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Antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis is a systemic autoimmune disease characterized by necrotizing inflammation of the small blood vessels. ANCA-associated vasculitis is subclassified into three variants: granulomatosis with polyangiitis, eosinophilic granulomatosis with polyangiitis, and microscopic polyangiitis (MPA). Myeloperoxidase (MPO) ANCA is a marker antibody for MPA. Interstitial pneumonia (IP) is occasionally complicated with MPA. However, only a few cases of idiopathic IP develop MPO-ANCA-positive conversion and MPA. Therefore, we present a case of a 70-year-old Japanese man with idiopathic IP who developed MPO-ANCA-positive conversion and MPA. We performed renal biopsy, which revealed pauci-immune crescentic glomerulonephritis. The patient was treated with intravenous methylprednisolone pulse therapy and oral prednisone, and the patient's laboratory data gradually improved with steroid therapy. The association between the production of MPO-ANCA and IP remains unclear, and the present case suggests that IP plays a role in inducing MPO-ANCA production. Patients with idiopathic IP should be followed-up carefully for an examination of increased MPO-ANCA levels and MPA development. In addition, early gastric cancer was detected during upper gastrointestinal endoscopy in our case, and it could also be important not to miss malignancy in patients with ANCA-associated vasculitis.

Supplementary Materials and Methods and Supplementary Figure Legends.

PDF file - 1030K, Pathway analyses using IPA software.

Nrf2 activation promotes resistance to chemical carcinogenesis in animal models, but activating mutations in Nrf2 also confer malignant characters to human cells by activating antioxidative/detoxifying enzymes and metabolic reprogramming. In this study, we examined how these contradictory activities of Nrf2, cancer chemoprevention and cancer cell growth enhancement, can be reconciled in an established mouse model of urethane-induced lung carcinogenesis. Using Keap1-knockdown (kd) mice, which express high levels of Nrf2, we found that urethane was rapidly excreted into the urine, consistent with an upregulation in the expression of urethane detoxification genes. Consequently, urethane-induced tumors were significantly smaller and less frequent in Keap1-kd mice than in wild-type mice. In contrast, tumor cells derived from Keap1-kd mice and transplanted into nude mice exhibited higher tumorigenicity compared with cells derived from wild-type mice. To identify the factors contributing to the tumor growth phenotype in the transplantation model, we performed a microarray analysis and found that many antioxidative stress genes were upregulated in the Keap1-kd–derived tumors. Therefore, we suggest that Nrf2 activation in cancer cells enhances their tumorigenicity, but global Nrf2 activation, as in Keap1-kd mice, simultaneously enhances anticancer immunity, thereby suppressing the growth potential of Keap1-kd tumors. Our findings provide relevant insight into the dual role of Nrf2 in cancer and warrant further studies of Nrf2 function during different stages of carcinogenesis. Cancer Res; 76(10); 3088–96. ©2016 AACR.

PDF file - 1311K, Expression of enzymes involved in the urethane metabolism.

PDF file - 806K, Summary of lung carcinogenesis in Nrf2+/+-(upper) and Nrf2-/--(lower) mice.

PDF file - 659K, Experimental design of urethane-induced lung carcinogenesis.

RT-qPCR analysis of urethane detoxification enzymes in the liver of the Keap1-wt mice and Keap1-kd mice.

PDF file - 93K, Primers for PCR and RT-PCR experiments.

Nrf2-target genes showing differential expression patterns between the Keap1-wt and the Keap1-kd tumors.

PDF file - 123K

PDF file - 35K, High expression genes involved in lung tumor of Nrf2+/+ and Nrf2-/- mice.

PDF file - 1637K, Urethane administration induces the cellular cluster formation consisting of inflammatory and epithelial cells in the perivascular region of the Nrf2-/--mouse lung.

This manual has been compiled by a joint production committee with the Diffuse Lung Disease Assembly of the Japanese Respiratory Society (JRS) to provide a practical manual for the epidemiology, diagnosis, and treatment of intractable diffuse pulmonary diseases. The contents are based upon the results of research into these diseases by the Diffuse Pulmonary Diseases Study Group (principal researcher: Sakae Homma) supported by the FY2014-FY2016 Health and Labor Sciences Research Grant on Intractable Diseases. This manual focuses on: 1) pulmonary alveolar microlithiasis, 2) bronchiolitis obliterans, and 3) Hermansky-Pudlak Syndrome with interstitial pneumonia. As these are rare/intractable diffuse lung diseases (2 and 3 were first recognized as specified intractable diseases in 2015), there have not been sufficient epidemiological studies made, and there has been little progress in formulating diagnostic criteria and severity scales; however, the results of Japan's first surveys and research into such details are presented herein. In addition, the manual provides treatment guidance and actual cases for each disease, aiming to assist in the establishment of future modalities. The manual was produced with the goal of enabling clinicians specialized in respiratory apparatus to handle these diseases in clinical settings and of further advancing future research and treatment.

Rationale: Acute exacerbation during the course of idiopathic pulmonary fibrosis causes a poor prognosis. Coagulation abnormalities and endothelial damage are involved in its pathogenesis. Thrombom...

Idiopathic pulmonary fibrosis (IPF) is a disease of unknown etiology which accounts for a large proportion of cases of idiopathic interstitial pneumonia. It has a very poor prognosis with a 5-year survival rate of 30% or below, and so far there has been no guideline in Japan offering an established effective therapy based on evidence. In addition to the establishment of basic therapies, there is also an urgent need to establish therapies to deal with complications, as death occurs in many cases due to acute exacerbation or comorbid lung cancer. It was therefore decided to formulate a guideline in order to promote evidence-based clinical practice, to further improve the quality of medical treatment in the clinical setting, and to allow the benefits to be enjoyed by the public.

Background: The heterogeneity in IPF poses a major challenge for management of IPF. Antifibrotic drugs suppress the disease progression, and they also improve the survival in some patients. However, no biomarker has been proved to predict the response to antifibrotics. Aims and Objectives: We evaluated the significance of serum markers as predictor for response to pirfenidone in patients in phase 3 trial in Japan. Methods: We analyzed the data from 267 patients with IPF in phase 3 trial of pirfenidone in Japan. Association of baseline serum SP-D levels was examined with changes from baseline in vital capacity (VC) and progression-free survival (PFS: the progression was defined as a ≥10% decline in VC from baseline and/or death). Results: When patients were divided into high and low SP-D groups by the median level at baseline (202 ng/mL), significantly better response (changes in VC at 52 weeks and PFS) to pirfenidone was observed in low SP-D group than in high SP-D group (Figure). Serum concentration of SP-D decreased during therapeutic course in pirfenidone groups, and the decline was significant from 8 weeks after the initiation of pirfenidone. Conclusions: Serum SP-D levels has the potential for a predictor of response to pirfenidone in patients with IPF, and for a biomarker to monitor the course of treatment.

Rationale: Despite a lack of beneficial evidence in idiopathic pulmonary fibrosis (IPF), long-term oxygen therapy (LTOT) is currently prescribed for many patients with IPF. Little is known about clinical course of them. Aim: To clarify the overall survival and prognostic factors of IPF patients after prescription of LTOT. Method: A prospective cohort multicenter study, enrolling patients with IPF who started LTOT between December 1, 2012 and November 30, 2015 from 21 institutes in Japan. The decision for starting LTOT depended on each site. Clinical data at starting LTOT and three-year follow-up data including death and cause of death were studied. Results: 147 eligible patients were recruited. 117 were male and the mean (SD) age was 71.2 (8.1) years. The mean (SD) percentage predicted FVC was 61.7 (15.6)%. 111 (76%) died with a median follow-up of 479 days. Causes of death were chronic respiratory insufficiency in 52%, acute exacerbation in 27%, and lung cancer in 5%. The median survival from starting LTOT was 537 days. By COX univariate analysis, low FVC, high COPD assessment test (CAT) score, resting hypoxemia (SpO2 This study was partially supported by a grant to the Diffuse Lung Diseases Research Group from the Ministry of Health, Labor and Welfare, Japan.

Background A phase III clinical trial of pirfenidone in patients with idiopathic pulmonary fibrosis (IPF) in Japan has revealed that pirfenidone attenuated the decline in vital capacity (VC) and improved progression-free survival (PFS). We conducted an extended analysis of the pirfenidone trial to investigate its efficacy with respect to IPF severity in the trial population. Methods Patients in the phase III trial were stratified by baseline pulmonary functions including %VC predicted, %diffusion capacity for carbon monoxide predicted, and oxygen saturation by pulse oximetry on exertion and were categorized into mild, moderate, and severe groups of functional impairment. The efficacy of pirfenidone for VC and PFS over 52 weeks was compared among the three sub-populations. Results Of 264 patients, 102 (39%), 90 (34%), and 72 patients (27%) were classified as having mild, moderate, and severe grades of functional impairment, respectively. This classification was associated with arterial oxygen partial pressure at rest and degree of dyspnea at baseline. While pirfenidone attenuated VC decline at all grades of severity, covariance analysis revealed pirfenidone to have better efficacy in the sub-population with mild-grade IPF. Mixed model repeated measures analysis confirmed that pirfenidone markedly attenuated VC decline in patients with mild-grade IPF compared to its effects in patients with moderate or severe IPF. Pirfenidone also improved PFS markedly in patients with mild-grade IPF. Conclusion This extended analysis suggested that pirfenidone exerted better therapeutic effects in patients with milder IPF. Further analysis with a larger population is needed to confirm these results.

Background Acute exacerbation of idiopathic pulmonary fibrosis (AE-IPF) is a lifethreatening event and one of the important endpoints in clinical trials involving IPF. Despite this, there has been little evaluation of the potential risk factors for AE-IPF in clinical trials. We evaluated the risk factors for AE-IPF in a phase III clinical trial of pirfenidone in Japanese IPF patients. Methods The study population comprised 267 patients. The effects of various baseline characteristics as possible risk factors for AE-IPF during the study, as well as those of a ≥10% decline in percent vital capacity (%VC) within 6 months, were evaluated using Cox׳s proportional hazard model. The ≥10% decline in %VC was calculated in two ways: (1) an absolute decline (e.g. from 60% predicted to 50%); and (2) a relative decline (e.g. from 60% predicted to 54%). Results Over 52 weeks, 14 patients experienced AE-IPF. Univariate analysis using Cox׳s proportional hazards model showed that both relative and absolute ≥10% decline in %VC within 6 months were significant risk factors for AE-IPF. Stepwise multivariate analysis demonstrated that absolute or relative decline in both %VC and alveolar to arterial oxygen pressure difference (AaDO 2 ) were significant risk factors for AE. The model using absolute decline [Hazard Ration (HR)=7.405, p =0.0007] and baseline AaDO 2 (HR=1.063, p =0.0266) had a better fit than the model using relative decline and baseline AaDO 2 . Conclusions Rapid %VC decline (≥10% within 6 months), and high baseline AaDO 2 , may be risk factors for AE-IPF.

Background: Pulmonary alveolar proteinosis (PAP) is a chronic rare lung disease characterized by the intra-alveolar accumulation of surfactant lipids and proteins. 10 year survival of autoimmune PAP was 89.7% (n=117, WASOG, 2017) in our institute, however, we recently reported that fibrosis develops in approximately 20% of patients with PAP in their long clinical courses, and the prognosis of them was poor (AJR. 207:544, 2016). To clarify the characteristics of fatal cases of PAP, we retrospectively analyzed the diseases cases from our Japanese cohort database. Subject and methods: We collected 579 cases with PAP from 95 Japanese institutes, and 81 cases (14.0%) were dead. Within 81 cases, we collected the detail data from 34 cases. Results: 60% was autoimmune/idiopathic PAP, 34% was secondary PAP. Median age of 34 fatal cases (65% male) was 59 (range 28-82) years old. 59% was smokers (Current and former), and 21% had dust exposure. At the diagnosis, 21% of patients had interstitial pneumonia/pulmonary fibrosis (IP/PF), 21% had collagen vascular diseases, 18% had incfectious disease, 3% had malignant diseases. However during the followup periods, 9% had IP/PF, 24% had incfectious disease, 24% had malignant diseases. Causa of the death was 26% was malignantn diseases, 18% in fections, 12% was PAP, 6% IP/PF, 6% was cerebro vascular diseases. Conclusions: Patients with PAP had more comorbidities than previously reported. Managemnents of them would be cricial for better prognosis. Grant: This study was supported by the grant from AMED #17930161 (YI)

Background Epidermal growth factor receptor (EGFR)–tyrosine kinase inhibitor (TKI) has demonstrated a promising therapeutic response in lung adenocarcinoma patients with EGFR gene mutations. However, the predictive factors for this therapy have not been established, except for the EGFR gene mutation status of carcinoma cells. Methods We first performed microarray analysis in EGFR-TKI–sensitive lung adenocarcinoma cell lines. The results indicated anterior gradient 2 (AGR2) as a potential surrogate marker of EGFR-TKI. Therefore, we then evaluated the correlation between the status of AGR2 immunoreactivity and clinicopathological factors including overall survival (OS), progression-free survival (PFS) and clinical response to EGFR-TKI, in 147 cases of surgically resected lung adenocarcinoma. The biological significance of AGR2 was further evaluated by transfecting small interfering RNA (siRNA) against AGR2 in these cells. Results The status of AGR2 immunoreactivity was significantly higher in lung adenocarcinoma cases with EGFR gene mutations than in those with the wild type (pConclusions AGR2 could serve as an adjunctive surrogate protein marker possibly reflecting EGFR gene mutations in lung adenocarcinoma patients. Results from in vitro analysis indicated that AGR2 could be a potential clinical biomarker of EGFR-TKI therapeutic sensitivity in lung adenocarcinoma cells.

Background There have been no prospective large-scale multicenter epidemiological studies on the clinical course and treatment from the time of diagnosis of idiopathic interstitial pneumonias (IIPs) in Japan. The purpose of this study was to clarify the current clinical situation of IIP in Japan. Methods This study was supported by a grant from the Ministry of Health, Labour and Welfare to the Diffuse Lung Diseases Research Group. Data including clinical findings, course, and treatment of IIP from a web database created by a collaborative effort of medical institutions across Japan that specialize in the care of interstitial pneumonias were collected and analyzed. Results A total of 436 IIP patients from 19 institutions were newly registered during a 5-year period. Idiopathic pulmonary fibrosis (IPF) was the most frequently encountered IIP, and 28% of the IPF cases were initially diagnosed by abnormal chest X-ray or CT in asymptomatic patients. Until the 2008 fiscal year, no treatment was given for most cases of IPF. After the end of 2008, when pirfenidone was approved for manufacture, the number of patients for whom no treatment was recommended declined, and pirfenidone therapy was initiated in 32.9% of cases in 2009. The median survival times for IPF from the onset symptoms and from the initial visit were 105 months and 69 months, respectively. Conclusions This study should provide valuable information for understanding the current state of IIP in Japan.

OBJECTIVES: Although some interstitial pneumonia (IP) cases are not detected on computed tomography (CT) before surgery, they are confirmed by pathological diagnosis after pulmonary resection. In the present study, we aimed to investigate patients who underwent pulmonary resection for non-small-cell lung cancer (NSCLC) and subsequently showed pathological findings of IP but no apparent interstitial changes on CT. METHODS: We retrospectively analysed 1688 patients with NSCLC who underwent pulmonary resection and presented with a radiological or pathological diagnosis of IP in 64 institutions between January 2000 and December 2009. We compared 135 patients without radiological findings but with pathological findings of IP (Group A) with 1553 patients with radiological findings of IP (Group B). RESULTS: The percent vital capacity and predicted diffusing capacity for carbon monoxide were higher in Group A than in Group B. Although there was no significant difference in the occurrence of acute exacerbation (AE) between both groups, the mortality after AE in Group A was significantly lower than that in Group B. The overall survival rates of patients in Groups A and B at 5 years were 59.1 and 40.9%, respectively (P= 0.0031). CONCLUSIONS: The mortality after AE in patients with only pathological findings of IP was significantly lower than in those with radiological findings of IP. Moreover, the patients with only pathological findings of IP had a better prognosis than those with radiological findings of IP. Thus, our findings suggest that patients with pathological findings of IP and without radiological abnormality had early-stage IP.

Introduction: Autoimmune pulmonary alveolar proteinosis (APAP), caused by macrophage dysfunction due to the anti-granulocyte-macrophage colony-stimulating factor autoantibody, is known to be complicated with opportunistic infection. We have already reported frequency of infection was 5.3% (Inoue Y, AJRCCM 2008). Subjects and Methods: Questionnaire about APAP cases complicated with infections, was mailed to 195 hospitals in Japan and was returned from 27 hospitals. Subjects of this study were APAP cases complicated with infections managed in the 27 hospitals. Pathogens, site of infection, and clinical course were examined. Results: Frequency of infection was 27 cases (7.2%) out of 375 APAP cases. Lung comorbidities were COPD (n=3), pneumoconiosis (n=1) and interstitial pneumonia (n=2), and three cases were treated with corticosteroids and/or immunosuppressant. Pathogen was bacteria (n=15), fungus (n=5), mycobacterium (n=6), Nocardia (n=2) and virus (n=1). Tuberculous lymphadenitis (n=2), meningeal cryptococcosis (n=1), aspergillus sinusitis (n=1), herpes simplex virus encephalitis (n=1) occurred out of the lung. Diagnosis of APAP preceded incidence of infection in 20 cases (74%). Disease severity of 6 cases (22.2%) improved after the occurrence of infection. Whole lung lavage could not be performed in 2 cases with infection, one case of which died with respiratory failure. Conclusions: Frequency of infection in APAP cases were similar to the previous report. Infection might improve or deteriorate the clinical course of APAP. Financial support: This study was partially granted from AMED; DLD/14526278 to Y. Inoue and T. Arai and PAP/14526182 to Y. Inoue.

Acute exacerbation of interstitial pneumonia (AEIP) is a leading cause of death after lung cancer resection in patients with interstitial lung disease. We retrospectively analyzed 1763 patients with non-small cell lung cancer with a clinical diagnosis of interstitial lung disease (ILD) who underwent lung cancer resection between 2000 and 2009 at 61 hospitals in Japan. AEIP occurred in 164 of 1763 (9.3%) patients with a mortality rate of 43.9% (72/164). Univariate and multivariate analyses were carried out to identify possible risk factors of fatal AEIP. We then analyzed the 164 patients who developed postoperative AEIP and identified the preoperative and postoperative risk factors. A multivariate regression analysis identified that the sex, percent vital capacity, neoadjuvant radiation, preoperative history of AEIP, preoperative use of steroids, usual interstitial pneumonia pattern on CT, and surgical procedures were independent preoperative risk factors for death due to AEIP. ILD patients with emphysema somehow showed a lower risk of fatal AEIP than those without emphysema in this study. This study revealed eight risk factors for fatal AEIP.

Autoimmune pulmonary alveolar proteinosis (aPAP) is a rare disease characterized by the excessive accumulation of surfactant proteins within the alveolar spaces and by higher titers of autoantibodies to granulocyte-macrophage colony-stimulating factor (GM-CSF) in the serum and bronchoalveolar lavage fluid. The antibodies inhibit the maturation and phagocytosis of alveolar macrophages. Although the standard therapy for aPAP has been whole-lung lavage (WLL), this procedure is invasive and needs to be repeated for several years. GM-CSF inhalation therapy is a new procedure for treating aPAP and can induce remission with less invasiveness, although it is generally less effective in severe cases. We evaluated five cases with remarkable improvement by using sequential GM-CSF inhalation therapy after WLL; however, the treatment failed when this therapy preceded WLL. Therefore, sequential GM-CSF inhalation after WLL may reinforce the efficiency of WLL in patients with severe aPAP.

Lung cancer patients with interstitial lung diseases (ILDs) who have undergone pulmonary resection often develop acute exacerbation of interstitial pneumonia (AE) in the post-operative period. To predict who is at high risk of AE, we propose a scoring system that evaluates the risk of AE in lung cancer patients with ILDs.We derived a score for 30-day risk of AE onset after pulmonary resection in lung cancer patients with ILDs (n = 1,022; outcome: risk of AE) based on seven risk factors for AE that were identified in a previous retrospective multi-institutional cohort study. A logistic regression model was employed to develop a risk prediction model for AE.A risk score (RS) was derived: 5 × (history of AE) + 4 × (surgical procedures) + 4 × (UIP appearance in CT scan) + 3 × (male sex) + 3 × (preoperative steroid use) + 2 × (elevated serum sialylated carbohydrate antigen, KL-6 level) + 1 × (low vital capacity). The RS was shown to be moderately discriminatory with a c-index of 0.709 and accurate with the Hosmer-Lemeshow goodness-of-fit test (p = 0.907). The patients were classified into three groups: low risk (RS: 0-10; predicted probability0.1; n = 439), intermediate risk (RS: 11-14; predicted probability 0.1-0.25; n = 559), and high risk (RS: 15-22; predicted probability0.25; n = 24).Although further validation and refinement are needed, the risk score can be used in routine clinical practice to identify high risk individuals and to select proper treatment strategies.

In this study, we found that there were significant positive correlations between the catch per unit effort (CPUE, a squid abundance index) for the neon flying squid (Ommastrephes bartramii) winter–spring cohort and the satellite-derived chlorophyll a concentrations in their spawning grounds located at 140–160°E where 21°C

Treatment of autoimmune pulmonary alveolar proteinosis (aPAP) by subcutaneous injection or inhaled therapy of granulocyte-macrophage colony-stimulating factor (GM-CSF) has been demonstrated to be safe and efficacious in several reports. However, some reports of subcutaneous injection described transient benefit in most instances. The durability of response to inhaled GM-CSF therapy is not well characterized.To elucidate the risk factors for recurrence of aPAP after GM-CSF inhalation, 35 patients were followed up, monitoring for the use of any additional PAP therapies and disease severity score every 6 months. Physiologic, serologic, and radiologic features of the patients were analyzed for the findings of 30-month observation after the end of inhalation therapy.During the observation, 23 patients remained free from additional treatments, and twelve patients required additional treatments. There were no significant differences in age, sex, symptoms, oxygenation indexes, or anti-GM-CSF antibody levels at the beginning of treatment between the two groups. Baseline vital capacity (% predicted, %VC) were higher among those who required additional treatment (P.01). Those patients not requiring additional treatment maintained the improved disease severity score initially achieved. A significant difference in the time to additional treatment between the high %VC group (%VC≥80.5) and the low %VC group was seen by a Kaplan-Meier analysis and a log-rank test (P.0005).These results demonstrate that inhaled GM-CSF therapy sustained remission of aPAP in more than one-half of cases, and baseline %VC might be a prognostic factor for disease recurrence.ISRCTN Register and JMACCT Clinical Trial Registry; No.: ISRCTN18931678 and JMAIIA00013; URL: http://www.isrctn.org and http://www.jmacct.med.or.jp.

Osimertinib is a third-generation tyrosine kinase inhibitor (TKI) of the epidermal growth factor receptor (EGFR) that has been approved for the treatment of metastatic non-small cell lung cancer (NSCLC) with EGFR mutation, and positive for the secondary T790M mutation of EGFR. In a preclinical study, it also showed efficacy against leptomeningeal carcinomatosis (LMC) derived from NSCLC resistant to first-generation and second-generation EGFR-TKIs. We report the case of a patient aged 55 years with symptomatic LMC derived from NSCLC. We detected T790M mutation of EGFR by liquid biopsy with blood sample. He showed a clinical and radiographic response to osimertinib.

Loss of transcription factor Bach2 results in a pulmonary alveolar proteinosis-like accumulation of surfactant proteins in the lungs due to altered function of alveolar macrophages., Pulmonary alveolar proteinosis (PAP) results from a dysfunction of alveolar macrophages (AMs), chiefly due to disruptions in the signaling of granulocyte macrophage colony–stimulating factor (GM-CSF). We found that mice deficient for the B lymphoid transcription repressor BTB and CNC homology 2 (Bach2) developed PAP-like accumulation of surfactant proteins in the lungs. Bach2 was expressed in AMs, and Bach2-deficient AMs showed alterations in lipid handling in comparison with wild-type (WT) cells. Although Bach2-deficient AMs showed a normal expression of the genes involved in the GM-CSF signaling, they showed an altered expression of the genes involved in chemotaxis, lipid metabolism, and alternative M2 macrophage activation with increased expression of Ym1 and arginase-1, and the M2 regulator Irf4. Peritoneal Bach2-deficient macrophages showed increased Ym1 expression when stimulated with interleukin-4. More eosinophils were present in the lung and peritoneal cavity of Bach2-deficient mice compared with WT mice. The PAP-like lesions in Bach2-deficient mice were relieved by WT bone marrow transplantation even after their development, confirming the hematopoietic origin of the lesions. These results indicate that Bach2 is required for the functional maturation of AMs and pulmonary homeostasis, independently of the GM-CSF signaling.

In 2007, we reported a large cohort of autoimmune pulmonary alveolar proteinosis (n=248, PAP) in Japan, and showed the incidence and prevalence were 0.24 - 0.49/million/year and 2.04 - 6.2/million (AJRCCM 2007), and 1.4%, 1.4%, and 5.7% of patients had interstitial lung diseases (ILD), autoimmune diseases, and infections. The aims of this study are; (1) To establish a nationwide consecutive registration system for PAP, updating the incidence and prevalence, and (2) To show the usefulness of the system via a surveillance of intractable cases. Methods: (1) All patients, who received the serum anti-GM-CSF autoantibodies tests and were definitely diagnosed, were annually consecutively registered to our database (2011-2014). Three institutes (Niigata, Kinki-Chuo, Aichi) measured the antibodies. (2) Surveillance for the intractable cases (dead, complications such as ILD, infection, etc.) was conducted via the system. Results: (1) Total 903 cases were registered. 88 cases/year have been newly diagnosed in average. The incidence and the prevalence were 0.69/million/year and 6.11/million. 92.9, 6.1, 0.4, and 0.6% were autoimmune, secondary, congenital, and unclassifiable PAP. (2)50% of the institutes responded, providing the data of 579 cases (64% of total patients). 14, 11.2, 10.2, 3.8, 6.7, and 7.9% had dead, respiratory failure, ILD, autoimmune diseases, infections, extra-pulmonary complications. Conclusions: We established a simple consecutive nation-wide registration system for PAP in Japan, providing updated annual epidemiological data and effective surveillance data. This study was granted from AMED (#15652554 , YI).

Numerous studies have been published investigating the pathologic alterations in various interstitial pneumonias, particularly in idiopathic pulmonary fibrosis (IPF). However, the few existing studies on capillary remodeling, which does not seem to have priority for pathologic diagnosis, are contradictory, with some reporting increased and others reduced vascularization. We hypothesized that these discrepancies were due to the temporal heterogeneity of the lesions in IPF. We subsequently developed original techniques for evaluating vascular density within the alveolar septa and discovered, for the first time, a heterogeneous increase in alveolar capillaries in the lungs of IPF patients. Notably, we consistently found that the fibrotic lesions in IPF lungs, which are composed mainly of dense collagen with myofibroblasts, featured a reduction in capillaries. This finding provides a plausible explanation for the intractability of IPF, as this reduced vascularization would result in poor delivery of anti-fibrotic agents to these lesions. We also reported the disappearance of subpleural and interlobular lymphatics in IPF lungs, which likely results in poor alveolar clearance in the diseased lungs. Finally, we assessed the autopsied lungs of patients with IPF who died because of acute exacerbation and observed increased and dilated alveolar capillaries. These capillaries are likely to be "leaky" owing to exposure to VEGF produced by regenerated alveolar type II epithelial cells. Furthermore, poor alveolar clearance may prolong the high mobility group box 1 (HMGB1)-induced lung injury in acute exacerbation of IPF. Our data obtained from the assessment of blood and lymphatic capillary alterations in IPF provide novel pathogenetic insights and may provide the basis for new therapeutic strategies targeting IPF.

This retrospective study aimed to assess the risk of tuberculosis infection for the employees of a Japanese hospital using baseline interferon-gamma release assay (IGRA). The risk was defined as exposure to the hospital environment.In total, 870 hospital employees including 161 new employees, 582 for baseline assay, and 127 for contact examination (709 subjects in the post-employment group) were examined from December 2010 to April 2012. The new employees were considered as the "non-exposure" group, whereas the post-employment group was considered as the "exposure" group. Multiple logistic regression analyses were used to calculate the odds ratio (OR) for IGRA positivity, adjusted for gender, smoking history, and alcohol intake (model 1), and for years of employment (model 2).The exposure group was significantly associated with an increased risk of positive IGRA results, even when adjusted for years of employment (OR: 4.1; 95% confidence interval: 1.4-17.6; P = 0.007). Subgroup analyses stratified by profession indicated a significantly increased OR for laboratory technicians, doctors, and nurses in both models. No correlation was observed between the length of employment and IGRA positivity.Exposure to the hospital environment increased the risk of tuberculosis infection for employees irrespective of the length of employment. Laboratory technicians, doctors, and nurses were at the highest risk of infection.

Background: Lung adenocarcinoma (LADCA) patients with epidermal growth factor receptor (EGFR) mutations are in general associated with relatively high clinical response rate to EGFR-tyrosine kinase inhibitors (TKIs) but not all responded to TKI. It has therefore become important to identify the additional surrogate markers regarding EGFR-TKI sensitivity. Methods: We first examined the effects of EGFR-TKIs, gefitinib and erlotinib, upon cell proliferation of lung adenocarcinoma cell lines. We then evaluated the gene profiles related to EGFR-TKI sensitivity using a microarray analysis. Results of microarray analysis led us to focus on carcinoembryonic antigen-related cell adhesion molecule (CEACAM) family, CEACAM 3, 5, 6, 7, and 19, as potential further surrogate markers of EGFR-TKI sensitivity. We then examined the correlation between the status of CEACAM 3, 5, 6, 7, and 19 immunoreactivity in LADCA and clinicopathological parameters of individual cases. Results: In the cases with EGFR mutations, the status of all CEACAMs examined was significantly higher than that in EGFR wild-type patients, but there were no significant differences in the status of CEACAMs between TKI responder and nonresponder among 22 patients who received gefitinib therapy. However, among 115 EGFR mutation-negative LADCA patients, both CEACAM6 and CEACAM3 were significantly associated with adverse clinical outcome (CEACAM6) and better clinical outcome (CEACAM3). Conclusion: CEACAMs examined in this study could be related to the presence of EGFR mutation in adenocarcinoma cells but not represent the effective surrogate marker of EGFR-TKI in LADCA patients. However, immunohistochemical evaluation of CEACAM3/6 in LADCA patients could provide important information on their clinical outcome.

A 60-year-old Japanese male presented with swelling of bilateral cervical lymph nodes was subsequently diagnosed as the late stage of primary small cell lung carcinoma (SCLC). He was then treated with cisplatin and irinotecan as first-line chemotherapy, but hypokalemia with muscle weakness of the bilateral legs became gradually noticeable following two months of effective chemotherapy. A computed tomography (CT) scan revealed enlargement of bilateral adrenal glands and abdominal and mediastinal lymph nodes, though primary lung tumor remained the same in size. An ectopic ACTH-producing syndrome (EAS) was subsequently revealed by the following endocrinological studies. Hypokalemia was clinically improved by the treatment with metyrapone and the second-line chemotherapy with amrubicin for SCLC was started, but the patient died 12 days after the second-line chemotherapy. Post-mortem examination revealed ACTH immunoreactivity in tumor cells of all the metastatic lesions. Non-neoplastic adrenal cortex demonstrated hyperplasia associated with lipid depletion and marked expression of steroidogenic enzymes, especially in cortical cells around tumor infiltration, suggestive of paracrine ACTH stimulation of cortisol production. This is the first report evaluating expression of steroidogenic enzymes in adrenal cortex especially adjacent to the adrenal metastasis in the patients with EAS due to SCLC. These findings suggest that ACTH producing adrenal metastasis can induce EAS more frequently and severely, and that the symptoms and examination of EAS should be monitored carefully in the patients with adrenal metastasis of SCLC.

Previous studies have demonstrated that mesenchymal stromal cells (MSCs) enhance cell survival through upregulation and secretion of stanniocalcin-1 (STC1). This study shows that MSC-derived STC1 promotes survival of lung cancer cells by uncoupling oxidative phosphorylation, reducing intracellular reactive oxygen species (ROS), and shifting metabolism towards a more glycolytic metabolic profile. MSC-derived STC1 upregulated uncoupling protein 2 (UCP2) in injured A549 cells in an STC1-dependent manner. Knockdown of UCP2 reduced the ability of MSCs and recombinant STC1 (rSTC1) to reduce cell death in the A549 population. rSTC1-treated A549 cells displayed decreased levels of ROS, mitochondrial membrane potential (MMP), and increased lactate production, all of which were dependent on the upregulation of UCP2. Our data suggest that MSCs can promote cell survival by regulating mitochondrial respiration via STC1.

Summary Background Autoimmune pulmonary alveolar proteinosis (aPAP) is caused by granulocyte/macrophage-colony stimulating factor (GM-CSF) autoantibodies in the lung. Previously, we reported that GM-CSF inhalation therapy improved alveolar-arterial oxygen difference and serum biomarkers of disease severity in these patients. It is plausible that inhaled GM-CSF improves the dysfunction of alveolar macrophages and promotes the clearance of the surfactant. However, effect of the therapy on components in bronchoalveolar lavage fluid (BALF) remains unclear. Objectives To figure out changes in surfactant clearance during GM-CSF inhalation therapy. Methods We performed retrospective analyses of BALF obtained under a standardized protocol from the same bronchus in each of 19 aPAP patients before and after GM-CSF inhalation therapy (ISRCTN18931678, JMA-IIA00013; total dose 10.5–21 mg, duration 12–24 weeks). For evaluation, the participants were divided into two groups, high responders with improvement in alveolar-arterial oxygen difference ≥13 mmHg ( n = 10) and low responders with that n = 9). Results Counts of both total cells and alveolar macrophages in BALF did not increase during the therapy. However, total protein and surfactant protein-A (SP-A) were significantly decreased in high responders, but not in low responders, suggesting that clearance of surfactant materials is correlated with the efficacy of the therapy. Among 94 biomarkers screened in bronchoalveolar lavage fluid, we found that the concentration of interleukin-17 and cancer antigen-125 were significantly increased after GM-CSF inhalation treatment. Conclusions GM-CSF inhalation decreased the concentration of total protein and SP-A in BALF, and increase interleukin-17 and cancer antigen-125 in improved lung of autoimmune pulmonary alveolar proteinosis.

Airway surface fluids are mainly secreted from submucosal glands, and play important roles in the defense of airways via the up-regulation of mucociliary transport, resulting in an exclusion of many microbes or foreign substances. Although there are many articles concerning the importance of Toll-like receptors (TLRs) in airway immune systems, whether TLRs directly cooperate with tracheal submucosal glands to increase secretion remains unknown. We investigated the effects of ligands of the three TLR subtypes (TLR2, TLR3, and TLR4) on the physiologic secretion of electrolytes by using a patch-clamp technique. Among these TLRs, only the TLR4 ligand, LPS, showed potentiating effects on acetylcholine (ACh)-induced ionic currents in a dose-dependent manner. These potentiating effects were completely abolished by pretreatment with a specific TLR4 antagonist or the anti-TLR4 antibody. LPS per se exerted no appreciable effect on baseline currents. Next, we demonstrated the abundant expression of TLR4 in submucosal gland acinar cells by using immunofluorescent staining and RT-PCR. Furthermore, we revealed that both nitric oxide synthase inhibitors and cyclic guanosine monophosphate (cGMP)-dependent protein kinase (cGK) inhibitors abolished the LPS-induced potentiating effects completely. Analyses of fluorescence intensities, using an intracellular nitric oxide (NO) indicator, demonstrated that LPS could further increase the ACh-induced synthesis of NO. These findings suggest that TLR4 takes part in airway mucosal defense systems as a unique exogenous potentiator of electrolyte-water secretion from submucosal gland acinar cells, and that NO/cGMP/cGK signaling is involved in this rapid TLR4 signaling pathway.

The lymphatics in the interlobular and subpleural parenchyma contribute to alveolar clearance in the lung, but the information on the remodeling of these lymphatics is quite limited in idiopathic pulmonary fibrosis lungs that contain severe fibrosis in these regions. We compared the alteration of these lymphatics and lymphangiogenesis among idiopathic pulmonary fibrosis and nonfibrotic interstitial pneumonias with a better prognosis.The lung tissue specimens of eighteen patients with idiopathic pulmonary fibrosis (ten surgical biopsies and eight autopsies), six with organizing pneumonia, six with cellular nonspecific interstitial pneumonia, and five normal controls were examined by morphometric analysis of the lymphatics identified by immunohistochemistry. In addition, three-dimensional reconstruction of lymphatics, apoptosis of lymphatic endothelial cells and the cells producing growth factors for lymphangiogenesis were also evaluated. Both the subpleural and the interlobular lymphatics in idiopathic pulmonary fibrosis lungs were significantly decreased in the severe fibroconnective lesions, with rare lymphangiogenesis. The three-dimensional images of the subpleural lymphatics in idiopathic pulmonary fibrosis clearly revealed destruction by fibrosis; apoptosis was observed in these lymphatic endothelial cells. In contrast, organizing pneumonia and cellular nonspecific interstitial pneumonia preserved these lymphatics, and active lymphangiogenesis occurred in the alveolar lesions.These results reveal severe damage of the subpleural and interlobular lymphatics in idiopathic pulmonary fibrosis lungs, and suggest impaired alveolar clearance as another pathogenesis of its refractoriness.

Rationale: Inhaled granulocyte/macrophage–colony stimulating factor (GM-CSF) is a promising therapy for pulmonary alveolar proteinosis (PAP) but has not been adequately studied. Objectives: To evaluate safety and efficacy of inhaled GM-CSF in patients with unremitting or progressive PAP. Methods: We conducted a national, multicenter, self-controlled, phase II trial at nine pulmonary centers throughout Japan. Patients who had lung biopsy or cytology findings diagnostic of PAP, an elevated serum GM-CSF antibody level, and a PaO2 of less than 75 mm Hg entered a 12-week observation period. Those who improved (i.e., alveolar–arterial oxygen difference [A–aDO2] decreased by 10 mm Hg) during observation were excluded. The rest entered sequential periods of high-dose therapy (250 μg Days 1–8, none Days 9–14; × six cycles; 12 wk); low-dose therapy (125 μg Days 1–4, none Days 5–14; × six cycles; 12 wk), and follow-up (52 wk). Measurements and Main Results: Fifty patients with PAP were enrolled in the study. During observation, nine improved and two withdrew; all of these were excluded. Of 35 patients completing the high- and low-dose therapy, 24 improved, resulting in an overall response rate of 62% (24/39; intention-to-treat analysis) and reduction in A–aDO2 of 12.3 mm Hg (95% confidence interval, 8.4–16.2; n = 35, P < 0.001). No serious adverse events occurred, and serum GM-CSF autoantibody levels were unchanged. A treatment-emergent correlation occurred between A–aDO2 and diffusing capacity of the lung, and high-resolution CT revealed improvement of ground-glass opacity. Twenty-nine of 35 patients remained stable without further therapy for 1 year. Conclusions: Inhaled GM-CSF therapy is safe, effective, and provides a sustained therapeutic effect in autoimmune PAP. Clinical trial registered with www.controlled-trials.com/isrctn (ISRCTN18931678), www.jmacct.med.or.jp/english (JMA-IIA00013).

Idiopathic pulmonary fibrosis (IPF) is thought to involve inflammatory infiltration of leukocytes, lung injury induced by reactive oxygen species (ROS), in particular superoxide anion, and fibrosis (collagen deposition). No treatment has been shown to improve definitively the prognosis for IPF patients. Superoxide dismutase (SOD) catalyzes the dismutation of superoxide anion to hydrogen peroxide, which is subsequently detoxified by catalase. Lecithinized SOD (PC-SOD) has overcome clinical limitations of SOD, including low tissue affinity and low stability in plasma. In this study, we examined the effect of PC-SOD on bleomycin-induced pulmonary fibrosis. Severity of the bleomycin-induced fibrosis in mice was assessed by various methods, including determination of hydroxyproline levels in lung tissue. Intravenous administration of PC-SOD suppressed the bleomycin-induced increase in the number of leukocytes in bronchoalveolar lavage fluid. Bleomycin-induced collagen deposition and increased hydroxyproline levels in the lung were also suppressed in animals treated with PC-SOD, suggesting that PC-SOD suppresses bleomycin-induced pulmonary fibrosis. The dose-response profile of PC-SOD was bell-shaped, but concurrent administration of catalase restored the ameliorative effect at high doses of PC-SOD. Intratracheal administration or inhalation of PC-SOD also attenuated the bleomycin-induced inflammatory response and fibrosis. The bell-shaped dose-response profile of PC-SOD was not observed for these routes of administration. We consider that, compared with intravenous administration, inhalation of PC-SOD may be a more therapeutically beneficial route of administration due to the higher safety and quality of life of the patient treated with this drug.