Neutrophils in FBAL-2, -3, and the estimated total FBAL cell fraction (FBAL-total) were negatively correlated with the forced vital capacity % predicted (r=-0.420, -0.362, -0.409, respectively). Although FBAL-total was not linked to the progression and end-stage of ILD, a high percentage of neutrophils in FBAL-3 was significantly associated with the development of end-stage ILD (HR 1.093, 95% CI: 1.003-1.190). Conclusions: A higher percentage of neutrophils in FBAL-3 is correlated with development of end-stage ILD in SSc-ILD as well as mortality.

DOI： 10.21037/jtd-20-2596

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BACKGROUND: Drug-induced pneumonia (d-pneumonia) and bacterial pneumonia (b-pneumonia) are often difficult to differentiate; therefore, this study examined the possibility of differentiating them using serum biomarkers. METHODS: The study included 22 and 16 patients diagnosed with b- and d-pneumonia, respectively, at our institution or affiliated institutions. For d-pneumonia, the causative drug was minocycline hydrochloride in four patients, gefitinib in two patients, nivolumab in two patients, pembrolizumab in two patients, sulfasalazine in two patients, loxoprofen in one patient, Bouiougitou in one patient, edoxaban tosilate hydrate in one patient, and abemaciclib in one patient. White blood cell (WBC), C-reactive protein (CRP), Krebs von den Lungen-6 (KL-6), surfactant protein (SP)-D, and SP-A levels were measured in each patient and compared between the groups. RESULTS: Significant differences were noted in the WBC and SP-D levels between the two groups (P < 0.05, P < 0.001), but not in the CRP, KL-6, or SP-A levels. CONCLUSION: The study results suggest that SP-D is a useful marker for differentiating b-pneumonia and d-pneumonia.

DOI： 10.1186/s41479-021-00087-6

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Language：Japanese   Publisher：(NPO)日本呼吸器内視鏡学会  

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In cancer patients, circulating cell-free DNA (cfDNA) includes tumor-derived DNA (tDNA). cfDNA has been used clinically for non-invasive gene mutation testing. The aim of this study was to characterize the features of the genetic alterations detected in cfDNA. This study included 6 patients with primary lung cancer who died due to cancer progression. Tumors were biopsied at autopsy. Genetic alteration profiles were obtained using next generation sequencing. The features of the tDNA genetic alterations detected in cfDNA included a higher frequency of being present in multiple tumors (67% truncal mutations, 36% shared mutations, and 4% individual mutations) and a higher variant allele frequency (VAF; 47.6% versus 4.1% for tDNA alterations detected in cfDNA versus not detected in cfDNA, respectively). The data revealed that the tumor-derived genetic alterations most easily detected in cfDNA were truncal mutations with a high VAF. These results showed that essential genetic alterations enriched in cfDNA could help to characterize cancer cells and that genetic testing using cfDNA has advantages in the detection of fundamental regulatory aberrations occurring during tumorigenesis.

DOI： 10.1038/s41598-021-87094-1

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Language：Japanese   Publisher：(一社)日本呼吸器学会  

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IMpower132 explored the safety and efficacy of atezolizumab plus pemetrexed and platinum-based chemotherapy as first-line treatment for advanced non-small-cell lung cancer (NSCLC). Key eligibility criteria for the phase 3, open-label, IMpower132 study included age ≥18 y, histologically or cytologically confirmed advanced non-squamous NSCLC per Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1, Eastern Cooperative Oncology Group performance status of 0/1, and no prior systemic treatment for stage IV NSCLC. Patients received atezolizumab (1200 mg) plus pemetrexed (500 mg/m2 ) and cisplatin (75 mg/m2 ) or carboplatin (area under the concentration curve, 6 mg/mL/min) (APP arm) or chemotherapy alone (PP arm). The co-primary study endpoints were overall survival (OS) and investigator-assessed progression-free survival (PFS) per RECIST 1.1 in the intention-to-treat population. A subgroup analysis was conducted in Japanese patients. In the Japanese subgroup (n = 101), median OS was 30.8 (95% CI, 24.3 to not estimable) mo in the APP arm (n = 48) and 22.2 (95% CI, 15.7-30.8) mo in the PP arm (n = 53; hazard ratio [HR], 0.63 [95% CI, 0.36-1.14]). PFS was 12.8 (95% CI, 8.6-16.6) mo in the APP arm vs 4.5 (95% CI, 4.1-6.7) mo in the PP arm (HR, 0.33 [95% CI, 0.21-0.58]). Grade 3/4 treatment-related adverse events (TRAEs) occurred in 68.8% of APP arm patients and 44.2% of PP arm patients. Consistent with global study results, atezolizumab plus pemetrexed and platinum-based chemotherapy improved efficacy and was well tolerated in Japanese patients with advanced NSCLC despite a higher incidence of grade 3/4 TRAEs.

DOI： 10.1111/cas.14817

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Language：Japanese   Publisher：(一社)日本呼吸器学会  

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AIM: To report two cases in which treatment with pembrolizumab for advanced non-small cell lung cancer (NSCLC) with bone metastasis of the long bone of the lower extremity in a state of impending fracture significantly ameliorated both lung tumor and bone metastasis. CASE REPORT: Case 1 was a 74-year-old woman diagnosed with metastasis of NSCLC in the left tibia and case 2 was a 71-year-old man diagnosed with metastasis of NSCLC in the right femur; their bone metastases were in a state of impending fracture. Disease in both cases was already in stage IVB and they received systemic therapy using pembrolizumab, whilst the bone metastases were treated conservatively. After 3 months, both patients showed a complete response with remarkable osteosclerotic changes in bone metastases and the size of lung tumors was reduced. CONCLUSION: These results might imply a novel strategy for systemic treatment with pembrolizumab is required, even in case of impending fracture in advanced NSCLC.

DOI： 10.21873/anticanres.14933

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Awareness of the immune-related adverse event of programmed cell death protein-1 (PD-1) inhibitor-induced pneumonitis is important. Herein, we report the clinical course of 3 patients suspected to have PD-1 inhibitor-induced pneumonitis after cessation of PD-1 inhibitor treatment. In case 1, a 62-year-old man was diagnosed with stage IVA adenocarcinoma. Nivolumab monotherapy was prescribed as second-line therapy and later discontinued due to financial reasons. Seven months after the final administration of nivolumab, the patient developed what we diagnosed as nivolumab-induced pneumonitis. The patient was immediately prescribed prednisolone (1 mg/kg p.o. daily), and the pneumonitis resolved after 1.5 months. In case 2, a 68-year-old man was diagnosed with stage IVB squamous cell carcinoma. Nivolumab monotherapy was prescribed as fourth-line therapy. After the second administration of nivolumab, the patient developed what we diagnosed as nivolumab-induced pneumonitis; nivolumab was discontinued, and the patient was immediately prescribed prednisolone (1 mg/kg p.o. daily). Eight months after the final administration of nivolumab, the patient again developed nivolumab-induced pneumonitis. The pneumonitis resolved without additional medication. In case 3, a 69-year-old man was diagnosed with stage IVB adenocarcinoma. Pembrolizumab monotherapy was initiated as sixth-line therapy, and it was discontinued after 4 cycles due to disease progression. Four months after the final dose of pembrolizumab, the patient developed what we diagnosed as pembrolizumab-induced pneumonitis. The patient immediately received a high intravenous dose of methylprednisolone (1,000 mg per day for three days). The pneumonitis and respiratory failure progressed, and he died 8 weeks after the onset of the pneumonitis. We report pneumonitis after discontinuation of ICIs in 3 patients. We confirm that, although uncommon, PD-1 inhibitor-induced irAEs can develop after treatment discontinuation. Further accumulation of cases and clarification of the clinical features of patients with irAEs, such as the time of onset, imaging findings, and treatment outcomes are needed.

DOI： 10.21037/tlcr-20-582

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Dynamic chest radiography (DCR) is a flat-panel detector (FPD) -based functional X-ray imaging, which is performed as an additional examination in chest radiography. The large field of view of FPDs permits real-time observation of motion/kinetic findings on the entire lungs, right and left diaphragm, ribs, and chest wall; heart wall motions; respiratory changes in lung density; and diameter of the intrathoracic trachea. Since the dynamic FPDs had been developed in the early 2000s, we focused on the potential of dynamic FPDs for functional X-ray imaging and have launched a research project for the development of an imaging protocol and digital image-processing techniques for the DCR. The quantitative analysis of motion/kinetic findings is helpful for a better understanding of pulmonary function, because the interpretation of dynamic chest radiographs is challenging and time-consuming for radiologists, pulmonologists, and surgeons. Recent clinical studies have demonstrated the usefulness of DCR combined with the digital image processing techniques for the evaluation of pulmonary function and circulation. Especially, there is a major concern in color-mapping images based on dynamic changes in radiographic lung density, where pulmonary impairments can be detected as color defects, even without the use of contrast media or radioactive medicine. Dynamic chest radiography is now commercially available for the use in general X-ray room and therefore can be deployed as a simple and rapid means of functional imaging in both routine and emergency medicine. This review article describes the current status and future prospects of DCR, which might bring a paradigm shift in respiratory diagnosis.

DOI： 10.6009/jjrt.2021_JSRT_77.11.1279

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Objectives: Cancer cells usually escape tumor-reactive T-cell responses using immune checkpoint proteins, such as programmed death protein-1 (PD-1) and its ligand, programmed death ligand-1 (PD-L1). These proteins can be blocked by immune checkpoint inhibitors (ICIs); the decision on ICI-based first-line treatment for advanced lung cancers depends on the PD-L1 levels in tumor specimens. Determining the PD-L1 expression conventionally requires histological specimens from resected tumors and core biopsy specimens. Non-small cell lung cancer (NSCLC) is usually diagnosed at stage III or IV; therefore, only small biopsy specimens, such as those obtained via endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) are available. However, the suitability of EBUS-TBNA specimens determining the PD-L1 expression levels in advanced lung cancers remains unclear. Materials and Methods: Here, we investigated the concordance rate of PD-L1 expression between EBUS-TBNA and matched transbronchial biopsy (TBB) specimens. Using the 22C3 anti-PD-L1 antibody (immunohistochemistry), we determined the PD-L1 expression levels in paired specimens obtained from 69 patients (50 with advanced NSCLC and 19 with small cell lung cancer [SCLC]), as well as the efficacy of ICIs in these patients. Results: The concordance rate of PD-L1 expression between the EBUS-TBNA and TBB specimens was 78.3%. The κ values referent to the PD-L1-positive expression rate between EBUS-TBNA and TBB specimens were 0.707 and 0.676 at cutoff limits of ≥1% and ≥50%, respectively. Among the 19 SCLC patients, 16 (84.2%) exhibited no PD-L1 expression in both EBUS-TBNA and TBB specimens. Notably, the progression-free survival of patients with ≥50% PD-L1 expression in the paired specimens who received ICI treatment was 8.3 months. Conclusion: Collectively, our results validate the use of EBUS-TBNA specimens for the determination of the PD-L1 expression levels in the context of NSCLC and SCLC.

DOI： 10.7150/jca.55738

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Objective: The aim of this study was to identify the relationships between parameters obtained from dynamic-ventilatory digital radiography (DR) and ventilatory disorders. Methods: This study comprised 273 participants with respiratory diseases who underwent spirometry and functional residual capacity measurements (104 with normal findings on spirometry as controls, 139 with an obstructive lung disorder, 30 with a restrictive lung disorder) were assessed by dynamic-ventilatory DR. Sequential chest radiography images of the patient's slow and maximum breathing were captured at 15 frames per second by a dynamic flat-panel imaging system. The system measured the following parameters: lung area at maximum inspiration divided by height (lung area_in/height), changes in tracheal diameter due to respiratory motions, rate of tracheal narrowing, diaphragmatic motion, and rate of change in lung area due to respiratory motion. Relationships between these parameters and ventilatory disorders were analyzed. Results: Lung area_in/height in patients with restrictive disorders showed significant decreases. Tracheal diameter change and tracheal narrowing rate in patients with obstructive disorders were significantly increased compared to both the control participants and patients with restrictive disorders. Patients with obstructive disorders and patients with restrictive disorders showed decreased diaphragmatic motion and lung area change rate. With the restrictive disorders as references, the area under the curve (AUC), sensitivity and specificity of lung area_in/height were 0.88, 0.77, and 0.88, respectively. With the obstructive disorders as references, the AUC, sensitivity and specificity of tracheal narrowing rate were 0.67, 0.53 and 0.81, respectively. Conclusion: Dynamic-ventilatory DR shows potential as a method for the detection and evaluation of ventilatory disorders in patients with respiratory diseases.

DOI： 10.2147/COPD.S309960

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Language：Japanese   Publisher：(NPO)日本肺癌学会  

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BACKGROUND: Cough variant asthma (CVA) is the most common cause of chronic cough and responds well to bronchodilator therapy. Previous studies on methacholine -induced cough have shown that heightened cough response due to bronchoconstriction is a feature of CVA. The aim of this study was to assess Mch-induced cough as an indicator of bronchodilator-responsive cough (BRC). METHODS: This was a single-center retrospective study of prolonged/chronic cough cases who underwent evaluation via spirometry, FeNO and bronchial challenge testing using Mch and capsaicin (C5). Resultant bronchoconstriction after Mch challenge was assessed by flow-volume curves measuring the expiratory flow of the partial flow-volume curve 40% above residual volume (PEF40) and FEV1. BRC was defined as a decrease in cough with bronchodilator therapy by 30% or more on a visual analog scoring scale. RESULTS: Of the 100 patients evaluated, 63 were diagnosed with BRC. Mch-induced cough at a decrease in PEF40 of 35% (PC35-PEF40) was predictive of BRC on AUROC analysis with an AUC of 0.82 (95% CI 0.73-0.90) and cut-off of 24. The AUC for C5, FeNO and PC20-FEV1 were 0.65, 0.47, and 0.58, respectively. CONCLUSION: Compared to C5, FeNO and PC20-FEV1, Mch-induced cough better supports a diagnosis of BRC.

DOI： 10.1016/j.pupt.2020.101962

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Language：Japanese   Publisher：(一社)日本アレルギー学会  

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Language：Japanese   Publisher：(NPO)日本肺癌学会  

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Language：Japanese   Publisher：(NPO)日本肺癌学会  

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We presented a rare case of pulmonary arteriovenous fistula in a patient who suffered from migraine with optic aura for longer than 20 years. This case suggests that the migraine could be expected to disappear after treatment for pulmonary arteriovenous fistula.

DOI： 10.1002/ccr3.3037

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Language：Japanese   Publisher：(一社)日本アレルギー学会  

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The combination therapy of Lopinavir/Ritonavir plus Favipiravir might be a treatment option for patients with COVID-19. Serum ferritin levels and lymphocytopenia are promising markers for disease severity and disease progression that are commonly available in general clinical practice.

DOI： 10.1002/ccr3.3358

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Language：Japanese   Publisher：(一社)日本アレルギー学会  

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BACKGROUND: In clinical trials, first-line treatment with pembrolizumab improved overall survival (OS) in patients with advanced non-small-cell lung cancer (NSCLC) with a programmed death ligand 1 (PD-L1) tumor proportion score of ≥ 50%. However, data on the efficacy of this treatment between clinical trials and actual clinical practice are inconsistent. PATIENTS AND METHODS: Ninety-five patients with histologically diagnosed advanced or recurrent NSCLC and a PD-L1 tumor proportion score of ≥ 50% who received pembrolizumab as first-line treatment were consecutively enrolled onto this multicenter retrospective study from February 2017 to December 2018. Clinical data were collected from electronic medical records. We assessed the objective response rate, progression-free survival (PFS), OS, and immune-related adverse events (irAE), and determined their associations with clinical characteristics. RESULTS: The objective response rate was 40.0%. The median PFS was 6.1 months, and OS did not reach the median. Multivariate analyses revealed that nonadenocarcinoma histology (hazard ratio, 1.78; 95% confidence interval, 1.05-3.03; P = .015) and ≥ 3 metastatic sites (hazard ratio, 3.97; 95% confidence interval, 1.97-8.01; P < .001) were independently correlated with poor PFS. Patients with irAE and patients without interstitial lung disease had significantly longer PFS (14.0 and 4.9 months, respectively; P = .011) than patients without irAE or patients with interstitial lung disease. CONCLUSION: The outcome of patients receiving first-line pembrolizumab treatment was worse in those with nonadenocarcinoma and with a large number of metastatic sites. Patients with irAE and without interstitial lung disease had a more favorable outcome.

DOI： 10.1016/j.cllc.2020.02.017

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Language：Japanese   Publisher：(一社)日本アレルギー学会  

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PURPOSE: Dynamic chest radiography (DCR) is a flat-panel detector (FPD)-based functional lung imaging technique capable of measuring temporal changes in radiographic lung density due to ventilation and perfusion. The aim of this study was to determine the diagnostic performance of DCR in the evaluation of pulmonary function based on changes in radiographic lung density compared to nuclear medicine lung scans. METHODS: This study included 53 patients with pulmonary disease who underwent DCR and nuclear medicine imaging at our institution. Dynamic chest radiography was conducted using a dynamic FPD system to obtain sequential chest radiographs during one breathing cycle. The maximum change in the average pixel value (Δmax ) was measured, and the percentage ofΔmax in each lung region, calculated relative to the sum of all lung regions (Δmax %), was calculated for each factor (ventilation and perfusion). The Δmax % was compared with the accumulation of radioactive agents (radioactive agents%) on ventilation and perfusion scans in each lung and lung region using correlation coefficients and scatter plots. The ratio of ventilation to perfusion Δmax % was calculated and compared with nuclear medicine ventilation-perfusion (V/Q) findings in terms of sensitivity and specificity for V/Q mismatch in each lung region. RESULTS: There was a high correlation between Δmax % and radioactive agents% for each lung (Ventilation: r = 0.81, perfusion: r = 0.87). However, correlation coefficients were lower (0.37 to 0.80) when comparing individual lung regions, with the upper lung regions showing the lowest correlation coefficients. The sensitivity and specificity of DCR for V/Q mismatch were 63.3% (19/30) and 60.1% (173/288), respectively. Motion artifacts occasionally increased Δmax %, resulting in false negatives. CONCLUSIONS: Ventilation and perfusion Δmax % correlated reasonably with radioactive agents% on ventilation and perfusion scans. Although the regional correlations were lower and the detection performance for V/Q mismatch was not enough for clinical use at the moment, these results suggest the potential for DCR to be used as a functional imaging modality that can be performed without the use of radioactive contrast agents. Further technical improvement is required for the implementation of DCR-based V/Q studies.

DOI： 10.1002/mp.14407

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Language：Japanese   Publisher：(NPO)日本呼吸器内視鏡学会  

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OBJECTIVE: The aim of this study was to determine the utility of dynamic-ventilatory digital radiography (DR) for pulmonary function assessment in patients with airflow limitation. METHODS: One hundred and eighteen patients with airflow limitation (72 patients with lung cancer before surgery, 35 patients with chronic obstructive pulmonary disease [COPD], 6 patients with asthma, and 5 patients with asthma-COPD overlap syndrome) were assessed with dynamic-ventilatory DR. The patients were instructed to inhale and exhale slowly and maximally. Sequential chest X-ray images were captured in 15 frames per second using a dynamic flat-panel imaging system. The relationship between the lung area and the rate of change in the lung area due to respiratory motion with respect to pulmonary function was analyzed. RESULTS: The rate of change in the lung area from maximum inspiration to maximum expiration (Rs ratio) was associated with the RV/TLC ratio (r = 0.48, p < 0.01) and the percentage of the predicted FEV1 (r = -0.33, p < 0.01) in patients with airflow limitations. The Rs ratio also decreased in an FEV1-dependent manner. CONCLUSION: The rate of change in the lung area due to respiratory motion evaluated with dynamic DR reflects air trapping. Dynamic DR is a potential tool for the comprehensive assessment of pulmonary function in patients with COPD.

DOI： 10.1159/000506881

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OBJECTIVES: Chronic obstructive pulmonary disease (COPD) increases the risk of lung cancer. The relationships between COPD and Asthma COPD Overlap (ACO), and between the histopathological types of lung cancer and driver mutations remain unclear and need further study. The aim of this retrospective study was to examine the relationships between the histopathological type, frequency of epidermal growth factor receptor (EGFR) driver mutations, and anaplastic lymphoma receptor tyrosine kinase (ALK) rearrangements in the lung cancers of patients with COPD and ACO. MATERIALS AND METHODS: Patients with pure COPD (n=198) or ACO (n=318) who were admitted to our hospital were reviewed retrospectively. RESULTS: Lung cancers were identified in 43 (21.7%) patients with pure COPD and 54 (17.0%) patients with ACO. The following lung cancers types were observed: patients with pure COPD had 19 (44.2%) adenocarcinomas, 13 (30.2%) squamous cell lung carcinomas (SCC), 8 (18.6%) small cell lung carcinomas (SCLC); patients with ACO had 23 (42.6%) adenocarcinomas, 23 (42.6%) SCC, 2 (3.70%) SCLC. SCLC was significantly more prevalent in patients with pure COPD (p<0.05) than in those with ACO. Differences between the numbers of other histological types of lung cancer and the numbers of driver mutations in the 2 groups of patients were not significant. CONCLUSION: The differences in the rate of lung cancer and prevalence of EGFR driver mutations between the patients with pure COPD and those with ACO were not significant.

DOI： 10.5152/TurkThoracJ.2019.18100

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A 65-year-old woman presented to a hospital with complaints of dyspnea and lumbar pain. Chest computed tomography (CT) showed left pleural effusion. Thoracentesis showed pleural effusion with elevated levels of amylase. Enhanced CT showed fluid accumulation from the thoracic crus of the diaphragm to the left iliopsoas muscle. Based on the postoperative notes following left nephrectomy performed 29 years ago, we suspected that the internal pancreatic fistula had resulted from the postoperative scar. Conservative management was performed. However, occlusion of the pancreatic fistula failed. Subsequently, she underwent pancreatic body tail spleen merger resection, and the pleural effusion disappeared.

DOI： 10.2169/internalmedicine.4258-19

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Purpose: Asthma-chronic obstructive pulmonary disease overlap (ACO), characterized by airway limitation, is an important condition with high incidence and mortality. Although some guidelines recommend triple therapy with inhaled corticosteroids/long-acting muscarinic antagonists/long-acting β2 agonists, this treatment approach is based on the extrapolation of data from studies of asthma or chronic obstructive pulmonary disease (COPD) alone. Methods: A 12-week, randomized, open-label cross-over pilot study was conducted in 19 patients with ACO to investigate the effect of triple therapy with glycopyrrolate (GLY) 50 µg/day on budesonide/formoterol fumarate (BUD/FORM) 640/18 µg/day. The study period included a 4-week wash-out, 4-week run-in, and 4-week treatment period. Respiratory function tests, fractional exhaled nitric oxide (FeNO), a COPD assessment test (CAT) and an asthma control questionnaire (ACQ) were carried out 0, 4, and 8 weeks after randomization. Results: A total of 19 patients with stable ACO (19 males and no females) with a mean age of 70.7 ± 7.6 years (± standard deviation, SD; range 55-83 years) participated in this study. All patients were ex-smokers with a smoking history of 63.1 ± 41.1 pack-years (± SD). Mean values for inspiratory capacity (IC), an index of hyperinflation of the lung that causes exertional dyspnea and reduced exercise, were 1.93 L (± 0.47 L) after the run-in, 1.85 L (± 0.51 L) after the BUD/FORM dual therapy period and 2.11 L (± 0.58 L) after the BUD/GLY/FORM triple therapy period. IC values after the BUD/GLY/FORM triple therapy were significantly higher than those after the run-in (p < 0.02). FeNO values, ACQ, and CAT scores were not significantly different among the run-in, wash-out, and triple-therapy periods. Conclusion: The present pilot study showed that triple therapy with BUD/GLY/FORM results in an improvement in lung function parameters including IC, indicating the potential value of triple therapy as standard treatment for ACO.

DOI： 10.2147/COPD.S231004

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Publishing type：Research paper (scientific journal)   Publisher：Elsevier BV  

DOI： 10.1016/s1470-2045(19)30634-5

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Purpose We investigated the safety, tolerability, pharmacokinetics, and efficacy of TAS-121, a novel, potent, and highly selective third-generation epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) in Japanese patients with advanced EGFR mutation-positive non-small-cell lung cancer (NSCLC) previously treated with EGFR-TKI. Methods This was an open-label, non-randomized, multi-center, dose escalation, phase I study conducted in three phases (dose escalation, expansion, and extension phases). TAS-121 was administered orally once daily (QD) or twice daily (BID) under fasting conditions in a 21-day treatment cycle. The primary endpoint was dose-limiting toxicities (DLTs) during Cycle 1 of the dose escalation phase. Results In total, 134 patients received treatment. Five and three patients presented a DLT with the QD and BID regimens, respectively. The DLTs were drug-induced liver injury, platelet count decreased, urticaria, interstitial lung disease, and left ventricular failure. The maximum tolerated dose (MTD) was 10 mg/day QD and 8 mg/day BID in the dose escalation phase. The most common adverse drug reactions (ADRs) were dermatological toxicity (89.6%), platelet count decreased (67.2%), and pyrexia (44%) among all patients. Rate of discontinuations due to ADRs at the MTD level were 11.1% with TAS-121 10 mg/day QD and 7.9% with TAS-121 8 mg/day BID. Among 86 T790M-positive patients (confirmed by blood serum sampling in most patients), the objective response rate (ORR) was 28% and highest at 8 mg/day BID (39%). Among 16 T790M-negative patients, the ORR was 19%. Conclusions TAS-121 was well tolerated up to the MTD and demonstrated antitumor activity in Japanese T790M-positive NSCLC patients. Clinical trial registration: JapicCTI-142651.

DOI： 10.1007/s10637-019-00732-4

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Language：English   Publisher：(NPO)日本肺癌学会  

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DOI： 10.1186/s40880-019-0423-3

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DOI： 10.1186/s40880-019-0413-5

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Language：Japanese   Publisher：(NPO)日本肺癌学会  

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Language：Japanese   Publisher：(NPO)日本肺癌学会  

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Language：Japanese   Publisher：(NPO)日本肺癌学会  

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Language：Japanese   Publisher：(NPO)日本肺癌学会  

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Language：Japanese   Publisher：(NPO)日本肺癌学会  

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Language：Japanese   Publisher：(NPO)日本肺癌学会  

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BACKGROUND: Cough variant asthma (CVA) is recognized as a precursor of bronchial asthma (BA). However, the cough response to bronchoconstriction differs between these similar diseases. Repeated bronchoconstriction and the resulting imbalance of endogenous lipid mediators may impact the cough response. METHODS: We investigated the influence of repeated bronchoconstriction on the cough response to bronchoconstriction using naïve guinea pigs. Bronchoconstriction was induced for 3 consecutive days and changes in the cough response and lipid mediators, such as PGE2, PGI2, and cysteinyl-LTs (Cys-LTs), in BAL fluid (BALF) were assessed. We investigated the effect of endogenous PGI2 on the cough response by employing a PGI2 receptor antagonist. In order to investigate the cough response over a longer period, we re-evaluated the cough response 2 weeks after repeated bronchoconstriction. RESULTS: The number of coughs induced by bronchoconstriction were significantly decreased by repeated bronchoconstriction. The levels of PGE2, PGI2, and Cys-LTs, and the ratio of PGI2/PGE2 were significantly increased, following repeated bronchoconstriction. This decrease in the cough response was suppressed by pretreatment with a PGI2 receptor antagonist. Two weeks after repeated bronchoconstriction, the cough response returned to the same level as before repeated bronchoconstriction along with a concomitant return of lipid mediators, such as PGE2, PGI2, and Cys-LTs and the ratio of PGI2/PGE2. CONCLUSIONS: Our results suggest that repeated bronchoconstriction and the resulting imbalance of endogenous lipid mediators contribute to the difference in cough responses to bronchoconstriction in CVA and BA.

DOI： 10.1016/j.alit.2019.09.002

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Epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKIs) are the standard of care for non-small-cell lung cancer (NSCLC) patients harboring EGFR mutations. However, almost all patients develop resistance after approximately 1 y of treatment, with >50% of cases due to the T790M secondary mutation of the EGFR gene. A large global Phase III study (AURA3) demonstrated that osimertinib significantly prolonged progression-free survival (PFS) over platinum-doublet chemotherapy in patients with T790M-positive NSCLC who had progressed on previous EGFR-TKI therapy. However, it is not clear whether efficacy or safety of osimertinib in Japanese patients is similar to the overall population. We report a pre-planned subgroup analysis of pooled Phase II data from the AURA Extension and AURA2 trials to investigate the efficacy and safety of osimertinib in Japanese patients. This study included 81 Japanese patients. Patients were administered 80 mg osimertinib orally once daily until disease progression. The main endpoints were objective response rate (ORR), PFS, and safety. The ORR was 63.6% and median PFS was 13.8 mo. Overall survival rate at 36 mo was 54.0%. The most common all-cause adverse events (AEs) were rash (grouped term; 65.4%), diarrhea (51.9%), paronychia (grouped term; 49.4%), and dry skin (grouped term; 39.5%). Most AEs were grade 1-2. Five patients (6.2%) developed interstitial lung disease, resulting in two deaths (2.5%). Osimertinib demonstrated favorable ORR and PFS in Japanese patients, similar to the overall population. Additionally, osimertinib has good efficacy and a manageable safety profile in Japanese patients with NSCLC who had acquired resistance due to the T790M mutation.

DOI： 10.1111/cas.14120

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PURPOSE: Chemoradiotherapy (CRT) is the standard treatment for locally advanced non-small cell lung cancer (NSCLC). Recently, anti-PD-1 antibody therapy became a key treatment for stage IV NSCLC as the combination of immune checkpoint inhibitors (ICIs) and platinum doublet chemotherapy. However, the efficacy and toxicity of anti-PD-1 therapy for recurrence after CRT in stage III NSCLC are not well examined. METHODS: Patients who received anti-PD-1 therapy for recurrence after CRT were identified in our clinical database. The safety and efficacy of anti-PD-1 therapy were retrospectively analyzed. RESULTS: From March 1, 2013 to April 30, 2018, there were 20 patients who received anti-PD-1 therapy for recurrence after CRT. The median duration from CRT to initial anti-PD-1 therapy was 9.3 months. 12 patients (60%) were alive and 7 patients (35%) were still receiving anti-PD-1 therapy at the data cutoff point (median follow-up, 13.5 months). The ORR for anti-PD-1 therapy was 45.0%. Median progression-free survival (PFS) and overall survival (OS) from initiation of anti-PD-1 therapy was 8.4 months and 26.2 months, respectively. PFS in patients who had a short interval from last CRT to initial anti-PD-1 therapy seemed to have better outcomes (duration from last CRT to initial anti-PD-1 therapy < 9.3 months vs. ≥ 9.3 months; median PFS, 17.0 months vs. 4.9 months). Grade 3 or 4 immune-related adverse events occurred in 5% of patients. Only grade 1 pneumonitis was observed. CONCLUSION: The efficacy of anti-PD-1 therapy for recurrence after CRT in stage III NSCLC might better than in stage IV NSCLC. The duration from CRT to initial anti-PD-1 therapy might be related to efficacy.

DOI： 10.1007/s10147-019-01537-4

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DOI： 10.1164/rccm.201904-0734IM

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OBJECTIVE: Asthma-chronic obstructive pulmonary disease (COPD) overlap (ACO) is of increasing interest because ACO patients have significantly worse outcomes, leading to greater social and economic burdens compared with asthma or COPD alone. Some guidelines for ACO recommend triple therapy with inhaled corticosteroids, long-acting β2 agonists, and long-acting muscarinic antagonists. However, this approach is based on extrapolating data from patients with asthma or COPD alone. Therapeutic studies for ACO have not previously been conducted. MATERIALS AND METHODS: A 12-week, randomized, open-label cross-over pilot study was conducted in 17 ACO patients to evaluate the effect of umeclidinium (UMEC) 62.5 µg once-daily added to fluticasone furoate/vilanterol (FF/VI) 200/25 µg once-daily. A 4-week run-in, a first and a second 4-week treatment period were included. Respiratory function, respiratory impedance, fractional exhaled nitric oxide, COPD assessment test, and asthma control test scores were evaluated 0, 4, and 8 weeks after randomization. RESULTS: Mean values of post-bronchodilator forced expiratory volume in 1 second as a percentage of the predicted value (%FEV1), after UMEC was added to FF/VI, were significantly higher than after the run-in (p < 0.01). Mean values of resonant frequency during inspiration (Fres), after UMEC was added to FF/VI, were significantly lower than after the run-in (p < 0.01). CONCLUSION: Adding UMEC to FF/VI provides greater improvement in lung function, indicating that triple therapy is a suitable regular treatment for ACO.

DOI： 10.5414/CP203382

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PURPOSE: To assess the utility of the cobas EGFR Mutation Test, with tissue and plasma, for first-line osimertinib therapy for patients with EGFR-mutated (EGFRm; Ex19del and/or L858R) advanced or metastatic non-small cell lung cancer (NSCLC) from the FLAURA study (NCT02296125). EXPERIMENTAL DESIGN: Tumor tissue EGFRm status was determined at screening using the central cobas tissue test or a local tissue test. Baseline circulating tumor (ct)DNA EGFRm status was retrospectively determined with the central cobas plasma test. RESULTS: Of 994 patients screened, 556 were randomized (289 and 267 with central and local EGFR test results, respectively) and 438 failed screening. Of those randomized from local EGFR test results, 217 patients had available central test results; 211/217 (97%) were retrospectively confirmed EGFRm positive by central cobas tissue test. Using reference central cobas tissue test results, positive percent agreements with cobas plasma test results for Ex19del and L858R detection were 79% [95% confidence interval (CI), 74-84] and 68% (95% CI, 61-75), respectively. Progression-free survival (PFS) superiority with osimertinib over comparator EGFR-TKI remained consistent irrespective of randomization route (central/local EGFRm-positive tissue test). In both treatment arms, PFS was prolonged in plasma ctDNA EGFRm-negative (23.5 and 15.0 months) versus -positive patients (15.2 and 9.7 months). CONCLUSIONS: Our results support utility of cobas tissue and plasma testing to aid selection of patients with EGFRm advanced NSCLC for first-line osimertinib treatment. Lack of EGFRm detection in plasma was associated with prolonged PFS versus patients plasma EGFRm positive, potentially due to patients having lower tumor burden.

DOI： 10.1158/1078-0432.CCR-19-1126

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DOI： 10.1093/jjco/hyz079

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Dramatic progress in targeted therapy and immunotherapy has been changing clinical practices in lung cancer. With the accumulation of clinical practice, it has become clear that pre-existing interstitial pneumonia (IP) could be a risk factor for drug-induced lung injury, which has enhanced awareness regarding the difficulty in treating lung cancer with comorbid IP. Unfortunately, there is only low-grade evidence in the field of lung cancer with comorbid IP, because almost all clinical trials exclude such patients. There have been very few specialized clinical trials for patients with lung cancer and underlying IPs thus far. Therefore, it is necessary to treat such cases empirically or to give up on the treatment itself. Considering these circumstances, establishing how to treat lung cancer with comorbid IP is an urgent issue. This paper is a summary of the official statement reported by the Diffuse Lung Disease/Thoracic Oncology Assembly and the Japanese Respiratory Society (JRS) in 2017, which attempts to approach lung cancer with comorbid IP systematically.

DOI： 10.1016/j.resinv.2019.06.001

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DOI： 10.1007/s40259-019-00363-4

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Thoracic diseases in patients with systemic lupus erythematosus (SLE), especially interstitial pneumonia (SLE-IP), are rare and have been poorly studied. The aims of this multicentre study were to evaluate SLE-IP and elucidate its clinical characteristics and prognosis. Fifty-five patients with SLE-IP who had attended the respiratory departments of participating hospitals were retrospectively evaluated in this multicentre study. Clinical information, high-resolution computed tomography (HRCT), and surgical lung biopsy/autopsy specimens were analysed by respiratory physicians, pulmonary radiologists, and pulmonary pathologists. IP patterns on HRCT and lung specimens were classified based on the international classification statement/guideline for idiopathic interstitial pneumonias. The most frequent form of SLE-IP at diagnosis was chronic IP (63.6%), followed by subacute (20.0%), and acute IP (12.7%). Radiologically, the most common HRCT pattern was "Unclassifiable" (54%). Histologically, "Unclassifiable" was the most frequently found (41.7%) among 12 patients with histologically proven IP. Interestingly, accompanying airway diseases were present in nine of these patients (75%). In multivariate analysis, current smoking (hazard ratio [HR] 6.105, p = 0.027), thrombocytopenia (HR 7.676, p = 0.010), anti-double-strand DNA titre (HR 0.956, p = 0.027), and nonspecific interstitial pneumonia (NSIP) + organizing pneumonia (OP) pattern on HRCT (vs. NSIP, HR 0.089, p = 0.023) were significant prognostic factors. In conclusion, chronic IP was the most frequent form of IP in patients with SLE-IP, and "Unclassifiable" was the commonest pattern radiologically and histologically.

DOI： 10.1038/s41598-019-43782-7

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OBJECTIVE: In Japan, most asthma deaths occur among the elderly. We should improve the control of asthma in elderly patients to reduce the number of deaths due to asthma. This retrospective study aimed to evaluate the efficacy of tiotropium RespimatⓇ (Tio-Res) in symptomatic, never-smoking, elderly asthmatics with irreversible airflow limitation despite the use of high-dose inhaled corticosteroids (ICS) plus long-acting β2-adrenoceptor agonists (LABA). METHODS: The Asthma Control Test™ (ACT), pulmonary function tests, morning and evening peak flow (mPEF, ePEF, respectively, evaluated with an ASSESS® peak flow meter), and respiratory impedance (assessed with MostGraph®) were measured before and after a minimum of one year of Tio-Res 5 µg/day administration. Sixteen symptomatic, never-smoking asthmatics, aged 75 or over with irreversible airflow limitation despite the use of high-dose ICS plus LABA, were analyzed. RESULTS: All patients were female (mean age, 81.6 years). Tio-Res led to statistically significant improvements in the total ACT score (19.9 to 23.6), FVC and FEV1 (1.97 to 2.14 L and 1.13 to 1.23 L, respectively), and mPEF and ePEF (229.9 to 253.8 L/min and 259.8 to 277.4 L/min, respectively). Tio-Res also resulted in statistically significant improvements in respiratory resistance at 5 Hz (R5), respiratory resistance at 20 Hz (R20), R5-R20, low-frequency reactant indices at 5 Hz (X5), resonant frequency (Fres) and low-frequency reactance area (ALX). CONCLUSIONS: Our retrospective study suggests that Tio-Res improves symptoms, pulmonary function, and respiratory impedance in symptomatic asthmatics aged 75 or over with irreversible airflow limitation despite the use of high-dose ICS plus LABA.

DOI： 10.1055/a-0665-4379

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BACKGROUND: Bronchial thermoplasty (BT) is a novel bronchoscopic therapy for severe uncontrolled asthma unresponsive to standard pharmacological treatments, including inhaled corticosteroids and long-acting beta-2 agonists. Although several studies have shown that BT improves asthma control, the optimal predictors of BT response remain unknown. PATIENTS AND METHODS: We reviewed 10 consecutive asthma patients treated with BT at Kanazawa University Hospital between January 2016 and March 2018 and attempted to identify factors that correlated with a positive BT response. RESULTS: All patients had the most severe persistent asthma according to the 2017 Japanese guidelines for adult asthma and were uncontrolled despite adequate treatments including high-dose inhaled corticosteroids and long-acting beta-2 agonists. Six patients had significant improvement in asthma control evaluated with the Asthma Control Questionnaire-6. Eight patients showed a significant improvement in asthma-specific health-related quality of life evaluated with the Asthma Quality of Life Questionnaire. The number of severe asthma exacerbations decreased in 6 patients. The maintenance dose of oral corticosteroids decreased in 1 patient. There were no severe adverse events related to the procedure. Six patients showed a positive BT response, and all 4 patients with increased cough receptor sensitivity to capsaicin responded to BT. No other factors, including age, smoking status, body mass index, age of asthma onset, disease duration, blood eosinophil count, total serum immunoglobulin E, prebronchodilator forced expiratory volume in 1 second, reversibility to beta-2 agonist, or fractional exhaled nitric oxide, were associated with a positive BT response. CONCLUSION: Increased cough receptor sensitivity to capsaicin may predict a positive BT response.

DOI： 10.1097/LBR.0000000000000577

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DOI： 10.1111/1346-8138.14641

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Pembrolizumab, a humanized monoclonal antibody against programmed death 1 (PD-1), has been shown to improve overall survival (OS) in patients with previously treated advanced non-small-cell lung cancer (NSCLC) with programmed death ligand 1 (PD-L1) tumor proportion score (TPS) ≥1%. We report safety and efficacy results from the phase 1b KEYNOTE-025 study, which evaluated pembrolizumab in Japanese patients with previously treated NSCLC. Eligible patients had histologically/cytologically confirmed advanced NSCLC with PD-L1 TPS ≥1% and had received ≥1 platinum-doublet chemotherapy. Patients received pembrolizumab 10 mg/kg once every 3 weeks for 2 years or until disease progression/unacceptable toxicity. Primary objectives were to evaluate the safety of pembrolizumab in patients with PD-L1 TPS ≥1% and the objective response rate (ORR) per RECIST version 1.1 in patients with PD-L1 TPS ≥50%. Thirty-eight patients were enrolled and received ≥1 pembrolizumab dose. The median (range) age was 66.0 (41-78) years, and 61% had received ≥2 prior systemic therapies. Eleven patients (29%) experienced grade 3-5 treatment-related adverse events (AE); 9 patients (24%) experienced immune-mediated AE and infusion reactions, with pneumonitis (11%; any grade) being most common. Among evaluable patients with PD-L1 TPS ≥50% (n = 11), ORR was 27% (95% CI, 6-61). Among evaluable patients with PD-L1 TPS ≥1% (n = 37), ORR was 22% (95% CI, 10-38). Median (95% CI) progression-free survival and OS were 3.9 (2.0-6.2) months and 19.2 (8.0-26.7) months, respectively. In summary, pembrolizumab was generally well tolerated and showed promising antitumor activity in Japanese patients with previously treated PD-L1-expressing NSCLC. Outcomes were consistent with those from the phase 3 KEYNOTE-010 study. (Trial registration number: ClinicalTrials.gov, NCT02007070.).

DOI： 10.1111/cas.13932

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Language：English   Publishing type：Research paper (other academic)   Publisher：SPIE  

DOI： 10.1117/12.2512711

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Other Link： https://dblp.uni-trier.de/db/conf/micad/micad2019.html#KitaharaTROMKM19

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Bronchiolitis obliterans (BO) is a significant life-threatening complication that occurs after allogeneic hematopoietic stem cell transplantation (allo-HSCT), and it is associated with increased morbidity and mortality. BO responds poorly to corticosteroids or immunosuppressants, and there are currently no established treatment approaches. We herein describe a patient with biopsy-proven BO after allo-HSCT who was successfully treated with tamibarotene, a novel synthetic retinobenzoic acid. Tamibarotene led to a dramatic improvement in lung function as well as cutaneous manifestations of chronic graft-vs-host disease. A large prospective clinical trial is therefore warranted to confirm the efficacy of tamibarotene in BO.

DOI： 10.1016/j.chest.2018.08.1052

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Background: Standard chemotherapy for advanced non-small-cell lung cancer (NSCLC) with preexisting interstitial lung disease (ILD) has not yet been established. Although a combination of carboplatin and paclitaxel is most frequently used for patients with advanced NSCLC and ILD, the safety and efficacy of carboplatin plus nanoparticle albumin-bound paclitaxel (nab-paclitaxel) are yet to be elucidated. Objectives: This study aimed to evaluate the safety and efficacy of carboplatin plus nab-paclitaxel for advanced NSCLC with ILD. Methods: This retrospective study included nine patients with advanced NSCLC and ILD who received carboplatin plus nab-paclitaxel as first-line chemotherapy at the National Hospital Organization Kanazawa Medical Center between April 2013 and December 2017. The ILD-GAP index was used to evaluate mortality risk of baseline ILD. Results: A usual interstitial pneumonia (UIP) pattern of ILD was observed in five (55.6%) patients on their baseline high-resolution computed tomography (HRCT) scans. The median ILD-GAP index was 4 (range, 1-5), and six (66.7%) patients had ILD-GAP index ≥4. We observed no ILD exacerbations or chemotherapy-related deaths. The overall response and disease control rates were 77.8% (95% CI, 40.0-97.2) and 88.9% (95% CI, 51.8-97.2), respectively. The median progression-free survival and overall survival were 5.8 months (95% CI, 2.1-7.7) and 8.0 months (95% CI, 2.6-16.8), respectively. Conclusions: Carboplatin plus nab-paclitaxel showed favorable safety and efficacy in patients who had advanced NSCLC and ILD with a high risk of mortality. Prospective studies are required to further confirm these results.

DOI： 10.1155/2019/5315903

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Background Asthma-COPD overlap (ACO) is a disease that shares clinical features of both asthma and COPD. The purpose of this study is to investigate the prevalence and clinical features of ACO. Methods We retrospectively reviewed data for 170 patients with persistent airflow limitation and diagnosed them according to "The Japanese Respiratory Society Guidelines for the Management of ACO 2018". Results Of the 170 patients, 111 were diagnosed as follows : COPD (74 patients, 66.6%), ACO (34 patients, 30.6%), and asthma (3 patients, 2.8%). There was no significant difference in clinical features between ACO and COPD patients. The following pulmonary function tests were significantly lower in ACO than in COPD patients : forced expiratory volume in 1 second/forced vital capacity, peak expiratory flow, maximal mid-expiratory flow, and the maximum expiratory flow at 50%and75%. The following respiratory impedance parameters were significantly higher in ACO than in COPD patients : respiratory resistance (Rrs) at 5 Hz (R5), Rrsat 20 Hz (R20), R5-R20, and low-frequency reactance area. Conclusions About 30% of patients with persistent airflow limitation were diagnosed with ACO. ACO patients had lower lung function and higher respiratory impedance compared with COPD patients. J. Med. Invest. 66 : 157-164, February, 2019.

DOI： 10.2152/jmi.66.157

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Purpose/Aim of the study: Methacholine chloride (MCh) inhalation causes bronchoconstriction and cough. Following MCh-induced bronchoconstriction, metabolic products of prostaglandin I2 (PGI2) increase in bronchoalveolar lavage fluid (BALF), suggesting that PGI2 plays a role in the cough response. Accordingly, we used an experimental guinea pig model to evaluate the role of PGI2 in the bronchoconstriction-triggered cough response. MATERIALS AND METHODS: Experiment 1: The concentration of PGF1α, a stable metabolite of PGI2, in BALF was assessed in animals exposed to nebulized MCh and animals exposed to nebulized saline. Experiment 2: Bronchoconstriction and cough were assessed in 3 groups of animals after MCh inhalation (a saline group, low-dose PGI2 group, and high-dose PGI2 group). Enhanced pause (Penh) was used as a measure of bronchoconstriction. Experiment 3: Bronchoconstriction and cough were assessed in 3 groups of animals (groups administered saline, a low dose of a specific antagonist of the PGI2 receptor (IP antagonist), and a high dose of a specific IP antagonist). RESULTS: The PGF1α concentration in BALF was significantly higher in the bronchoconstriction group than in the control group. In animals administered high-dose PGI2, the MCh-induced increase in Penh was significantly suppressed, and the number of coughs induced by bronchoconstriction was significantly decreased. In animals treated with a high dose of an IP antagonist, the MCh-induced increase in Penh was not affected, and the number of coughs increased. CONCLUSIONS: Our results suggest that PGI2 ameliorates a bronchoconstriction-triggered cough. The measurement and administration of PGI2 may assist in the diagnosis and treatment, respectively, of the cough response triggered by bronchoconstriction.

DOI： 10.1080/01902148.2019.1590883

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DOI： 10.1016/j.ajog.2018.12.009

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DOI： 10.1016/j.amjms.2018.05.004

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Language：Japanese   Publisher：(NPO)日本肺癌学会  

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DOI： 10.21037/jtd.2018.09.56

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Language：Japanese   Publisher：(NPO)日本肺癌学会  

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Language：Japanese   Publisher：(NPO)日本肺癌学会  

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Language：Japanese   Publisher：(NPO)日本肺癌学会  

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Language：Japanese   Publisher：(NPO)日本肺癌学会  

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Language：Japanese   Publisher：(NPO)日本肺癌学会  

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Language：Japanese   Publisher：(NPO)日本肺癌学会  

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Language：Japanese   Publisher：(公社)日本放射線技術学会  

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DOI： 10.1016/j.cllc.2018.04.009

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OBJECTIVES: Pulmonary carcinosarcoma is a rare lung malignancy and little analysis has been performed to identify associated genomic alterations. We used next-generation sequencing (NGS) to analyze a pulmonary carcinosarcoma harboring an epidermal growth factor receptor (EGFR) mutation. MATERIALS AND METHODS: The lung carcinosarcoma used for this study contained components of adenocarcinoma and chondrosarcoma and originated from a 73-year-old female. Both components carried deletion mutations in exon 19 of EGFR and both had equally strong EGFR protein expression. This study analyzed the biological and genetic characteristics of both components, using NGS and immunohistochemical (IHC) staining. RESULTS AND CONCLUSION: IHC staining revealed that both total EGFR and deletion mutation specific EGFR proteins were equally expressed in both components. Intriguingly, identification of genomic alterations with NGS found five identical alterations in four genes (EGFR, CBLB, TP53, and MEN1) that were shared by the two components, and that each component had a large number of individual alterations. Additionally, we focused on an alpha-thalassemia/mental retardation syndrome X-linked (ATRX) mutation which was only present in the sarcoma component. ATRX protein expression was also only detected in the sarcoma component. This is the first report of the exhaustive genomic alterations in a pulmonary carcinosarcoma harboring an EGFR mutation. The results show that our case had the same EGFR status in both components. The EGFR mutation is the driver mutation in both components. In our case, we found that TP53 may be a common alteration and ATRX may be a specific alteration in the sarcoma component.

DOI： 10.1016/j.lungcan.2018.05.026

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Blackwell Publishing Ltd  

Osimertinib is a potent, irreversible epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) selective for EGFR‑TKI sensitizing (EGFRm) and T790M resistance mutations. The primary objective of the cytology cohort in the AURA study was to investigate safety and efficacy of osimertinib in pretreated Japanese patients with EGFR T790M mutation-positive non-small cell lung cancer (NSCLC), with screening EGFR T790M mutation status determined from cytology samples. The cytology cohort was included in the Phase I dose expansion component of the AURA study. Patients were enrolled based on a positive result of T790M by using cytology samples, and received osimertinib 80 mg in tablet form once daily until disease progression or until clinical benefit was no longer observed at the discretion of the investigator. Primary endpoint for efficacy was objective response rate (ORR) by investigator assessment. Twenty-eight Japanese patients were enrolled into the cytology cohort. At data cut-off (February 1, 2016), 12 (43%) were on treatment. Investigator-assessed ORR was 75% (95% confidence interval [CI] 55, 89) and median duration of response was 9.7 months (95% CI 3.8, not calculable [NC]). Median progression-free survival was 8.3 months (95% CI 4.2, NC) and disease control rate was 96% (95% CI 82, 100). The most common all-causality adverse events were paronychia (46%), dry skin (46%), diarrhea (36%) and rash (36%). Osimertinib provided clinical benefit with a manageable safety profile in patients with pretreated EGFR T790M mutation-positive NSCLC whose screening EGFR T790M mutation-positive status was determined from cytology samples. (ClinicalTrials.gov number NCT01802632).

DOI： 10.1111/cas.13511

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Elsevier Ireland Ltd  

Objectives: Osimertinib is a third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor that can overcome resistance due to the Thr790Met (T790M) mutation. However, osimertinib occasionally shows limited efficacy in a small population of patients. We investigated the correlation between the ratio of T790M to EGFR activating mutation and the response to osimertinib. Materials and methods: Between April 2016 and April 2017, 44 patients started osimertinib therapy at the Cancer Institute Hospital of the Japanese Foundation for Cancer Research. We performed EGFR mutation analysis of cytological samples from 33 patients using droplet digital PCR. We calculated the ratio of T790M to EGFR activating mutations and correlated it with the systemic response to osimertinib. Results: In tumors from the 33 patients, the average ratio of T790M to EGFR activating mutations was 0.420. Twenty-one of the 33 patients had tumors with a T790M ratio of ≥0.4. The osimertinib response rate was significantly higher (92.3%) in patients with a T790M ratio of ≥0.4 than in those with a T790M ratio of &lt
0.4 (52.6%
p = 0.0237). We examined the correlation between the T790M ratio and the tumor reduction rate and obtained a coefficient of r = 0.417 (p = 0.0175). In patients with a T790M ratio of ≥0.4, the median progression-free survival was 355 days, which was longer, but not significant, than that in patients with a T790M ratio of &lt
0.4 (median: 264 days). In patients with a T790M ratio of ≥0.4, the median treatment duration from first-line therapy onward was 931 days, which was significantly longer than that in patients with a T790M ratio of &lt
0.4 (median, 567.5 days) (p = 0.044). Conclusion: The T790M ratio to EGFR activating mutation in tumor may correlate with the response to osimertinib, and patients with a higher T790M ratio have a longer treatment history.

DOI： 10.1016/j.lungcan.2017.12.018

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Language：Japanese   Publisher：(一社)日本呼吸器学会  

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Background: The epidermal growth factor receptor (EGFR) T790M mutation is associated with resistance to EGFR tyrosine kinase inhibitors (EGFR-TKIs) in non-small cell lung cancer (NSCLC). However, tissues for the genotyping of the EGFR T790M mutation can be difficult to obtain in a clinical setting. The aims of this study were to evaluate a blood-based, non-invasive approach to detecting the EGFR T790M mutation in advanced NSCLC patients using the PointMan™ EGFR DNA enrichment kit, which is a novel method for the selective amplification of specific genotype sequences. Methods: Blood samples were collected from NSCLC patients who had activating EGFR mutations and who were resistant to EGFR-TKI treatment. Using cell-free DNA (cfDNA) from plasma, EGFR T790M mutations were amplified using the PointMan™ enrichment kit, and all the reaction products were confirmed using direct sequencing. The concentrations of plasma DNA were then determined using quantitative real-time PCR. Results: Nineteen patients were enrolled, and 12 patients (63.2%) were found to contain EGFR T790M mutations in their cfDNA, as detected by the kit. T790M mutations were detected in tumor tissues in 12 cases, and 11 of these cases (91.7%) also exhibited the T790M mutation in cfDNA samples. The concentrations of cfDNA were similar between patients with the T790M mutation and those without the mutation. Conclusions: The PointMan™ kit provides a useful method for determining the EGFR T790M mutation status in cfDNA.

DOI： 10.21037/jtd.2018.01.144

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© Journal of Thoracic Disease. Backgrounds: Lung cancer (LC) adversely impacts survival in patients with idiopathic pulmonary fibrosis. However, little is known about LC in patients with connective tissue disease-associated interstitial lung disease (CTD-ILD). The aim of this study was to evaluate the prevalence of and risk factors for LC in CTDILD, and the clinical characteristics and survival of CTD-ILD patients with LC. Methods: We conducted a single-center, retrospective review of patients with CTD-ILD from 2003 to 2016. Patients with pathologically diagnosed LC were identified. The prevalence, risk factors, and clinical features of LC and the impact of LC on CTD-ILD patient outcomes were observed. Results: Of 266 patients with CTD-ILD, 24 (9.0%) had LC. CTD-ILD with LC was more likely in patients who were older, male, and smokers; had rheumatoid arthritis, a usual interstitial pneumonia pattern, emphysema on chest computed tomography scan, and lower diffusing capacity of the lung carbon monoxide (DLco)% predicted; and were not receiving immunosuppressive therapy. Multivariate analysis indicated that the presence of emphysema [odds ratio (OR), 8.473; 95% confidence interval (CI), 2.241-32.033] and nonuse of immunosuppressive therapy (OR, 8.111; 95% CI, 2.457-26.775) were independent risk factors for LC. CTD-ILD patients with LC had significantly worse survival than patients without LC (10-year survival rate: 28.5% vs. 81.8%, P < 0.001). Conclusions: LC is associated with the presence of emphysema and nonuse of immunosuppressive therapy, and contributes to increased mortality in patients with CTD-ILD.

DOI： 10.21037/jtd.2017.12.134

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A feature of cough variant asthma is a heightened cough response to bronchoconstriction. The mediators of this response are unknown. This study was designed to elucidate the role of lipid mediators in bronchoconstriction-triggered cough response in an experimental animal model. We examined the influence of bronchoconstriction on cell components and mediators including prostaglandin E2 (PGE2) in bronchoalveolar lavage fluid (BALF). We studied the cough response to bronchoconstriction (CRB) by measuring the correlation between the increase in enhanced pause (Penh), an index of bronchoconstriction, and cough counts induced by methacholine (Mch) inhalation in conscious guinea pigs. We then examined the effects of intraperitoneal pretreatment with 16, 16-dimethyl-prostaglandin E2 (dm-PGE2) on CRB and cough counts. The total number of cells and cell components in the BALF were not influenced by bronchoconstriction. While levels of PGE2, prostaglandin I2, and cysteinyl leukotrienes were significantly increased, levels of prostaglandin D2, thromboxane B2, and substance P in the BALF were not. Dm-PGE2 significantly decreased the Mch-induced increase in Penh. Following bronchoconstriction by additional Mch inhalation, dm-PGE2 produced an increase in CRB and cough counts in a dose-dependent manner. Additionally, the heightened CRB following dm-PGE2 treatment was suppressed by pretreatment with PGE2 receptor (E-prostanoid EP) -1 and EP-3 antagonists in a dose-dependent manner, but not by EP-2 and EP-4 antagonists. The EP-1 antagonist also decreased cough counts. These results suggest that PGE2 acts as an exacerbating factor for bronchoconstriction-triggered cough. EP1 and EP3 may provide new therapeutic targets for cough variant asthma.

DOI： 10.1016/j.pupt.2017.09.003

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BACKGROUND: Asthma in the elderly population has been focused because it affects quality of life and results in a higher hospitalization rate and mortality. Fluticasone furoate (FF)/vilanterole (VI) is a novel inhaled corticosteroids (ICS)/long-acting β2 agonist (LABA) combination being developed for once-daily administration for asthma with greater anti-inflammatory activity and longer duration of bronchidilation. The ElliptaTM dry powder inhaler (DPI) has also been available as a new device with high levels of satisfaction and preference. METHODS: A 12-week, randomized, open-label cross-over, pilot study was conducted in 18 elderly patients with bronchial asthma to compare the effectiveness of once-daily FF/VI 200/25 µg via the ElliptaTM DPI vs. twice-daily fluticasone propionate (FP)/salmeterol (SAL) 500/50 µg via the DiskusTM DPI. The study period included a 4-week run-in, the first 4-week treatment, and the second 4-week treatment. Respiratory functions, fractional exhaled nitric oxide (FeNO) and asthma control test (ACT) scores were measured 0, 4, and 8 weeks after randomization. Preferences for their device were also assessed using a self-completed questionnaire. RESULTS: Spirometric paramters, FeNO levels and ACT scores were not significantly different during the run-in period, the FP/SAL treatment period, and the FF/VI treatment period. FF/VI treatment via the ElliptaTM DPI was preferred to the FP/SAL treatment via the DiskusTM DPI (p<0.01). CONCLUSIONS: These data indicate that FF/VI treatment via the ElliptaTM DPI is preferred in elderly patients with asthma based on its ease-of-use, suggesting the potential to improve patient adherence and, as a result, overall disease management.

DOI： 10.1055/s-0043-118536

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Language：English   Publisher：Elsevier Inc  

DOI： 10.1016/j.jtho.2017.07.034

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Language：Japanese   Publisher：(NPO)日本肺癌学会  

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Language：Japanese   Publisher：(NPO)日本肺癌学会  

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Language：Japanese   Publisher：(NPO)日本肺癌学会  

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Language：Japanese   Publisher：(NPO)日本肺癌学会  

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Language：Japanese   Publisher：(NPO)日本肺癌学会  

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Language：Japanese   Publishing type：Research paper (scientific journal)   Publisher：Japan Lung Cancer Society  

Background. Pulmonary pleomorphic carcinoma (PPC) is a rare tumor of the lung and generally carries a poor prognosis. In addition, cases of PPC complicated by humoral hypercalcemia of malignancy (HHM) with an increased serum level of parathyroid hormone-related protein (PTHrP) produced by the tumor are rare. Case. A 59-year-old male smoker presented to us with a chief complaint of pain extending from the right shoulder to the back. Chest computed tomography (CT) showed an 11-cm mass shadow in the right apex area infiltrating the chest wall and an enlarged left adrenal gland. A CT-guided biopsy showed poorly differentiated tumor cells with sarcomatous changes, which led to the diagnosis of PPC (cT4N0Mlb, clinical stage IV, ADR). When admitted for treatment, the patient developed mild consciousness disturbance and was found to have an increased serum level of PTHrP and hypercalcemia
based on these findings, the patient was diagnosed with HHM. He was administered an intravenous infusion of zoledronic acid in saline to control the hypercalcemia. After the serum calcium levels normalized, he was administered six courses of carboplatin + paclitaxel + bevacizumab combination chemotherapy. The chemotherapy proved effective. Conclusion. Although chemotherapy is known to have poor efficacy in patients with advanced PPC, three-drug combination therapy including bevacizumab proved useful in our patient.

DOI： 10.2482/haigan.57.221

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Language：Japanese   Publisher：(株)最新医学社  

肺がんの確定診断は,気管支鏡検査,経皮針生検などによる病理診断,およびコンピュータ断層撮影(CT),磁気共鳴画像法(MRI),フルオロデオキシグルコースポジトロン断層撮影(FDG-PET)などによる病期診断により行われる.進行期非小細胞肺がんにおいては,EGFR遺伝子変異,ALK融合遺伝子,プログラム細胞死リガンド1(PD-L1)発現の分子診断も必要となる.肺がんの組織診断,病期診断および分子診断を正確に行うことは,適切な治療方針を決めるうえで,最も重要である.本稿では,肺がんの病理診断,病期診断,分子診断のために,行うべき検査の選択や手順に関して述べる.(著者抄録)

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：ELSEVIER IRELAND LTD  

We report the case of a 62-year-old man treated with nivolumab as fourth-line therapy for stage IV squamous cell carcinoma of the lung. Because of the onset of nivolumab-induced pneumonitis after 2 doses, nivolumab was discontinued. After discontinuation, the tumor gradually continued to decrease in size without any additional treatment for lung cancer. The patient obtained a long-lasting shrinking of the tumor over 6 subsequent treatment-free months after only 2 administrations of nivolumab. This type of response has not been seen for conventional anticancer drug treatments for NSCLC, and we speculate that a small group of patients with NSCLC will obtain sufficient efficacy from a few doses of nivolumab. (C) 2017 Elsevier B.V. All rights reserved.

DOI： 10.1016/j.lungcan.2017.02.013

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：LIPPINCOTT WILLIAMS & WILKINS  

Rationale: Immunoglobulin G4-related disease (IgG4-RD) is a systemic condition involving various organs and vessels including the pancreas, bile duct, salivary glands, periorbital tissues, kidneys, lungs, lymph nodes, meninges, and aorta. Recently, some cases of IgG4-RD have been reported, in which only pulmonary lesions were present. It is not known whether IgG4-RD can be diagnosed on the basis of pulmonary lesions only, because increases in serum IgG4 levels and infiltration of IgG4-positive plasma cells into the lung tissue also occur in other inflammatory conditions. A case of IgG-RD that was followed-up for 7 years after onset is described.
Patient concerns: Initially, only pulmonary lesions were present; however, other lesions in the submandibular glands, pancreas, periarterial region, and other areas occurred over time, with a gradual increase in serum IgG4 levels.
Diagnoses, interventions, and outcomes: Histopathology results from the patient's submandibular gland confirmed the diagnosis of IgG4-RD. Following diagnosis, the patient was treated with corticosteroids immediately, and his symptoms disappeared rapidly.
Lessons: Because other diseases, including malignancies, mimic IgG4-RD in clinical and histopathological features, an absolute diagnosis is necessary to avoid missing the presence of underlying diseases. This case more provides insight into the clinical pathology of IgG4-RD.

DOI： 10.1097/MD.0000000000007086

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Language：English   Publisher：AMER THORACIC SOC  

DOI： 10.1164/rccm.201610-1973IM

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Language：Japanese   Publisher：(NPO)日本呼吸器内視鏡学会  

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Language：Japanese   Publisher：(一社)日本呼吸器学会  

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：ELSEVIER SCIENCE INC  

BACKGROUND: Imatinib, a tyrosine kinase inhibitor, has been proposed as a potential anti-fibrotic agent for fibroproliferative diseases, including bronchiolitis obliterans (BO). However, the underlying anti fibrotic mechanisms of the agent remain unclear. We evaluated whether bone (BM) derived progenitor cells, fibrocytes, might be a target of imatinib in the attenuation of BO.
METHODS: We used a murine BO model induced by heterotopic tracheal transplantation and assessed the origin of fibroblasts by using green fluorescent protein BM chimeric mice. We also evaluated the effects of imatinib on lurninal obstruction and fibrocyte accumulation. The effects of imatinib on fibrocyte migration and differentiation were assessed by culturing fibrocytes in vitro.
RESULTS: In the murine BO model, tracheal allografts showed epithelial injury and developed complete lurninal occlusion 28 days after transplantation. Most of the mesenchymal cells that had accumulated in the tracheal allograft were derived from BM cells. Imatinib treatment ameliorated the airway luminal occlusion and significantly reduced the number of fibrocytes in the allografts. In vitro studies showed that imatinib inhibited migration of cultured blood fibrocytes via the platelet-derived growth factor/platelet-derived growth factor receptor axis Imatinib also inhibited differentiation of, fibrocytes via suppression of c-Abl activity that was essential for the differentiation of monocytes to fibrocytes.
CONCLUSIONS: Imatinib prevents airway luminal: obstruction by inhibiting the migration and differentiation of fibrocytes. Fibrocytes may be a novel target in the prevention and treatment of BO. (C) 2016 International Society for Heart and Lung Transplantation. All rights reserved.

DOI： 10.1016/j.healun.2016.06.001

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：W B SAUNDERS CO LTD  

Background: Pleuroparenchymal fibroelastosis (PPFE) is a rare interstitial pneumonia with upper lobe predominance and fibroelastosis. Although definite diagnosis requires surgical lung biopsy (SLB), SLB is often difficult because of its complications such as refractory pneumothorax. Objective: To evaluate urinary desmosines (degradation product of mature elastin) as a novel biomarker in patients with PPFE.
Methods: Biopsy-proven patients with PPFE (n = 14) were prospectively enrolled. Levels of urinary desmosines in patients with PPFE were measured with liquid chromatography-tandem mass spectrometry (LC-MS/MS) and compared with those in patients with idiopathic pulmonary fibrosis (IPF), patients with chronic obstructive pulmonary disease (COPD), and controls.
Results: Levels of urinary desmosines were significantly higher in patients with PPFE than those in patients with IPF (48.4 vs. 28.6 ng/mg creatinine, p = 0.034), patients with COPD (8.0 ng/mg creatinine, p &lt; 0.001), or controls (17.4 ng/mg creatinine, p &lt; 0.001). Desmosines discriminated between PPFE and IPF (area under the curve [AUC] = 0.708), and between PPFE and controls (AUC = 0.956). However, levels of desmosines were not correlated with physiological parameters in patients with PPFE.
Conclusions: Urinary desmosines may be a useful diagnostic biomarker in patients with PPFE. Measurement of desmosines combined with specific clinical and radiological features of PPFE may lead to an accurate diagnosis without SLB in patients with PPFE. (C) 2016 Elsevier Ltd. All rights reserved.

DOI： 10.1016/j.rmed.2016.12.013

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Language：Japanese   Publisher：(NPO)日本呼吸器内視鏡学会  

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：TAYLOR & FRANCIS INC  

Background: We demonstrated that heightened cough response to bronchoconstriction is a fundamental feature of cough variant asthma (CVA). To evaluate this physiological feature of CVA in daily clinical practice, it is necessary to clarify the cough response to bronchoconstriction in healthy subjects. We evaluated cough response to methacholine (MCh)-induced bronchoconstriction in healthy subjects. A forced oscillometry technique was used to measure airway resistance changes with Mch. Methods: Healthy never-smokers (21 men, 20 women; mean 22.3 +/- 3.7 years) participated. None had a &gt; 3-week cough history, clinically significant respiratory or cardiovascular disorders, or disorders that might put subjects at risk or influence the study results or the subjects' ability to participate. Twofold increasing concentrations of Mch chloride diluted in phosphate-buffered saline (0.039 to 160 mg/mL) were inhaled from nebulizers at 1-minute intervals during subjects' tidal breathing after the baseline respiratory resistance (Rrs) was recorded. Mch inhalation continued until Rrs reached twice the baseline value and forced expiratory volume in 1 second (FEV1) decreased to &lt; 90% of baseline value. Spirometry was measured before Mch inhalation and immediately after Rrs had increased twofold. Coughs were counted during and for 30 minutes after Mch inhalation. The cough reflex sensitivity to capsaicin was also examined. Results: The number of coughs was 11.1 +/- 14.3 (median, 7.0; range, 0 to 71; reference range, 0 to 39.7). There was no significant difference in the cough response between the sexes. The reproducibility of the cough response to bronchoconstriction was sufficient. No correlation existed between the bronchoconstriction-induced cough response and capsaicin cough-reflex sensitivity. Conclusions: Using the Astograph method, cough response to bronchoconstriction could be measured easily, safely and highly reproducibly in healthy subjects.

DOI： 10.1080/01902148.2017.1342289

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Language：Japanese   Publisher：特定非営利活動法人 日本肺癌学会  

&lt;p&gt;&lt;b&gt;&lt;i&gt;Background. &lt;/i&gt;&lt;/b&gt;Pulmonary pleomorphic carcinoma (PPC) is a rare tumor of the lung and generally carries a poor prognosis. In addition, cases of PPC complicated by humoral hypercalcemia of malignancy (HHM) with an increased serum level of parathyroid hormone-related protein (PTHrP) produced by the tumor are rare. &lt;b&gt;&lt;i&gt;Case. &lt;/i&gt;&lt;/b&gt;A 59-year-old male smoker presented to us with a chief complaint of pain extending from the right shoulder to the back. Chest computed tomography (CT) showed an 11-cm mass shadow in the right apex area infiltrating the chest wall and an enlarged left adrenal gland. A CT-guided biopsy showed poorly differentiated tumor cells with sarcomatous changes, which led to the diagnosis of PPC (cT4N0M1b, clinical stage IV, ADR). When admitted for treatment, the patient developed mild consciousness disturbance and was found to have an increased serum level of PTHrP and hypercalcemia; based on these findings, the patient was diagnosed with HHM. He was administered an intravenous infusion of zoledronic acid in saline to control the hypercalcemia. After the serum calcium levels normalized, he was administered six courses of carboplatin+paclitaxel+bevacizumab combination chemotherapy. The chemotherapy proved effective. &lt;b&gt;&lt;i&gt;Conclusion. &lt;/i&gt;&lt;/b&gt;Although chemotherapy is known to have poor efficacy in patients with advanced PPC, three-drug combination therapy including bevacizumab proved useful in our patient.&lt;/p&gt;

DOI： 10.2482/haigan.57.221

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Language：Japanese   Publisher：特定非営利活動法人 日本肺癌学会  

&lt;p&gt;&lt;b&gt;&lt;i&gt;Background. &lt;/i&gt;&lt;/b&gt;The prognosis of pleomorphic carcinoma of the lung is poor. &lt;b&gt;&lt;i&gt;Case. &lt;/i&gt;&lt;/b&gt;A 59-year-old man was referred to our hospital and presented with back pain and hemosputum. After an evaluation, he was diagnosed with pleomorphic carcinoma of the lung (cT2bN2M1b stage IV [ADR]). He was systemically administered three cycles of carboplatin plus paclitaxel, but metastases in the right adrenal gland and liver worsened. Severe anemia was also confirmed. Gastric and duodenal metastases of pleomorphic carcinoma were confirmed using an upper and lower gastrointestinal endoscope. Swollen lower gingiva emerged at the same time and was diagnosed as metastasis of pleomorphic carcinoma as well. The patient was administered two cycles of nivolumab as a second-line treatment; nonetheless, the liver metastases progressed. One week after the last treatment, small-intestinal perforation occurred due to small-intestinal metastases, which was thought to be causally related to the severe anemia. &lt;b&gt;&lt;i&gt;Conclusion. &lt;/i&gt;&lt;/b&gt;We observed a rare case of pleomorphic carcinoma of the lung that developed into small-intestinal perforation with gastroduodenal, hepatic, and gingival metastases. In this case, nivolumab administration was ineffective.&lt;/p&gt;

DOI： 10.2482/haigan.57.860

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Language：Japanese   Publisher：特定非営利活動法人 日本肺癌学会  

&lt;p&gt;&lt;b&gt;&lt;i&gt;Background. &lt;/i&gt;&lt;/b&gt;The prognosis of pleomorphic carcinoma of the lung is poor. &lt;b&gt;&lt;i&gt;Case. &lt;/i&gt;&lt;/b&gt;A 59-year-old man was referred to our hospital and presented with back pain and hemosputum. After an evaluation, he was diagnosed with pleomorphic carcinoma of the lung (cT2bN2M1b stage IV [ADR]). He was systemically administered three cycles of carboplatin plus paclitaxel, but metastases in the right adrenal gland and liver worsened. Severe anemia was also confirmed. Gastric and duodenal metastases of pleomorphic carcinoma were confirmed using an upper and lower gastrointestinal endoscope. Swollen lower gingiva emerged at the same time and was diagnosed as metastasis of pleomorphic carcinoma as well. The patient was administered two cycles of nivolumab as a second-line treatment; nonetheless, the liver metastases progressed. One week after the last treatment, small-intestinal perforation occurred due to small-intestinal metastases, which was thought to be causally related to the severe anemia. &lt;b&gt;&lt;i&gt;Conclusion. &lt;/i&gt;&lt;/b&gt;We observed a rare case of pleomorphic carcinoma of the lung that developed into small-intestinal perforation with gastroduodenal, hepatic, and gingival metastases. In this case, nivolumab administration was ineffective.&lt;/p&gt;

DOI： 10.2482/haigan.57.860

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Language：Japanese   Publisher：特定非営利活動法人 日本呼吸器内視鏡学会  

&lt;p&gt;&lt;b&gt;&lt;i&gt;Background.&lt;/i&gt;&lt;/b&gt; Endobronchial metastasis (EM) of extrathoracic malignancy is rare. &lt;b&gt;&lt;i&gt;Case.&lt;/i&gt;&lt;/b&gt; We herein report a case of EM of clear cell renal cell carcinoma (RCC) in a 68-year-old man. The patient has a history of left nephrectomy due to clear cell RCC 22 years prior. He presented with bloody sputa, dysbasia, anesthesia of the limbs, and pain in the left shoulder joint. A computed tomography (CT) scan revealed a tumor mass in the lower lobe of the right lung, as well as osteolytic signs of the cervical vertebrae, thoracic vertebrae, and bilateral ribs. The patient was referred to our hospital for a closer examination and treatment of disseminated tumors and spinal cord compression due to the vertebral lesions. Bronchoscopy showed a tumor in the right B&lt;sup&gt;10&lt;/sup&gt;. A transbronchial biopsy revealed EM of clear cell RCC. &lt;b&gt;&lt;i&gt;Conclusion.&lt;/i&gt;&lt;/b&gt; The case presented here illustrates that relapse of renal cancer can occur after a long-term disease-free period of over 20 years and suggests that patients with RCC should be carefully monitored for relapse.&lt;/p&gt;

DOI： 10.18907/jjsre.39.1_34

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We present a rare case of gingival cancer with pulmonary metastases that developed life-threatening complete atrioventricular block and ventricular fibrillation as a result of myocardial metastases. This case suggests that implantable cardioverter defibrillators significantly improve the quality of life in these patients and maintain their performance status.

DOI： 10.1002/ccr3.695

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Language：Japanese   Publisher：(NPO)日本肺癌学会  

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：ELSEVIER SCIENCE BV  

Paradoxical reactions (PRs) to antituberculosis (anti-TB) drugs during treatment are well known phenomena, but a PR presenting as a new pulmonary lesion after completion of treatment is extremely rare, and little is known about the management of such cases. A 44-year-old man was diagnosed with pulmonary TB. His sputum cultures became negative 45 days after the initiation of standard anti-TB treatment. Upon the patient's completion of 6 months of anti-TB therapy, computed tomography revealed a new irregularly shaped mass in the lower left pulmonary lobe. A transbronchial lung biopsy (TBLB) revealed caseous necrosis and granulomatosis surrounded by epithelioid and multinucleated giant cells. Cultures of both the TBLB specimen and bronchoalveolar lavage fluid remained negative for TB. The CT shadow disappeared 6 months later without further administration of anti-TB drugs. Careful observation without therapy may be sufficient for a patient treated for TB who develops a PR upon completion of treatment, if the patient has achieved a bacteriological remission. (C) 2016 Japanese Society of Chemotherapy and The Japanese Association for Infectious Diseases. Published by Elsevier Ltd. All rights reserved.

DOI： 10.1016/j.jiac.2016.03.012

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Language：Japanese   Publisher：(NPO)日本肺癌学会  

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DOI： 10.1016/j.alit.2016.04.009

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Language：Japanese   Publisher：(一社)日本癌治療学会  

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Language：Japanese   Publisher：(NPO)日本肺癌学会  

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：ELSEVIER IRELAND LTD  

Objectives: Ramucirumab plus docetaxel prolongs survival in patients with non-small cell lung cancer (NSCLC) with disease progression after platinum-based therapy. This phase II, double-blind, randomized, placebo-controlled study assessed efficacy and safety of second-line ramucirumab-docetaxel in Japanese patients with NSCLC.
Materials and methods: Patients with NSCLC with progression after platinum-based therapy (28 Japanese sites; 19 December, 2012 to 22 May, 2015) were randomized (computer-generated sequence) to ramucirumab 10 mg/kg or placebo, followed by docetaxel 60 mg/m(2) (Day 1, 21-day cycle). Prior epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) monotherapy was prohibited in the primary population, but EGFR mutation-positive NSCLC patients who were treated with EGFR-TKI were enrolled as a separate exploratory population. Primary endpoint was progression-free survival (PFS); secondary outcomes included overall survival, tumor response rates, and safety. Investigator tumor assessments were used for the efficacy endpoints.
Results: In the primary population (N = 160 randomized, n=157 treated), median (95% CI) PFS was longer with ramucirumab-docetaxel (5.22 [3.52-6.97] months; n=76) than with placebodocetaxel (4.21 [2.83-5.62] months; n = 81); hazard ratio 0.83 (95% CI 0.59-1.16). Median (95% CI) overall survival was 15.15 (12.45-26.55) months with ramucirumab-docetaxel and 14.65 con (11.93-24.44) months with placebo-docetaxel (hazard ratio [95% CI] 0.86 [0.56-1.32]). Objective response rate (28.9% vs 18.5%) and disease control rate (78.9% vs 70.4%) were numerically greater with ramucirumab-docetaxel than with placebo-docetaxel. Incidence and severity of most adverse events were similar, but febrile neutropenia was more common with ramucirumab-docetaxel (34.2%) than with placebo-docetaxel (19.8%).
Conclusion: Second-line ramucirumab-docetaxel improved PFS similar to that seen in the REVEL trial with a manageable safety profile in Japanese patients with NSCLC. (C) 2016 Elsevier Ireland Ltd. All rights reserved.

DOI： 10.1016/j.lungcan.2016.07.019

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DOI： 10.1016/j.resinv.2016.03.003

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Objectives: To describe the pulmonary CT findings in patients with anti-ARS-antibody-positive interstitial lung disease (anti-ARS-ILD)
Methods: The CT findings of 64 patients with anti-ARS-ILD were retrospectively reviewed. The images were retrospectively reviewed independently by 2 chest radiologists, and the final decision on the CT findings was made by a third chest radiologist.
Results: There were 16 male and 48 female patients, aged 54.2 +/- 13.4 years. Sixteen patients had anti Jo-1, 24 had anti-EJ, 9 had anti-PL-7, 7 had anti-PL-12, 5 had anti-KS, and 3 had anti-OJ antibodies. Overall, 63 patients (98.4%) had CT findings predominantly in the lower lobe; 61 patients (95.3%) showed peripheral opacities, and 47 patients (73.4%) showed peribronchovascular opacities. Ground-glass attenuation, consolidation, and reticulation showed similar distribution patterns. Regarding detailed CT findings, 89.1% of patients had lower volume loss, 76.6% had interlobular septal thickening, and 67.2% had thickening of bronchovascular bundles. The final radiologic diagnoses were as follows: inconsistent with usual interstitial pneumonia (UIP) in 63 patients (98.4%), which included nonspecific interstitial pneumonia (NSIP) in 35 patients (55.6%), organizing pneumonia (OP) in 4 patients (6.3%), and OP with fibrosis in 22 patients (34.9%).
Conclusions: The characteristic CT findings of patients with anti-ARS-ILD were areas of ground-glass attenuation and reticulation, predominantly distributed as lower and peribronchovascular lesions, which is compatible with NSIP. One-third of patients showed OP with fibrosis. (C) 2016 The Authors. Published by Elsevier Ireland Ltd. This is an open access article under the CC BY-NC-ND license.

DOI： 10.1016/j.ejrad.2016.05.012

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Medknow Publications  

Introduction: Patients with end-stage interstitial lung disease (ILD) do not appear to receive adequate palliative care despite apparent suffering before death. The aim of this study was to evaluate their signs, symptoms, and treatment received before death. Methods: Patients with ILD and lung cancer (LC) who were hospitalized and died in our hospital were enrolled retrospectively. Signs and symptoms and treatments at 7 days, 3 days, and 1 day before death were evaluated and compared between the two groups of patients. Results: A total of 23 patients with ILD and 59 patients with LC group were eligible for participation. Significantly more LC patients had loss of consciousness than ILD patients on 7 days (ILD: LC = 1 [5.6%]:24 [41%], P = 0.013), 3 days (1 [5.6%]:33 [56%], P &lt
0.001). Significantly more ILD patients had dyspnea than LC patients on 3 days (16 [89%]:38 [64%], P = 0.047) 1 day before death (21 [91%]:33 [56%], P = 0.001). On 1 day before death, significantly more LC patients received morphine than ILD patients (2 [8.7%]: 14 [24%], P = 0.015). More ILD patients received sedation (11 [48%]: 11 [19%], P = 0.007). Conclusions: End-stage ILD patients may experience dyspnea more frequently than terminal LC patients, and they need sedation. Morphine should be administered to ILD patients who have dyspnea. Additional prospective studies are needed.

DOI： 10.4103/0973-1075.185035

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：TAYLOR & FRANCIS INC  

Background: Atopic cough (AC) and cough variant asthma (CVA) were identified as major causes of chronic non-productive cough in a Japanese study. A characteristic feature of CVA is the presence of a heightened cough response to bronchoconstriction. On the other hand, the cough response to bronchoconstriction in AC remains unclear. Methods: Methacholine (Mch)-induced cough in AC was measured and compared with that in CVA. Diagnoses of AC and CVA were made based on patient history, physical examination, response to bronchodilator therapy, cough reflex sensitivity to capsaicin, spirometry, and airway responsiveness to methacholine. Results: Thirteen AC patients and 12 CVA patients in whom the criteria were met were recruited to the study. After inhalation of Mch at PC35-PEF40 that means milder bronchoconstriction than PC20-FEV1, cough was triggered a few times in AC. (cough number: 1/32 min (0-40)). Conversely, significantly greater number of coughs was provoked in CVA, compared with AC (cough number: 35.5/32 min (25-125), p &lt; 0.05). Conclusions: The cough response to bronchoconstriction is reduced in AC compared to CVA. This feature may be useful in the diagnosis of chronic cough.

DOI： 10.1080/01902148.2016.1195460

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Language：Japanese   Publisher：(一社)日本アレルギー学会  

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Language：Japanese   Publisher：(NPO)日本呼吸器内視鏡学会  

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Language：Japanese   Publishing type：Research paper (scientific journal)   Publisher：Japanese Journal of Cancer and Chemotherapy Publishers Inc.  

An increasing number of patients with lung cancer are undergoing outpatient chemotherapy. It is very important to retain the quality of life (QOL) of these patients. Japanese traditional medicine, TJ-48, has been reported to improve the QOL of patients with advanced cancer. However, the effect of TJ-48 in patients with lung cancer undergoing outpatient chemotherapy is unknown. The present study was conducted to investigate the factors influencing the QOL of these patients. We used "The QOL questionnaire for cancer patients treated with anticancer drugs" (QOL-ACD) with 16 patients with non-small cell lung cancer. The medical factors related to the overall QOL scores and other variables indicating "activity," "physical condition," "psychological condition," "social relationships," "psychological condition," and "face scale" were analyzed. Significant improvement was observed in the total QOL score, mainly owing to the improvement in the patients' "physical condition".

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Language：Japanese   Publisher：(一社)日本呼吸器学会  

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Language：Japanese   Publisher：The Japan Society for Respiratory Endoscopy  

Background. Pulmonary pneumatoceles are thin-walled, air-filled cavities that mainly occur as a complication of pulmonary infection in infants and children. Pneumatoceles caused by bronchial foreign body are rare. Case. A 70-year-old man who had been under treatment for chronic obstructive pulmonary disease and bronchial asthma was hospitalized for an asthma attack. He presented with bloody sputum the morning after the discharge. Chest radiography revealed a cavitary lesion with a niveau in the lower part of the left lung. Chest CT revealed a pneumatocele with a small volume of fluid in the left lingular lobe and foreign bodies in the left lower bronchus. Although bronchoscopic treatment was recommended, bloody sputum disappeared and soybeans which had been taken at home on the day of discharge were expectorated on a cough attack, resulting in the decreased size of the pneumatocele. Conclusion. We report a case of pneumatocele caused by bronchial foreign bodies. Soybean aspiration was the cause of the pneumatocele and bloody sputum.

DOI： 10.18907/jjsre.38.1_32

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Other Link： http://search.jamas.or.jp/link/ui/2016186718

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BACKGROUND: Patients with epidermal growth factor receptor (EGFR) activation mutation-positive non-small-cell lung cancer (NSCLC) respond well to EGFR tyrosine kinase inhibitors (EGFR-TKIs), but eventually become resistant in most cases. The hepatocyte growth factor/c-Met (HGF/c-Met) pathway is reported as a poor prognostic factor in various cancers. As c-Met is involved in EGFR-TKI resistance, a c-Met inhibitor and EGFR-TKI combination may reverse the resistance. This study evaluated the efficacy and safety of a c-Met selective inhibitor, tivantinib (ARQ 197), in combination with erlotinib, in Japanese EGFR mutation-positive patients with NSCLC who progressed while on EGFR-TKIs. METHODS: This study enrolled 45 patients with NSCLC with acquired resistance to EGFR-TKIs, who were orally administered a daily combination of tivantinib/erlotinib. The primary end point was the overall response rate (ORR) and secondary end points included disease control rate, progression-free survival (PFS) and overall survival (OS). The patients underwent a mandatory second biopsy just after progression on EGFR-TKIs. The predictive biomarkers were extensively analysed using tumour and blood samples. RESULTS: The ORR was 6.7% (95% CI 1.4% to 18.3%), and the lower limit of 95% CI did not exceed the target of 5%. The median PFS (mPFS) and median OS (mOS) were 2.7 months (95% CI 1.4 to 4.2) and 18.0 months (95% CI 13.4 to 22.2), respectively. Both were longer in c-Met high patients (c-Met high vs low: mPFS 4.1 vs 1.4 months; mOS 20.7 vs 13.9 months). Partial response was observed in three patients, all of whom were c-Met and HGF high. The common adverse events and their frequencies were similar to those known to occur with tivantinib or erlotinib alone. CONCLUSIONS: Although this study did not prove clinical benefit of tivantinib in patients with acquired resistance to EGFR-TKIs, activated HGF/c-Met signalling, a poor prognostic factor, may define a patient subset associated with longer survival by the tivantinib/erlotinib combination. TRIAL REGISTRATION NUMBER: NCT01580735.

DOI： 10.1136/esmoopen-2016-000063

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：SPRINGER INT PUBLISHING AG  

Epidermal growth factor receptor (EGFR) T790M mutation is associated with resistance to EGFR tyrosine kinase inhibitors' (EGFR-TKIs) in non-small cell lung cancer (NSCLC). The aims of this study are to develop a blood-based, non-invasive approach to detecting the EGFR T790M mutation in advanced NSCLC patients, using PointMan (TM) EGFR DNA Enrichment Kit which is a novel method for selective amplification of genotype specific sequences.
Pairs of blood samples and tumor tissues were collected from NSCLC patients with an EGFR activating mutation and who were resistant to EGFR-TKI treatment. EGFR T790M mutation in plasma DNA were detected using the PointMan (TM) EGFR DNA Enrichment Kit. The concentrations of plasma DNA were determined using quantitative real-time PCR.
Of the 52 patients enrolled in this study, 41 of the patients' plasma samples were collected at post EGFR-TKIs. Nineteen (46.3 %) of the 41 patients had an EGFR T790M mutation in their plasma DNA as detected using the PointMan (TM) EGFR DNA Enrichment Kit after disease progression to EFGR-TKI. Of 11 cases with a detected T790M mutation from tumor tissues, 10 (90.9 %) also had a detectable T790M mutation in the plasma DNA. There was no difference in the progression-free survival between patients with T790M and those without T790M.
The PointMan (TM) proved to be a useful method for determining plasma EGFR T790M mutation status

DOI： 10.1007/978-3-319-42044-8_31

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：JAPAN SOC INTERNAL MEDICINE  

A 50-year-old man presented to our hospital in 1995. Invasive thymoma was diagnosed and extended thymectomy and left upper lobe partial resection were performed. In 2013, he complained of dyspnea. Chest computed tomography showed postoperative recurrence of invasive thymoma. Several chemotherapies were administered. Severe anemia and an increase in the total bilirubin level were observed with chemotherapies. In additional, an examination showed that the direct Coombs test was positive. Cold agglutinin was also high. We herein experienced a rare case of postoperative recurrence of invasive thymoma with cold agglutinin disease and autoimmune hemolytic anemia.

DOI： 10.2169/internalmedicine.55.6654

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Language：Japanese   Publisher：日本肺癌学会 = The Japan Lung Cancer Society  

&lt;p&gt;&lt;b&gt;&lt;i&gt;Background. &lt;/i&gt;&lt;/b&gt;Primary lung cancers commonly invade the lung parenchyma and, on reaching the visceral pleura, cause pleural dissemination. We herein report a surgical case of primary lung cancer which showed a unique growth pattern of spreading predominantly within the interlobular pleura. &lt;b&gt;&lt;i&gt;Case. &lt;/i&gt;&lt;/b&gt;A 65-year-old male patient was referred to our department because of an abnormal shadow in the right middle lung field detected on chest X-ray film during the follow-up period of angina. Contrast-enhanced computed tomography revealed slightly enhanced nodule shadows with a beaded appearance in the right minor and major fissures. During the observation period, the size of this abnormal shadow increased slowly with no evidence of lymph node enlargement or distant metastasis. Therefore, the patient underwent surgical resection (right upper and middle lobectomy with partial resection of the right lower lobe) for diagnostic and therapeutic purposes, and lymph node dissection was performed. On a histopathological examination, the tumor was found to be located only partly within the lung parenchyma of the upper lobe but predominantly within the interlobular pleura. The tumor cells were arranged in a tubular or papillary pattern, and immunohistochemical examinations revealed the tumor cells to be positive for TTF-1 and SP-A, leading to a diagnosis of primary pulmonary adenocarcinoma (pT3N0M0). In addition, EML4-ALK translocation was positive, whereas EGFR mutation was negative. The patient received adjuvant chemotherapy with the oral administration of UFT for two years after surgery with no evidence of recurrence. &lt;b&gt;&lt;i&gt;Conclusion. &lt;/i&gt;&lt;/b&gt;The invasive growth of primary lung cancer within the interlobular pleura is a rare form of progression. In our present case, it was difficult to distinguish between primary lung cancer and other lesions of pleural origin.&lt;/p&gt;

DOI： 10.2482/haigan.56.368

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD  

Background: Asthma-chronic obstructive pulmonary disease overlap syndrome (ACOS) is important because patients with ACOS have significantly worse outcomes compared with those with asthma or chronic obstructive pulmonary disease (COPD) alone. Inhaled corticosteroids (ICS), together with a long-acting 62 agonist (LABA), are recommended, but no therapeutic studies for ACOS have been conducted. Recently, fluticasone furoate/vilanterole (FF/VI) has been approved as the first once-daily ICS/LABA combination therapy for asthma and COPD.
Methods: A 12-week, randomized, open-label cross-over study was conducted in 16 patients with ACOS to compare the effectiveness of once-daily FF/VI 200/25 mu g vs. twice-daily fluticasone propionate/salmeterol (FP/SAL) 500/50 mu g. The study period included a 4-week run-in, the first 4-week treatment, and the second 4-week treatment. Respiratory functions, including forced expiratory volume in 1 s (FEV1) and respiratory impedance using the forced oscillation technique (FOT), were measured, as was fractional exhaled nitric oxide (FeNO). A COPD assessment test (CAT) scores and asthma control test (ACT) scores were recorded 0, 4, and 8 weeks after randomization.
Results: The mean values for the FEV1 were 1.33 (+/- 0.29) L in the run-in period, 1.38 (+/- 0.39) L after the FP/SAL treatment period, and 1.47 (+/- 0.38) L after the FF/VI treatment period. The FEV1 value after the FF/VI treatment was significantly greater than the value after the run-in period (p &lt; 0.01). FOT parameters, FeNO levels, CAT scores, ACT scores, and other blood tests were not significantly different during the run-in period, the FP/SAL treatment period, and the FF/VI treatment period.
Conclusions: FF/VI, the first once-daily ICS/LABA, can provide substantial improvement in lung functions, indicating that FF/VI should be considered for the regular treatment of ACOS. (C) 2015 Elsevier Ltd. All rights reserved.

DOI： 10.1016/j.pupt.2015.10.005

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CiNii Books

J-GLOBAL

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Language：Japanese   Publisher：(NPO)日本肺癌学会  

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DOI： 10.1038/bmt.2015.120

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BACKGROUND: Pleuroparenchymal fibroelastosis (PPFE) is a rare idiopathic interstitial pneumonia defined by pleural and subpleural parenchymal fibrosis predominantly in the upper lobes. Although the radiological and pathological characteristics of PPFE have become increasingly recognized, its pulmonary physiological features are not well understood. METHODS: We reviewed nine patients with radiologically and histologically proven PPFE, and evaluated pulmonary physiological data. RESULTS: Of the nine patients, six were male and three were female. The median age at presentation was 61 years. Common symptoms were dyspnea on exertion, weight loss, and nonproductive cough. Recurrent pneumothorax was found in eight patients and pneumonia in four. Median pulmonary function test results were as follows: forced vital capacity, 55.4% predicted; total lung capacity (TLC), 67.1% predicted; residual volume (RV), 102.3% predicted; and RV/TLC, 143.6% predicted. RV/TLC was increased without evidence of small airway disease according to clinico-radiologic-pathologic evaluation. The median partial pressure of oxygen in arterial blood and the alveolar-arterial gradient of oxygen were within normal limits, although there was a slightly elevated partial pressure of carbon dioxide in arterial blood (PaCO2). PPFE progressed in all patients despite treatment with pirfenidone, corticosteroids, and immunosuppressive agents. Seven patients died during the follow-up, five because of hypercapnic respiratory failure. CONCLUSIONS: PPFE is characterized by severe mechanical restriction with high RV/TLC, causing increased PaCO2 and eventual hypercapnic respiratory failure. These physiological findings may be useful as an adjunct in the diagnosis of PPFE.

DOI： 10.1016/j.resinv.2015.02.003

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Other Link： https://search.jamas.or.jp/default/link?pub_year=2015&ichushi_jid=J00298&link_issn=&doc_id=20150818320023&doc_link_id=%2Fcf0brond%2F2015%2Fs03704%2F001%2F0480-0480%26dl%3D0&url=https%3A%2F%2Fwww.medicalonline.jp%2Fjamas.php%3FGoodsID%3D%2Fcf0brond%2F2015%2Fs03704%2F001%2F0480-0480%26dl%3D0&type=MedicalOnline&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00004_2.gif

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Language：Japanese   Publishing type：Research paper (scientific journal)   Publisher：Japanese Journal of Cancer and Chemotherapy Publishers Inc.  

A 48-year-old woman was admitted to our hospital for sixth-line chemotherapy. A chest X-ray film and computed tomographic (CT) scan revealed a right-sided massive tumor with multiple lung tumors. Repeated treatment with carboplatin (AUC 6) on day 1 and nab-paclitaxel (100 mg/m2) on days 1, 8, and 15, every 28 days were effective in this patient. Chemotherapy with nab-paclitaxel may be effective for patients with multi-recurrent adenocarcinoma.

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Language：Japanese   Publisher：(公社)日本医学放射線学会  

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Language：Japanese   Publisher：特定非営利活動法人 日本呼吸器内視鏡学会  

DOI： 10.18907/jjsre.37.Special_S234

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：INFORMA HEALTHCARE  

Aims: Inflammatory mediators are involved in the pathophysiology of neutrophilic bronchial disorders presenting with chronic productive cough. Accumulating evidence indicates that prostanoids are key elements in the pathophysiology of these disorders. However, little is known about the role of prostacyclin in neutrophilic bronchial inflammation. Methods: The effect of beraprost, a chemically and biologically stable analog of prostacyclin, on cough response to inhaled capsaicin was examined in 14 patients with chronic bronchitis, a neutrophilic bronchial disorder, in a randomized, placebo-controlled crossover study. Capsaicin cough threshold, defined as the lowest concentration of capsaicin eliciting five or more coughs, was measured as an index of the airway cough reflex sensitivity. Results: After a 2-week treatment with beraprost (80 mu g twice a day orally), the cough threshold was significantly (P &lt; .05) decreased as compared with placebo [12.2 (geometric standard error of the mean [GSEM] 1.5) mu M vs. 24.4 (GSEM 1.3)]. Conclusions: These findings indicate that prostacyclin is involved in the pathophysiology of cough reflex sensitivity in patients with chronic bronchitis, a frequently encountered neutrophilic bronchial disorder presenting with chronic productive cough.

DOI： 10.3109/01902148.2014.946632

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Language：Japanese   Publisher：(NPO)日本肺癌学会  

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Language：Japanese   Publishing type：Research paper (scientific journal)   Publisher：Japan Lung Cancer Society  

Background. The invasion of thymoma into the bronchial lumen is rare. Case 1. An 85-year-old female was diagnosed with postoperative recurrence of thymoma in 2013. Extended thymectomy and right upper lobectomy were performed in 2002. By 2013, she had developed cough and wheezing, and an abnormal shadow was recognized in the right lung on a chest radiograph. Chest computed tomography (CT) showed a mass obstructing the airway of the right main bronchus, and postoperative recurrence of thymoma was confirmed on bronchoscopy. The patient received chemotherapy, after which follow-up CT showed the thymoma in the right main bronchus to have nearly disappeared. Case 2. A 69-year-old male was diagnosed with postoperative recurrence of thymoma in 2013. Extended thymectomy was performed in 1995. However, a mass was subsequently detected at the left cardiophrenic angle and left aspect of T2 in 2003. Although the patient underwent tumor resection, he experienced postoperative recurrence of thymoma with the dissemination of pleural metastasis in 2013. On admission, his chief complaint was dyspnea on exertion. Chest CT showed a pleural tumor as well as a tumor obstructing the bronchus on the left side. Postoperative recurrence of thymoma was confirmed on bronchoscopy, and the patient subsequently received chemotherapy. Follow-up chest CT demonstrated shrinkage of the tumor in the left main bronchus. Conclusions. We experienced two cases of invasive thymoma with postoperative recurrence and expansion into the bronchial lumen. Necrotic tissue was a characteristic finding on the surface of the tumor expanding into the bronchial lumen in both cases. In such cases, it is essential to perform a biopsy in order to establish the differential diagnosis.

DOI： 10.2482/haigan.54.191

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Language：Japanese   Publishing type：Research paper (scientific journal)   Publisher：Japan Lung Cancer Society  

Background. Cases of malignant mesothelioma exiting or invading the posterior mediastinum are rare. Case. An 81-year-old male visited our hospital due to pain in the lower back. Plain chest computed tomography (CT) showed nodules in the right pleura and a vertebral mass invading the eleventh dorsal vertebra. We performed a thoracoscopic pleural biopsy, as the nodules in the right pleura were suspected to be pleural malignant lesions. The patient was consequently diagnosed with malignant pleural mesothelioma. In addition, the posterior mediastinal mass was suspected to be malignant lymphoma, and a bone marrow puncture showed a diagnosis of non-Hodgkin's lymphoma. Although a biopsy of the posterior mediastinal mass was not performed due to the patient's poor general condition, we administered antitumor drugs to treat the malignant mesothelioma. Hence, the patient was ultimately diagnosed with malignant mesothelioma based on a CT-guided percutaneous biopsy of the mediastinal mass. The posterior mediastinal mass was thought to be primary malignant mesothelioma, while the pleural nodules were considered metastases. No tumor progression was detected during one cycle of pemetrexed treatment followed by six cycles of combined carboplatin and pemetrexed therapy. Conclusions. Although it was difficult to differentiate the pleural nodules and posterior mediastinal mass from other posterior mediastinal tumors in this case, we ultimately diagnosed the lesions to be malignant pleural mesothelioma based on thoracoscopic pleural and CT-guided percutaneous biopsies. We reported this case because invasion of malignant mesothelioma into the posterior mediastinum is rare, and no previous reports of the coexistence of malignant mesothelioma and non-Hodgkin's lymphoma are available. Therefore, the association between these entities is unclear.

DOI： 10.2482/haigan.54.218

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：ELSEVIER IRELAND LTD  

Objectives: Recent advances in endobronchial ultrasonography with a guide sheath (EBUS-GS) have enabled better visualization of distal airways, while virtual bronchoscopic navigation (VBN) has been shown useful as a guide to navigate the bronchoscope. However, indications for utilizing VBN and EBUS-GS are not always clear. To clarify indications for a bronchoscopic examination using VBN and EBUS-GS, we evaluated factors that predict the diagnostic yield of a transbronchial biopsy (TBB) procedure for peripheral lung cancer (PLC) lesions.
Methods: We retrospectively reviewed the charts of 194 patients with 201 PLC lesions (&lt;= 3 cm mean diameter), and analyzed the association of diagnostic yield of TBB with [F-18]-fluoro-2-deoxy-D-glucose (F-18-FDG) positron emission tomography and chest computed tomography (CT) findings.
Results: The diagnostic yield of TBB using VBN and EBUS-GS was 66.7%. High maximum standardized uptake value (SUVmax), positive bronchus sign, and ground-glass opacity component shown on CT were all significant predictors of diagnostic yield, while multivariate analysis showed only high F-18-FDG uptake (SUVmax &gt;= 2.8) and positive bronchus sign as significant predictors. Diagnostic yield was higher for PLC lesions with high F-18-FDG uptake (SUVmax &gt;= 2.8) and positive bronchus sign (84.6%) than for those with SUVmax &lt;2.8 and negative bronchus sign (33.3%). High F-18-FDG uptake was also correlated with tumor invasiveness.
Conclusions: High F-18-FDG uptake predicted the diagnostic yield of TBB using VBN and EBUS-GS for PLC lesions. F-18-FDG uptake and bronchus sign may indicate for the accurate application of bronchoscopy with those modalities for diagnosing PLC. (C) 2014 Elsevier Ireland Ltd. All rights reserved.

DOI： 10.1016/j.lungcan.2014.03.025

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：MARY ANN LIEBERT, INC  

Background: Lung cancer is the leading cause of cancer-related death.(1) Accurate prediction of survival in the terminal stage is important, because it may help patients make a rational decision. Although several prognostic scores have been described as effective indicators of outcome, these scores were intended for patients with other types of cancers. There is no prognostic score for patients with terminal-stage lung cancer. Objective: The aim of this study was to determine prognostic factors for patients with terminal-stage lung cancer. Setting/Subjects: Patients in our palliative care unit (PCU) were selected retrospectively and divided into two independent groups, training and testing. Univariate and multivariate analyses were performed on data from the training group to detect independent prognostic factors, while data from patients in the testing group were analyzed to validate whether these prognostic factors predicted near-term death. Results: Ninety-three patients (69 in the training group and 24 in the testing group) were included in the analyses. Multivariate analysis showed that fatigue, anorexia, desaturation, hyponatremia, and hypoalbuminemia were independent prognostic factors in the training group. Mean survival time in patients who had more than three of these five factors was 9.22.6 days (p=0.012). In the testing group, the presence of more than three of these five factors predicted death within two weeks, with a sensitivity of 100% and specificity of 75%. Conclusions: This study revealed that fatigue, anorexia, desaturation, hyponatremia, and hypoalbuminemia may be short-term prognostic factors in terminally ill lung cancer patients. In particular, the presence of more than three of these factors predicted death within two weeks.

DOI： 10.1089/jpm.2013.0448

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Language：Japanese   Publisher：特定非営利活動法人 日本呼吸器内視鏡学会  

DOI： 10.18907/jjsre.36.4_441_5

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Language：Japanese   Publishing type：Research paper (scientific journal)   Publisher：Japanese Journal of Cancer and Chemotherapy Publishers Inc.  

Increasing number of patients with advanced non-small cell lung cancer are receiving outpatient maintenance chemotherapy. It is very important to maintain these patients' quality of life (QOL). Pemetrexed has been reported to be an effective maintenance chemotherapy. However, its effects on the QOL of patients with non-small cell lung cancer who are undergoing outpatient maintenance chemotherapy are unknown
therefore, we conducted this study. To investigate factors that influence the QOL of these patients, we provided a QOL questionnaire, "The QOL Questionnaire for Cancer Patients Treated with Anticancer Drugs (QOL-ACD)" to 7 patients with non-small cell lung cancer. The medical factors related to the overall QOL scores, as well as other categories indicating "activity", "physical condition", "psychological condition", "social relationship", and "face scale", were analyzed. No significant reductions in any of the factors were observed in this study.

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Language：Japanese   Publisher：特定非営利活動法人 日本呼吸器内視鏡学会  

DOI： 10.18907/jjsre.36.Special_S268_1

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：ELSEVIER IRELAND LTD  

We report the case of a 52-year-old woman with lung adenocarcinoma treated with EGFR tyrosine kinase inhibitor (TKI) therapy. After disease progression, histological examination of a secondary biopsy specimen revealed small-cell lung cancer (SCLC) that was sensitive to standard SCLC treatment. Tumor markers, including ProGRP and NSE, were elevated. Transformation to SCLC is a mechanism for acquired resistance to EGFR-TKI therapy. Secondary biopsy is important for evaluation of genetic and histological changes and selection of appropriate treatment. Furthermore, ProGRP and NSE may be useful for early detection of SCLC transformation in cases resistant to EGFR-TKI therapy. (C) 2013 Elsevier Ireland Ltd. All rights reserved.

DOI： 10.1016/j.lungcan.2013.06.003

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：SPRINGER JAPAN KK  

We describe a 50-year-old woman with rapidly progressive pulmonary Mycobacterium abscessus (M. abscessus) infection accompanied by pleural effusion and organizing pneumonia (OP). CT scan showed consolidation, centrilobular shadows, ground-glass opacity (GGO), and cavities. A transbronchial lung biopsy showed nonnecrotizing granuloma surrounded by infiltrative lymphocyte-dominant inflammatory cells, and lymphocytes in bronchoalveolar lavage fluid (BALF) were increased. We considered OP occurred secondary to M. abscessus infection because clarithromycin, amikacin, and imipenem/cilastatin administration resulted in partial improvement. We added corticosteroids to the regimen, which resulted in a remarkable improvement. We report a case of pulmonary M. abscessus infection involving pleural effusion that responded favorably to medical therapy including corticosteroids.

DOI： 10.1007/s10156-012-0539-8

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Language：Japanese   Publisher：(NPO)日本肺癌学会  

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD  

Pirfenidone, an antifibrotic drug with anti-inflammatory and antioxidant effects, delays fibrosis in idiopathic pulmonary fibrosis (IPF). Patients with IPF have a greater cough reflex sensitivity to inhaled capsaicin than healthy people, and cough is an independent predictor of IPF disease progression; however, the effects of pirfenidone on cough reflex sensitivity are unknown.
After challenge with an aerosolized antigen in actively sensitized guinea pigs, pirfenidone was administered intraperitoneally, and the cough reflex sensitivity was measured at 48 h after the challenge. Bronchoalveolar lavage (BAL) was performed, and the tracheal tissue was collected.
Pirfenidone suppressed the capsaicin-induced increase in cough reflex sensitivity in a dose-dependent manner. Additionally, increased levels of prostaglandin E-2, substance P, and leukotriene B-4, but not histamine, in the BAL fluid were dose dependently suppressed by pirfenidone. The decrease in neutral endopeptidase activity in the tracheal tissue was also alleviated by pirfenidone treatment. The total number of cells and components in the BAL fluid was not influenced.
These results suggest that pirfenidone ameliorates isolated cough based on increased cough reflex sensitivity associated with allergic airway diseases, and potentially relieve chronic cough in IPF patients who often have increased cough reflex sensitivity. Prospective studies on cough-relieving effects of pirfenidone in patients with IPF are therefore warranted. (C) 2013 Elsevier Ltd. All rights reserved.

DOI： 10.1016/j.pupt.2013.06.009

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：ELSEVIER IRELAND LTD  

Purpose: In a large multicenter international phase III study (CA031) of nab-paclitaxel (nab-P, 130 nm albumin-bound paclitaxel particles) + carboplatin (C) vs solvent-based paclitaxel (sb-P) +C, conducted in 6 countries including Japan, nab-PC produced significantly higher overall response rate (ORR), primary end point compared with sb-PC, and acceptable safety profile. The aim of this analysis was to evaluate the efficacy and tolerability of nab-PC vs sb-PC in Japanese patients with advanced non-small-cell lung cancer (NSCLC) who were enrolled in the CA031 study.
Patients and methods: In the CA031 study, a total of 1052 patients were randomized to receive either nab-P 100 mg/m(2) weekly or sb-P 200 mg/m(2) every 3 weeks both in combination with C at area under the concentration-time curve (AUC) = 6 on day 1 of each 3-week cycle. This analysis included 149 Japanese patients with previously untreated stage IIIB or IV NSCLC.
Results: The baseline and histologic characteristics of patients were well balanced between the two arms. ORR was higher with nab-PC vs sb-PC (35% vs 27%; response rate ratio = 1.318). Progression-free survival (median 6.9 vs 5.6 months; hazard ratio [HR] = 0.845) and overall survival (median 16.7 vs 15.9 months; HR= 0.930) were better with nab-PC vs sb-PC. Of the grade &gt;= 3 treatment-related adverse events, anemia and thrombocytopenia were more common in nab-PC arm, but sensory neuropathy was less common.
Conclusion: The nab-PC treatment yielded promising results regarding the efficacy endpoint, and it was generally well tolerated as first-line therapy for Japanese patients with advanced NSCLC. (C) 2013 Elsevier Ireland Ltd. All rights reserved.

DOI： 10.1016/j.lungcan.2013.02.020

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Language：Japanese   Publisher：(一社)日本呼吸器学会  

中枢気道病変に対する生検では一般的に通常の生検鉗子を用いるが、合併症として中枢気道内出血が問題となる。ホットバイオプシー鉗子生検は、少ない出血で生検が施行でき注目されているが、我が国では報告がない。我々は中枢気道病変に対して、高周波およびホットバイオプシー鉗子を用いて生検を施行した53例を対象に、その有用性に関して後ろ向きに検討した。53例中33例(62.3%)で出血を認めたがすべて容易に止血し、53例中50例(94.3%)で病理診断が得られた。ホットバイオプシー鉗子生検は、少ない出血で病理診断が得られ、重要な合併症である出血の抑制効果が認められた。(著者抄録)

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Other Link： https://search.jamas.or.jp/default/link?pub_year=2013&ichushi_jid=J05953&link_issn=&doc_id=20130719210003&doc_link_id=%2Fci6respo%2F2013%2F000204%2F003%2F0333-0337%26dl%3D0&url=https%3A%2F%2Fwww.medicalonline.jp%2Fjamas.php%3FGoodsID%3D%2Fci6respo%2F2013%2F000204%2F003%2F0333-0337%26dl%3D0&type=MedicalOnline&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00004_2.gif

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Neutropenia is a rare side effect of gefitinib and was scarcely reported in many large-scale randomized phase III trials using gefitinib monotherapy as first-line treatment. A 77-year-old female was referred to our institution due to abnormal shadow of the right lung, diagnosed by CT scan and biopsy histopathology as adenocarcinoma of the lung (cT3N1M1b). Mutation analysis with PCR-Invader assay of tumor DNA samples revealed short in-frame deletion in exon 19. Based on the diagnosis, first-line treatment was initiated using oral gefitinib (250. mg, daily). During the initial 27 days of gefitinib therapy, the only side effect was a mild skin rash. After 28 days, there was marked tumor shrinkage, indicative of a partial response to gefitinib
however, grade 4 neutropenia was also detected. The patient was switched to the oral erlotinib monotherapy (150. mg/day) as second-line chemotherapy with careful monitoring of neutropenia. Discontinuation of the gefitinib, without the need for granulocyte colony-stimulating factor support, was successful in allowing the neutrophils and leukocytes counts to recover to normal by day 47. The patient continued oral erlotinib for more than 9 months and there has been no evidence of neutropenia, leukopenia, or disease progression. Clinicians should be aware that gefitinib-induced neutropenia in patients with non-small cell lung cancer can be treated successful by switching to erlotinib. © 2013 Elsevier Ireland Ltd.

DOI： 10.1016/j.lungcan.2013.02.014

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Language：Japanese   Publisher：(NPO)日本呼吸器内視鏡学会  

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Other Link： https://search.jamas.or.jp/default/link?pub_year=2013&ichushi_jid=J00298&link_issn=&doc_id=20130603320218&doc_link_id=%2Fcf0brond%2F2013%2F0035s1%2F219%2F5200-5200%26dl%3D0&url=https%3A%2F%2Fwww.medicalonline.jp%2Fjamas.php%3FGoodsID%3D%2Fcf0brond%2F2013%2F0035s1%2F219%2F5200-5200%26dl%3D0&type=MedicalOnline&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00004_2.gif

Language：Japanese   Publisher：(NPO)日本肺癌学会  

背景。小細胞肺癌は中枢型がほとんどで、発育が早く、多くは早期にリンパ節や他臓器に転移を認め、予後の悪い腫瘍である。症例。82歳、男性。喉頭癌に対し放射線化学療法を行った後、経過観察の胸部CTスキャンにて右肺中葉末梢に集簇する複数の小結節影(最大径0.5cm)を認めた。炎症性変化を疑い経過観察とされたが、経過でそれぞれの結節が徐々に増大し、1年半後に全ての結節が癒合して2.4cmの結節となった。このため悪性腫瘍を疑い、CTガイド下肺針生検を施行したところ、小細胞癌と診断された。頭部MRI、FDG-PET検査から臨床病期T1bN0M0、IA期と診断し、胸腔鏡補助下右肺中葉切除およびリンパ節郭清を施行した。病理病期T1aN0M0、IA期と診断された。結論。CT上、稀な発育形式を呈した小細胞肺癌切除例を経験したので、報告する。(著者抄録)

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Background: The discovery of driver oncogenes has increased the need to obtain a sufficient amount of tissue specimens for lung cancer diagnosis. Although endoscopic ultrasound (with bronchoscope)-guided fine-needle aspiration (EUS-B-FNA) is reportedly a feasible and well-tolerated modality, additional advantages of EUS-B-FNA are yet to be thoroughly investigated. The purpose of this study was to evaluate the ability of EUS-B-FNA to obtain sufficient tissue specimens for pathologic and molecular diagnoses of lung cancer. Methods: Among lung cancer patients who were diagnosed between December 2010 and December 2012 in our institute, patients who underwent EUS-B-FNA to diagnose lung cancer were enrolled (n=26). EUS-BFNA was performed when bronchoscopic diagnosis was impossible or difficult to obtain sufficient samples. Epidermal growth factor receptor (EGFR) mutations and echinoderm microtubule-associated protein-like 4 and the anaplastic lymphoma kinase (EML4-ALK) fusion gene were evaluated using EUS-B-FNA samples of non-small cell lung cancer. Results: EUS-B-FNA was performed on 28 lesions in 26 patients. Among the target lesions, 23 were mediastinal lymph nodes including nodal stations 2L, 4L, 7, 8, and 10L. The remaining 5 were intrapulmonary lesions. EUS-B-FNAs were completed without complications in all the patients. The diagnostic yield of EUS-B-FNA in diagnosing lung cancer was 100% (26/26). Additional diagnostic gain of EUS-B-FNA was 69.2% (18/26) as compared to bronchoscopy alone. EGFR mutations and EML4-ALK fusion gene could be evaluated in all patients with non-small cell lung cancer (n=20) using EUS-B-FNA samples. One case with EGFR mutation and 1 case with ALK fusion gene were diagnosed. Six non-small cell carcinomas were also diagnosed by bronchoscopy, but all bronchoscopic samples were insufficient to evaluate mutation analyses. Conclusions: EUS-B-FNA is a practical and feasible method to obtain abundant tumorous tissue samples for pathologic diagnosis and molecular analysis, particularly when the target lesions are inaccessible by other modalities because of their locations or because of the patient's poor physical condition. © 2013 Lippincott Williams &amp
Wilkins.

DOI： 10.1097/LBR.0b013e31829182a0

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Language：Japanese   Publisher：(一社)日本呼吸器学会  

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Language：English   Publisher：EUROPEAN RESPIRATORY SOC JOURNALS LTD  

DOI： 10.1183/09031936.00146912

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We report the case of a Japanese male with epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI)-sensitive lung adenocarcinoma, who had an EGFR mutation and presented in the emergency department with acute cardiac tamponade as the recurrence during EGFR-TKI therapy. We could detect a second mutation, T790M in exon 20 in the pericardial effusion. This is the first report to detect the resistant mutation T790M in pericardial effusion. We suggest that the pericardial effusion may therefore be useful as surrogate tissue for detecting EGFR mutation. © 2013 S. Karger AG, Basel.

DOI： 10.1159/000345947

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Language：Japanese   Publisher：特定非営利活動法人 日本呼吸器内視鏡学会  

DOI： 10.18907/jjsre.35.Special_S278_2

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：JAPAN SOC INTERNAL MEDICINE  

One-third of lung cancer patients present with life-threatening central airway obstruction (CAO). Two elderly patients were referred to our institution with symptoms caused by CAO. In each case, thoracic computed tomography and a bronchoscopic examination revealed a tumor obstructing the central airway. The tumors were resected endoscopically, and the patients' respiratory and performance status remarkably improved. Both patients were diagnosed with an advanced stage of lung adenocarcinoma harboring epidermal growth factor receptor (EGFR) mutations. They received gefitinib monotherapy, with partial responses sustained for more than 12 months. Combination therapy with endoscopic tumor resection and gefitinib is beneficial in patients with EGFR-mutant lung cancer and CAO.

DOI： 10.2169/internalmedicine.52.0557

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Language：Japanese   Publishing type：Research paper (scientific journal)   Publisher：Japanese Journal of Cancer and Chemotherapy Publishers Inc.  

An increasing number of patients with lung cancer are undergoing outpatient chemotherapy. It is very important to maintain good quality of life (QOL) for these patients, and Japanese traditional medicine, TJ-41, has been reported to improve the QOL of patients with advanced cancer. However, the effect of TJ-41 on patients with lung cancer undergoing outpatient chemotherapy is unknown. Therefore, we conducted this study. To investigate the factors influencing the QOL of these patients, we distributed a QOL questionaire, "The QOL Questionnaire for Cancer Patients Treated with Anticancer Drugs" (QOL-ACD) to 11 patients with non-small cell lung cancer. The medical factors related to the overall QOL scores and other categories, indicating "activity", "physical condition", "psychological condition", "social relationships", "psychological condition" and "face scale" were analyzed. A significant decrease in each of the factors was not observed in this study.

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On March 11, 2011, a 9.0-magnitude earthquake struck east Japan, following tsunami. Many people are forced to live in evacuation shelters without enough life-saving drugs. Asthma control for management of health crisis is required, because asthma exacerbation is a major cause of morbidity, can need acute care and results in death. However, it remains obscure what parameter should be used in primary clinic of evacuation shelters. The objective of this study is to elucidate the practical efficacy of asthma assessment tool in primary clinic for victims of this disaster. Asthma control test (ACT), a brief and patient-based tool to evaluate asthma control, was conducted for 17 patients with asthma in evacuation shelters at Tohoku district. Total sum of ACT scores were significantly decreased after this disaster. Significant decreases were observed for the items; "Asthma keeps you from getting much done at work", "Shortness of breath", "Asthma symptoms wake you up" and "Patient rating of control". ACT, an easy and practicable tool, clearly demonstrated the asthma exacerbation in evacuation shelters without the use of lung function testing. ACT may contribute to the management of health crisis not only for this East Japan disaster but also for the other forthcoming unavoidable disasters.

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Background: The effects of inductive hyperthermia on lung cancer have yet to be fully investigated. Magnetic nanoparticles used in inductive hyperthermia are made-to-order and expensive. This study was performed to investigate the use of ferucarbotran in inductive hyperthermia and to clarify whether inductive hyperthermia using ferucarbotran promotes antitumor effects in vivo using a lung cancer cell line. Methods: We injected A549 cells subcutaneously into the right thighs of BALB/c nu/nu nude mice. Forty mice with A549 xenografts were then classified into three groups. Group 1 was the control group. All mice in groups 2 and 3 had ferucarbotran injected into their tumors, and mice in group 3 were then subjected to alternating magnetic field irradiation. We evaluated tumor temperature during the hyperthermic procedure, the time course of tumor growth, histologic findings in tumors after hyperthermic treatment, and adverse events. Results: Intratumor temperature rose rapidly and was maintained at 43°C-45°C for 20 minutes in an alternating magnetic field. Tumor volumes in groups 1 and 2 increased exponentially, but tumor growth in group 3 was significantly suppressed. No severe adverse events were observed. Histologic findings for the tumors in group 3 revealed mainly necrosis. Conclusion: Inductive hyperthermia using ferucarbotran is a beneficial and promising approach in the treatment of lung cancer. Ferucarbotran is a novel tool for further development of inductive hyperthermia. © 2013 Araya et al, publisher and licensee Dove Medical Press Ltd.

DOI： 10.2147/OTT.S42815

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Language：Japanese   Publishing type：Research paper (scientific journal)  

Background. Small-cell lung cancer is usually centrally located and grows rapidly, often metastasizing to the lymph nodes and other organs. Case. An 82-year-old male received chemoradiotherapy for laryngeal cancer. Five years after treatment, follow-up chest CT revealed a number of small areas of nodular opacity (maximum size: 0.5 cm) clustered at the periphery of the middle lobe of the right lung. Since inflammatory changes were suspected, periodic CT examinations were performed. However, the lung nodules slowly grew, and a year and a half later, all of the nodules were found to have consolidated into one large nodule measuring 2.4 cm in size
therefore, malignancy was suspected. The pathological findings obtained using a CT-guided needle biopsy of the lungs led to a diagnosis of small-cell cancer. Brain MRI and FDG-PET scans revealed no clinical metastasis (clinical stage IA: T1bNOMO). The patient underwent video-assisted right middle lobectomy of the lungs and lymph node dissection, and a definitive diagnosis of pathological stage IA (T1aNOMO) disease was made. Conclusion. We herein reported a case of small-cell lung cancer with a peculiar progressive pattern. © 2013 The Japan Lung Cancer Society.

DOI： 10.2482/haigan.53.127

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Language：Japanese   Publisher：特定非営利活動法人 日本呼吸器内視鏡学会  

DOI： 10.18907/jjsre.35.Special_S154_3

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Language：Japanese   Publisher：特定非営利活動法人 日本呼吸器内視鏡学会  

DOI： 10.18907/jjsre.35.Special_S234_1

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Language：Japanese   Publisher：(NPO)日本肺癌学会  

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Language：Japanese   Publisher：(一社)日本癌治療学会  

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Language：Japanese   Publisher：(NPO)日本肺癌学会  

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Language：Japanese   Publisher：(NPO)日本肺癌学会  

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Language：English   Publisher：(NPO)日本肺癌学会  

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Language：Japanese   Publisher：(NPO)日本肺癌学会  

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Language：Japanese   Publisher：(NPO)日本肺癌学会  

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Language：Japanese   Publisher：(一社)日本癌治療学会  

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：LIPPINCOTT WILLIAMS & WILKINS  

Introduction: Most non-small-cell lung cancer tumors with epidermal growth factor receptor mutations are responsive to EGFR tyrosine kinase inhibitors, such as gefitinib and erlotinib, but almost all such tumors ultimately acquire resistance. We previously found that a gefitinib-resistant cell line, PC-9/Met in which MET (MNNG-HOS transforming gene) is amplified, was more sensitive than its parent cell line (PC-9) to 7-ethyl-10-hydroxy-camptothecin (SN-38), an active metabolite of irinotecan. The purpose of this study was to investigate the mechanisms responsible for the increased sensitivity of the gefitinib-resistant cell line to SN-38.
Methods: The sensitivity of PC-9 and PC-9/Met to SN-38 was assessed by performing water soluble tetrazolium salt (WST-1) assays. Topoisomerase I (topo I) activities were determined for the cell lines cultured in the presence of hepatocyte growth factor and for those of which MET expression was knocked down by introducing a MET-specific small interfering RNA.
Results: PC-9/Met exhibited higher topo I activities, and higher topo I gene and protein expression levels than PC-9 did. Suppression of MET expression by a MET-specific small interfering RNA led to a decrease in the topo I protein expression in the PC-9/Met cells. The stimulation of PC-9 with hepatocyte growth factor caused an increase in the topo I protein level via the activation of MET.
Conclusions: The increased sensitivity of PC-9/Met cells to SN-38 compared with that of PC-9 cells was partially because of topo I activities resulting from increased topo I mRNA and protein expression caused by MET signaling.

DOI： 10.1097/JTO.0b013e31825cca4c

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Language：Japanese   Publisher：(NPO)日本呼吸器内視鏡学会  

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Other Link： https://search.jamas.or.jp/default/link?pub_year=2012&ichushi_jid=J00298&link_issn=&doc_id=20120807300073&doc_link_id=%2Fcf0brond%2F2012%2Fs03404%2F056%2F0408-0408%26dl%3D0&url=https%3A%2F%2Fwww.medicalonline.jp%2Fjamas.php%3FGoodsID%3D%2Fcf0brond%2F2012%2Fs03404%2F056%2F0408-0408%26dl%3D0&type=MedicalOnline&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00004_2.gif

Language：Japanese   Publisher：(株)癌と化学療法社  

症例は61歳、女性。他院にて気管分岐部周囲の腫瘤と気管の狭窄、および上大静脈の狭窄の精査中に呼吸困難と顔面浮腫の急激な増悪を認め、当科を受診。緊急的に硬性鏡下気管ステント留置術による気道確保を施行し、腫瘍生検を施行した。病理学的に未分化な非小細胞肺癌と診断された。シスプラチンとエトポシドによる全身化学療法と56Gyの放射線療法を直ちに開始した。腫瘍は治療開始後に速やかに縮小した。気管ステント留置6ヵ月後に骨転移が出現し、ゲフィチニブを開始した。2年10ヵ月後にステントは抜去でき、気管ステント留置より6年以上経過した現在、腫瘍の増大なく生存している。(著者抄録)

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Language：Japanese   Publisher：(NPO)日本呼吸器内視鏡学会  

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Other Link： https://search.jamas.or.jp/default/link?pub_year=2012&ichushi_jid=J00298&link_issn=&doc_id=20120525370214&doc_link_id=%2Fcf0brond%2F2012%2F0034s1%2F214%2F5201-5201%26dl%3D0&url=https%3A%2F%2Fwww.medicalonline.jp%2Fjamas.php%3FGoodsID%3D%2Fcf0brond%2F2012%2F0034s1%2F214%2F5201-5201%26dl%3D0&type=MedicalOnline&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00004_2.gif

Language：Japanese   Publisher：(NPO)日本肺癌学会  

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Background. Evidence of gastric metastasis from lung cancer is rarely observed at initial diagnosis. Case 1. A 74-year-old woman with anorexia was referred to our hospital due to upper lobe atelectasis of the left lung noted on a chest X-ray film. Bronchoscopic examination revealed obstruction of the left upper bronchus by a tumor. A biopsy specimen from the mass demonstrated small cell cancer. Upper gastrointestinal endoscopy showed an elevated lesion forming a central depression ("bull's eye") in the antrum. Immunohistochemical examination confirmed metastasis from small cell lung cancer. Despite chemotherapy with carboplatin and etoposide, the patient did not respond to treatment and died of lung cancer 3 months after admission. Case 2. A 76-year-old man with a chief complaint of epigastralgia was given a diagnosis of small cell lung cancer of the right lower lobe. Endoscopic examination revealed an elevated lesion forming a "bull's eye" in the gastric corpus. A biopsy specimen from the tumor demonstrated metastasis from small cell lung cancer, and he died of lung cancer 1 month after diagnosis. Conclusion. Opportunities to identify gastric metastasis from lung cancer are likely to increase with the increasing incidence of lung cancer. On diagnosis of gastric metastasis, upper gastrointestinal endoscopy is useful for proper staging and treatment. The possibility of gastric metastasis should be considered when patients complain of anorexia or epigastralgia at initial diagnosis. © 2012 The Japan Lung Cancer Society.

DOI： 10.2482/haigan.52.220

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Language：Japanese   Publisher：(NPO)日本肺癌学会  

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：LIPPINCOTT WILLIAMS & WILKINS  

Introduction: TSU-68 is an oral small-molecule inhibitor that targets vascular endothelial growth factor receptor 2, platelet-derived growth factor receptor beta, and fibroblast growth factor receptor 1. An open-label, single-arm, phase I study was performed to evaluate escalating doses of TSU-68 in combination with standard chemotherapy in patients with advanced non-small cell lung cancer.
Methods: Eligible patients received TSU-68 at 200 or 400 mg twice daily and continuously in combination with carboplatin (area under the curve, 6mg . min/mL) plus paclitaxel (200 mg/m(2)) on day 1 every 21 days.
Results: Thirty-seven patients were enrolled at the two dose levels of TSU-68. No dose-limiting toxicities were observed with TSU-68 at the 200 mg twice a day dose level. At 400 mg twice a day, one of six patients experienced a dose-limiting toxicity (anorexia of grade 3) during the first cycle. The 400 mg twice a day dose level was determined to be the recommended dose, and a total of 34 patients were treated at this dose. Overall, adverse events were mild to moderate in severity, with the most frequently observed such events being myelosuppression, neuropathy, and gastrointestinal disorders. No drug-related bleeding was observed. The objective response rate was 39.4% (95% confidence interval, 22.9-57.9%), and median progression-free survival was 5.6 months (95% confidence interval, 3.6-7.2 months). Coadministration of TSU-68, carboplatin, and paclitaxel had no substantial impact on the pharmacokinetics of these drugs.
Conclusions: TSU-68 can be safely combined with standard doses of carboplatin-paclitaxel, with the combination manifesting promising antitumor activity.

DOI： 10.1097/JTO.0b013e318238154d

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Language：Japanese   Publishing type：Research paper (scientific journal)   Publisher：Japanese Journal of Cancer and Chemotherapy Publishers Inc.  

A 61-year-old female was admitted to our hospital due to dyspnea and facial edema. A chest CT scan showed stenosis of the trachea and superior vena cava due to a tumor around the trachea. She underwent partial resection of the tracheal tumor via a rigid bronchoscope introduced into the trachea, and placement of a Dumon Y-stent. Undifferentiated non-small cell lung cancer was diagnosed. After airway management, she underwent cisplatin-based chemoradiotherapy and total 56 Gy stereotactic radiotherapy for the tumor. The tumor size was reduced by 40% immediately after chemoradiotherapy. Six months after the tracheal stent insertion, bone metastases were pointed out, and we changed the chemotherapy regimen to gefitinib. She has been in good condition without tumor growth for more than six years after tracheal stent insertion.

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Language：Japanese   Publishing type：Research paper (scientific journal)  

Because it is considered that there is a close connection between gustation and olfactation, and that a decline in the function of either sensation influences the other one, it would be useful to clarify the relation between gustatory and olfactory disorders in patients receiving cancer chemotherapy. Therefore, we investigated the frequency of gustatory and olfactory disorders in patients administered anticancer drugs at the Division of Outpatient Chemotherapy of Kanazawa University. Among 136 patients who consented to participate in the investigation, 75 patients (55%) complained of a gustatory disorder, and 26 patients (19%) complained of an olfactory disorder. The occurrences of olfactory disorder were significantly greater in patients who had gustatory disorder than in patients who did not. The expression frequency of gustatory disorders was significantly higher among those taking docetaxel (85%) when compared with patients on other regimens. Although not statistically significant, the incidence of olfactory disorder was higher in patients taking docetaxel (31%), irinotecan+/-leucovorin (I-LV)+ 5-fluorouracil (5-FU) (31%), I-oxaliplatin+I-LV+5-FU (28%), trastuzumab (23%), and weekly paclitaxel (22%). Medical staff should recognize that olfactory disorders are similar to gustatory disorders, as they both have adverse reactions induced by anticancer drugs.

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Language：Japanese   Publishing type：Research paper (scientific journal)  

A 64-year-old man was admitted to our hospital for 6th-line chemotherapy. Chest X-ray film and computed tomographic (CT) scan showed right-sided pleural thickening with multiple lung tumors. Repeated treatment with carboplatin (AUC 6), paclitaxel (200mg/m 2) and bevacizumab (150 mg/kg) on day 1 every 21 days was effective for this patient. Chemotherapy with bevacizumab may be effective for patients with multi-recurrent adenocarcinoma.

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：LIPPINCOTT WILLIAMS & WILKINS  

Introduction: The epidermal growth factor receptor (EGFR) mutation status is a validated biomarker for the stratification of EGFR-tyrosine kinase inhibitor (EGFR-TKIs) treatment in patients with non-small cell lung cancer (NSCLC); however, its use is limited in patients with wild-type EGFR, and new biomarkers are needed. We hypothesized that the serum concentration of heparan sulfate (HS), which activates oncogenic growth factor receptor signaling through EGFR and non-EGFR signaling pathways, may be a novel glycobiological biomarker for EGFR-TKIs treatment in NSCLC.
Methods: The pretreatment serum HS concentrations were determined using enzyme-linked immunosorbent assay in 83 patients with stage IV non-small cell lung adenocarcinoma who received EGFR-TKIs treatment. The relationship between the serum HS concentrations and patient characteristics, tumor response, progression-free survival (PFS), and overall survival (OS) were analyzed.
Results: Patient sex, performance status, smoking history, and EGFR mutation status were associated with tumor response. The serum HS concentrations were significantly higher among patients with progressive disease than among those without progressive disease (p = 0.003). Furthermore, the serum HS concentrations were strongly associated with a poor PFS and OS in a univariate Cox analysis (p = 0.0022 and p = 0.0003, respectively). A stratified multivariate Cox model according to the EGFR mutation status showed that higher HS concentrations were significantly associated with a shorter PFS and OS (p = 0.0012 and p = 0.0003).
Conclusion: We concluded that a high-serum HS concentration was strongly related to a poor treatment outcome of EGFR-TKIs and may be a promising noninvasive and repeatable glycobiological biomarker in cancer treatment.

DOI： 10.1097/JTO.0b013e3182286d41

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：NATURE PUBLISHING GROUP  

BACKGROUND: Currently, no effective treatments exist for non-small cell lung cancer (NSCLC) after failure of gefitinib therapy. Pre-clinical studies have demonstrated that gefitinib-resistant NSCLC cells are more sensitive to irinotecan than parental cells, and that combined administration of irinotecan and gefitinib has a synergistic additive effect. We conducted a phase I study to evaluate the combination of irinotecan and gefitinib as a therapeutic option for NSCLC patients with progressive disease (PD) after initial gefitinib treatment.
METHODS: Eligibility criteria included histologically confirmed NSCLC, age range of 20-74 years, refractory to or relapsed after gefitinib treatment, one or more previous chemotherapy regimens, Eastern Cooperative Oncology Group performance status 0-2, adequate organ function, and informed consent. Patients were treated with irinotecan on days 1 and 15, and treated daily with gefitinib from day 2 every 4 weeks. The treatment was continued until disease progression. The gefitinib dose was fixed at 250 mg. Irinotecan dosing started at 50 mg m(-2) and was escalated in patients by 25 mg m(-2) increments up to a maximum dose of 150 mg m(-2).
RESULTS: Twenty-seven patients were enrolled: male/female = 14/13; median age = 60 (45-75); histology, adenocarcinoma/non-adenocarcinoma = 25/2; performance status 0-1/2 = 19/8; previous response to gefitinib, partial response/stable disease/PD = 21/2/4. Dose-limiting toxicities were observed in 2 patients at level 3. Maximum tolerated dose was not determined, and the full dose of irinotecan could be combined with the full dose of gefitinib. The disease control rate (DCR) and response rate (RR) were 69.2 and 26.9%, respectively. For 12 patients at level 5 (the recommended phase II dose), the DCR and RR were 75.0% and 41.7%, respectively. The median treatment cycles were 4; median time to treatment failure, 57 days (95% confidence interval (CI), 32-82 days); median overall survival, 244 days (95% CI, 185-303 days); and 1-year survival rate, 32.6%.
CONCLUSION: The combination of irinotecan and gefitinib was well tolerated and potentially beneficial for NSCLC patients failing initial gefitinib monotherapy. British Journal of Cancer (2011) 105, 1131-1136. doi:10.1038/bjc.2011.375 www.bjcancer.com Published online 13 September 2011 (C) 2011 Cancer Research UK

DOI： 10.1038/bjc.2011.375

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Language：Japanese   Publisher：(NPO)日本肺癌学会  

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Language：Japanese   Publisher：(NPO)日本肺癌学会  

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Language：Japanese   Publisher：(一社)日本癌治療学会  

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Language：Japanese   Publisher：(NPO)日本肺癌学会  

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Language：Japanese   Publisher：(NPO)日本肺癌学会  

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We report here a case of chronic eosinophilic pneumonia with significant endobronchial involvement. A 59-year-old man was admitted complaining of fever, productive cough, wheezing, and dyspnea. There were ground-glass opacities in bilateral upper fields and tram track shadows in the left lower lung field on chest x-ray, and ground-glass opacities in bilateral upper lobes, thickening of the bronchial walls, and centrilobular nodules on computed tomographic scan of the chest. There was marked eosinophilia in the peripheral blood and bronchoalveolar lavage fluid and was diagnosed as chronic eosinophilic pneumonia. Bronchoscopy also revealed white nodules at the orifice of the right S6 and the left S1+2 bronchi. The histologic examination of these nodules revealed eosinophilic inflammation into the bronchial wall. This is a rare case of chronic eosinophilic pneumonia with endobronchial eosinophilic involvement. © 2011 by Lippincott Williams &amp
Wilkins.

DOI： 10.1097/LBR.0b013e318222a05d

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Language：Japanese   Publisher：(NPO)日本肺癌学会  

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Language：Japanese   Publisher：(NPO)日本肺癌学会  

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Language：Japanese   Publisher：(NPO)日本肺癌学会  

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：AMER ASSOC CANCER RESEARCH  

Purpose: The epidermal growth factor receptor (EGFR) mutation status has emerged as a validated biomarker for predicting the response to treatment with EGFR-tyrosine kinase inhibitors (EGFR-TKI) in patients with non-small cell lung cancer. However, the responses to EGFR-TKIs vary even among patients with EGFR mutations. We studied several other independently active biomarkers for EGFR-TKI treatment.
Experimental Design: We retrospectively analyzed the serum concentrations of 13 molecules in a cohort of 95 patients with non-small cell lung adenocarcinoma who received EGFR-TKI treatment at three centers. The pretreatment serum concentrations of amphiregulin, beta-cellulin, EGF, EGFR, epiregulin, fibroblast growth factor-basic, heparin-binding EGF-like growth factor, hepatocyte growth factor (HGF), platelet-derived growth factor beta polypeptide, placental growth factor, tenascin C, transforming growth factor-alpha, and vascular endothelial growth factor (VEGF) were measured using enzyme-linked immunosorbent assay and a multiplex immunoassay system. The associations between clinical outcomes and these molecules were evaluated.
Results: The concentrations of HGF and VEGF were significantly higher among patients with progressive disease than among those without progressive disease (P &lt; 0.0001). HGF and VEGF were strongly associated with progression-free survival (PFS) and overall survival (OS) in a univariate Cox analysis (all tests for hazard ratio showed P &lt; 0.0001). A stratified multivariate Cox model according to EGFR mutation status (mutant, n = 20; wild-type, n = 23; unknown, n = 52) showed that higher HGF levels were significantly associated with a shorter PFS and OS (P &lt; 0.0001 for both PFS and OS). These observations were also consistent in the subset analyses.
Conclusions: Serum HGF was strongly related to the outcome of EGFR-TKI treatment. Our results suggest that the serum HGF level could be used to refine the selection of patients expected to respond to EGFR-TKI treatment, warranting further prospective study. Clin Cancer Res; 16(18); 4616-24. (c) 2010 AACR.

DOI： 10.1158/1078-0432.CCR-10-0383

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：BMJ Publishing Group  

A 41-year-old woman had a general health examination and was diagnosed with a non-functioning adrenocortical carcinoma (ACC). Despite surgery and chemotherapy with mitotane, the ACC progressed with metastases to the lymphnodes, liver and lung. Initially, she developed adrenal insufficiency and was treated with hydrocortisone. As the ACC progressed, it produced superabundant cortisol, resulting in clinically overt Cushing's syndrome. As the liver metastases grew, the patient developed hypoglycaemia with suppression of endogenous insulin secretion. She had to be given large quantities of glucose intravenously to remain normoglycaemic. The serum insulin-like growth factor (IGF)-II/IGF-I ratio had increased to 84. We identified big IGF-II, a primary hormonal mediator of non-islet cell tumour hypoglycaemia (NICTH), in the serum and tumour using western blotting. This is the first case of ACC that showed both Cushing's syndrome and NICTH associated with big IGF-II.

DOI： 10.1136/bcr.07.2009.2100

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Language：Japanese   Publisher：特定非営利活動法人 日本呼吸器内視鏡学会  

DOI： 10.18907/jjsre.32.Special_S178_2

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Language：Japanese   Publisher：The Japan Lung Cancer Society = 日本肺癌学会  

&lt;i&gt;&lt;b&gt;Background&lt;/b&gt;&lt;/i&gt;. Primary synovial sarcoma of the pleura and lung is extremely rare. &lt;i&gt;&lt;b&gt;Case&lt;/b&gt;&lt;/i&gt;. A 35-year-old man was admitted to our hospital because of an abnormal opacity in the right lung. A malignant intrathoracic tumor was suspected and a video-assisted thoracoscopic biopsy was performed. The right thoracic cavity was occupied by a fragile tumor. Histologically, the tumor showed dense proliferation of spindle cells with high rate of mitosis. Immunohistochemical examination was performed, but no definitive diagnosis was obtained. Progression of the tumor was very rapid and he died of respiratory failure 2 months after first presentation. On autopsy, the right lung was compressed and collapsed by the tumor. An &lt;i&gt;SYT-SSX2&lt;/i&gt; fusion gene transcript was detected by reverse transcription polymerase chain reaction (RT-PCR) and direct sequencing using RNA extracted from resected tissue specimens. There was no evidence of tumor except in the pleura. The final diagnosis was primary pleural synovial sarcoma. &lt;i&gt;&lt;b&gt;Conclusion&lt;/b&gt;&lt;/i&gt;. We report an extremely rare case of primary pleural synovial sarcoma.&lt;br&gt;

DOI： 10.2482/haigan.50.906

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Language：Japanese   Publisher：(NPO)日本肺癌学会  

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Language：Japanese   Publisher：(NPO)日本肺癌学会  

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Language：Japanese   Publisher：(NPO)日本肺癌学会  

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Language：Japanese   Publisher：The Japanese Society of Clinical Pharmacology and Therapeutics  

DOI： 10.3999/jscpt.40.99S

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Other Link： http://search.jamas.or.jp/link/ui/2009308906

Language：Japanese   Publisher：(一社)日本呼吸器学会  

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Language：Japanese   Publisher：(一社)日本内科学会  

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Language：Japanese   Publisher：(有)科学評論社  

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Language：Japanese   Publishing type：Research paper (scientific journal)   Publisher：Japanese Journal of Cancer and Chemotherapy Publishers Inc.  

An increasing number of patients with lung cancer are undergoing outpatient chemotherapy as an alternative to inpatient therapy. To investigate the factors influencing the quality of life (QOL) for these patients, we administered a QOL questionnaire, "The QOL Questionnaire for Cancer Patients Treated with Anticancer Drugs" (QOL-ACD) to 8 older adult patients with non-small cell lung cancer. The medical factors related to the overall QOL scores and other categories indicating "activity," "physical condition," "psychological condition," "social relationship," "psychological condition" and "face scale" were analyzed. No significant decrease in each factor was observed in this study.

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Language：Japanese   Publishing type：Research paper (scientific journal)  

Background. Even though the head and neck are common metastatic sites in lung cancer patients, paranasal metastases are rare. We report a patient with lung cancer who had paranasal sinus metastases. Case. A 56-year-old man with lung cancer presented with nasal hemorrhage 1.5 years after the initiation of chemotherapy. On CT, mass shadows were seen in bilateral frontal sinuses, maxillary antra, the left ethmoidal sinus, the sphenoidal sinus, and the nasal cavity. Biopsies of the lesion in the nasal cavity showed adenocarcinoma, confirming that the lesions in the paranasal sinuses were lung cancer metastases. The cranial MRI done at the time of the first admission was reviewed, and a small nodule was found in left ethmoidal sinus. Conclusion. Paranasal sinus metastases are found in a patient with NSCLC who don't have symptoms related to the paranasal sites. Paranasal sites should be carefully evaluated in patients with advanced NSCLC. © 2008 The Japan Lung Cancer Society.

DOI： 10.2482/haigan.48.715

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Language：Japanese   Publisher：(一社)日本脊椎脊髄病学会  

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Other Link： https://search.jamas.or.jp/index.php?module=Default&action=Link&pub_year=2008&ichushi_jid=J03627&link_issn=&doc_id=20080327360279&doc_link_id=%2Ffg7sekit%2F2008%2Fs01902%2F117%2F0477-0477%26dl%3D0&url=http%3A%2F%2Fwww.medicalonline.jp%2Fjamas.php%3FGoodsID%3D%2Ffg7sekit%2F2008%2Fs01902%2F117%2F0477-0477%26dl%3D0&type=MedicalOnline&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00004_2.gif

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Language：Japanese   Publishing type：Research paper (scientific journal)  

Background. Brain metastasis is often seen in patients with lung cancer
however, the reported incidence of pituitary metastasis is rare. We present a case with central hypopituitarism secondary to pituitary metastasis from lung cancer. Case. A 78-year-old woman had been receiving treatment on an outpatient basis at a local hospital for the control of diabetes mellitus since 1998. A chest roentgenogram revealed a huge mass in the middle lung field of the left lung in February, 2006 and she was referred to us. A bronchoscopic biopsy in March revealed adenocarcinoma. Systemic examinations showed multiple lung metastases and bone metastases, and brain MRI also showed focal metastasis to the right occipital lobe, thus indicating a clinical stage of T4N3M1 (stage IV). She was admitted to our department due to severe appetite loss for 1 week. She complained of polyuria, thirst, and polydipsia. We performed a hematological examination including basal endocrinological conditions, a high concentration saline loading test, the response to desmopressin administration, and the findings of brain MRI, which led to a diagnosis of metastasis of lung cancer to the pituitary gland with central diabetes insipidus. Although chemotherapy did not improve the symptoms of diabetes insipidus, the intranasal administration of desmopressin improved them. Her appetite loss promptly improved after the administration of desmopressin. Conclusion. We should suspect the possibility of a metastatic pituitary tumor in a patient has diabetes insipidus. If such tumors can be accurately identified, appropriate treatment can result in an improvement in the quality of life for patients with advanced lung cancer. © 2007 The Japan Lung Cancer Society.

DOI： 10.2482/haigan.47.125

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Language：Japanese   Publisher：(株)癌と化学療法社  

症例:56歳、男性。乾性咳嗽、右頸部腫瘤を自覚したため当院を受診した。胸部X線にて左下肺野に腫瘤性陰影を認めた。経気管支肺生検および頸部リンパ節生検により進行肺大細胞癌と診断した。一次治療として、carboplatin+vinorelbine、二次治療としてdocetaxel、三次治療としてTS-1+cisplatinによる3レジメンの化学療法を行ったが、右頸部腫瘤の増大を認めた。このため四次治療として、cisplatin(80mg/m2,day 1)+gemcitabine(800mg/m2,day 1,8)による化学療法を開始した。4サイクル終了時点で左肺の原発巣、右頸部腫瘤ともに著明な縮小を認め、PRと判断した。結論:われわれは、四次治療としてのcisplatin+gemcitabine併用化学療法が奏効した進行非小細胞肺癌の1例を経験した。PSが良好である症例に対する三次治療以降の化学療法に関しては、今後検討すべき課題であるといえる。(著者抄録)

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Other Link： https://search.jamas.or.jp/index.php?module=Default&action=Link&pub_year=2007&ichushi_jid=J00296&link_issn=&doc_id=20070221450013&doc_link_id=%2Fab8gtkrc%2F2007%2F003402%2F013%2F0217-0219%26dl%3D0&url=http%3A%2F%2Fwww.medicalonline.jp%2Fjamas.php%3FGoodsID%3D%2Fab8gtkrc%2F2007%2F003402%2F013%2F0217-0219%26dl%3D0&type=MedicalOnline&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00004_2.gif

Language：Japanese   Publishing type：Research paper (scientific journal)  

CASE: A 56-year-old Japanese man who was suffering from dry cough and right neck mass visited our hospital. Chest X-ray revealed a lung mass shadow in the lower left lung field. We diagnosed it as an advanced large cell carcinoma after conducting transbronchial lung biopsy and neck lymphnode biopsy. A right neck mass enlarged after three chemotherapy regimens of carboplatin and vinorelbine for first-line, docetaxel for second-line, and TS-1 and cisplatin for third-line. Finally, cisplatin (80 mg/m(2), day 1) and gemcitabine (800 mg/m(2), day 1, 8) were administered as fourth-line therapy. Partial response was observed after completing four chemotherapy cycles. CONCLUSION: In this case, the fourth-line chemotherapy, consisting of cisplatin and gemcitabine, proved effective for refractory NSCLC. Further research should be conducted regarding third-line chemotherapy for NSCLC patients with good performance status.

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Language：Japanese   Publisher：一般社団法人 日本アレルギー学会  

DOI： 10.15036/arerugi.56.399_4

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：JAPAN SOC INTERNAL MEDICINE  

We describe a 73-year-old woman with systemic sclerosis (SSc)-polymyositis (PM) overlap syndrome, primarily SSc followed by PM. She had suffered from SSc and had interstitial pneumonia (IP), which was stable. Eight years after the initial diagnosis of SSc, proximal muscle weakness, myalgia, and dyspnea on effort developed. A chest computed tomography (CT) showed reticular shadows, and serum markers of IP such as KL-6 and surfactant protein-D were elevated at 1,170 U/mL and 176 ng/mL, respectively. Bronchoalveolar lavage fluid showed a remarkably increased number of lymphocytes. Exacerbation of SSc-IP 8 years after the initial diagnosis of SSc is not usual, and a marked increase in the number of lymphocytes in bronchoalveolar lavage fluid is also uncommon in SSc-IP, indicating overlap of another connective tissue disease. The diagnostic criteria for PM were satisfied; thus, SSc-PM overlap syndrome was diagnosed. We emphasize the need to investigate whether another connective tissue disease has developed when symptoms or laboratory findings cannot be explained by the usual clinical course of an existing connective tissue disease.

DOI： 10.2169/internalmedicine.46.0135

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：ELSEVIER SCI LTD  

The aim of this study was to evaluate gastrointestinal metastases from primary lung cancer confirmed by autopsy. We identified and examined patients with a diagnosis of primary lung cancer over 33 years. We also reviewed patients with gastrointestinal metastases including the stomach, small bowel, and large bowel. This study comprised 470 patients with lung cancer. We detected 56 (11.9%) cases with gastrointestinal metastases. There were 12 (30%) cases with gastrointestinal metastases among 40 cases with large cell carcinoma. The histological type of large cell carcinoma led to a significantly higher rate of gastrointestinal metastases compared with that of non-large cell carcinoma (P = 0.004, odds ratio 3.524). Life threatening gastrointestinal metastases occurred in 12 cases and five occurred in large cell carcinoma. Gastrointestinal metastases from primary lung cancer may occur in the clinical course and result in life threatening gastrointestinal metastases, particularly if patients have the histological type of large cell carcinoma. (c) 2006 Elsevier Ltd. All rights reserved.

DOI： 10.1016/j.ejca.2006.08.030

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Language：English   Publisher：Kinki University  

L858R point mutation in exon 21 of the EGFR gene, accounting for approximately 40% of non-small cell lung cancer (NSCLC)-associated EGFR mutations, has been known to hyper-respond to gefitinib, a selective EGFR tyrosine kinase inhibitor. From this view point, it is important to detect EGFR mutations. Immunohistochemistry (IHC) is commonly used to analyze the molecular status of several clinical specimens. We have developed specific antibodies recognizing the mutant EGFR (L858R) protein and characterized the antibodies by ELISA, Western blot, immunocytochemistry, and immunohistochemistry. Using any of these evaluation methods, we found an antibody, AbyD02889, which could detect the EGFR (L858R) protein with specificity. AbyD02889 may be a useful tool to detect the EGFR (L858R) mutation of NSCLC in the clinical situation. IHC using the mutant-specific anti-EGFR antibody will be a powerful assay to predict or select subpopulation sensitive to EGFR-TKI.

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Background. Cancer-associated retinopathy (CAR) is one of the paraneoplastic syndromes. CAR is known to be associated with epithelial cancers, mostly small cell lung cancer. We encountered one rare case of small cell lung cancer associated with CAR. Case. A 77-year-old man complained of dimming of vision in June 2003. He was suspected to have CAR because his electroretinography (ERG) showed a negative waveform, and his multifocal ERG (visual evoked response imaging system: VERIS) showed a diffuse negative waveform. After detailed whole-body examinations including mediastinoscopic biopsy, limited-stage small cell lung carcinoma was diagnosed. Although antirecoverin antibody, which is a characteristic of CAR, was not detected in his serum, the presence of recoverin in the mediastinoscopic biopsy specimen was verified by immunohistochemistry. After two cycles of chemotherapy consisting of carboplatin and etoposide followed by sequential radiotherapy were performed, the tumor responded completely. This patient's vision did not improve in spite of the complete response. Conclusion. Upon diagnosis of CAR without serum anti-recoverin antibody, it can be helpful to verify the presence of recoverin in tumor tissue by immunohistochemistry for the definitive diagnosis of CAR. © 2006 The Japan Lung Cancer Society.

DOI： 10.2482/haigan.46.741

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Language：Japanese   Publisher：(公社)日本医学放射線学会  

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：OXFORD UNIV PRESS  

Objective: The aim of this study was to evaluate the efficacy and toxicity of gemcitabine combined with irinotecan in patients with previously treated non-small-cell lung cancer (NSCLC).
Methods: Patients who failed to respond to platinum-containing first-line chemotherapy were enrolled and treated with gemcitabine 1000 mg/m(2) and irinotecan 150 mg/m(2) on days 1 and 15. Cycles were repeated every 4 weeks.
Results: Twenty-seven of 30 registered patients were evaluated. There were previous combination treatments of platinum and taxane regimens in 21 out of 27 patients, with 17 patients treated with carboplatin and paclitaxel and 4 patients treated with cisplatin or carboplatin and docetaxel. A total of 87 cycles was administered and the median number of cycles administered per patient was 3.5 cycles. Objective responses were observed in 5 out of 27 patients (18.5%). No severe hematologic and non-hematologic toxicities were observed (grade 3 leukopenia in 3 patients; grade 3 anemia in 3 patients; grade 3 thrombocytopenia in 2 patients; grade 3 diarrhea in 1 patient). The median survival time was 7.7 months and 1-year survival rate was 34.8%.
Conclusion: Bi-weekly gemcitabine and irinotecan was well tolerated and had an acceptable response rate and a reasonable median survival time for patients with NSCLC who had previously been treated with platinum-based chemotherapy.

DOI： 10.1093/jjco/hyl062

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