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Background: Transbronchial lung cryobiopsy (TBLC) is a new technique for obtaining high-quality and large-sized lung tissues, as compared to transbronchial forceps biopsy (TBFB), and is useful in the diagnosis of diffuse lung disease (DLD). We aimed to evaluate the safety of TBLC as compared to TBFB in DLD patients in Japan using a nationwide database., Methods: Data were retrospectively collected from the Japanese Diagnosis Procedure Combination database from April 1, 2020 to March 31, 2022. Eligible patients (n = 9673) were divided into the following two groups: those who underwent TBFB (TBFB group, n = 8742) and TBLC (TBLC group, n = 931). To compare the outcomes between the two groups, a stabilized inverse probability of treatment weighting (IPTW) was applied using propensity scores. The primary outcome was in-hospital mortality, and the secondary outcomes were 28-day mortality, complications (mechanical ventilation, pneumothorax, and bleeding), and length of hospital stay after bronchoscopy., Results: The crude in-hospital mortality rates were 3.2% and 0.9% in the TBFB and TBLC groups, respectively. The stabilized IPTW analysis showed no significant difference in the in-hospital mortality rates between the two groups; the odds ratio of the TBLC group as compared with the TBFB group was 0.73 (95% confidence interval: 0.34-1.60; p = 0.44). Moreover, the secondary outcomes did not significantly differ between the two groups., Conclusions: TBLC for DLD patients had a similar mortality and complication rates as TBFB., Competing Interests: Declaration of competing interest Dr. H. Yasunaga reports receiving grants from the Ministry of Health, Labor, and Welfare, Japan and the Ministry of Education, Culture, Sports, Science, and Technology, Japan during the conduct of the study. The other authors have no conflicts of interest., (Copyright © 2024 The Japanese Respiratory Society. Published by Elsevier B.V. All rights reserved.)

Objective Bronchoscopic lung volume reduction (BLVR) using a one-way endobronchial valve (EBV) can provide clinically meaningful benefits to chronic obstructive pulmonary disease (COPD) patients. Although the Japanese Pharmaceuticals and Medical Devices Agency approved EBVs in November 2022, information regarding the number of Japanese patients with severe COPD eligible for BLVR treatment is still lacking. We therefore screened computed tomography (CT) images of patients with severe COPD using a quantitative CT (QCT) analysis to estimate the proportion of candidates eligible for BLVR treatment with an EBV. Methods CT scans of COPD patients with Global Initiative for Chronic Obstructive Lung Disease (GOLD) stages 3 and 4 were retrospectively analyzed using QCT to evaluate fissure integrity and tissue destruction. The difference in volume-weighted percentage was measured using the density scores of the target lobe and ipsilateral non-target lobe at -910 Hounsfield units. The target lobe was defined as the most affected lobe, with an emphysema destruction score of >50% for each patient. Results High-resolution CT scans of 32 patients (GOLD 3=19, GOLD 4=13) were analyzed. The target lobe could not be identified in 1 patient, whereas the target lobes for 8 patients were not surrounded by fissures with ≥80% completeness. Conversely, in 13 patients, the target lobes were surrounded by fissures with >95% completeness. The remaining 10 patients had fissure completeness between 80% and 95% at the target lobes and were considered candidates for collateral ventilation assessment. Conclusion A QCT analysis showed that 23 of 32 patients with severe COPD could be considered for a thorough examination of BLVR treatment with EBV.

Introduction: The standard therapy for stage I NSCLC is surgery, but some operable patients refuse this option and instead undergo radiotherapy. Carbon-ion radiotherapy (CIRT) is a type of radiotherapy. The Japanese prospective nationwide registry study on CIRT began in 2016. Here, we analyzed real-world clinical outcomes of CIRT for operable patients with stage I NSCLC., Methods: All patients with operable stage I NSCLC treated with CIRT in Japan between 2016 and 2018 were enrolled. The dose fractionations for CIRT were selected from several options approved by the Japanese Society for Radiation Oncology. CIRT was delivered to the primary tumor, not to lymph nodes., Results: The median follow-up period was 56 months. Among 136 patients, 117 (86%) had clinical stage IA NSCLC and 19 (14%) had clinical stage IB NSCLC. There were 50 patients (37%) diagnosed clinically without having been diagnosed histologically. Most tumors (97%) were located in the periphery. The 5-year overall survival, cause-specific survival, progression-free survival, and local control rate were 81.8% (95% confidence interval [CI]: 75.1-89.2), 91.2% (95% CI: 86.0-96.8), 65.9% (95% CI: 58.2-74.6), and 95.8% (95% CI: 92.3-99.5), respectively. Multivariate analysis identified age as a significant factor for overall survival (p = 0.018), whereas age and consolidation/tumor ratio (p = 0.010 and p = 0.004) were significant factors for progression-free survival. There was no grade 4 or higher toxicity. Grade 3 radiation pneumonitis occurred in one patient., Conclusions: This study reports the long-term outcomes of CIRT for operable NSCLC in the real world. CIRT for operable patients has been found to have favorable outcomes, with tolerable toxicity., (Copyright © 2023 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.)

Considering recently published two guidelines for the diagnosis of hypersensitivity pneumonitis (HP), the Japanese Respiratory Society (JRS) has now published its own Japanese clinical practice guide for HP. Major types of HP in Japan include summer-type, home-related, bird-related, farmer's lung, painter's lung, humidifier lung, and mushroom grower's lung. Identifying causative antigens is critical for increasing diagnostic confidence, as well as improving prognosis through appropriate antigen avoidance. This guide proposes a comprehensive antigen questionnaire including the outbreak sources reported in Japan. Drawing on the 2021 CHEST guideline, this guide highlights the antigen identification confidence level and adaptations for environmental surveys. The detection of specific antibodies against causative antigens is an important diagnostic predictor of HP. In Japan, the assessments of bird-specific IgG (pigeons, budgerigars) and the Trichosporon asahii antibody are covered by medical insurance. Although this guide adopts the 2020 ATS/JRS/ALAT guideline diagnostic criteria based on the combination of imaging findings, exposure assessment, bronchoalveolar lavage lymphocytosis, and histopathological findings, it added some annotations to facilitate the interpretation of the content and correlate the medical situation in Japan. It recommends checking biomarkers; seasonal changes in the KL-6 concentration (increase in winter for bird-related HP/humidifier lung and in summer for summer-type HP) and high KL-6 concentrations providing a basis for the suspicion of HP. Antigen avoidance is critical for disease management of HP. This guide also addresses the pharmacological management of HP, highlighting the treatment strategy for fibrotic HP including combination therapies with anti-inflammatory/immunosuppressive and antifibrotic drugs., Competing Interests: Conflict of Interest Hiromi Tomioka received lecture fees from Nippon Boehringer Ingelheim Co., Ltd. Yasunari Miyazaki received research grants from Nippon Boehringer Ingelheim Co., Ltd. and Chugai Pharmaceutical Co., Ltd. and lecture fees from Nippon Boehringer Ingelheim Co., Ltd. and Astra Zeneca Co., Ltd. Yoshikazu Inoue received lecture fees from Nippon Boehringer Ingelheim Co., Ltd. Hiroyuki Sano received lecture fees from AstraZeneca Co., Ltd., Glaxo Smith Kline Co., Ltd., Nippon Boehringer Ingelheim Co., Ltd. and Novartis Pharma Co., Ltd.. Takeshi Johkoh received lecture fees from Nippon Boehringer Ingelheim Co., Ltd. Takeshi Hisada received lecture fees from AstraZeneca Co., Ltd. Junya Fukuoka received honoraria from National Institute of Advanced Industrial Science and Technology and Future Corporation. Yuki Iijima received a research grant from Shionogi & Co.,Ltd. Masahiro Ishizuka received a research grant from GlaxoSmithKline Co.,Ltd. Tsukasa Okamoto received endowments from Nippon Boehringer Ingelheim Co., Ltd., Chugai Pharmaceutical Co., Ltd., Wako Filter Technology Co.,Ltd., and Car Conveni Club Co.,Ltd. Toshiaki Kikuchi received lecture fees from AstraZeneca Co.,Ltd., Chugai Pharmaceutical Co.,Ltd and Nippon Boehringer Ingelheim Co., Ltd and a research grant from Astra Zeneca Co.,Ltd. and endowments from Ono Pharmaceutical Co.,Ltd, Shionogi & Co.,Ltd., Chugai Pharmaceutical Co., Ltd. and Nippon Eli Lilly Co.,Ltd. Noriho Sakamoto a research grant from PPD-SNBL Co., Ltd.. Noboru Hattori received lecture fees from Astra Zeneca Co.,Ltd, Glaxo Smith Kline Co.,Ltd., Shionogi & Co.,Ltd., Chugai Pharmaceutical Co.,Ltd and Nippon Boehringer Ingelheim Co., Ltd. and endowments from Ono Pharmaceutical Co.,Ltd, Taiho Pharmaceutical Co.,Ltd and Nippon Eli Lilly Co.,Ltd.. Hiroshi Mukae received lecture fees from Astellas Pharma Inc., Astra Zeneca Co.,Ltd., MSD Co.,Ltd., Kyorin Pharmaceutical Co.,Ltd., Shionogi & Co.,Ltd., Daiichi Sankyo Co.,Ltd., Taisho Pharmaceutical Co., Ltd., Nippon Boehringer Ingelheim Co., Ltd and Pfizer Co., Ltd. and research grants from Otsuka Pharmaceutical Co., Ltd., Shionogi & Co.,Ltd. and Nippon Boehringer Ingelheim Co., Ltd. and endowments from Astellas Pharma Inc., Kyorin Pharmaceutical Co.,Ltd., Shionogi & Co.,Ltd., Daiichi Sankyo Co.,Ltd., Taisho Pharmaceutical Co., Taiho Pharmaceutical Co.,Ltd, Chugai Pharmaceutical Co.,Ltd, FUJIFILM Toyama Chemical Co.,Ltd, and Meiji Seika Pharma Co.,Ltd. Masao Yamaguchi received lecture fees from AstraZeneca Co.,Ltd. Yoshihiro Nishimura received lecture fees from Astra Zeneca Co.,Ltd., Glaxo Smith Kline Co.,Ltd., Novartis Pharma Co.,Ltd. and Nippon Boehringer Ingelheim Co., Ltd and research grants from Teijinn Pharma Co., Ltd and endowments from Glaxo Smith Kline Co.,Ltd., Taiho Pharmaceutical Co.,Ltd, Chugai Pharmaceutical Co.,Ltd and Nippon Eli Lilly Co.,Ltd. Masayuki Hanaoka received lecture fees from AstraZeneca Co., Ltd. and Nippon Boehringer Ingelheim Co., Ltd and endowments from Bayer Pharma Co., Ltd.. Masashi Bando received lecture fees from AstraZeneca Co., Ltd. Shionogi & Co.,Ltd. and Nippon Boehringer Ingelheim Co., Ltd. Ryoko Egashira, Tetsuji Kawamura, Tamiko Takemura, Naohiko Inase, Masaru Ejima, Horoshi Ohnishi, Ryo Okuda, Susumu Sakamoto, Tsuyoshi Shirai, Kozo Suhara, Reoto Takei, Tomoya Tateishi, Kentaro Tanaka, Toshiharu Tsutsui, Yoshihisa Nukui, Haruhiko Furusawa, Yasushi Horimasu, Akemi Matsuo, Takashi Yamana, Yasuyuki Yoshizawa and Masahiro Kaneko have no conflicts of interest., (© 2023 Published by Elsevier B.V. on behalf of The Japanese Respiratory Society.)

Background: Transbronchial lung cryobiopsy (TBLC) is known to be associated with a high incidence of adverse events. However, few studies have investigated the correlation between obesity and the risk of TBLC-related adverse events, especially in Asians, who are known to have characteristic differences in height and weight as compared to individuals of other ethnicities., Methods: We retrospectively assessed 102 Japanese patients who underwent TBLC for the diagnosis of interstitial lung disease to evaluate the correlation between patient characteristics and the occurrence of TBLC-related adverse events (hemorrhage, pneumothorax, and acute exacerbation of interstitial lung disease)., Results: TBLC-related adverse events occurred in 19 patients (18.6 %), with hemorrhage being the most common adverse event (in 14 patients, 13.7 %). There was no correlation between age, sex, or pulmonary function test results and the occurrence of adverse events. The body mass index (BMI) cut-off predicting the occurrence of all adverse events was 26.6 kg/m 2 (sensitivity of 0.389 and specificity of 0.852), and that predicting the occurrence of adverse events of hemorrhage was 26.8 kg/m 2 (sensitivity of 0.462 and specificity of 0.907). Among patients with a BMI >26.8 kg/m 2 , adverse events of hemorrhage occurred in 37.5 % of cases, which was higher than among those with a BMI <26.8 kg/m 2 ., Conclusions: Obesity is a risk factor for the incidence of TBLC-related adverse events, particularly adverse events of hemorrhage, in Japanese patients. The BMI cut-off values that predicted an increased frequency of TBLC-related adverse events and hemorrhage specifically were 26.6 and 26.8 kg/m 2 , respectively., Competing Interests: Declaration of competing interest The authors have no conflicts of interest., (Copyright © 2023 The Japanese Respiratory Society. All rights reserved.)

Background: Computed tomography (CT) imaging and artificial intelligence (AI)-based analyses have aided in the diagnosis and prediction of the severity of COVID-19. However, the potential of AI-based CT quantification of pneumonia in assessing patients with COVID-19 has not yet been fully explored. This study aimed to investigate the potential of AI-based CT quantification of COVID-19 pneumonia to predict the critical outcomes and clinical characteristics of patients with residual lung lesions., Methods: This retrospective cohort study included 1,200 hospitalized patients with COVID-19 from four hospitals. The incidence of critical outcomes (requiring the support of high-flow oxygen or invasive mechanical ventilation or death) and complications during hospitalization (bacterial infection, renal failure, heart failure, thromboembolism, and liver dysfunction) was compared between the groups of pneumonia with high/low-percentage lung lesions, based on AI-based CT quantification. Additionally, 198 patients underwent CT scans 3 months after admission to analyze prognostic factors for residual lung lesions., Results: The pneumonia group with a high percentage of lung lesions (N = 400) had a higher incidence of critical outcomes and complications during hospitalization than the low percentage group (N = 800). Multivariable analysis demonstrated that AI-based CT quantification of pneumonia was independently associated with critical outcomes (adjusted odds ratio [aOR] 10.5, 95% confidence interval [CI] 5.59-19.7), as well as with oxygen requirement (aOR 6.35, 95% CI 4.60-8.76), IMV requirement (aOR 7.73, 95% CI 2.52-23.7), and mortality rate (aOR 6.46, 95% CI 1.87-22.3). Among patients with follow-up CT scans (N = 198), the multivariable analysis revealed that the pneumonia group with a high percentage of lung lesions on admission (aOR 4.74, 95% CI 2.36-9.52), older age (aOR 2.53, 95% CI 1.16-5.51), female sex (aOR 2.41, 95% CI 1.13-5.11), and medical history of hypertension (aOR 2.22, 95% CI 1.09-4.50) independently predicted persistent residual lung lesions., Conclusions: AI-based CT quantification of pneumonia provides valuable information beyond qualitative evaluation by physicians, enabling the prediction of critical outcomes and residual lung lesions in patients with COVID-19., (© 2023. BioMed Central Ltd., part of Springer Nature.)

OBJECTIVES This study intended to assess the clinicopathological features of the histological subtypes of adenocarcinoma of the lung in a large registry population. METHODS The Japanese Joint Committee of Lung Cancer Registry performed a nationwide retrospective registry study on the prognosis and clinicopathological profiles of 11 663 patients who underwent resection for primary lung neoplasm in 2004. The registry data of 7921 (62.5%) patients with adenocarcinoma were analysed regarding the prognosis and clinicopathological features according to the histological subtype of adenocarcinoma. The histological subtypes were defined according to the 1999 World Health Organization classification (third edition), where bronchioloalveolar carcinoma (BAC) is defined as adenocarcinoma with a pure bronchioloalveolar growth pattern without invasion. RESULTS The distribution of the histological subtype was acinar in 471 patients (7.5%), papillary in 2004 (32.2%), BAC in 1385 (22.3%), solid adenocarcinoma with mucin in 103 (1.7%) and adenocarcinoma with mixed subtypes (AMS) in 2257 (36.3%). The 5-year overall survival rates according to histological subtype were 63.4% for acinar, 72.9% for papillary, 90.3% for BAC, 54.4% for solid adenocarcinoma with mucin and 73.7% for AMS. While the survival rate in patients with BAC was significantly better than those for the other histological subtypes, acinar and solid adenocarcinoma with mucin had significantly worse prognoses than the other histological subtypes. The histological subtype was an independent predictor of survival in a multivariate analysis (P < 0.001). Regarding BAC, the pathological stage included not only Stage IA/IB (n = 1275; 92.1%), but also Stage II–IV (n = 110; 7.9%). One hundred twenty-five patients (9.0%) with BAC had recurrence, including both local and distant recurrence. CONCLUSIONS The histological subtype in adenocarcinoma significantly correlated with the prognosis. In BACs with recurrence or pathological stage II–IV, these tumours might have been classified as invasive adenocarcinoma rather than as BAC. The need for the rigorous pathological evaluation of adenocarcinomas that are considered to be a preinvasive or minimally invasive tumour should be addressed in the new lung adenocarcinoma classification to be proposed by the International Association for the Study of Lung Cancer, the American Thoracic Society and the European Respiratory Society. [ABSTRACT FROM PUBLISHER]

Identifying the host genetic factors underlying severe COVID-19 is an emerging challenge 1-5 . Here we conducted a genome-wide association study (GWAS) involving 2,393 cases of COVID-19 in a cohort of Japanese individuals collected during the initial waves of the pandemic, with 3,289 unaffected controls. We identified a variant on chromosome 5 at 5q35 (rs60200309-A), close to the dedicator of cytokinesis 2 gene (DOCK2), which was associated with severe COVID-19 in patients less than 65 years of age. This risk allele was prevalent in East Asian individuals but rare in Europeans, highlighting the value of genome-wide association studies in non-European populations. RNA-sequencing analysis of 473 bulk peripheral blood samples identified decreased expression of DOCK2 associated with the risk allele in these younger patients. DOCK2 expression was suppressed in patients with severe cases of COVID-19. Single-cell RNA-sequencing analysis (n = 61 individuals) identified cell-type-specific downregulation of DOCK2 and a COVID-19-specific decreasing effect of the risk allele on DOCK2 expression in non-classical monocytes. Immunohistochemistry of lung specimens from patients with severe COVID-19 pneumonia showed suppressed DOCK2 expression. Moreover, inhibition of DOCK2 function with CPYPP increased the severity of pneumonia in a Syrian hamster model of SARS-CoV-2 infection, characterized by weight loss, lung oedema, enhanced viral loads, impaired macrophage recruitment and dysregulated type I interferon responses. We conclude that DOCK2 has an important role in the host immune response to SARS-CoV-2 infection and the development of severe COVID-19, and could be further explored as a potential biomarker and/or therapeutic target., (© 2022. The Author(s).)

Background. Gemcitabine (GEM) is widely used as a chemotherapeutic agent. However, pulmonary toxicity has been rarely observed with GEM use. This article aims to determine the incidence and causes of drug-induced pulmonary toxicity, and to classify the high-resolution computed tomography (HRCT) findings for antitumor therapy-associated pulmonary toxicity based on characteristic patterns and pathological considerations, with a special focus on GEM-associated pulmonary toxicity (GAPT). Methods. Medical records of all patients with drug-induced pulmonary toxicity seen at Kyorin University hospital between April 2006 and December 2011 were retrospectively reviewed. The study examined correlations between HRCT and the assessed pathological or clinical findings, with a specific focus on antitumor drugs. Results. We identified 66 patients with drug-induced pulmonary toxicity. Among the antitumor drugs, GEM was the primary offending agent (n = 8) for pulmonary toxicity followed by docetaxel and gefitinib. HRCT patterns for the eight GAPT patients included the non-specific interstitial pneumonia (NSIP; n = 5) and the hypersensitivity pneumonitis (HP)-like pattern (n = 3). In contrast, four patients in the study were found to have the HP-like pattern, with three cases associated with GEM and one case associated with imatinib mesylate. The transbronchial lung biopsy or video-assisted thoracic surgery specimens for these patients showed granuloma or organizing tissue with a random distribution that was independent of the respiratory bronchiole. These results appeared to correspond to the HRCT-determined centrilobular nodules. Conclusion. GEM was the leading cause of drug-induced pulmonary toxicity in the patients examined in this study. This toxicity appears as NSIP or an HP-like pattern during HRCT examinations. This HP-like pattern may be useful for diagnosing GEM-induced pulmonary toxicity, as well as demonstrating granuloma or organizing tissue during lung pathology examinations. [ABSTRACT FROM AUTHOR]

Background: Neuroendocrine neoplasms (NENs) are rare and can originate from any body part. However, there are only few epidemiological studies, especially on lung and mediastinal NENs. This study investigated the epidemiological trends and differences between lung and mediastinal NENs in Japan., Methods: Patients with lung and mediastinal NENs were identified in a national hospital-based cancer registry between 2009 and 2015 in Japan. NENs were subclassified into neuroendocrine tumors (NETs) and neuroendocrine carcinomas (NECs). NECs were further subdivided into large neuroendocrine carcinomas (LCNECs) and small cell carcinomas (SCCs). We examined the patient characteristics: sex, age, histology, year of diagnosis, diagnostic opportunity, and initial treatment., Results: We identified 48,433 patients with 47,888 lung (98.9%) and 545 mediastinal (1.1%) NENs. The commonest subtype of lung NENs was SCCs (87%), followed by LCNECs (10%) and NETs (3%). In the mediastinum, SCCs were also the commonest (48%), followed by NETs (38%) and LCNECs (14%). The number of lung NEN annually increased; however, that of mediastinal NENs did not change over time. The mean age of patients with lung NETs was lower than that of patients with lung LCNECs and SCCs (NETs, 62 ± 14 years; LCNECs, 70 ± 9 years; SCCs, 71 ± 9 years; p < .001). The lung and mediastinal NENs were mainly detected based on symptoms, except for lung NETs. Surgical intervention, including multimodal therapy, was performed for 89.3% of lung NETs (surgery alone: 83.6%), while only 15.6% of lung NECs were treated with surgery. For the mediastinum, 75.9% of NETs were treated with surgery, with 27.1% of cases treated with surgery plus multimodal therapy. Surgery was performed more frequently for mediastinal NECs (37%) than for lung NECs (15.6%)., Conclusions: This study highlights differences in trends of lung and mediastinal NENs. This study's findings support the importance of epidemiological evaluations based on the primary sites and histological subtypes., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Background: The usefulness and safety of transbronchial lung cryobiopsy (TBLC) for reassessment of diffuse parenchymal lung disease (DPLD) with progression is still unknown. Our purpose was to clarify the usefulness and safety of TBLC for reassessment of DPLD with progression., Methods: This retrospective study included 31 patients with DPLD diagnosed by surgical lung biopsy who progressed in the clinical course and underwent TBLC for reassessment between January 2017 and September 2019 at Kanagawa Cardiovascular & Respiratory Center. Two pulmonologists independently selected the clinical diagnosis, treatment strategy, and confidence level of the treatment strategy based on clinical and radiological information with and without pathological information from TBLC. A consensus was reached among the pulmonologists regarding the clinical diagnosis, treatment strategy, and confidence level of the treatment strategy. Complications of TBLC were also examined., Results: Seven (22.6%), 5 (16.1%), and 6 (19.4%) of clinical diagnosis was changed after TBLC for Pulmonologist A, for Pulmonologist B, and for consensus, respectively. The treatment strategy was changed in 7 (22.6%), 8 (25.9%), and 6 (19.4%) cases after TBLC for Pulmonologist A, for Pulmonologist B and for consensus, respectively. The definite or high confidence level of the consensus treatment strategy was 54.8% (17/31) without TBLC and 83.9% (26/31) with TBLC. There were 6 cases of moderate bleeding, but no other complications were noted., Conclusions: Pathological information from TBLC may contribute to decision-making in treatment strategies for the progression of DPLD, and it may be safely performed., (© 2022. The Author(s).)

Background: The optimal mode of surgery for ground-glass opacity dominant peripheral lung cancer defined with thoracic thin-section computed tomography remains unknown., Methods: We conducted a single-arm confirmatory trial to evaluate the efficacy and safety of sublobar resection for ground-glass opacity dominant peripheral lung cancer. Lung cancer with maximum tumor diameter 2.0 cm or less and with consolidation tumor ratio 0.25 or less based on thin-section computed tomography were registered. The primary end point was 5-year relapse-free survival. The planned sample size was 330 with the expected 5-year relapse-free survival of 98%, threshold of 95%, 1-sided α of 5%, and power of 90%. The trial is registered with University Hospital Medical Information Network Clinical Trials Registry, number University Hospital Medical Information Network 000002008., Results: Between May 2009 and April 2011, 333 patients were enrolled from 51 institutions. Median age was 62 years (interquartile range, 56-68), and 109 were smokers. Median maximum tumor diameter was 1.20 cm (1.00-1.54). Median maximum tumor diameter of consolidation was 0 (0.00-0.20). The primary end point, 5-year relapse-free survival, was estimated on 314 patients who underwent sublobar resection. Operative modes were 258 wide wedge resections and 56 segmentectomies. Median pathological surgical margin was 15 mm (0-55). The 5-year relapse-free survival was 99.7% (90% confidence interval, 98.3-99.9), which met the primary end point. There was no local relapse. Grade 3 or higher postoperative complications based on Common Terminology Criteria for Adverse Effect v3.0 were observed in 17 patients (5.4%), without any grade 4 or 5., Conclusions: Sublobar resection with enough surgical margin offered sufficient local control and relapse-free survival for lung cancer clinically resectable N0 staged by computed tomography with 3 or fewer peripheral lesions 2.0 cm or less amenable to sublobar resection and with a consolidation tumor ratio of 0.25 or less., (Copyright © 2020. Published by Elsevier Inc.)

Objective: The study objective was to compare cancer control between segmentectomy and wedge resection in patients with clinical stage IA non-small cell lung cancer., Methods: Between 2010 and 2015, 457 patients with clinical stage IA (8th edition) non-small cell lung cancer undergoing wedge resection or segmentectomy were identified at 3 institutions. Propensity scores were calculated on the basis of the extent of resection (wedge resection or segmentectomy) and included adjustment for confounding variables, such as age, sex, smoking status, pulmonary functions, laterality, tumor size, maximum standardized uptake value on 18 F-fluorodeoxyglucose positron emission tomography, presence of ground-glass opacity on high-resolution computed tomography, histology, and visceral pleural invasion for multivariable analysis and matching. The primary end point was cumulative incidence of recurrence., Results: In all cohorts, postoperative recurrence occurred in 36 of 195 patients (18.5%) undergoing wedge resection and 14 of 262 patients (5.3%) undergoing segmentectomy. Cumulative incidence of recurrence was significantly lower in patients undergoing segmentectomy (5-year cumulative incidence of recurrence, 5.3%) than in those undergoing wedge resection (5-year cumulative incidence of recurrence, 19.1%; P < .001). In propensity score-adjusted multivariable analysis, segmentectomy was identified as an independent favorable prognostic factor for cumulative incidence of recurrence (hazard ratio, 0.47; 95% confidence interval, 0.24-0.90; P = .022). In propensity score matching of 163 pairs, cumulative incidence of recurrence was significantly lower in patients undergoing segmentectomy (5-year cumulative incidence of recurrence, 6.6%) than in those undergoing wedge resection (5-year cumulative incidence of recurrence, 13.2%; P = .041)., Conclusions: Cancer control was better in segmentectomy than in wedge resection. Segmentectomy is the preferred oncologic procedure as sublobar resection to treat clinical stage IA non-small cell lung cancer., (Copyright © 2020 The American Association for Thoracic Surgery. Published by Elsevier Inc. All rights reserved.)

Among early-stage lung cancers that show ground-glass nodules on chest computed tomography, the lung cancer surgical study group of the Japan Clinical Oncology Group previously reported that nodules of ≤2 cm with a consolidation/tumor ratio of ≤0.25 were considered radiologically non-invasive cancers with a low risk of metastasis. However, there is no consensus based on high-quality evidence about the optimal timing of surgical intervention for radiologically non-invasive cancers. In June 2020, we launched a multi-institutional, single-arm confirmatory trial to evaluate the efficacy and safety of watchful waiting for patients with radiologically non-invasive lung cancer. It is planned that a total of 720 patients will be enrolled from 49 institutes over a 5-year period. The primary endpoint is 10-year overall survival (OS). The secondary endpoints are 5-year OS, operation-free survival, proportion of extensive lung resection, proportion of unresectable progression, lung cancer-specific survival and adverse events., (© The Author(s) 2021. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Introduction: The novel coronavirus disease (COVID-19) could cause a severe acute respiratory infectious disease, showing a high mortality rate of 12-45% among cases who required intensive care unit admission. COVID-19 pneumonia PATIENTS AND METHODS: For the purpose of identifying clinical manifestations and radiological findings of COVID-19 pneumonia, we reviewed all cases of COVID-19 pneumonia which were published by the homepage of the Japanese Association for Infectious Diseases from Feb 5 2020 until April 30 2020, including our cases. All patients were diagnosed based on positive results of the novel coronavirus-real-time RT-PCR with chest computed tomography (CT) findings., Results: A total of 92 patients were enrolled in this study. The median age was 66 years (range 16-92 years). For all, 50 (54%) were males. The most common underlying disease was hypertension in 32 (36%). Any comorbidity was seen in 60 (67%). The mortality rate was 4 (6%). In terms of clinical symptoms on an initial visit, fever and cough were confirmed in 66 (72%) and 37 (40%). Forty-three (47%) had no respiratory symptoms. As for radiological findings by chest CT scan, ground-glass opacities (GGO)s, peripheral distribution, bilateral lung involvements were seen in 88 (96%), 76 (83%) and 78 (85%), respectively., Conclusion: It is difficult to diagnose as COVID-19 pneumonia due to poor respiratory symptoms. Chest CT findings typically show GGO, peripheral and bilateral shadows. Patients should have chest CT performed if suspected for early diagnosis and therapeutic intervention, resulting in a favorable outcome and prevention of secondary nosocomial transmitted infection., Competing Interests: Declaration of competing interest All co-authors have none declared., (Copyright © 2020. Published by Elsevier B.V.)

Background: It is difficult to distinguish between multicentric Castleman's disease (MCD) and IgG4-related lung disease (IgG4-LD), an IgG4-related disease (IgG4-RD) in the lung., Methods: We focused on IL-6, which is elevated in MCD, to distinguish between MCD and IgG4-LD by RNAscope, a highly sensitive RNA in situ method. Six cases of MCD and four cases of IgG4-LD were selected., Results: In all cases of MCD and IgG4-LD, 10 or more IgG4-positive cells were found in one high-power field. All MCD cases were inconsistent with the pathological IgG4-related comprehensive diagnostic criteria, but 2 of 6 cases had an IgG4/IgG ratio greater than 40%. In all IgG4-LD cases, histological features were consistent with the pathological IgG4-RD comprehensive diagnostic criteria. IL-6 expression was observed in all MCD and IgG4-LD cases except for one IgG4-LD biopsy. IL-6-expressing cells were mainly identified in the stroma. Sites of IL-6 expression were not characteristic and were sparse. IL-6 expression tended to be higher in MCD compared with IgG4-LD. A positive correlation was found between the IL-6 H-score and serum IL-6 level., Conclusion: Differences in IL-6 expression may help distinguish between MCD and IgG4-LD. In addition, the presence of high IL-6 levels may help elucidate the pathological mechanisms of IgG4-LD., (© 2021. The Author(s).)

We encountered an outbreak of paragonimiasis among Cambodian technical intern trainees (TITs) at a food-processing factory in Fukuoka, Japan. The patients were 20-28 years old, seven females and two males, who had been in Japan for one to four years. All of them had consumed raw or undercooked Japanese mitten crab they purchased at a local grocery store near their training place. CT images showed multiple lesions not only in the lungs but in the extrapulmonary organs as well, such as subcutaneous tissues, abdominal muscles, and mesentery, in most of the patients. Their medical records indicated that all of them acquired infection in Japan, not in Cambodia. Diagnosis was made serologically and the patients were treated with praziquantel successfully. Foreign workers and TITs are increasing in Japan so rapidly, that food borne-infections, including paragonimiasis, should be considered in people from developing countries who have exotic dietary habits., (Copyright © 2021 The Authors. Published by Elsevier B.V. All rights reserved.)

Nivolumab can cause interstitial lung disease (ILD), which may be fatal; however, mortality risk factors have not been identified. This postmarketing study evaluated the poor prognostic factors of ILD in nivolumab-treated patients with non-small cell lung cancer (NSCLC) in Japan. Clinical and chest imaging findings for each ILD case were assessed by an expert central review committee, and prognosis was evaluated by radiographic findings, including the presence/absence of peritumoral ground-glass opacity (peritumoral-GGO). Poor prognostic factors were identified by univariate and multivariate Cox regression analysis. Of the 238 patients with nivolumab-induced ILD, 37 died. The main radiographic patterns of ILD were cryptogenic organizing pneumonia/chronic eosinophilic pneumonia-like (53.4%), faint infiltration pattern/acute hypersensitivity pneumonia-like (20.2%), diffuse alveolar damage (DAD)-like (10.9%), and nonspecific interstitial pneumonia-like (6.3%). The main poor prognostic factors identified were DAD-like pattern (highest hazard ratio: 10.72), ≤60 days from the start of nivolumab treatment to the onset of ILD, pleural effusion before treatment, lesion distribution contralateral or bilateral to the tumor, and abnormal change in C-reactive protein (CRP) levels. Of the 37 deaths due to ILD, 17 had DAD-like radiographic pattern, three had peritumoral-GGO, and five had a change in radiographic pattern from non-DAD at the onset to DAD-like. Patients with NSCLC who develop ILD during nivolumab treatment should be managed carefully if they have poor prognostic factors such as DAD-like radiographic pattern, onset of ILD ≤60 days from nivolumab initiation, pleural effusion before nivolumab treatment, lesion distribution contralateral or bilateral to the tumor, and abnormal changes in CRP levels., (© 2020 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.)

An outbreak of coronavirus disease 2019 (COVID-19) that began in Wuhan, China, has spread rapidly to many countries. We herein report four cases of COVID-19 confirmed in Japan among passengers of the cruise ship Diamond Princess and describe the clinical features, clinical course, and progression of chest computed tomographic images, chest radiographs, and treatment. Although these four patients had symptoms that included a fever, malaise, runny nose, and cough, one patient had no symptoms on admission. Two of the four patients needed mechanical ventilation due to respiratory deterioration. One of the patients who required mechanical ventilation was transferred to a higher-level medical institution. Except for that patient, the other three patients were able to return home under their own power. Every patient took lopinavir/ritonavir, which was considered the most effective treatment at the time. We used it after receiving approval from the ethics committee in our hospital. In this case report, we emphasize that some patients need to be carefully monitored, even if their respiratory condition is stable at the initial presentation, as their respiratory status may deteriorate rapidly within a few days after oxygen administration begins.

The prognosis of microscopic polyangiitis (MPA) with interstitial lung disease (ILD) is significantly worse than that of MPA without ILD. However, the clinical characteristics in MPA-ILD, especially poor prognostic factors, are not elucidated. We evaluated demographic, clinical, laboratory, and radiological findings, treatments, and outcomes of 80 patients with MPA, and investigated prognostic factors of respiratory-related death in patients with myeloperoxidase (MPO)-anti-neutrophil cytoplasmic antibody (ANCA) positive MPA-ILD. Ground-glass opacity and fibrosis were evaluated as scores on high-resolution computed tomography (HRCT). The presence of ILD was consistent with a high risk of respiratory-related death (hazard ratio, 4.8; P = 0.04). Multivariable logistic regression analyses using propensity scoring showed right or left lower lobe fibrosis score to be significantly associated with respiratory-related death (P = 0.0005 and 0.0045, respectively). A right or left lower lobe fibrosis score ≥ 2, indicating the presence of honeycombing at 1 cm above the diaphragm, was determined to be the best cut-off value indicating a poor prognosis. The 5-year survival rate was significantly lower in patients with right or left lower lobe fibrosis score ≥ 2 (survival rates: 37% and 19%, respectively) than those with a score < 2 (71% and 68%, respectively) (P = 0.002 and 0.0007, respectively). These findings suggest that the presence of honeycomb lesions in bilateral lower lobes on chest HRCT was associated with respiratory-related death in patients with MPO-ANCA positive MPA-ILD.

Introduction: The severity of coronavirus disease (COVID-19) in Japanese patients is unreported. We retrospectively examined significant factors associated with disease severity in symptomatic COVID-19 patients (COVID-Pts) admitted to our institution between February 20 and April 30, 2020., Methods: All patients were diagnosed based on the genetic detection of severe acute respiratory syndrome coronavirus 2. Information on the initial symptoms, laboratory data, and computed tomography (CT) images at hospitalization were collected from the patients' records. COVID-Pts were categorized as those with critical or severe illness (Pts-CSI) or those with moderate or mild illness (Pt-MMI). All statistical analyses were performed using R software., Results: Data from 61 patients (16 Pt-CSI, 45 Pt-MMI), including 58 Japanese and three East Asians, were analyzed. Pt-CSI were significantly older and had hypertension or diabetes than Pt-MMI (P < 0.001, 0.014 and < 0.001, respectively). Serum albumin levels were significantly lower in Pt-CSI than in Pt-MMI (P < 0.001), whereas the neutrophil-to-lymphocyte ratio and C-reactive protein level were significantly higher in Pt-CSI than in Pt-MMI (P < 0.001 and P < 0.001, respectively). In the CT images of 60 patients, bilateral lung lesions were more frequently observed in Pt-CSI than in Pt-MMI (P = 0.013). Among the 16 Pt-CSI, 15 received antiviral therapy, 12 received tocilizumab, five underwent methylprednisolone treatment, six received mechanical ventilation, and one died., Conclusions: The illness severity of Japanese COVID-Pts was associated with older age, hypertension and/or diabetes, low serum albumin, high neutrophil-to-lymphocyte ratio, and C-reactive protein., Competing Interests: Declaration of competing interest T.H. received honoraria and research funding as the primary investigator in this institution from Ono Pharmaceutical Co. Ltd. (Osaka, Japan), Lilly Japan Co. Ltd. (Hyogo, Japan), AstraZeneca Co. Ltd. (Osaka, Japan), Taiho Pharmaceutical Co. Ltd. (Tokyo, Japan), Chugai Pharmaceutical Co. Ltd. (Tokyo, Japan), and MSD Oncology Co. Ltd. (Tokyo, Japan). TH did not receive honoraria or research funding associated with this study. The other authors have no conflicts of interest to declare., (Copyright © 2020 Japanese Society of Chemotherapy and The Japanese Association for Infectious Diseases. Published by Elsevier Ltd. All rights reserved.)

Many interstitial lung diseases (ILDs) are characterized by chronic progressive fibrosis. The antifibrotic agents may prevent disease progression of these diseases. Nintedanib is a triple tyrosine kinase inhibitor and has an antifibrotic effect. The proven beneficial effects of nintedanib in idiopathic pulmonary fibrosis (IPF) and systemic sclerosis (SSc)-associated ILD, nintedanib was intended for use in many other fibrotic lung diseases consistent with the concept described below. With this trial, the concept and definition of progressive fibrosing ILD (PF-ILD) were created, a type of fibrosing diseases that progresses with fibrosis measured in forced vital capacity and high-resolution CT findings and worsening of respiratory symptoms at a certain rate or faster. PF-ILDs are composed of idiopathic interstial pneumonias such as non-specific interstitial pneumonia and unclassifiable interstitial pneumonia and inhalation lung diseases such as chronic hypersensitivity pneumonia and connective tissue disease-associated ILD such as rheumatoid arthritis-related ILD and SSc-related ILD and sarcoidosis and so on. Nintedanib significantly reduced the annual rate of decline in forced vital capacity over 52 weeks compared with placebo. Nintedanib received marketing approval in the United States and Japan for the treatment of PF-ILDs. This review summarizes the new concept of PF-ILDs and effectiveness of nintedanib to PF-ILDs and discussion points to be solved in the future when using nintedanib for PF-ILDs.

Background: Idiopathic pleuroparenchymal fibroelastosis (PPFE) is a rare form of idiopathic interstitial pneumonia that is characterized by predominantly upper lobe pleural and subpleural lung parenchymal fibrosis. Pneumothorax is one of the major respiratory complications in PPFE patients; however, its clinical features are poorly understood., Objective: We aimed to investigate the complication of pneumothorax in patients with idiopathic PPFE., Methods: A retrospective multicenter study involving 89 patients who had been diagnosed with idiopathic PPFE was conducted. We investigated the cumulative incidence, clinical features, and risk factors of pneumothorax after the diagnosis of idiopathic PPFE., Results: Pneumothorax developed in 53 patients (59.6%) with 120 events during the observation period (41.8 ± 35.0 months). The cumulative incidence of pneumothorax was 24.8, 44.9, and 53.9% at 1, 2, and 3 years, respectively. Most events of pneumothorax were asymptomatic (n = 85; 70.8%) and small in size (n = 92; 76.7%); 30 patients (56.6%) had recurrent pneumothorax. Chest drainage was required in 23 pneumothorax events (19.2%), and a persistent air leak was observed in 13 (56.5%). Patients with pneumothorax were predominantly male and frequently had pathological diagnoses of PPFE and prior history of pneumothorax and corticosteroid use; they also had significantly poorer survival than those without pneumothorax (log-rank test; p = 0.001). Multivariate analysis revealed that a higher residual volume/total lung capacity ratio was significantly associated with the development of pneumothorax after the diagnosis., Conclusion: Pneumothorax is often asymptomatic and recurrent in patients with idiopathic PPFE, leading to poor outcomes in some cases., (© 2021 S. Karger AG, Basel.)

Coronavirus disease 2019 (COVID-19) is a severe infectious disease of the respiratory tract caused by a novel coronavirus, severe acute respiratory syndrome coronavirus 2, and has a high mortality rate. The disease emerged from Wuhan, China, in late 2019, and spread to Japan, including Hokkaido, in January 2020. In February 2020, 3 children were diagnosed with COVID-19 in Furano, Hokkaido, Japan. During this period, influenza and human metapneumovirus infections were prevalent among children in the Furano region. Two of the 3 patients experienced co-infection with other respiratory viruses, including influenza virus A or human metapneumovirus. To the authors' knowledge, the cases described in the present report were the first pediatric patients with COVID-19 in Japan. In children with COVID-19, the possibility of co-infection with other respiratory pathogens should be considered.

Discohesive growth pattern (Disco-p) is often observed in lung adenocarcinoma (ADC) and mimics tumor budding (TB), stromal invasive-type micropapillary pattern (SMPP), and complex glandular pattern. However, the clinical impact of Disco-p in lung ADC has not been well studied. To investigate the prognostic significance of Disco-p, we analyzed 1062 Japanese patients with resected lung ADC. Disco-p was defined as an invasive growth pattern composed of single tumor cells, or trabeculae or small nests of tumor cells associated with desmoplastic fibrous stroma. We recorded the percentage of Disco-p in 5% increments independent of the major histologic pattern and investigated its correlation with different clinicopathological factors. We also analyzed the overall survival (OS) and disease-free survival (DFS). Disco-p was observed in 203 tumors (19.1%). Disco-p was significantly associated with male sex, smoking, lymph node metastasis, large tumor size, high TNM stage, lymphovascular and pleural invasion, spread through air spaces, and TB (all, p < 0.001). Of the total cases, only eight cases exhibited a dubious pattern between SMPP and Disco-p. Disco-p was also associated with wild-type EGFR (p < 0.001) and ALK fusion (p = 0.008). Patients harboring tumors with Disco-p had significantly worse prognoses (OS and DFS (both, p < 0.001)) compared with those without Disco-p. On multivariate analysis, Disco-p was an independent prognostic factor of worse OS (hazard ratio (HR), 2.572; 95% confidence interval (CI), 1.789-3.680; p < 0.001), and DFS (HR, 3.413; 95% CI, 2.482-4.683; p < 0.001), whereas TB was not an independent unfavorable prognostic factor. Disco-p was an independent unfavorable prognostic factor in patients with resected lung ADC, although a careful evaluation is necessary to distinguish it from similar patterns. We proposed that Disco-p should be recognized as a new invasive pattern and accurately recorded for the better management of patients with lung ADCs.

An autopsy of a patient in Japan with coronavirus disease indicated pneumonia lung pathology, manifested as diffuse alveolar damage. We detected severe acute respiratory syndrome coronavirus 2 antigen in alveolar epithelial cells and macrophages. Coronavirus disease is essentially a lower respiratory tract disease characterized by direct viral injury of alveolar epithelial cells.

Germline mutations and copy number changes in DNA damage repair (DDR) genes such as BRCA2 are associated with aggressive forms of prostate cancer (PCa). Although the prevalence of BRCA2 variants in PCa is increasing in Japan, the genomic and biological implications in Japanese patients are unclear. An 81-year-old male presented with prostatic adenocarcinoma with neuroendocrine differentiation accompanied by metastatic lung nodule and brain metastases. Platinum-based doublet chemotherapy combined with etoposide resulted in partial and complete remissions of brain and lung metastases, respectively. Next-generation sequencing of biopsy and peripheral blood samples demonstrated a somatic BRCA2 mutation at c.7008-2A>C and a germline mutation at p.E2877*. The patient's son had been diagnosed with breast cancer 2.5 years ago and was found to have the same germline BRCA2 mutation. BRCA2 mutation increases the risks of aggressive PCa and other cancer types in Japanese males. These forms may be highly responsive to platinum-based chemotherapy., (© 2019 The Authors. Pathology International published by Japanese Society of Pathology and John Wiley & Sons Australia, Ltd.)

Toxoplasma gondii strains have been isolated all over the world and their virulence has been examined mainly using laboratory mice. However, T. gondii differs in virulence depending on the host animal species. Therefore, to evaluate the virulence of each strain in domestic animals, it is necessary to examine using not only mice but also the concerned animals. We have shown that TgCatJpOk4, a T. gondii strain recently isolated in Okinawa, Japan, has a high virulence against laboratory mice, comparable to highest virulent RH strain in mice; however, the virulence to domestic animals remains unknown. In this study, we examined the virulence using the Microminipig. After infection, four out of five infected pigs showed severe clinical symptoms: inappetence, hypoactivity and tachypnea. Eventually, three out of the five infected pigs succumbed before the end of the observation. Among the three dead pigs, histological analysis revealed that interstitial pneumonia and spotty necrosis in the liver indicating that the TgCatJpOk4 strain has a high virulence not only in laboratory mice, but in pigs as well., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Histoplasmosis is occasionally encountered in non-endemic countries owing to more frequent international travel and migration, as well as an increase in the number of vulnerable hosts (e.g., patients with cellular immunodeficiencies). However, the diagnosis of endemic mycoses may be challenging because of its rarity and the limited availability of diagnostic tests. We report a case of disseminated histoplasmosis in a human immunodeficiency virus (HIV)-infected Japanese man who had often travelled to histoplasmosis-endemic countries. We also reviewed the reported cases of HIV-associated histoplasmosis in Japan. To the best of our knowledge, this is the ninth case report of co-infection with Histoplasma and HIV in Japan and the second involving a Japanese patient. This case emphasizes the importance of noting the details of not only the present residence of patients, but also their previous residence and travels. If histoplasmosis is suspected, physicians should inform laboratory personnel that fungal cultures should be incubated for 6 weeks, and compliance with biosafety guidelines for handling the specimens should be practiced. Since death occurs in nearly 50% of HIV-associated histoplasmosis cases in Japan, early recognition, timely diagnosis, and appropriate treatment are mandatory.

Pulmonary dirofilariasis is an infection caused by Dirofilaria immitis, which is an endemic parasite in Japan. We experienced 13 surgical cases of pulmonary dirofilariasis in our hospital. Of the 13 patients, 61.5% were men. The responsible lesions were located in the right lung in all cases, and 76.9% of them were in the lower lobe. Histologically, 12 cases showed necrotic nodules with peripheral granuloma with worms inside the pulmonary artery. One case did not show a necrotic nodule but showed only thickening and hyalinization of the pulmonary artery wall with a degenerated worm inside. Eosinophils were found histologically in all cases. Thirteen cases of dirofilariasis in one institution seem to be the largest number in Japan, based on previous reports. One reason for this increased prevalence may be the hot and humid climate of our prefecture considering the ecology of the mosquito as a vector. Elastic staining and eosinophils in peripheral granulomatous areas can contribute to the diagnosis when the worms are degenerated.

Background and Objective: In fibrotic interstitial lung disease (f-ILD), pulmonary artery diameter to ascending aorta diameter ratio (PA/A) ≥ 1 during the stable stage is associated with worse outcomes; however, the effect of acute exacerbation (AE) on the PA/A is unknown., Methods: Patients with a diagnosis of AE of f-ILD and with a computed tomography (CT) scan performed during stable period to confirm background fibrosis, as well as a CT scan at admission, were included. The pulmonary arterial diameter, ascending aortic diameter and PA/A were measured using CT during AE and CT prior to AE, when available, to evaluate the changes. Demographic data, co-morbidities and clinical outcome (90-day mortality) were analysed., Results: Of the 123 patients included, 45 had a PA/A ≥ 1 during AE and compared to the PA/A < 1 group, they were younger, had lower % vital capacity (VC) and % forced vital capacity (FVC), required more long-term oxygen therapy and other treatments, and had lower PaO 2 /FiO 2 (P/F) ratios. During AE, the PA/A increased from that during stable periods (P < 0.001), and a PA/A ≥ 1 was significantly associated with 90-day mortality both before and after adjustment for age, the P/F ratio at admission, long-term oxygen therapy usage and the type of background f-ILD (P = 0.018 and 0.025)., Conclusion: To the best of our knowledge, this is the first longitudinal examination of the PA/A ratio and evaluation during AE of f-ILD. Our data show that a PA/A ≥ 1 during AE predicted poor survival outcome in f-ILD., (© 2019 Asian Pacific Society of Respirology.)

Purpose: The Japan Clinical Oncology Group Study 0201 has proposed radiologic criteria on thin-slice computed tomography to diagnose pathologic less invasive lung adenocarcinoma that could be a candidate for sublobar resection based on the previous tumor, node, metastasis classification system (TNM). The aim of this study was to propose the new radiologic criteria for predicting pathologic less invasive cancer according to the 8th edition TNM., Patients and Methods: We analyzed 744 patients who had peripheral clinical Tis-T1cN0M0 non-small-cell lung cancer of 3 cm or less and underwent complete resection by lobectomy from 2003 to 2011. We defined lung cancer with no nodal involvement and no vessel invasion pathologically as a pathologic less invasive cancer and investigated the radiologic criteria on the basis of the solid component size and by the consolidation-to-tumor (C/T) ratio (calculated with the maximum solid component diameter divided by the maximum tumor diameter) by using preoperative thin-slice computed tomography to predict them with a specificity of 97% or more, and evaluated overall survival., Results: Patients with clinical Tis/T1mi/T1a disease had no pathologic invasive cancer except for one patient (specificity, 99%). From the investigation with the C/T ratio, only the criterion of C/T ratio 0.5 or less met the standard (specificity, 100%). The final specificity after combining these criteria was 99.6%, and they showed excellent prognosis (5-year overall survival rate, 96.2%)., Conclusion: Lung cancer with clinical Tis/T1mi/T1a or a C/T ratio of 0.5 or less can be completely cured by sublobar resection with sufficient margin because of its less invasive nature pathologically., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Background: In the Berlin definition, acute respiratory distress syndrome (ARDS) is stratified into three stages according to oxygenation severity at the onset. The relevance between ARDS severity and prognosis varies among published reports and has not been verified, especially in Asian patients., Methods: In this study, we examined the associations between the Berlin definition criteria and prognosis and clinical parameters, including high-resolution computed tomography (HRCT) scores of fibroproliferative changes of the lungs. One hundred fifty-three patients (45 females; mean age, 67 y/o), who met the Berlin definition and received treatment in our intensive care unit between January 2012 and December 2015, were enrolled., Results: The severity of ARDS was mild in 42 patients, moderate in 71, and severe in 40. The underlying diseases included pneumonia in 56 patients and aspiration in 43. Forty-two (27.5%) patients were deceased within 30 days, and the 30-day mortality was 10% in mild ARDS, 23% in moderate, and 55% in severe, which were significantly different (P <  0.05). In the non-survivors, APACHE II, SOFA, and SAPS II scores were higher than in the survivors (P <  0.001). Multivariate analyses revealed that elevated blood lactate level (≥ 2.0 mmol/L) and increased HRCT scores were significantly associated with weaning failure and 30-day mortality of the patients with ARDS., Conclusions: These results suggested that the severity criteria in the Berlin definition might be associated with the prognosis of the patients. Blood lactate levels and HRCT score might be predictive of the outcome of patients with ARDS.

Background: In patients with idiopathic pulmonary fibrosis (IPF), continuing treatment with antifibrotic agents is crucial to decrease the reduction of forced vital capacity and mortality rate. However, predictive factors for the discontinuation of antifibrotic agents are unknown. This study aims to investigate the clinical characteristics and predictive factors for the discontinuation of antifibrotic agents in patients with IPF., Methods: This was a double-center retrospective study that enrolled patients with IPF treated with pirfenidone or nintedanib between 2009 and 2017. We compared clinical parameters between the medication-continuing group and the discontinued group. The predictive factors were determined using Cox proportional hazards analyses., Results: A total of 66 subjects were included: 43 received pirfenidone and 23 received nintedanib. At 1 year, 23 of 66 patients had discontinued due to adverse events ( n  = 12), disease progression ( n  = 9), or death ( n  = 2). The characteristics of the discontinuation group were poor performance status (PS) and delay from diagnosis to treatment. In the receiver operating characteristic (ROC) analysis associated with the discontinuation of antifibrotic agents, PS was the highest area under the ROC curve (AUC) value (cut-off value, 2; AUC, 0.83; specificity, 63%; sensitivity, 87%). This finding was consistent even when analyzing, except for examples of death and adjusting for the type of antifibrotic agent. The treatment persistence rate by PS was PS 0-1 = 90%, PS 2 = 65%, and PS 3 = 19%. Analysis of the relationship between PS and administration period of antifibrotic agents revealed that delays from diagnosis to treatment led to worsening of dyspnea, a decline in lung function, and deterioration of PS., Conclusions: PS may be informative for predicting discontinuation of medication. Our data reinforced the importance of early initiation of antifibrotic treatment, and we suggest PS should be used as a guide for starting antifibrotic agents in everyday practice. The reviews of this paper are available via the supplementary material section.

Birt-Hogg-Dubé (BHD) syndrome is a rare genetic disorder characterized by cutaneous fibrofolliculomas, pulmonary cysts and renal cell carcinomas. Affected individuals inherit germline mutations in the folliculin gene (FLCN). Approximately 150 pathogenic FLCN variants have been identified worldwide. Many Japanese probands of BHD syndrome were first identified by pulmonologists and/or radiologists during treatment of pneumothoraces. Lung specimens obtained through video-assisted thoracoscopic surgery (VATS) have characteristic features unique to BHD syndrome; however, pathologists often miss key findings and diagnose patients with "bullae/blebs". The pleural and subpleural cysts of BHD syndrome-associated lung diseases are often modified by tissue remodeling and can be difficult to distinguish from emphysematous bullae/blebs. Intraparenchymal unruptured cysts tend to retain distinctive features that are different from other cystic lung diseases. Here, we review the clinicopathological findings of BHD syndrome in a Japanese population based on data from 200 probands diagnosed by genetic testing and a total of 520 symptomatic family members identified through BHD-NET Japan (http://www.bhd-net.jp/). Detailed morphology of pulmonary cysts obtained from VATS and autopsied lung specimens are described, and pathological clues for differentiating miscellaneous cystic lung disorders are discussed., (© 2019 Japanese Society of Pathology and John Wiley & Sons Australia, Ltd.)

Background: In 2016, the diagnostic criteria for the acute exacerbation (AE) of idiopathic pulmonary fibrosis (IPF) were revised. However, there have been published few clinical reports on AE-IPF published using the new criteria. The aim of this study was to investigate the incidence of, risk factors for, and mortality due to newly defined AE. Moreover, differences between triggered AE and idiopathic AE were investigated., Methods: The retrospective study was conducted including all IPF patients diagnosed with surgically-proven usual interstitial pneumonia through multi-disciplinary discussion between January 2006 and December 2015. Data were retrieved from a clinical chart review., Results: A total of 107 patients with newly diagnosed 107 IPF patients were included. The cumulative incidence of initial AE were 9.6% at 1 year, 16.8% at 2 years, 23.9% at 3 years, and 37.3% at 4 years after diagnosis. Three risk factors for AE-IPF development were identified: 1) the minimum peripheral ozygen saturation level of ≤88% during the 6-minute walk test at the time of diagnosis; 2) forced vital capacity (FVC) decreasing by ≥10% in 1 year; and 3) diffusion capacity of the lungs for carbon monoxide (DLco) decreasing by ≥15% in 1 year. There were no significant differences in background (excluding C-reactive protein), survival and treatment between patients with triggered AE and those with idiopathic AE., Conclusions: The 6-minute walk test and an annual decline in FVC and DLco were predictive factors for AE incidence. The causes of AE-IPF did not affect the prognosis or treatment options in clinical practice., (Copyright: © 2019.)

Patients with autoimmune disease-related interstitial lung disease (AID-ILD) occasionally develop radiologic pleuroparenchymal fibroelastosis (PPFE)-like lesions. However, the significance of AID as an etiology of PPFE has not been fully elucidated. The aim of this study is to verify the increase of elastic fibers in AID-ILD patients and evaluate the prevalence of histological PPFE in patients with AID-ILD. We selected cases of clinically diagnosed AID-ILD and idiopathic pulmonary fibrosis (IPF), in which an autopsy had been performed or in which the patient had undergone pneumonectomy for lung transplantation. We quantified the collagen fibers and elastic fibers in each lobe as the percentage of the non-aerated lung area (collagen fiber score and elastic fiber score, respectively) in histological specimens from a total of 73 patients (AID-ILD, n = 24; IPF, n = 49). There were no significant differences in the collagen fiber scores of the AID-ILD and IPF groups. Meanwhile, the elastic fiber scores of the AID-ILD group were significantly greater than those of the IPF group in the whole lung (17.3 ± 7.70 vs 11.6 ± 4.55), and the upper (16.6 ± 8.11 vs 11.2 ± 5.18), and lower (18.0 ± 9.68 vs 12.0 ± 5.55) lobes (all p < 0.01). Histological PPFE pattern was found in 12 of 24 AID-ILD patients (50%), and histological PPFE pattern as a dominant pattern of fibrosis was found in 2 of the 24 patients (8%). Thus, PPFE can be a manifestation of AID-ILD.

Background: Despite reported associations between intrapulmonary vascular shunting (IPVS) and morbidity and mortality in pediatric liver transplantation (LT), there are no guidelines for screening., Objective: To investigate IPVS before and after pediatric LT., Methods: Retrospective records review of all pediatric LT (n = 370) from 2005 to 2015 at a single institute in Japan. All children with cirrhosis and clinical suspicion of IPVS without cardiac or pulmonary conditions were included. 99mTechnetium labelled macroaggregated albumin (99mTcMAA) scans were performed before and after LT. The severity of IPVS was graded using shunt ratios., Results: Twenty-four children fulfilled inclusion criteria and underwent Tc99MAA scans. All revealed mild (<20%) to moderate (20%-40%) grades of IPVS. Following LT, the mean shunt ratio regressed from 20.69 ± 6.26% to 15.1 ± 3.4% (P = .06). The median (range) follow-up was 17 (4-85) months. Mortality was zero. The incidence of portal vein thrombosis (4.2%) biliary strictures (12.5%) and graft loss (4.1%) in the study group was not statistically significant compared to the remainder of the 370 transplants (3.2%, 9.4% and 3%, respectively). Sub-group analysis revealed hepatopulmonary syndrome (HPS) in 2 out of 24 children. The mean shunt ratios before and after LT were 39.2 ± 0.77% and 16.2 ± 8.5%, respectively (P = .08). There was 1 complication (intra-abdominal abscess)., Conclusions: HPS is less likely in mild to moderate IPVS. LT may achieve comparable results when performed in the presence of mild to moderate IPVS., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Background and Objective: Corticosteroids and immunosuppressive agents are considered mainstays of therapy for connective tissue disease-related interstitial lung disease (CTD-ILD); however, tacrolimus with corticosteroid therapy has not been fully investigated. Our objectives were to examine the multidimensional therapeutic benefit and tolerability of the combined therapy for the initial treatment of patients with CTD-ILD., Methods: In this retrospective case series, we identified consecutive CTD-ILD patients treated with tacrolimus plus intravenous (i.v.) methylprednisolone (1000 mg i.v. 3 days a week for 2 weeks) followed by low-dose prednisolone (10 mg/day). We assessed the multidimensional therapeutic benefit and tolerability including lung physiology, exercise capacity, exercise oxygen desaturation, modified Medical Research Council (MMRC) and St George's Respiratory Questionnaire (SGRQ)., Results: A total of 26 ILD patients with the underlying CTD diagnoses included 11 with rheumatoid arthritis, 9 with dermatomyositis, 4 with Sjögren's syndrome and 2 others. From baseline to 12 months, the combined therapy significantly improved forced vital capacity (FVC; 77.8% to 94.6%, P < 0.001), diffusing capacity of the lung for carbon monoxide (DL CO ; 66.1% to 75.1%, P < 0.001), 6-min walk distance (6MWD; 530 to 568 m, P = 0.02), lowest oxygen saturation on pulse oximetry (SpO 2 ; 85% to 89%, P = 0.01), MMRC (1.3 to 0.8, P = 0.01) and SGRQ (38 to 21, P < 0.001). During the study period, only one patient's therapy was discontinued due to an adverse event and none had a life-threatening adverse event attributed to the combined therapy., Conclusion: In our cohort of CTD-ILD, two courses of pulse dose methylprednisolone therapy followed by prednisone and oral tacrolimus appeared to be well tolerated, and to have multidimensional efficacy., (© 2018 Asian Pacific Society of Respirology.)

This study aimed to determine whether periodontal status is related to a decline in lung function in a general Japanese population. We followed a total of 1,650 community-dwelling individuals (≥40 years) without chronic obstructive pulmonary disease, with at least one teeth, for 3 years. Periodontal status was assessed at baseline by clinical attachment loss (CAL) and probing pocket depth (PPD) at two sites for each tooth, and the mean values were calculated for each subject. Lung function was measured at baseline and follow-up using spirometry, and longitudinal decline in forced expiratory volume in one second (FEV 1 ) was calculated. Multivariate Poisson regression with robust error variance was used to estimate risk ratio (RR). After adjusting for potential confounders including smoking status, there was a tendency for the adjusted RR of developing rapid lung function decline (≥160 mL/3years, the highest quartile of the distribution of FEV 1 declines) to increase as mean CAL levels increased (P trend = 0.039). Likewise, a positive association was observed between mean PPD levels and RR of developing rapid lung function decline (P trend = 0.047). Our findings suggest deterioration of periodontal status could be a risk factor for rapid lung function decline in the general Japanese population.

Background: This document provides clinical recommendations for the diagnosis of idiopathic pulmonary fibrosis (IPF). It represents a collaborative effort between the American Thoracic Society, European Respiratory Society, Japanese Respiratory Society, and Latin American Thoracic Society., Methods: The evidence syntheses were discussed and recommendations formulated by a multidisciplinary committee of IPF experts. The evidence was appraised and recommendations were formulated, written, and graded using the Grading of Recommendations, Assessment, Development, and Evaluation approach., Results: The guideline panel updated the diagnostic criteria for IPF. Previously defined patterns of usual interstitial pneumonia (UIP) were refined to patterns of UIP, probable UIP, indeterminate, and alternate diagnosis. For patients with newly detected interstitial lung disease (ILD) who have a high-resolution computed tomography scan pattern of probable UIP, indeterminate, or an alternative diagnosis, conditional recommendations were made for performing BAL and surgical lung biopsy; because of lack of evidence, no recommendation was made for or against performing transbronchial lung biopsy or lung cryobiopsy. In contrast, for patients with newly detected ILD who have a high-resolution computed tomography scan pattern of UIP, strong recommendations were made against performing surgical lung biopsy, transbronchial lung biopsy, and lung cryobiopsy, and a conditional recommendation was made against performing BAL. Additional recommendations included a conditional recommendation for multidisciplinary discussion and a strong recommendation against measurement of serum biomarkers for the sole purpose of distinguishing IPF from other ILDs., Conclusions: The guideline panel provided recommendations related to the diagnosis of IPF.

Background: Patients with idiopathic pulmonary fibrosis (IPF) have a high risk of developing lung cancer, but few studies have investigated the long-term outcomes of repeated surgery in such patients. The purpose of this study was to evaluate the surgical outcomes of repeated lung cancer surgery in patients with IPF., Methods: From January 2001 to December 2015, 108 lung cancer patients with IPF underwent pulmonary resection at two institutions; 13 of these patients underwent repeated surgery for lung cancer, and their data were reviewed., Results: The initial procedures of the 13 patients were lobectomy in 8, segmentectomy in 2, and wedge resection in 3. The subsequent procedures were wedge resection in 10 and segmentectomy in 3. The clinical stage of the second tumor was stage IA in 12 and stage IB in 1. Postoperatively, 3 patients (23.1%) developed acute exacerbation (AE) of IPF and died. The rate of decrease in percent vital capacity was significantly higher in patients with AE than in those without AE (p = 0.011). The 3-year overall survival rate was 34.6%. The causes of death were cancer-related in 7, AE of IPF in 3, and metachronous lung cancer in 1., Conclusions: Despite limited resection, a high incidence of AE was identified. The early and long-term outcomes of repeated surgery in lung cancer patients with IPF were poor because of the high risk of AE of IPF and lung cancer recurrence. Long-term intensive surveillance will be required to determine whether surgical intervention is justified in patients with multiple primary lung cancers and IPF.

Background: Pleuroparenchymal fibroelastosis (PPFE) is a rare subset of idiopathic interstitial pneumonias. No large-scale clinical studies of PPFE have been published. The aim of the study was to clarify the clinical and physiological characteristics of PPFE in Japan METHODS: This was a retrospective, nationwide, and multicenter study in Japan. We reviewed 52 patients with PPFE, diagnosed after multidisciplinary discussions., Results: Flat chest index, defined as the ratio of anteroposterior diameter to transverse diameter of thoracic cage at the level of 6th thoracic vertebra, correlated positively with body mass index (BMI) (r = 0.340, p = 0.013) and percentage of predicted value of forced vital capacity (FVC %pred) (r = 0.355, p = 0.012), and negatively with the ratio of residual volume to total lung capacity (RV/TLC) (r = -0.312, p = 0.042). RV/TLC correlated negatively with BMI (r = -0.746, p < 0.0001) and FVC %pred (r = -0.507, p = 0.0005), and positively with age, and physiological variables (GAP) scores (r = 0.332, p = 0.030). The median survival time and the cumulative 5-year survival rate were 96 months and 58%, respectively. Patients with KL-6 level >600 (U/mL) survived shorter than those with <600 (p < 0.001)., Conclusion: Low BMI, decreased FVC and increased RV/TLC in PPFE may be related to the progression of flattened chest cage which impairs distension of chest cage at inspiration. Elevated serum levels of KL-6 suggest a poor prognosis of PPFE., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Previous studies attempted to characterize the subjects with sarcoidosis according to differences in sex, age, and the presence of specific organ involvement. However, significant interactions among these factors precluded a clear conclusion based on simple comparison. This study aimed to clarify the age- and sex-stratified prevalence of specific organ involvement and the heterogenous nature of sarcoidosis. Using the data of 9,965 patients who were newly registered into a database at the Ministry of Health, Labour and Welfare, Japan between 2002 and 2011, we evaluated the age- and sex-specific prevalence of the eye, lung, and skin involvement of sarcoidosis. We also attempted corresponding analysis considering multiple factors. As compared with several decades ago, the monophasic age distribution in men became biphasic, and the biphasic distribution in women, monophasic. The prevalence of pulmonary and cutaneous lesions was significantly associated with age, whereas the prevalence of ocular involvement showed a biphasic pattern. The prevalence of bilateral hilar lymphadenopathy was significantly higher, whereas the prevalence of diffuse lung shadow was significantly lower, in subjects with ocular involvement than those without ocular involvement. Corresponding analysis visually clarified the complex interactions among factors. Our results contribute to a better understanding of the heterogeneous features of sarcoidosis.

Objectives: Tumor spread through air spaces (STAS) is a newly identified invasion pattern in lung adenocarcinoma. This study aimed to analyze and validate the clinical impact of tumor STAS in surgically resected lung squamous cell carcinoma (SQCC)., Materials and Methods: We retrospectively reviewed 220 patients with lung SQCC. Tumor STAS was defined as detached tumor cells within the air spaces in the lung parenchyma beyond the edge of the main tumor. Statistical analyses were conducted to investigate the proportion of STAS and the relationship between the presence of STAS and clinicopathological factors, including clinical outcome., Results: STAS was identified in 42 of 220 patients (19.1%). The patients with STAS had a significantly worse 5-year recurrence-free survival (RFS) and 5-year overall survival (OS) than those without STAS (5-year RFS: 37.4% vs. 68.4%; p = 0.0006; 5-year OS: 50.2% vs. 71.4%, p = 0.0078) in stage I, but not in stage II and III. A multivariate analysis showed that the presence of STAS was an independent predictive factor of recurrence (hazard ratio = 3.27; 95% confidence interval, 1.7-6.29; p = 0.0004) and an independent prognostic factor (hazard ratio = 3.01; 95% confidence interval, 1.54-5.89; p = 0.0013) in stage I, but not in stage II and III., Conclusion: We found that STAS was detected in 19.1% of surgical resected SQCC, and it was associated with recurrence and worse survival in stage I SQCC, but not in stage II and III SQCC. Therefore, we suggest that STAS is a useful predictor of recurrence and prognosis in stage I lung SQCC., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Background: Cases of acute respiratory tract infection caused by Pteropine orthoreovirus (PRV) of the genus Orthoreovirus (family: Reoviridae) have been reported in Southeast Asia, where it was isolated from humans and bats. It is possible that PRV-associated respiratory infections might be prevalent in Southeast Asia. The clinical course of PRV is not fully elucidated., Methods: The virulence, pathology, and pathogenesis of two PRV strains, a human-borne PRV strain (isolated from a patient, who returned to Japan from Bali, Indonesia in 2007) and a bat-borne PRV (isolated from a bat [Eonycteris spelaea] in the Philippines in 2013) were investigated in BALB/c mice using virological, pathological, and immunological study methods., Results: The intranasal inoculation of BALB/c mice with human-borne PRV caused respiratory infection. In addition, all mice with immunity induced by pre-inoculation with a non-lethal dose of PRV were completely protected against lethal PRV infection. Mice treated with antiserum with neutralizing antibody activity after inoculation with a lethal dose of PRV showed a reduced fatality rate. In this mouse model, bat-borne PRV caused respiratory infection similar to human-borne PRV. PRV caused lethal respiratory disease in an animal model of PRV infection, in which BALB/c mice were used., Conclusions: The BALB/c mouse model might help to accelerate research on the virulence of PRV and be useful for evaluating the efficacy of therapeutic agents and vaccines for the treatment and prevention of PRV infection. PRV was shown for the first time to be a causative virus of respiratory disease on the basis of Koch's postulations by the additional demonstration that PRV caused respiratory disease in mice through their intranasal inoculation with PRV.

Background and Objectives: Pulmonary Mycobacterium avium complex (pMAC) disease manifests as various types of lesions, such as infiltrates, nodules, cavities, and bronchiectasis. However, the important determinants for clinical parameters in lung involvement are poorly understood. The objective of this study was to obtain quantitative parameters by 3-dimensional CT, and investigate the relationship between these parameters and the pulmonary function tests (PFTs) and health-related quality of life., Material and Methods: Quantitative analysis using CT was performed in 67 pMAC patients. The relationship between new quantitative parameters for evaluating lung involvement using 3-dimensional CT and PFTs or St George's Respiratory Questionnaire (SGRQ) was evaluated., Results: The ratio of infiltration to total lung volume showed significant correlation with the PFT results, especially the percent-predicted forced vital capacity (%FVC; ρ = -0.52), residual volume (ρ = -0.51), and total lung capacity (ρ = -0.59). The cavity volume was strongly correlated with the %FVC (ρ = -0.78) in the cavity group, while the ratio of infiltration to total lung volume was strongly correlated with the %FVC (ρ = -0.53) in the non-cavity group. The ratio of infiltration to total lung volume was significantly correlated with all SGRQ parameters (ρ = 0.41-0.52) in the non-cavity group., Conclusions: Infiltration was an important parameter for the PFTs and SGRQ in pMAC patients according to the 3-dimensional CT analysis. Moreover, cavity volume was an important parameter of the PFTs in the cavity group. Therefore, infiltration and cavity volume are key features for the management of pMAC disease., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Objectives: Invasive lepidic predominant adenocarcinoma (LPA) of the lung is thought to progress in a stepwise fashion from adenocarcinoma in situ (AIS) and minimally invasive adenocarcinoma (MIA). The aim of this study was to investigate the microenvironmental changes during the development from AIS to LPA., Materials and Methods: Clinicopathological characteristics of AIS (n=51), MIA (n=59), LPA smaller than 3cm (LPA-S, n=113), and LPA larger than 3cm (LPA-L, n=47) were analyzed. We then evaluated the expression levels of epithelial-mesenchymal transition (EMT)-related molecules (E-cadherin, S100A4), invasion-related molecules (laminin-5, ezrin), stem-cell-related molecules (ALDH-1), and growth factor receptors (c-Met, EGFR) in cancer cells of each group (n=20). The number of tumor-promoting stromal cells, including podoplanin-positive cancer-associated fibroblasts (PDPN+ CAFs), CD204-positive tumor-associated macrophages (CD204+ TAMs), and CD34+ microvessel cells, were also analyzed., Results: No significant difference in these characteristics was found between LPA-S and LPA-L. Laminin-5 expression in the non-invasive carcinoma component of MIA was significantly higher than that of AIS (p<0.001). During the progression from MIA to LPA-S, the expression level of laminin-5 in the invasive carcinoma component was significantly elevated (p<0.01). Moreover, tumor-promoting stromal cells were more frequently recruited in the invasive area of LPA-S (PDPN+ CAFs; p<0.05, CD204+ TAMs; p<0.001, CD34+ microvessel; p<0.05). Ezrin expression in the invasive carcinoma component of LPA-L was significantly increased (p<0.05) compared to LPA-S; however, the number of tumor-promoting stromal cells were not different between these two groups., Conclusion: Our current results indicated that microenvironmental molecular changes occur during the progression from MIA to LPA-S and suggested that this process may play an important role in disease progression from AIS to LPA., (Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.)

Lacaziosis, formerly called as lobomycosis, is a zoonotic mycosis, caused by Lacazia loboi, found in humans and dolphins, and is endemic in the countries on the Atlantic Ocean, Indian Ocean and Pacific Ocean of Japanese coast. Susceptible Cetacean species include the bottlenose dolphin (Tursiops truncatus), the Indian Ocean bottlenose dolphin (T. aduncus), and the estuarine dolphin (Sotalia guianensis); however, no cases have been recorded in other Cetacean species. We diagnosed a case of Lacaziosis in a Pacific white-sided dolphin (Lagenorhynchus obliquidens) nursing in an aquarium in Japan. The dolphin was a female estimated to be more than 14 years old at the end of June 2015 and was captured in a coast of Japan Sea in 2001. Multiple, lobose, and solid granulomatous lesions with or without ulcers appeared on her jaw, back, flipper and fluke skin, in July 2014. The granulomatous skin lesions from the present case were similar to those of our previous cases. Multiple budding and chains of round yeast cells were detected in the biopsied samples. The partial sequence of 43-kDa glycoprotein coding gene confirmed by a nested PCR and sequencing, which revealed a different genotype from both Amazonian and Japanese lacaziosis in bottlenose dolphins, and was 99 % identical to those derived from Paracoccidioides brasiliensis; a sister fungal species to L. loboi. This is the first case of lacaziosis in Pacific white-sided dolphin.