Nationwide survey in Japan of the causative diseases of bloody sputum and hemoptysis in departments of respiratory medicine at university hospitals and core hospitals.

BACKGROUND: The Guidelines for the Management of Cough and Sputum (2019) of the Japanese Respiratory Society (JRS) were the first internationally published guidelines for the management of sputum. However, the data used to determine the causative diseases of bloody sputum and hemoptysis in these guidelines were not obtained in Japan. METHODS: A retrospective analysis was performed using the clinical information of patients with bloody sputum or hemoptysis who visited the department of respiratory medicine at a university or core hospital in Japan. RESULTS: Included in the study were 556 patients (median age, 73 years; age range, 21-98 years; 302 males (54.3%)). The main causative diseases were bronchiectasis (102 patients (18.3%)), lung cancer (97 patients (17.4%)), and non-tuberculous mycobacterial disease (89 patients (16%)). Sex and age differences were observed in the frequency of causative diseases of bloody sputum and hemoptysis. The most common cause was lung cancer in males (26%), bronchiectasis in females (29%), lung cancer in patients aged <65 years (19%), and bronchiectasis in those aged >65 years (20%). CONCLUSIONS: The present study is the first to investigate the causative diseases of bloody sputum and hemoptysis using data obtained in Japan. When investigating the causative diseases of bloody sputum and hemoptysis, it is important to take the sex and age of the patients into account.

LAG3 is an independent prognostic biomarker and potential target for immune checkpoint inhibitors in malignant pleural mesothelioma: a retrospective study.

BACKGROUND: Lymphocyte-activation gene 3 (LAG3) is an immune checkpoint receptor; novel LAG3 immune checkpoint inhibitors (ICIs) exhibit therapeutic activity in melanoma. The role of LAG3and ICIs of LAG3 are unknown in malignant pleural mesothelioma (MPM). This study aimed to uncover the prognostic landscape of LAG3 in multiple cancers and investigate the potential of using LAG3 as an ICIs target in patients with MPM. METHODS: We used The Cancer Genome Atlas (TCGA) cohort for assessing mRNA expression and our cohort for immunohistochemical expression. TCGA cohort were analyzed using the Wilcoxon rank-sum test to compare mRNA expression between normal and tumor tissues in multiple cancers. We used 86 MPM cases from TCGA and 38 MPM cases from our cohort to analyze the expression of LAG3 in tumor-infiltrating lymphocytes. The mean LAG3 mRNA expression was set as the cut-off and samples were classified as positive/negative for immunohistochemical expression. Overall survival (OS) of patients with MPM was determined using the Kaplan-Meier method based on LAG3 mRNA and immunohistochemical expression. OS analysis was performed using the multivariate Cox proportional hazards model. The correlation of LAG3 expression and mRNA expression of tumor immune infiltration cells (TIICs) gene markers were estimated using Spearman correlation. To identify factors affecting the correlation of LAG3 mRNA expression, a multivariate linear regression model was performed. RESULTS: LAG3 mRNA was associated with prognosis in multiple cancers. Elevated LAG3 mRNA expression was correlated with a better prognosis in MPM. LAG3 expression was detected immunohistochemically in the membrane of infiltrating lymphocytes in MPM. LAG3 immunohistochemical expression was correlated with a better prognosis in MPM. The multivariate Cox proportional hazards model revealed that elevated LAG3 immunohistochemical expression indicated a better prognosis. In addition, LAG3 mRNA expression was correlated with the expression of various gene markers of TIICs, the most relevant to programmed cell death 1 (PD-1) with the multivariate linear regression model in MPM. CONCLUSIONS: LAG3 expression was correlated with prognosis in multiple cancers, particularly MPM; LAG3 is an independent prognostic biomarker of MPM. LAG3 regulates cancer immunity and is a potential target for ICIs therapy. PD-1 and LAG3 inhibitors may contribute to a better prognosis in MPM. TRIAL REGISTRATION: This study was registered with UMIN000049240 (registration day: August 19, 2022) and approved by the Institutional Review Board (approval date: August 22, 2022; approval number: 2022-0048) at Tokyo Women's Medical University.

Analysis of the diagnosis of Japanese patients with primary ciliary dyskinesia using a conditional reprogramming culture.

BACKGROUND: Primary ciliary dyskinesia (PCD) is diagnosed through multiple methods, including transmission electron microscopy (TEM), a high-speed video microscopy analysis (HSVA), immunofluorescence (IF), and genetic testing. A primary cell culture has been recommended to avoid the misdiagnosis of secondary ciliary dyskinesia derived from infection or inflammation and improve diagnostic accuracy. However, primary cells fail to differentiate into ciliated cells through repeated passages. The conditional reprogramming culture (CRC) method, a combination of a Rho-kinase inhibitor and fibroblast feeder cells, has been applied to cystic fibrosis. The goal of this study was to evaluate the value of CRC in diagnosing PCD in Japanese patients. METHODS: Eleven patients clinically suspected of having PCD were included. Airway epithelial cells were obtained from an endobronchial forceps biopsy and cultured at the air-liquid interface (ALI) combined with CRC. Ciliary movement, ultrastructure, and mutated ciliary protein evaluation were performed using HSVA, TEM, and IF, respectively. Genetic testing was performed on some patients. RESULTS: CRC yielded dense and well-differentiated ciliated cells with a high success rate (∼90%). In patients with PCD, the ciliary ultrastructure phenotype (outer dynein arm defects or normal ultrastructure) and IF findings (absence of the mutated ciliary protein) were confirmed after CRC. In DNAH11-mutant cases with normal ultrastructure by TEM, the HSVA revealed stiff and hyperfrequent ciliary beating with low bending capacity in CRC-expanded cells, thereby supporting the diagnosis. CONCLUSIONS: CRC could be a potential tool for improving diagnostic accuracy and contributing to future clinical and basic research in PCD.

A surgical case of lung cancer with poor general status associated with parathyroid hormone-related protein.

Parathyroid hormone-related protein (PTHrP), which is released in the presence of malignant disease, is associated with hypercalcemia. Complete resection of the tumor in such patients is rarely performed because of their poor general condition. We herein report a case of lung cancer associated with PTHrP in a patient whose condition dramatically improved after surgery. We also review the literature on the benefits of various surgical options. Although only a few cases of complete resection in such patients have been reported, the mental and physical condition of the patients improved postoperatively and the median survival time was longer than 12 months. A poor general status is frequently considered a contraindication for surgery, even in a palliative setting; however, we conclude that resection of lung cancer may lead to improved symptom control and survival when the patient's condition is induced by hypercalcemia secondary to PTHrP secretion from the tumor.

CT assessment of axillary lymphadenopathy in patients with rheumatoid arthritis: association with disease activity and severity.

BACKGROUND: 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. OBJECTIVE: 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. METHODS: 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. RESULTS: 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. CONCLUSION: AL in patients with RA was correlated with local arthritis activity, as well as background characteristics and systemic disease activity.

Real-world practice patterns for patients with advanced non-small cell lung cancer: multicenter retrospective cohort study in Japan.

BACKGROUND: Recommended therapies for advanced/metastatic non-small cell lung cancer (NSCLC) have changed with the advent of targeted therapies. The objectives of this retrospective chart review study were to describe treatment patterns, biomarker testing practices, and health care resource use for advanced NSCLC at 5 sites in Japan. PATIENTS AND METHODS: We studied anonymized medical record data of patients aged ≥18 years who initiated systemic therapy for newly diagnosed stage IIIB or IV NSCLC from January 2011 through June 2013. Data were analyzed descriptively by histology and mutation status. Overall survival was estimated using the Kaplan-Meier method. RESULTS: We studied 175 patients, including 43 (25%), 129 (74%), and 3 (2%) with squamous, nonsquamous, and unknown NSCLC histology, respectively; 83% had stage IV NSCLC. Overall, 123 patients (70%) were male; the median age was 70 years (range, 47-86); and 33 (19%) were never-smokers. In the nonsquamous cohort, 105 (81%) and 25 (19%) of patients were tested for epidermal growth factor receptor (EGFR) mutation and anaplastic lymphoma kinase (ALK) rearrangement, respectively; 44 (42%) had EGFR-positive NSCLC and 2 (8%) had ALK-positive NSCLC, including 26/46 (57%) women and 21/46 (46%) never-smokers. In the squamous cohort, 17 (40%) and 4 (9%), respectively, were tested; 1 EGFR-positive tumor was detected. After first-line therapy, 105 (60%) patients received second-line, and 54/105 (51%; or 31% overall) received third-line therapy. EGFR tyrosine kinase inhibitors were most commonly prescribed for EGFR-positive NSCLC across all lines. In the nonsquamous EGFR/ALK-negative/unknown cohort, most received first-line platinum combinations, particularly younger patients (78% ≥75 years vs 93% <75 years old). The average hospitalization was 21 days/admission. The median (95% CI) overall survival from start of first-line therapy was 9.9 months (7.6-11.7) for all patients and 17.9 months (9.9-24.4) for patients with EGFR/ALK-positive status. CONCLUSION: Biomarker testing is common for nonsquamous NSCLC at the 5 Japanese study sites. Treatment is personalized by mutation status and age, per guideline recommendations.

The efficacy of transbronchial needle aspiration with endobronchial ultrasonography using a guide sheath for peripheral pulmonary lesions suspected to be lung cancer.

BACKGROUND: The efficacy of transbronchial needle aspiration (TBNA) with endobronchial ultrasonography using a guide sheath (EBUS-GS) for cases of peripheral pulmonary lesions (PPLs) has not been well established. The purpose of this study was to evaluate the efficacy of TBNA with EBUS-GS for PPLs. METHODS: We evaluated 130 patients suspected to have lung cancer who underwent transbronchial brushing (brushing), transbronchial biopsy (TBB), and TBNA with EBUS-GS. The pathological diagnostic yields of TBNA were compared to that of TBB and brushing. The histological diagnosis of TBNA was compared to that of surgical specimens. The results of epidermal growth factor receptor (EGFR) gene mutation in TBNA samples were compared to that in TBB or surgical specimens. RESULTS: The diagnostic yields of this study were 62.9% for brushing, 80.0% for TBB, and 77.1% for TBNA. Histological diagnosis was 84.8% for TBB and/or TBNA and pathological diagnosis was 86.7% for all the procedures. TBB and TBNA had significance higher than brushing (p < 0.05). TBB and TBNA had a tendency of higher diagnostic yields than brushing if EBUS probe was adjacent to PPLs (p = 0.058). Histological evaluations were obtained from TBNA specimens from 50 of 105 patients (47.6%) and these were identical to those of surgical specimens from 29 of 32 patients (90.6%). The results of EGFR gene mutation in TBNA specimens were identical to the same tissue obtained by surgery or TBB. CONCLUSIONS: TBNA with EBUS-GS for PPLs was a useful tool for accurate diagnosis and EGFR gene mutation analysis. This method may improve diagnostic accuracy and be useful for molecular testing. This study was approved by the institutional review board (Date of approval: May 27, 2013, approval number: 2816) of Tokyo Women's Medical University Hospital.

Intravenous Immunoglobulin Monotherapy for Granulomatous Lymphocytic Interstitial Lung Disease in Common Variable Immunodeficiency.

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.

Rosai-Dorfman Disease of the Lung Overlapping with IgG4-related Disease: The Difficulty in Its Differential Diagnosis.

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.

Effectiveness of Combined Therapy with Pirfenidone and Erythromycin for Unclassifiable Interstitial Pneumonia Induced by HTLV-1-associated Bronchioloalveolar Disorder (HABA).

Human T-cell lymphotropic virus type 1 (HTLV-1) is a retrovirus involved in the pathogenesis of adult T-cell leukemia (ATL) and HTVL-1-associated bronchioloalveolar disorder (HABA). The clinical and pathological findings of HABA have been characterized as either a diffuse panbronchiolitis (DPB) pattern or idiopathic interstitial pneumonia (IIP) pattern. Treatments for HABA include corticosteroids for the IIP pattern and erythromycin for the DPB pattern. We herein report a case of HABA-associated unclassifiable interstitial pneumonia that improved with combined therapy with pirfenidone and erythromycin. This is the first report on the effectiveness of combined therapy with pirfenidone and erythromycin for HABA.

FISH analysis of intrapulmonary malignant mesothelioma without a clinically detectable primary pleural lesion: an autopsy case.

Patients with malignant mesothelioma typically present with a pleural effusion or pleural thickening and masses. A rare autopsy case of mesothelioma presenting with multiple bilateral lung nodules without clinically detectable pleural lesions is presented. A definitive diagnosis of the video-assisted thoracic surgery specimen could not be made, though a pattern of fibrosis mimicking organizing pneumonia was identified. Despite corticosteroid therapy, follow-up chest computed tomography showed enlargement of multiple nodules accompanied by the appearance of pleural thickening and effusions. The patient died of respiratory failure 11 months after initial presentation. Autopsy and retrospective analysis of the video-assisted thoracic surgery specimen using a p16 fluorescence in situ hybridization assay showed p16 homozygous deletion. The final diagnosis was sarcomatoid mesothelioma, and the lung nodules were intrapulmonary metastases from a clinically undetectable pleural sarcomatoid mesothelioma. It is important both to consider the possibility of mesothelioma with unusual clinical, radiological and pathological presentations and to remember that p16 fluorescence in situ hybridization analysis can play an important role in the diagnosis of mesothelioma.

EGFR mutation of adenocarcinoma in congenital cystic adenomatoid malformation/congenital pulmonary airway malformation: a case report.

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.

Early detection of COPD is important for lung cancer surveillance.

It is well known that chronic obstructive pulmonary disease (COPD) is a significant risk factor for lung cancer. Approximately 1% of COPD patients develop lung cancer every year, which may be associated with genetic susceptibility to cigarette smoke. Chronic inflammation caused by toxic gases can induce COPD and lung cancer. Inflammatory mediators may promote the growth of bronchioalveolar stem cells, and activation of nuclear factor-κB and signal transducer and activator of transcription 3 play crucial roles in the development of lung cancer from COPD. Low-dose computed tomography (LDCT) is an effective procedure for the early detection of lung cancer in high-risk patients. However, determining which patients should be screened for lung cancer in a primary care setting is difficult. In this article, we review the epidemiology and aetiology of lung cancer associated with COPD, verify the efficacy of lung cancer screening by LDCT, and discuss the importance of early detection of COPD for lung cancer surveillance. We propose that, for the prevention of both diseases, COPD screening in smokers should be initiated as early as possible, so they can stop smoking and so that candidates for an efficient lung cancer screening programme can be identified.

[Pulmonary rehabilitation: exercise training, nutritional intervention and patient education].

The optimal care of patients with COPD generally requires combining pharmacologic and non pharmacologic therapies and the latter provides as pulmonary rehabilitation. Pulmonary rehabilitation, which includes exercise training, patient education, psychosocial support, nutritional intervention, and outcome assessments. Pulmonary rehabilitation has demonstrated effectiveness over multiple outcome areas such as dyspnea, exercise capacity, and health-related quality of life compared with other interventions such as pharmacologic therapy. However, it is not enough access for pulmonary rehabilitation, so effort should be made for easy access of this effective medical care.

Endobronchial hamartoma with obstructive pneumonia due to Nocardia asiatica.

A 60-year-old man who had diabetes had a history of hospitalization for pneumonia in the right lower lobe at the age of 57 years. He visited our facility complaining of fever and cough. He was admitted owing to pneumonia in the right lung. Computed tomography and bronchoscopy performed after admission revealed a tumor in the right basal bronchus. Nocardia asiatica was detected in a sputum culture. Complete resection of the bronchial tumor could not be achieved with a high-frequency snare, although the patient was preoperatively diagnosed as having hamartoma. The patient subsequently underwent resection of the right lower lobe due to his deteriorated clinical condition. The postoperative course was favorable, and there has been no recurrence of nocardiosis or bronchial hamartoma for 3 years.

[Sustainable efficacy of oral varenicline for smoking cessation].

Varenicline (Champix) is an alpha4beta2 nicotinic receptor antagonist that is used orally for treatment of nicotine dependence. We conducted a study to examine the sustainable efficacy of varenicline in smoking cessation. The subjects were 148 outpatients (113 men, 35 women; average age; 54.4 +/- 14.0 years) at 6 different hospitals, and their adverse events were monitored in each hospital. The 4-week continuous abstinence rates of smoking cessation were 17.6%, 75.0%, and 84.6% in groups treated for 4 or fewer weeks, 5 to 8 weeks, and 9 to 12 weeks, respectively, with the rate showing a significant increase according to treatment period. Among 83 patients who had adverse events, the abstinence rates were 76.9%, 92.3%, 54.5%, and 55.6% in an observed (OB) group, a nosotropic medication (NM) group, a dose-reduction (RD) group, and a drug-discontinuation (DC) group, respectively. Among 56 patients with nausea, the respective rates were 80.8%, 100.0%, 61.1%, and 50.0%, respectively, with a significantly higher success rate in the NM group than in the RD or DC groups (each p < 0.05). To sustain the efficacy of varenicline in patients with adverse events, we recommend a therapeutic strategy in which the active nosotropic medicine is administered over 12 weeks at the regular dosage.

[End of life care for patients with COPD].

Chronic obstructive pulmonary disease(COPD) is a common cause of morbidity and mortality. It currently fourth leading cause of death in world wide and importance for end of life care for end-stage patients with COPD is increasing. Patients with COPD experience acute exacerbation once disease progressed. Once patients with COPD admitted to the hospital by acute exacerbation, prognosis of these patients is poor and these patients should be considered as an end-stage COPD. When compared with advanced lung cancer patients, patients with COPD have more deterioration of quality of life, more symptoms such as despnea, general fatigue, appetiteloss, anxiety, and deterioration of activities of daily living. However, these patients with COPD are more treated with life sustained interventions, palliation for these symptoms are not sufficients. In caring patients with severe COPD, consideration should be given to implementing palliative treatments more aggressively. In order to improve end of life care for patients with advanced COPD, it is also important to establish local support system for caring these patients.

A clinical study of idiopathic pulmonary fibrosis based on autopsy studies in elderly patients.

OBJECTIVES: The prevalence of idiopathic pulmonary fibrosis (IPF) tends to be greater in the elderly although the precise outcome is not known. The present study investigated the outcome of IPF in elderly patients whose pathological diagnosis corresponded to usual interstitial pneumonia (UIP) on autopsy findings. METHODS: In a consecutive autopsy series, (n = 4,554 cases), complete information was obtained in 86 cases in which the clinical and pathological diagnosis was IPF and UIP, respectively. RESULTS: Mean subject age was 80.5 years and there were 52 males and 34 females. Median survival time (MST) was 3.5 years overall. Dyspnea ranking by the MRC dyspnea scale (DR) on admission was closely related to the outcome. When MST was compared between DR0 and DR1, or DR2 and DR3, the former patient group survived significantly longer than the latter (p < 0.05). Twenty percent of patients died of severe respiratory failure. Other causes of death were disease progression of IPF (10.5%), bacterial pneumonia (23.3%) and lung cancer (17.4%). The patients in the young-elderly group (age < 75) survived for a significantly longer period than those in the old-elderly group (age > or = 75) (MST; 5.5 vs 2.0 years; p < 0.001). Both lung cancer and pneumonia were significantly more prevalent among IPF patients than among non-IPF patients; these IPF with lung cancer profoundly reflected the smoking history of IPF patients. CONCLUSIONS: The poor outcome in IPF in elderly patients was characterized by more severe dyspnea, advanced age and co-morbidity.

[A case of infected bulla caused by Mycobacterium gordonae].

A 65-year-old man was admitted to Tokyo Metropolitan Geriatric Medical Center because of dyspnea on effort, loss of appetite and general fatigue. Chest radiography on admission showed niveau formation in, and infiltration around, the bulla. Percutaneous drainage of the intrabullous fluid was performed and Mycobacterium gordonae was repeatedly cultured from it. The patient was treated with RFP, INH and CAM and the intrabullous fluid and infiltration around the bulla was markedly improved. Seven cases of pulmonary infection by M. gordonae have been reported in Japan, but this is the first case of bulla infected by this organism.