Yoshiro Mochizuki

Safety and pharmacokinetics of nintedanib and pirfenidone in idiopathic pulmonary fibrosis

A randomised, double-blind, phase II, dose escalation trial was conducted to assess the safety, tolerability and pharmacokinetics of the tyrosine kinase inhibitor nintedanib, alone and when added to ongoing pirfenidone therapy, in Japanese patients with idiopathic pulmonary fibrosis. 50 Japanese patients were randomised to receive nintedanib or placebo in one of three cohorts (nintedanib 50 mg twice daily or 100 mg twice daily for 14 days, or 150 mg twice daily for 28 days). Patients receiving pirfenidone at inclusion were stratified to every nintedanib dose group and placebo. Adverse events were reported in nine out of 17 patients receiving nintedanib alone and 10 out of 21 patients receiving nintedanib added to pirfenidone. All adverse events were mild or moderate in intensity. Gastrointestinal disorders were the most common adverse event. Maximum plasma concentration and area under the curve at steady state for nintedanib and its metabolites tended to be lower when nintedanib was added to pirfenidone. Nintedanib had no effect on the pharmacokinetics of pirfenidone. In conclusion, further study is needed to evaluate the safety and tolerability profile of nintedanib when added to pirfenidone in patients with idiopathic pulmonary fibrosis. There was a trend toward lower exposure of nintedanib when it was added to pirfenidone. Nintedanib had acceptable safety and tolerability in Japanese patients with IPF http://ow.ly/DNG4k

A nationwide epidemiological survey of chronic hypersensitivity pneumonitis in Japan

BACKGROUND In 1999, a Japanese epidemiological survey of chronic hypersensitivity pneumonitis (HP) showed that summer-type HP was the most prevalent variant of the disease. The number of reported cases of chronic HP has recently been increasing, and the clinical features of the disease seem to have changed. We conducted another nationwide epidemiological survey of chronic HP in Japan to determine better estimates of the frequency and clinical features of the disease. METHODS A questionnaire was sent to qualified hospitals throughout Japan, and data on cases of chronic HP diagnosed between 2000 and 2009 were collected. RESULTS In total, 222 cases of chronic HP from 22 hospitals were studied. Disease subtypes included bird-related HP (n=134), summer-type HP (n=33), home-related HP (n=25), farmers lung (n=4), isocyanate-induced HP (n=3), and other types (n=23). The median proportion of lymphocytes in bronchoalveolar lavage fluid was high (24.5%). The primary findings of computed tomography of the chest were ground-glass attenuation and interlobular septal thickening. Centrilobular fibrosis was the major pathological finding on examination of surgical lung biopsy specimens from 93 patients. The median survival time was 83 months. CONCLUSIONS The proportion of bird-related HP was higher than that in the previous epidemiological survey, and the proportions of isocyanate-induced HP and farmers lung were lower. A crucial step in diagnosing chronic HP is to thoroughly explore the possibility of antigen exposure.

A case of diffuse panbronchiolitis, associated with severe pulmonary hypertension, managed with bilateral lung transplantation from a brain-dead donor

Diffuse panbronchiolitis (DPB) is a chronic respiratory disease that mainly involves the respiratory bronchioles, and has historically been associated with a very poor prognosis. The development of long-term low dose macrolide therapy in the 1980s has dramatically improved the prognosis of DPB. Nevertheless, some cases are resistant to macrolide therapy, and ultimately develop severe respiratory failure and pulmonary hypertension; in such cases lung transplantation is a viable treatment option. Here we report the case of a 40-year-old patient with a 20-year history of DPB, who underwent bilateral lung transplantation due to severe respiratory failure with pulmonary hypertension.

Genetic homology between bacteria in pus from the pyothorax and bacteria in the oral cavity in patients with pyothorax

Introduction: The bacteria responsible for pyothorax may be derived from the oral cavity; however, it has not been proven yet. Objective: Our aim was to study if there is genetic homology between the bacteria in pus from the pyothorax and the bacteria in the oral cavity using Next-Generation Sequencing technology (NGS) in patients with pyothorax. Methods: Two patients with pyothorax were studied. We aspirated pus from the pyothorax by fine-needle biopsy and sampled the bacteria in the oral cavity with a sponge. Cultured bacteria from the pus were isolated and identified by their 16S rRNA gene sequence. Then, we obtained its whole genome sequence by NGS using the MiSeq (illumina) platform. Based on this sequence and an already-known sequence of the same bacterial species, we generated five specific primers for the isolated pyothorax strain. We amplified total DNA that had been extracted from the oral bacteria using these specific primers by the PCR method and performed DNA sequencing. Results: In both patients, we identified the Streptococcus anginosus group from the pus. In each patient, the sequence of the oral bacterial DNA that had been amplified by specific primers for the pyothorax strain completely matched the DNA sequence of the isolated pyothorax strain, while it did not match already-known sequences of the same bacterial species. Conclusion: This study demonstrated genetic homology between the bacteria in pus from the pyothorax and oral bacteria at the strain level in pyothorax patients. This study proved for the first time that pyothorax is caused by oral bacteria, although the number of cases was limited.

Prognostic implications of smoking in patients with advanced lung adenocarcinoma excluding positive mutations

Background: Lung adenocarcinoma in never-smoker patients often expresses mutations including EGFR or ALK, which leads to better prognosis in never-smoker patients with indication of tyrosine kinase inhibitors (TKI). But little is known about the influence of smoking on prognosis in patients with advanced lung adenocarcinoma excluding positive mutations. Objective: This study examined the influence of smoking on overall survival of patients with stage IV lung adenocarcinoma excluding those treated with TKI on the basis of positivity of mutations. Methods: We retrospectively analyzed 129 consecutive stage IV lung adenocarcinoma cases with wild-type EGFR and without positive ALK mutations treated in our hospital between January 2011 and December 2014. Results: Out of 129 patients, 104 (81%) had a smoking history. Median age (range) and male-to-female ratio were 64 years (40-89) and 94:10 in the smoker group and 71 years (42-80) and 3:21 in the never-smoker group. PD-1 inhibitor was administrated in one smoking patient. Overall survival rate was significantly higher in never-smoker patients (p=0.031, log-rank), and median survival of patients with smoking history was 9.3 months, and 19.1 months in never-smoker patients. Conclusions: These data suggest that smoking history was a poor prognostic factor in advanced lung adenocarcinoma patients excluding positive mutations.

Familial interstitial pneumonia complicated by lung cancer in 2 sisters.

A 29-year-old woman was referred to our hospital because of progressive dyspnea on exertion, and her 36-year-old sister was also referred for the evaluation of an abnormal chest radiograph. Radiologic and pathologic findings of the 2 sisters resembled each other closely. In both cases, computed tomography revealed diffuse reticulation, micronodules, diffusely distributed interlobular septal thickening, and an ill-defined nodule in the left lower lobe. Radiologic-pathologic correlation revealed that the reticulation and micronodules corresponded to centrilobular and perilobular fibrosis without architectural lung distortion and that the nodules represented pulmonary adenocarcinoma. To our knowledge, this is the first report of familial interstitial pneumonia complicated by lung cancer in 2 family members, suggesting a possible etiologic association between familial interstitial pneumonia and lung cancer.

Comparison of Family History and Past History in Lung Cancer Patients and Emphysema Patients.

肺癌および肺気腫症例の入院患者について既往歴, 家族歴を比較検討した. 気腫群は呼吸不全などのため入院を要した症例であり, 肺癌群より高齢, 喫煙指数高値であった. 既往歴では虚血性心疾患が肺癌群で有意に多かった. 消化性潰瘍の既往は両群に頻度の差はないが罹患年齢分布に相違がみられ, 肺癌群では50才に, 肺気腫群では40才台と60～70才の2相性にピークがみられた. 家族歴では良性疾患についての両群間の差はみられなかったが, 肺癌群には肺気腫群の約2倍の頻度で癌患者がみられた. 肺癌家族にみられる癌の種類は本邦における一般的な癌頻度と大差なかった. この傾向は血縁者のみでなく配偶者にもみられた. 喫煙は肺癌の危険因子とされるが, 逆に重喫煙にもかかわらず肺癌を発症していない者は肺癌発症に対する感受性が低下している可能性も否定できない. 対象とした肺気腫群はこのモデル例と考えられ, 上記の比較は肺癌危険因子を探る上で示唆的と考える.