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The prognosis of patients with connective tissue disease (CTD) has improved significantly in recent years, but interstitial lung disease (ILD) associated with connective tissue disease (CTD-ILD) remains a refractory condition, which is a leading cause of mortality. Because it is an important prognostic factor, many observational and interventional studies have been conducted to date. However, CTD is a heterogeneous group of conditions, which makes the clinical course, treatment responses, and prognosis of CTD-ILD extremely diverse. To summarize the current understanding and unsolved questions, the Japanese Respiratory Society and the Japan College of Rheumatology collaborated to publish the world's first guide focusing on CTD-ILD, based on the evidence and expert consensus of pulmonologists and rheumatologists, along with radiologists, pathologists, and dermatologists. The task force members proposed a total of 27 items, including 7 for general topics, 9 for disease-specific topics, 3 for complications, 4 for pharmacologic treatments, and 4 for non-pharmacologic therapies, with teams of 2-4 authors and reviewers for each item to prepare a consensus statement based on a systematic literature review. Subsequently, public opinions were collected from members of both societies, and a critical review was conducted by external reviewers. Finally, the task force finalized the guide upon discussion and consensus generation. This guide is expected to contribute to the standardization of CTD-ILD medical care and is also useful as a tool for promoting future research by clarifying unresolved issues.

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., This postmarketing study showed that diffuse alveolar damage (DAD)‐like pattern, ≤60 days from the start of nivolumab treatment to the onset of interstitial lung disease (ILD), pleural effusion before treatment, lesion distribution contralateral or bilateral to the tumor, and abnormal change in C‐reactive protein levels were common poor prognostic factors of ILD in nivolumab‐treated patients with non–small cell lung cancer (NSCLC). Of the 37 deaths due to ILD, 17 had DAD‐like radiographic pattern, 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.

Nivolumab, a human monoclonal antibody against programmed death‐1, is approved for the treatment of non–small cell lung cancer (NSCLC). Although nivolumab is generally well tolerated, it can cause interstitial lung disease (ILD), a rare but potentially fatal immune‐related adverse event. Currently, there are limited data available on the treatment of nivolumab‐induced ILD and its outcome. This retrospective cohort study based on a post–marketing study described the treatment of nivolumab‐induced ILD and its outcome in NSCLC patients in Japan through the assessment of clinical and chest imaging findings by an expert central review committee. Treatment details for patients who experienced a relapse of ILD were also analyzed. Of the 238 patients identified as having nivolumab‐induced ILD, 37 patients died of ILD. Corticosteroids were used in 207 (87.0%) patients. Of those, 172 (83.1%) patients responded well and survived and 35 (16.9%) died (most died during corticosteroid treatment). A total of nine patients experienced a relapse; at the time of relapse, four patients were taking nivolumab. Of those who were receiving corticosteroids at the time of relapse, three of four patients were taking low doses or had nearly completed dose tapering. All patients (except one, whose treatment was unknown) received corticosteroids for the treatment of relapse, but one patient died. Patients with NSCLC who experience nivolumab‐induced ILD are treated effectively with corticosteroids, and providing extra care when ceasing or reducing the corticosteroid dose may prevent relapse of ILD., Use of nivolumab in the treatment of non–small cell lung cancer may be associated with interstitial lung disease. Our post–marketing study suggests that nivolumab‐induced interstitial lung disease can be treated effectively with corticosteroids. To prevent a relapse, extra care should be provided when ceasing or reducing the corticosteroid doses.

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.

Objective Adverse drug reactions (ADRs) during real-world osimertinib use were investigated in Japan. Methods Patients with epidermal growth factor receptor (EGFR) T790M-positive non-small cell lung cancer treated with second-line or later oral osimertinib per the Japanese package insert (80 mg once daily) were included. Data were collected between 28 March 2016 and 31 August 2018. Results The median observation period in the safety analysis population (n = 3578) was 343.0 days. ADRs (defined as adverse events whose causality to osimertinib could not be denied by the attending physicians or manufacturer) were reported in 58.1% (2079/3578) of patients. ADRs of interstitial lung disease events were reported in 6.8% (245/3578; Grade ≥ 3, 2.9% [104/3578]) of patients, of whom 29 (11.8%) died (0.8% of patients overall). ADRs of QT interval prolonged, liver disorder and haematotoxicity were reported in 1.3% (45/3578; Grade ≥ 3, 0.1% [5/3578]), 5.9% (212/3578; Grade ≥ 3, 1.0% [35/3578]) and 11.4% (409/3578; Grade ≥ 3, 2.9% [104/3578]) of patients, respectively. In the efficacy analysis population (n = 3563), 119 (3.3%) patients had complete responses, 2373 (66.6%) had partial responses and 598 (16.8%) had stable disease. The objective response rate was 69.9%; disease control rate was 86.7%; and median progression-free survival (PFS) was 12.3 months. At 6 and 12 months, PFS rates were 77.4% (95% confidence interval [CI], 75.9–78.9) and 53.2% (95% CI, 51.3–55.1) and overall survival rates were 88.3% (95% CI, 87.2–89.4) and 75.4% (95% CI, 73.8–77.0), respectively. Conclusions These data support the currently established benefit-risk assessment of osimertinib in this patient population., Real-world safety and efficacy data from Japanese patients with EGFR T790M-positive NSCLC support the currently established benefit-risk assessment of osimertinib in this patient population.

Radiologic diagnosis of chronic hypersensitivity pneumonitis (CHP) presenting a usual interstitial pneumonia (UIP) pattern is challenging. The aim of this study was to identify the high-resolution CT (HRCT) findings which are useful to discriminate CHP–UIP from idiopathic pulmonary fibrosis (IPF). This study included 49 patients with well-established bird-related CHP–UIP, histologically confirmed, and 49 patients with IPF. Two groups of observers independently assessed HRCT, evaluated the extent of each abnormal HRCT finding. When their radiological diagnosis was CHP–UIP, they noted the HRCT findings inconsistent with IPF. Correct CT diagnoses were made in 79% of CHP–UIP and 53% of IPF. Although no apparent difference was seen in the extent of each HRCT finding, upper or mid-lung predominance, extensive ground-glass abnormality, and profuse micronodules were more frequently pointed out as inconsistent findings in CHP–UIP than IPF (p = 0.007, 0.010, 0.001, respectively). On regression analysis, profuse micronodules [OR 13.34 (2.85–62.37); p = 0.001] and upper or mid-lung predominance of findings [OR 2.86 (1.16–7.01); p = 0.022] remained as variables in the equation. In this cohort, some IPF cases were misdiagnosed as CHP–UIP. Profuse micronodules and upper or mid-lung predominance are important clues for the differentiation of CHP–UIP from IPF.

Aim: To assess the clinical features/imaging characteristics of pneumonitis reported during nationwide nivolumab postmarketing surveillance in Japan. Patients & methods: Clinical and radiological data were collected from pneumonitis cases reported during/after nivolumab treatment for melanoma or non-small-cell lung cancer. The expert central review committee evaluated each case. Results: Among 144 cases analyzed, 91 (63.2%) had radiological patterns considered typical for drug-induced pneumonitis and 53 (36.8%) patients had previously unobserved patterns with one or more atypical features, including 23 cases (16.0%) with ground glass opacity confined to the area around the tumor (peritumoral infiltration). A higher proportion of patients with (vs without) peritumoral infiltration had an antitumor response to nivolumab. Conclusion: Images of nivolumab-induced pneumonitis showed previously unobserved radiological patterns.

To characterize and categorize the CT findings of pulmonary leukemic infiltration (PLI) in patients with acute myeloid leukemia (AML). Among 435 patients with AML, 20 patients with PLI were retrospectively selected, and clinical characteristics and CT findings were analyzed. PLI was categorized into four patterns according to CT findings: type A, multiple nodules and/or masses; type B, bilateral perihilar airspace opacities (GGA or consolidation) without any nodules or masses; type C, mixture of type A and B; and type D, PLI without visible abnormal lung opacity. The difference in overall survival among four CT patterns was also examined. The frequency of complex karyotypes was higher in AML patients with PLI than in whole AML patients. Percentages of patients with CT findings of type A, B, C, and D were 35%, 20%, 35%, and 10%, respectively. There was a clear difference in the localization of opacities according to the type of infiltrates, i.e., nodules/masses were mainly detected in the lower/peripheral portion. Conversely, GGA was mainly located in the upper/central portion. The median overall survival from diagnosis of PLI was 262 days (range 12–1148). The CT pattern was not significantly associated with survival (p = 0.3), with the exception of patients with type C tending to have significantly better outcomes compared to patients with type B (p = 0.05). This classification can contribute in accurate non-invasive diagnosis and possibly in the estimation of prognosis.

Background Chemotherapy-induced acute exacerbation (AEx) of idiopathic interstitial pneumonias (IIPs) seriously compromises the success of treatment of Japanese lung cancer patients. Here, we conducted a nationwide surveillance to clarify the risk of AEx and compare it with the survival benefit of chemotherapy for this population. Methods Advanced nonsmall cell lung cancer (NSCLC) or small cell lung cancer (SCLC) patients with IIPs were retrospectively analysed. For the surveillance of first-line chemotherapy in 2009, we gathered clinical data from 396 patients who received chemotherapy at 19 institutions between January 1990 and July 2009. In a consecutive retrospective study in 2012, we analysed data from 278 patients from 17 institutions who received second-line chemotherapy between April 2002 and March 2012. Results Of the 396 patients analysed, 13.1% developed chemotherapy-related AEx. Combination chemotherapies of carboplatin plus paclitaxel (CP) or carboplatin plus etoposide (CE) were frequently used as first-line treatments. The lowest incidence of AEx was 3.7% in CE, followed by 8.6% in CP. In the retrospective study, 16.2% of the 278 patients developed a second-line chemotherapy-related AEx. The overall response rate by second-line chemotherapy was 7.4% in NSCLC and 25.7% in SCLC. The median overall survival from second-line and first-line chemotherapy was 8.0 and 14.3 months in NSCLC, and 8.7 and 16.0 months in SCLC, respectively. Conclusion Combination chemotherapies consisting of CP or CE are candidates for standard first-line treatments for patients with advanced lung cancer accompanied by IIP. Second-line chemotherapy should be considered for patients remaining fit enough to receive it., The Japanese are at high risk of acute exacerbation of IPF. Therefore, chemotherapy for Japanese lung cancer patients with IIPs is challenging. However, appropriate chemotherapy may give a survival benefit, despite the risk of acute deterioration of IIPs. http://bit.ly/3cROaCy

Background: There is currently no consensus on the morphology of severe fibrotic pulmonary sarcoidosis, and we examined computed tomography (CT) findings and progression. Methods: We analyzed findings in 10 consecutive patients (three men, seven women) with pulmonary sarcoidosis requiring oxygen therapy for chronic respiratory failure, who were extracted from &gt, 2500 sarcoidosis patients (three hospitals, 2000&ndash, 2018). Patients with comorbidities causing chronic respiratory failure were excluded. Results: Predominant findings were consolidations along the bronchovascular bundles comprising &lsquo, central-peripheral band&rsquo, traction bronchiectasis, peripheral cysts/bullae, and upper lobe shrinkage. Traction bronchiectasis arose from opacities comprising &lsquo, Clustering of traction bronchiectasis at the distal side formed honeycomb lung-like structures in three patients. Upper lobe shrinkage progressed in seven patients together with progression of consolidations, &lsquo, traction bronchiectasis clusters, and cysts, while patients without shrinkage included two patients with severe multiple cysts without traction bronchiectasis. Restrictive ventilatory impairment developed in most patients. Pulmonary hypertension (PH) was detected radiologically in five patients, and chronic progressive pulmonary aspergillosis (CPPA) in four patients. Conclusions: During progression, consolidations comprising &lsquo, progressed together with traction bronchiectasis clusters and peripheral cysts, resulting in upper lobe shrinkage. This may lead to respiratory failure with possible complications such as PH and CPPA.

Rationale and Objectives The objectives of this study were to compare the visibility and quantification of subsolid nodules (SSNs) on computed tomography (CT) using adaptive iterative dose reduction using three-dimensional processing between 7 and 42 mAs and to assess the association of size-specific dose estimate (SSDE) with relative measured value change between 7 and 84 mAs (RMVC7–84) and relative measured value change between 42 and 84 mAs (RMVC42–84). Materials and Methods As a Japanese multicenter research project (Area-detector Computed Tomography for the Investigation of Thoracic Diseases [ACTIve] study), 50 subjects underwent chest CT with 120 kV, 0.35 second per location and three tube currents: 240 mA (84 mAs), 120 mA (42 mAs), and 20 mA (7 mAs). Axial CT images were reconstructed using adaptive iterative dose reduction using three-dimensional processing. SSN visibility was assessed with three grades (1, obscure, to 3, definitely visible) using CT at 84 mAs as reference standard and compared between 7 and 42 mAs using t test. Dimension, mean CT density, and particular SSDE to the nodular center of 71 SSNs and volume of 58 SSNs (diameter >5 mm) were measured. Measured values (MVs) were compared using Wilcoxon signed-rank tests among CTs at three doses. Pearson correlation analyses were performed to assess the association of SSDE with RMVC7–84: 100 × (MV at 7 mAs − MV at 84 mAs)/MV at 84 mAs and RMVC42–84. Results SSN visibilities were similar between 7 and 42 mAs (2.76 ± 0.45 vs 2.78 ± 0.40) (P = .67). For larger SSNs (>8 mm), MVs were similar among CTs at three doses (P > .05). For smaller SSNs ( Conclusions Comparable quantification was demonstrated irrespective of doses for larger SSNs. For smaller SSNs, nodular exaggerating effect associated with decreased SSDE on CT at 7 mAs compared to 84 mAs could result in comparable visibilities to CT at 42 mAs.

Axillary lymph nodes (ALNs) are often seen on chest computed tomography (CT) in rheumatoid arthritis (RA) patients. Early reports described lymphadenopathy as one of the systemic manifestations rather than regional lymphadenopathy secondary to drainage from the affected joints. Subsequently, the importance of the immunological events occurring in draining lymph nodes in the development of arthritis was documented. To identify the relationships of local disease activity and background characteristics, including systemic disease activity, systemic disease activity, with axillary lymphadenopathy (AL) in RA using CT. RA patients who had undergone chest CT were retrospectively analyzed. The maximum short axis of the ALNs was measured, and the number of positive ALNs ≥ 5 mm was counted. Tender and swollen joints in the upper limbs were counted as indicators of local disease activity. Background characteristics and systemic disease activity were assessed based on the selected RA indicators. Correlations between AL and both local disease activity and background characteristics including systemic disease activity were analyzed. Of 135 patients, 58 had positive ALNs (average size 7.97 mm, range up to 15 mm). The presence of positive unilateral ALNs was correlated with the severity of ipsilateral upper limb arthritis. Multivariate analysis showed correlations between AL and both local disease activity and serological findings such as serum C-reactive protein (CRP) and immunoglobulin (Ig) G. AL in patients with RA was correlated with local arthritis activity, as well as background characteristics and systemic disease activity.

Common variable immunodeficiency (CVID) is a heterogeneous subset of immunodeficiency disorders. Recurrent bacterial infection is the main feature of CVID, but various non-infectious complications can occur. A 42-year-old woman presented with cough and abnormal chest X-ray shadows. Laboratory tests showed remarkable hypogammaglobulinemia. Computed tomography revealed multiple consolidation and nodules on the bilateral lung fields, systemic lymphadenopathy, and splenomegaly. A surgical lung biopsy specimen provided the final diagnosis of lymphoproliferative disease in CVID, which was grouped under the term granulomatous lymphocytic interstitial lung disease. Interestingly, the lung lesions of this case resolved immediately after the initiation of intravenous immunoglobulin monotherapy.

We herein report a case of Rosai-Dorfman disease (RDD) overlapping with IgG4-related disease (IgG4-RD), which presented as diffuse interstitial lung disease with a perilymphatic pattern, followed by submandibular gland and eyelid swelling. The pathological findings of the submandibular gland biopsy specimen were indicative of IgG4-RD alone. We diagnosed the patient with RDD with overlapping IgG4-RD. However, the optimal method for differentiating between these two entities is still controversial. It is important that clinicians are aware that RDD should be included in the differential diagnoses of diffuse interstitial lung disease with a perilymphatic pattern and that RDD can overlap with IgG4-RD.

Purpose To assess inter-observer variability in identifying traction bronchiectasis on computed tomography (CT) using additional criteria for chronic fibrosing interstitial pneumonia. Methods Seven experts categorized CT image set representing 39 patients into three groups on the basis of the presence of traction bronchiectasis, using a three-point scale: 3-definitely/probably yes; 2-possibly yes; and 1-definitely/probably no. This scale served as a reference standard. The image set included cases of chronic fibrosing interstitial pneumonia, non-interstitial lung disease, and difficult-to-determine cases. Forty-eight observers similarly assessed the same image set, first according to the Fleischner Society definition, and second with additional criteria, in which traction bronchiectasis was observed exclusively in chronic fibrosing interstitial pneumonia. The agreement level between the reference standard and each observer's evaluation in each session was calculated using weighted kappa values which were compared between the two sessions using a paired t test. Results The mean weighted kappa value for all observers was significantly higher in the second reading session (mean 0.75) than in the first reading session (mean 0.62) (p < 0.001). Conclusion Inter-observer agreement in identifying traction bronchiectasis improves when using the additional criteria which specify chronic fibrosing interstitial pneumonia as the underlying disease.

Aims There have been few reports on immunoglobulin-G4 (IgG4)-related interstitial pneumonia (IP), and its clinical features remain unclear. The objective of this study was to assess whether IP with marked IgG4-positive plasma cell infiltration without extrathoracic lesions of IgG4-related disease (RD) should be diagnosed as a subtype of IgG4-RD or a separate entity. Methods and results All consecutive patients with surgical lung biopsy-proven idiopathic IP with an IgG4/IgG-positive cell ratio of >40% and >50 IgG4+ plasma cells in a high-power field without extrathoracic lesions of IgG4-RD were reviewed retrospectively. Five patients were enrolled into this study. All patients were male with a history of smoking. Four patients met the comprehensive diagnostic criteria for IgG4-RD. The remaining patient lacked data related to the serum IgG4 level. Histologically, a non-specific IP pattern was observed in all patients. The key morphological features of IgG4-RD, such as storiform fibrosis and obliterative phlebitis with lymphoplasmacytic infiltration in a loose background texture, were absent in every patient. In contrast, venule obstruction by densely packed lymphoplasmacytic infiltration was observed in two patients. Marked scarring and remodelling of the lung were also noted, which is not seen typically in IgG4-RD. A favourable response to corticosteroid monotherapy was observed in all patients; however, two patients developed lung cancer during the course of observation. Conclusions IP with marked IgG4-positive plasma cell infiltration without extrathoracic lesions of IgG4-RD had different pathological features from those of IgG4-RD, and it is appropriate to regard this as a separate entity.

To identify differences in the radiological findings of invasive pulmonary aspergillosis (IPA) among patients classified by severity of neutropenia, and differences in underlying disease.We retrospectively reviewed computed tomography (CT) scans from the time of the diagnosis of IPA in 83 hematological malignancy patients with probable or proven IPA according to the EORTC-MSG criteria. We evaluated CT findings (radiological pattern, number of lesions, distribution, and presence of low attenuation area [LAA]), and compared the radiological findings of patients classified by degree of neutropenia with two different indicators (neutrophil count at the onset, and c-d-index) and underlying disease.Neutropenia at the onset of IPA was associated with an increased frequency of LAA (p 0.05), especially in FN (p 0.01). Cases with a c-d-index of ≧5500 showed an increased incidence of the angio-invasive pattern. In contrast, cases with a c-d-index of 0 showed an increased incidence of the airway-invasive pattern (p 0.05). The airway-invasive pattern was more frequent in cases with MM, while the angio-invasive pattern was more frequent in cases with AML (p 0.01). Lower-predominant distribution was more frequent and random distribution was less frequent in cases with AML, random distribution was more frequent and lower-predominant distribution was less frequent in cases with ALL, and upper-predominant distribution was more frequent in cases with MDS (p 0.05).CT features of IPA vary according to the degree of neutropenia and underlying disease.

BackgroundA randomised controlled trial in Japan showed that inhaled N-acetylcysteine monotherapy stabilised serial decline in forced vital capacity (FVC) in some patients with early idiopathic pulmonary fibrosis (IPF). However, the efficacy and tolerability of combination therapy with an antifibrotic agent and inhaled N-acetylcysteine are unknown.MethodsThis 48-week, randomised, open-label, multicentre phase 3 trial compared the efficacy and tolerability of combination therapy with pirfenidone plus inhaled N-acetylcysteine 352.4 mg twice daily with the results for pirfenidone alone in patients with IPF. The primary end-point was annual rate of decline in FVC. Exploratory efficacy measurements included serial change in diffusing capacity of the lung for carbon monoxide (DLCO) and 6-min walk distance (6MWD), progression-free survival (PFS), incidence of acute exacerbation, and tolerability.Results81 patients were randomly assigned in a 1:1 ratio to receive pirfenidone plus inhaled N-acetylcysteine (n=41) or pirfenidone (n=40). The 48-week rate of change in FVC was −300 mL and −123 mL, respectively (difference −178 mL, 95% CI −324–−31 mL; p=0.018). Serial change in DLCO, 6MWD, PFS and incidence of acute exacerbation did not significantly differ between the two groups. The incidence of adverse events (n=19 (55.9%) for pirfenidone plus N-acetylcysteine; n=18 (50%) for pirfenidone alone) was similar between groups.ConclusionsCombination treatment with inhaled N-acetylcysteine and pirfenidone is likely to result in worse outcomes for IPF.

Background and Objective: A randomized controlled trial in Japan showed that inhaled N-acetylcysteine (NAC) monotherapy stabilized the serial decline in FVC in some IPF patients not receiving immunosuppressive or antifibrotic agents. The effects of combination therapy with an antifibrotic agent and inhaled NAC are thus unclear. This multicenter, prospective, randomized, controlled clinical trial of Japanese patients with IPF assessed the efficacy and safety of combination therapy with pirfenidone and inhaled NAC. Methods and Main Results: Eighty-one patients (age >40 years) started on pirfenidone 1200–1800 mg /day for clinically or pathologically diagnosed IPF were randomly assigned in a 41:40 ratio to receive concomitant inhaled NAC 352.4 mg twice daily or pirfenidone alone for 48 weeks. The primary endpoint was change from baseline in FVC at 48 weeks. The exploratory efficacy measurements at 48 weeks were (1) absolute and relative change from baseline in VC, %VC, TLC, %TLC, DLco, and %DLco, (2) relative change from baseline in chest HRCT images, (3) change from baseline in 6-MWD and desaturation, (4) change from baseline in mMRC grade, (5) change from baseline in serum biomarkers (SP-D, KL-6), (6) occurrence of acute exacerbation, (7) progression-free survival (disease progression defined as a decline in FVC of 5% to 10％, worsening mMRC grade, or death), (8) mortality, and (9) adverse events. Patient enrollment started in January 2015 and was completed in June 2017. Conclusions: This trial will evaluate the efficacy and safety of combined therapy with pirfenidone and inhaled NAC in patients with IPF.

The aim of this study was to investigate distinguishing clinicopathological features, in addition to histological invasiveness, in adenocarcinoma in situ (AIS) and minimally invasive adenocarcinoma (MIA) of the lung.Patients with lung adenocarcinoma who underwent surgery at our hospital between 2007 and 2014 were reviewed, focusing on computed tomography (CT) images, operative procedures and clinical outcomes, histopathology, Ki-67 immunostaining, and EGFR-mutation status. EGFR mutations were examined using a peptide nucleic acid-locked nucleic acid PCR clamp method. Group comparisons were investigated by Mann-Whitney U or Fisher's exact tests.Of 629 patients with lung adenocarcinoma who underwent surgery, 91 (14%) of 103 AIS (n = 34) or MIA (n = 69) tumors were reviewed. The ratio of male to female patients with MIA compared to AIS was significantly higher (p 0.02). Of 103 tumors, 99 (96%) were non-mucinous. By CT, 74% of AIS appeared as pure ground-glass nodules and 75% of MIAs as part-solid ground-glass nodules. Pathological tumor diameters and Ki-67 labeling index (LI) values were significantly greater for MIAs compared to AIS (p 0.001 for both). A Ki-67 LI of ≥2.8% indicated the presence of an MIA rather than an AIS. EGFR mutations were more frequently detected in MIAs (33/69, 48%) than AIS (9/34, 26%; p = 0.055). The ratio of exon 19 deletions to exon 21 missense mutations in MIAs tended to be higher than those in AIS (p = 0.06). Patients did not experience a local recurrence or metastasis after AIS and MIAs were removed by wedge resection, segmentectomy or lobectomy. Five-year recurrence-free survival rates were 100%.Despite similar surgical outcomes for AIS and MIAs, we found differences in terms of gender, tumor diameters, CT findings, Ki-67 LI and a subset of EGFR mutations, highlighting the validity of classifying the two subtypes.

Background Airway disease (AD) has drawn attention both clinically and etiologically in rheumatoid arthritis (RA), but is still poorly understood. Objectives We aimed to elucidate the clinical and radiographic characteristics of AD in patients with RA. Methods We retrospectively reviewed high-resolution computed tomography (HRCT) images and clinical data of 131 consecutive RA patients in whom HRCT were scanned for clinical purposes and screening. Overlap patients with other collagen tissue diseases and patients complicated with active infection or lung cancer were excluded. Patients who had a history of drug-induced lung disease, thoracic radiation, or exposure to dust were also excluded. HRCT images were reviewed independently by a pulmonologist and a radiologist in blind fashions, and cases of disagreement were discussed to reach a final consensus. AD was radiographically sub-categorised into 3 sub-groups: central AD, small AD, and middle lobe and lingular bronchiectasis. The associations between AD and interstitial lung disease (ILD) and each pair of the subtypes of AD were analysed by Fisher’s exact test. The risk factors for AD and subtypes of AD were identified by multivariate logistic regression analyses. Results The mean age of the patients was 65 years old, the mean disease duration of the patients was 123 months, 69% of the patients were women, and 42% of the patients had past/current histories of smoking. The mean Disease Activity Score 28 (DAS28)-erythrocyte sedimentation rate (ESR) value was 2.87. AD and ILD were observed in 53 (40%) and 36 (27%) patients, respectively, and both in 19 (15%) patients. AD and ILD were not significantly associated (p=0.11). By multivariate logistic regression analyses, rheumatoid factor (RF) was identified as risk factors for whole AD (odds ratio [OR] 2.7; 95% confidence interval [CI], 1.0 to 6.9; p=0.04). Central AD, small AD, and middle lobe and lingular bronchiectasis were observed in 45 (34%), 31 (24%), and 17 (13%) patients, respectively. Each pair of these 3 subtypes were significantly associated with each other (p Conclusions Radiologically defined AD was frequent comorbidity in RA patients, and multiple subtypes of AD were observed and coexisted. Furthermore, AD may be related to the pathology of RA, and different AD subtypes may have distinct risk factors. Prospective studies with early RA patients were warranted to further clarify these findings and clinical impact of AD. Disclosure of Interest None declared

Objective Little has been reported on the radiological and pathological findings of interstitial pneumonia in mixed connective tissue disease (MCTD). There may be possible difference in treatment response and prognosis between the imaging patterns of systemic sclerosis (SSc)-like and polymyositis/dermatomyositis (PM/DM)-like. The purpose of this study was to examine whether the radiological images of interstitial pneumonia in MCTD presented SSc-like or PM/DM-like pattern, and to assess whether the imaging patterns corresponded to clinical and pathological features. Materials and methods This retrospective study included 29 patients with interstitial pneumonia who underwent surgical lung biopsy; 10 with SSc, 10 with PM/DM, and 9 with MCTD. High resolution computed tomography (HRCT) images were classified as SSc, PM/DM, or the other pattern by two radiologists independently without clinical information. The pathology of the lung specimens from MCTD patients were evaluated and compared with the imaging pattern. Results The concordance rate between clinical diagnosis and radiological pattern was 100% in SSc patients, and 80% in PM/DM patients. Among patients with MCTD, imaging patterns were classified as SSc pattern in 4 (MCTD-SSc), PM/DM pattern in 4 (MCTD-PM/DM) and other in one. The imaging patterns did not always correlate with the clinical findings in MCTD patients. Pathologically, plasma cell infiltration and organizing pneumonia were relatively more frequent in MCTD-PM/DM, and smooth muscle hyperplasia was relatively more frequent in MCTD-SSc. Conclusion HRCT images in MCTD patients can be classified as SSc pattern or PM/DM pattern. MCTD-SSc and MCTD-PM/DM were corresponded to similar pathological findings of SSc and PM/DM.

Background/Aim: We report on a case of pulmonary tumor embolism caused by squamous cell carcinoma of the uterine cervix. Patients and Methods: A 60-year-old female diagnosed with stage IVB (cT4N1M1) squamous cell carcinoma of the uterine cervix was admitted to our institution with a chief complaint of progressive dyspnea that developed within a few days after admission. Results: A chest CT scan showed dilated pulmonary arteries, right ventricular enlargement and mosaic ground-glass opacities in both lungs. An echocardiogram revealed elevated right ventricular pressure and a floppy mass in the right ventricle. Pulmonary tumor embolism was highly suspected. However, she died from respiratory failure on the fourth day after admission. Autopsy revealed diffuse tumor emboli in bilateral pulmonary arteries and arterioles. Conclusion: Pulmonary tumor embolism should be considered when patients with malignant disease develop unexplained dyspnea, hypoxemia, and pulmonary hypertension.

Varying kinds of airway disease are frequently seen in rheumatoid arthritis (RA) patients. It is mandatory to know immunologic and pathologic features of RA in order to explain frequent occurrence of airway diseases in RA patients. Causes of airway diseases encompass infectious and noninfectious process. Noninfectious process may be related to hyperreactive state to endogenous/exogenous agents in RA patients. This noninfectious destructive disease of airway may become one of predisposing factors of respiratory tract infection. Respiratory tract infection can accelerate autoimmune inflammatory process in airway and vice versa.

The aim was to characterize the computed tomographic (CT) findings from Japanese patients with lymphangioleiomyomatosis (LAM).CT scans of the chest, abdomen, and pelvis from 124 patients with sporadic LAM (S-LAM, mean age, 37.4 years) and 14 patients with tuberous sclerosis complex (TSC)-LAM (mean age, 35.6 years) were analyzed.Pulmonary nodules (18.8%) and hepatic angiomyolipoma (AML, 24.3%) were more common in our patients than those in previous reports. Compared with TSC-LAM, S-LAM group had a higher frequency of pulmonary nodules (28.6% vs 32.3%, P0.01) and lower frequencies of air-space consolidation (21.4% vs 2.4%, P0.01), pneumothorax (28.6% vs 8.1%, P=0.02), pulmonary hilar lymphadenopathy (14.3% vs 0.8%, P0.01), renal AML (85.7% vs 17.4%, P0.01), hepatic AML (71.4% vs 17.4%, P0.01), and retrocrural lymphadenopathy (14.3% vs 1.4%, P=0.04). Axial lymphatic abnormalities (i.e., thoracic duct dilatation, lymphadenopathy, and lymphangioleiomyoma) were most common in the pelvis and tended to decrease in incidence with increased distance from the pelvis.The incidence of some CT findings in Japanese patients differed from those in previous reports. Axial lymphatic abnormalities noted here suggest that the origin of LAM cells may be the pelvis.

Background The aim of this study was to elucidate whether there is a relationship between the extent of pleural plaques and pulmonary asbestos body concentration (PABC). Methods The subjects were 207 lung cancer patients with occupational asbestos exposure. We determined the plaque extent by findings on chest images using our own criteria. PABCs were measured in resected or autopsy lung specimens. Results There was a significant relationship between plaque extent and PABC. Seventy-five percent of the patients determined to have extensive plaques based on our criteria had a PABC of ≥5,000 asbestos bodies per gram of dry lung tissue, which is one of the certification criteria of lung cancer caused by asbestos for workers' compensation in Japan. Conclusions In lung cancer patients, the plaque extent had a significant positive relationship with the PABC. The plaque extent would be useful as a proxy for PABC for lung cancer compensation purposes. Am. J. Ind. Med. 58:444–455, 2015. © 2015 Wiley Periodicals, Inc.

Invasive tracheobronchial aspergillosis that is entirely limited or predominantly confined to tracheobronchial lesions is a relatively rare form of invasive pulmonary aspergillosis. Extended parenchymal opacities that are radiological manifestations of invasive aspergillosis sometimes occur following invasive tracheobronchial aspergillosis. However, it remains unclear whether or not invasive tracheobronchial aspergillosis is the initial stage of invasive pulmonary aspergillosis. A 61‐year‐old woman was admitted because of severe diarrhea and dehydration. Three days after admission, she complained of dyspnea. A computed tomography (CT) scan of the chest showed bronchial wall thickening. She developed respiratory failure despite antibiotic therapy. A CT scan showed obstructions of bronchial lumens and bronchiectasis in the right upper lobe. A spergillus fumigatus was identified from samples obtained in bronchoscopic examination. Bronchial lesions rapidly progressed to be extended. A spergillus infection with multiple parenchymal opacities was observed on CT scan. She responded to treatment with antifungal drugs.

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.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 level600 (U/mL) survived shorter than those with600 (p 0.001).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.

Background Measuring the size of invasiveness on computed tomography (CT) for the T descriptor size was deemed important in the 8th edition of the TNM lung cancer classification. We aimed to correlate the maximal dimensions of the solid portions using both lung and mediastinal window settings on CT imaging with the pathologic invasiveness (> 0.5 cm) in lung adenocarcinoma patients. Materials and Methods The study population consisted of 378 patients with a histologic diagnosis of adenocarcinoma in situ (AIS), minimally invasive adenocarcinoma (MIA), invasive adenocarcinoma (IVA)-lepidic, IVA-acinar and/or IVA-papillary, and IVA-micropapillary and/or solid adenocarcinoma. A panel of 15 radiologists was divided into 2 groups (group A, 9 radiologists; and group B, 6 radiologists). The 2 groups independently measured the maximal and perpendicular dimensions of the solid components and entire tumors on the lung and mediastinal window settings. The solid proportion of nodule was calculated by dividing the solid portion size (lung and mediastinal window settings) by the nodule size (lung window setting). The maximal dimensions of the invasive focus were measured on the corresponding pathologic specimens by 2 pathologists. Results The solid proportion was larger in the following descending order: IVA-micropapillary and/or solid, IVA-acinar and/or papillary, IVA-lepidic, MIA, and AIS. For both groups A and B, a solid portion > 0.8 cm in the lung window setting or > 0.6 cm in the mediastinal window setting on CT was a significant indicator of pathologic invasiveness > 0.5 cm (P Conclusion A solid portion > 0.8 cm on the lung window setting or solid portion > 0.6 cm on the mediastinal window setting on CT predicts for histopathologic invasiveness to differentiate IVA from MIA and AIS.

Since imaging finding of drug-induced lung injury (DLI) is varying and nonspecific, diagnosis of DLI must be performed by the integration of clinical, imaging, and pathologic findings, when available. The roles of imaging evaluation in the diagnosis and treatment of DLI include detection of preexisting chronic fibrosing interstitial pneumonia as risk of DLI, early detection of DLI, diagnosis of DAD-type DLI for the estimation of prognosis, aids to differential diagnosis, follow-up examination including evaluation of treatment effect, and so on.

BACKGROUND Pleuroparenchymal fibroelastosis (PPFE) is a rare form of interstitial pneumonia and sometimes coexists with a histologic usual interstitial pneumonia (UIP) pattern. This study aimed to describe the distinct clinical features of PPFE with UIP pattern compared with idiopathic pulmonary fibrosis (IPF). METHODS We conducted a retrospective review of the medical records of 110 consecutive patients with IPF with a histologic UIP pattern on surgical lung biopsy specimen. Patients meeting radiologic criteria for the diagnosis of PPFE based on high-resolution CT scan and with a histologic UIP pattern were included. RESULTS Nine of eleven patients meeting radiologic criteria for the diagnosis of PPFE were histologically confirmed as having PPFE with UIP pattern. The PPFE with UIP pattern group showed a significantly higher residual volume (1.8 L vs 1.3 L, P 2 (44.6 mm Hg vs 41.7 mm Hg, P = .04), and higher complication rate of pneumothorax and pneumomediastinum than the 99 patients with IPF/UIP. The ratio of anteroposterior to transthoracic diameter in patients with PPFE with UIP pattern was significantly lower than that in patients with IPF/UIP ( P = .04). Survival time tended to be shorter in patients with PPFE with UIP pattern. CONCLUSIONS The results support the view that PPFE with UIP pattern is a disease entity distinct from IPF/UIP and may well be classified as PPFE.

Introduction Although interstitial lung disease (ILD) is a known serious adverse effect of epidermal growth factor receptor tyrosine kinase inhibitors, the risk factors for its development are poorly defined. To determine the risk factors for the development of drug-induced ILD and poor-prognosis (fatal) drug-induced ILD after erlotinib treatment, we assessed the baseline pulmonary status in patients with non–small cell lung cancer enrolled in a postmarketing clinical study of erlotinib. Patients and Methods In the present prospective cohort study, the baseline pulmonary status of all patients was evaluated using conventional or high-resolution computed tomography. The patients were monitored for the development of drug-induced ILD for 120 days after the start of treatment. All diagnoses of drug-induced ILD were confirmed by an independent ILD safety review committee. The risk factors were determined using logistic regression analysis. Results A total of 645 patients were enrolled, of whom 627 were evaluable. The committee confirmed the diagnoses of drug-induced ILD in 19 patients, 6 of whom had fatal outcomes. Multivariate logistic regression analysis revealed that pre-existing ILD and limited residual normal lung were significant risk factors for the development of drug-induced ILD. An additional multivariate logistic regression analysis revealed that limited residual normal lung was a significant risk factor for the development of poor-prognosis (fatal) drug-induced ILD. Conclusion Pre-existing ILD and the amount of residual normal lung (≤ 50%) were identified as risk factors for the development of drug-induced ILD. The amount of residual normal lung (≤ 50%) was identified as a risk factor for the development of poor-prognosis (fatal) drug-induced ILD.

Objective: We investigated the incidence and clinical features of drug-induced lung injury during cetuximab therapy in Japanese patients with colorectal cancer in a prospective multicenter registry based on a central registration system. Methods: We investigated and followed up patients with or suspected of having drug-induced lung injury among 2006 patients with cetuximab-treated colorectal cancer. A subcommittee of medical oncologists, pulmonologists and a radiologist evaluated and discussed each case of drug-induced lung injury that occurred during cetuximab therapy. Results: Sixty-six patients were identified and further examinations of drug-induced lung injury were conducted during the registration period. We analyzed time to onset, patient characteristics and factors associated with mortality. Cetuximab-related drug-induced lung injury occurred in 24 (1.2%) patients, and was rated as Grade 3 or worse in 15 (0.7%) patients. Fourteen patients received steroid pulse therapy. Ten patients with drug-induced lung injury died, of whom eight received steroid pulse therapy. The incidence of drug-induced lung injury was significantly higher in elderly patients, and in patients with prior interstitial lung disease. There was no particular trend in the time to onset. Patients with early onset of drug-induced lung injury (within 90 days) after starting cetuximab therapy had higher mortality than patients with later onset (over 90 days). Conclusions: The incidence of drug-induced lung injury in cetuximab-treated patients was 1.2%. Because drug-induced lung injury is potentially serious, it is important to promptly initiate appropriate treatments. Considering that early onset drug-induced lung injury during cetuximab therapy is associated with a poor prognosis, close monitoring is mandatory for these patients.

BackgroundThe different characteristics of usual interstitial pneumonia in patients with primary Sjögren׳s syndrome (UIP/pSS) compared with idiopathic pulmonary fibrosis (UIP/IPF) are not fully understood. This study aimed to compare characteristics, prognosis, and treatment responses in these patients.MethodsAmong 129 consecutive patients who underwent surgical lung biopsy to diagnose diffuse lung diseases at Kanagawa Cardiovascular and Respiratory Center between 1998 and 2002, we identified 10 and 19 patients with UIP/pSS and UIP/IPF, respectively. Baseline characteristics, chest high-resolution computed tomography (HRCT) and pathological findings, and the clinical course were compared between the two groups. Responses to immunosuppressive therapy were analyzed by comparing pulmonary function and clinical status before and one year after treatment initiation.ResultsMore patients in the UIP/pSS group tended to be female and older than those in the UIP/IPF group (mean age, 68 years vs. 62 years). In addition, they more commonly exhibited enlarged mediastinal lymph nodes and bronchial wall thickening on HRCT. Pathologically, in the UIP/pSS group, interstitial inflammation, plasma cell infiltration, lymphoid follicles with germinal centers, cysts, bronchiolitis, and pleuritis were significantly more prominent, whereas smooth muscle hyperplasia and fibroblastic foci were milder (all P

An 80-year-old man underwent right upper lobectomy for the resection of multiple cysts accompanied by a nodule. The pathological diagnosis was adenocarcinoma with surrounding atypical epithelial cell proliferation in a Type 1 congenital cystic adenomatoid malformation/congenital pulmonary airway malformation. There was epidermal growth factor receptor mutation in the adenocarcinoma and surrounding atypical epithelial cells that had proliferated. Malignant transformation of congenital cystic adenomatoid malformation/congenital pulmonary airway malformation may be related to the epidermal growth factor receptor pathway in this case, with atypical epithelial cell proliferation as a precursor. We emphasize the importance of complete resection of congenital cystic adenomatoid malformation/congenital pulmonary airway malformation and the possibility of treatment with epidermal growth factor receptor tyrosine kinase inhibitors in epidermal growth factor receptor-mutated cases.

Bronchiolitis obliterans syndrome (BOS) is a rare pulmonary complication of hematopoietic stem cell transplantation (HSCT) with high mortality. Chronic bacterial airway infection (CAI) causes exacerbation and progression of several airway diseases, and bacterial airway colonization was shown to be associated with BOS after lung transplantation. We assessed the association between CAI and clinical course in patients with BOS after HSCT. This retrospective study included 910 patients undergoing allogeneic HSCT between 2005 and 2013 at our institution. BOS diagnosis was reevaluated according to the 2014 US National Institutes of Health criteria. Sputum and bronchial lavage culture results, pulmonary function, and survival were compared between patients with and without CAI. Median follow-up was 974.5 (261.5–2748.5) days. BOS was diagnosed in 27 (3.0%) patients, including 18 males. Median age at BOS diagnosis was 45 (40.5–58) years. Nine patients had ≥2 positive sputum cultures for bacteria or one positive bronchial lavage culture for nontuberculous mycobacteria (CAI+), whereas 9 patients had negative sputum/bronchial lavage culture or only one positive sputum culture (CAI−). Median change in forced expiratory volume in 1 s within 6 months after BOS diagnosis and overall survival were significantly worse in CAI+ patients than in CAI− patients (−250 vs +260 mL, P = .002, and 1340 days vs not reached, P = .04, respectively). No other factors including patient demographics or transplant protocol affected prognosis. There were no differences in clinical characteristics of patients with and without CAI, except for the time from transplantation to BOS diagnosis (214 vs 768 days for CAI+ and CAI−, respectively; P = .02). CAI was associated with worse outcomes in patients with BOS after HSCT. Further prospective studies should assess the association between the airway microbiome and changes in pulmonary function after HSCT to improve prognosis.