Plasma sE-cadherin and the plasma sE-cadherin/sVE-cadherin ratio are potential biomarkers for chronic obstructive pulmonary disease.

BACKGROUND: Chronic obstructive pulmonary disease (COPD) is characterized by airway inflammation with endothelial dysfunction. Cadherins are adhesion molecules on epithelial (E-) and vascular endothelial (VE-) cells. Soluble (s) cadherin is released from the cell surface by the effects of proteases including matrix metalloproteinases (MMPs). OBJECTIVE: The aim of this study was to examine the associations of sE-/sVE-cadherin levels in plasma with the development of COPD. METHODS: Plasma sE-/VE-cadherin levels were measured by an enzyme-linked immunosorbent assay in 115 patients with COPD, 36 symptomatic smokers (SS), 63 healthy smokers (HS) and 78 healthy non-smokers (HN). sE-cadherin and MMP-7 levels in epithelial lining fluid (ELF) were measured in 24 patients (12 COPD and 12 control). RESULTS: Plasma sE-cadherin levels and sE-cadherin/sVE-cadherin ratios were significantly higher in COPD and SS than in HS and HN groups, while plasma sVE-cadherin levels were lower in COPD than in HS and HN groups (p < 0.0001). sE-cadherin levels paralleled the severity of airflow limitation in both plasma (p < 0.01) and ELF (p < 0.05), while plasma sVE-cadherin levels were inversely correlated with the extent of emphysema (p < 0.05). MMP-7 levels were correlated with sE-cadherin levels in ELF. CONCLUSIONS: Plasma sE-cadherin levels and sE-cadherin/sVE-cadherin ratios are potential biomarkers for COPD.

Analysis of comorbid factors that increase the COPD assessment test scores.

BACKGROUND: The chronic obstructive pulmonary disease (COPD) Assessment Test (CAT) is a concise health status measure for COPD. COPD patients have a variety of comorbidities, but little is known about their impact on quality of life. This study was designed to investigate comorbid factors that may contribute to high CAT scores. METHODS: An observational study at Keio University and affiliated hospitals enrolled 336 COPD patients and 67 non-COPD subjects. Health status was assessed by the CAT, the St. Georges Respiratory Questionnaire (SGRQ), and all components of the Medical Outcomes Study Short-Form 36-Item (SF-36) version 2, which is a generic measure of health. Comorbidities were identified based on patients' reports, physicians' records, and questionnaires, including the Frequency Scale for the Symptoms of Gastro-esophageal reflux disease (GERD) and the Hospital Anxiety and Depression Scale. Dual X-ray absorptiometry measurements of bone mineral density were performed. RESULTS: The CAT showed moderate-good correlations with the SGRQ and all components of the SF-36. The presence of GERD, depression, arrhythmia, and anxiety was significantly associated with a high CAT score in the COPD patients. CONCLUSIONS: Symptomatic COPD patients have a high prevalence of comorbidities. A high CAT score should alert the clinician to a higher likelihood of certain comorbidities such as GERD and depression, because these diseases may co-exist unrecognized. TRIAL REGISTRATION: Clinical trial registered with UMIN (UMIN000003470).

Plasma cytokine profiles related to smoking-sensitivity and phenotypes of chronic obstructive pulmonary disease.

Chronic obstructive pulmonary disease (COPD) develops only in smoking-sensitive smokers and manifests heterogeneous phenotypes, including emphysema and non-emphysema types. We aimed to identify biomarkers related to the smoking-sensitivity and phenotypes of COPD. Among 240 smokers suggestive of COPD, we studied on four groups defined by % forced expiratory volume in one second (FEV1) and computed tomography-based pulmonary emphysema. Plasma concentrations of 33 inflammatory markers were measured in four groups as well as Non-smokers using multiplex protein arrays. IL-5, IL-7 and IL-13 were identified to be associated with smoking sensitivity and IL-6 and IL-10 were candidate biomarkers for airway-lesion dominant COPD.

Cluster analysis of long COVID in Japan and association of its trajectory of symptoms and quality of life.

BACKGROUND: Multiple prolonged symptoms observed in patients who recovered from COVID-19 are defined as long COVID. Although diverse phenotypic combinations are possible, they remain unclear. This study aimed to perform a cluster analysis of long COVID in Japan and clarify the association between its characteristics and background factors and quality of life (QOL). METHODS: This multicentre prospective cohort study collected various symptoms and QOL after COVID-19 from January 2020 to February 2021. This study included 935 patients aged ≥18 years with COVID-19 at 26 participating medical facilities. Hierarchical cluster analysis was performed using 24 long COVID symptom at 3 months after diagnosis. RESULTS: Participants were divided into the following five clusters: numerous symptoms across multiple organs (cluster 1, n=54); no or minor symptoms (cluster 2, n=546); taste and olfactory disorders (cluster 3, n=76); fatigue, psychoneurotic symptoms and dyspnoea (low prevalence of cough and sputum) (cluster 4, n=207) and fatigue and dyspnoea (high prevalence of cough and sputum) (cluster 5, n=52). Cluster 1 included elderly patients with severe symptoms, while cluster 3 included young female with mild symptoms. No significant differences were observed in the comorbidities. Cluster 1 showed the most impaired QOL, followed by clusters 4 and 5; these changes as well as the composition of symptoms were observed over 1 year. CONCLUSIONS: We identified patients with long COVID with diverse characteristics into five clusters. Future analysis of these different pathologies could result in individualised treatment of long COVID. TRIAL REGISTRATION NUMBER: The study protocol is registered at UMIN clinical trials registry (UMIN000042299).

Long-term Findings in Bullous Sarcoidosis: A Case Report and Literature Review.

Pulmonary sarcoidosis may occasionally present with large bullae, but the clinical implications of this finding remain unclear. We herein report the complete clinical course of a case of pulmonary bullous sarcoidosis. Chest computed tomography initially showed subpleural and peribronchovascular lung opacities, and bullae spontaneously developed in adjacent less-affected regions, probably via a retraction mechanism. Bullae progression was refractory to corticosteroid treatment and associated with deterioration of respiratory symptoms. The later phase involved repeated bacterial and fungal infections of the bullous lungs, eventually causing respiratory failure and mortality. Postmortem examinations revealed aggressive pulmonary Mycobacterium avium infection and diffuse alveolar damage.

Mesenchymal-epithelial transition Exon 14-Skipping Mutation-positive Invasive Mucinous Adenocarcinoma of the Lung: First Case Treated with Mesenchymal-epithelial Transition-tyrosine Kinase Inhibitors.

Mesenchymal-epithelial transition (MET) exon 14-skipping mutation (METex14) is rare in pulmonary invasive mucinous adenocarcinomas (IMAs), and the clinical impact of MET-tyrosine kinase inhibitors (TKIs) remains unknown. We herein report a 75-year-old woman with IMA harboring METex14 who was treated with the MET-TKI tepotinib. The lung tumor regressed over six months; however, the patient ultimately died of exacerbated interstitial lung disease (ILD), possibly associated with tepotinib. An autopsy revealed diffuse alveolar damage in preexisting chronic fibrosis. We discuss how to pre-evaluate ILD deterioration risks and monitor TKI-induced lung toxicity during treatment.

Spindle cell carcinoma with cystic brain metastasis: Successful treatment with stereotactic radiotherapy and anti­programmed cell death­1 antibodies: A case report.

Cystic brain metastasis is a rare condition that mainly originates from lung or breast adenocarcinomas. By contrast, pulmonary spindle cell carcinoma, a rare type of non-small cell carcinoma, has not been reported with this condition. Cystic brain metastases are characterized by larger tumor sizes with increased peritumoral edema compared with solid metastases. Therefore, specific treatment strategies are required for intracranial disease control. Immunotherapy has recently been demonstrated to be crucial for treating pulmonary sarcomatoid carcinomas based on high programmed cell death-ligand 1 (PD-L1) expression observed in these cancers. The present report describes the case of an 82-year-old man diagnosed with pulmonary spindle cell carcinoma, a rare subtype of sarcomatoid carcinoma. At 7 months after the diagnosis, the patient complained of a walking disturbance for which de novo brain metastasis with peritumoral edema was the causative agent. The brain tumor had a large cystic component, and thus, an Ommaya reservoir catheter was implanted for cyst aspiration but collapsed early without sufficient volume reduction. The patient was transferred to receive twice-split gamma knife treatment, which shrank the solid compartment and reduced the cyst volume, thereby relieving neurological defects. The patient was subsequently treated with immunotherapy targeting programmed cell death-1 based on the high PD-L1 expression in the lung tumor specimen. The thoracic tumors regressed following immunotherapy and progression-free survival was maintained for 16 months. To the best of our knowledge, the present report provides the first description of focal and systemic therapies for pulmonary spindle cell carcinoma with cystic brain metastasis. The report also discusses the treatment strategies for cystic brain metastases and reviews cases of pulmonary spindle cell carcinoma treated with immune checkpoint inhibitors.

Dysautonomia associated with immune checkpoint inhibitors.

OBJECTIVE: The purpose of this study is to report the clinical characteristics of dysautonomia associated with immune checkpoint inhibitors (ICIs). METHODS: We reported two patients with autoimmune autonomic ganglionopathy (AAG) occurring as immune-related adverse events (irAEs). We also performed a review of previous case reports presenting dysautonomia during ICI therapy. Moreover, we conducted pharmacovigilance analyses using the US Food and Drug Administration Adverse Events Reporting System (FAERS) to investigate dysautonomia associated with ICI. RESULTS: Two patients in our care developed both AAG and autoimmune encephalitis following ICI therapy for lung cancers. We comprehensively reviewed 13 published cases (M:F = 11:2, mean onset age of 53 years) with ICI-associated dysautonomia including AAG (n = 3) and autonomic neuropathy (n = 10). Of these, ICI monotherapy was performed in seven and combination ICI use in six. In 6 of 13 patients, dysautonomia appeared within one month after the start of ICIs. Orthostatic hypotension was observed in 7 and urinary incontinence or retention in five. All patients except three showed gastrointestinal symptoms. Anti-ganglionic acetylcholine receptor antibodies were undetectable. All but two patients received immune-modulating therapy. Immuno-modulating therapy was effective in three patients with AAG and two patients with autonomic neuropathy, but ineffective in the others. Five patients died, of either the neurological irAE (n = 3) or cancer (n = 2). The pharmacovigilance analyses using FAERS showed that ipilimumab monotherapy and the combination of nivolumab and ipilimumab constituted significant risks for developing dysautonomia, consistent with the review of literature. CONCLUSION: ICIs can cause dysautonomia including AAG, and autonomic neuropathy is a neurological irAE.

Pulmonary Mycobacterium kyorinense infection secondary to cavitary pulmonary tuberculosis.

Mycobacterium kyorinense (M. kyorinense) was first reported in patients with pulmonary infection or lymphadenitis in 2009. To date, fewer than 20 cases of pulmonary or extra-pulmonary infections have been reported with the bacterium, and the clinical features remain unclear. We report a case of pulmonary M. kyorinense infection in a 45-year-old man who had a history of cavitary pulmonary tuberculosis seven years ago. The patient visited a hospital due to hemosputum and a prolonged productive cough. Chest computed tomography revealed large and thick-walled cavities, with surrounding parenchymal infiltration in the right upper and lower lung lobes. The microbiological diagnosis of M. kyorinense was based on positive culture results from multiple respiratory tract specimens. The patient's treatment started with antimycobacterial medicines, clarithromycin, moxifloxacin, and intravenous amikacin, in accordance with the drug susceptibility profile and previous case reports. The treatment stabilized the patient's symptoms and improved the thoracic imaging. In addition, the sputum culture was negative after the treatment. We reviewed the literature and summarized the clinical features of M. kyorinense infection in 18 patients. All patients with extrapulmonary infections were immunocompromised. In contrast, pulmonary infection occurred in immunocompetent patients who often had a predisposing lung disease. Cavitary lesions were observed at diagnosis only in patients with prior cystic or cavitary lung disease, including pulmonary tuberculosis. This study contributes to the body of case knowledge of M. kyorinense infection and summarizes the clinical features in the literature.

Heart Failure With Reduced Ejection Fraction Caused by Osimertinib in a Patient With Lung Cancer: A Case Report and Literature Review.

Osimertinib is widely used for the treatment of advanced lung cancers harboring epidermal growth factor receptor (EGFR) mutations. Because of its inhibitory activity on the human epidermal growth factor receptor 2 pathway, osimertinib-induced cardiotoxicity is concerning. Large-scale international clinical studies revealed a subclinical decline in the left ventricular ejection fraction (LVEF) with osimertinib, which allowed a continuation of the drug. Only a few studies have reported symptomatic heart failure with reduced ejection fraction (HFrEF) with osimertinib, and its clinical impact in real-world settings remains unclear. A 91-year-old man was diagnosed with lung adenocarcinoma harboring an EGFR L858R mutation and was started on osimertinib. The treatment conferred substantial tumor regression; however, the patient presented with symptomatic HFrEF six weeks after osimertinib initiation. Transthoracic echocardiography demonstrated diffuse hypokinesis of the left ventricular walls with a significantly reduced ejection fraction from the baseline. Initial evaluation showed no causative cause of heart failure, and we suspected osimertinib-associated cardiomyopathy. Discontinuation of the drug along with the cardioprotective approach improved cardiac symptoms and restored the LVEF to baseline within a week. Here, we comprehensively review the literature and discuss the clinical features of HFrEF following osimertinib administration. Physicians should be aware of rare complications associated with osimertinib therapy.

Pneumothorax as a rare presentation of bronchial schwannoma.

Tracheobronchial schwannomas are rare diseases. Common signs and symptoms of this tumor include cough, wheezing, and dyspnea. In contrast, pneumothorax is an exceptional presentation. This study reports the first case of bronchial schwannoma presenting with pneumothorax. A 79-year-old woman was diagnosed with pneumothorax by chest radiography. Chest computed tomography unexpectedly revealed a tumor occluding the right main bronchus. Following the pathological diagnosis of bronchial schwannoma, the patient underwent thoracoscopic tumor enucleation. The airway lumens are consequently secured postoperatively. We reviewed the literature and discussed the mechanisms and treatment options for bronchial benign tumor-associated pneumothorax. Pneumothorax should be aware of a rare presentation of non-malignant tracheobronchial tumors.

Most Important Things and Associated Factors With Prioritizing Daily Life in Patients With Advanced Lung Cancer.

PURPOSE: Patients' values and priorities in their lives should be appreciated from an early phase of incurable diseases such as advanced cancer. However, studies examining these characteristics have been lacking. This study attempted to determine what patients with advanced lung cancer valued most, once they had been diagnosed, and any associated factors. METHODS: Patients with newly diagnosed advanced lung cancer (N = 248) were enrolled in a questionnaire survey conducted at 16 hospitals in Japan. Their priorities were assessed using a free-text response to the question what is the most important thing to you now? at the time of diagnosis and 3 months after diagnosis. The free-text responses were classified into 10 categories for quantification. The clinical characteristics associated with the category describing daily life were further examined. RESULTS: Free-text comments were obtained from 103 (44.0%) and 66 (42.6%) patients at the time of diagnosis and at 3 months, respectively. The most frequent categories were family (at diagnosis: 50.5%; at 3 months: 50.0%) and daily life (at diagnosis: 33.0%; at 3 months: 36.4%), followed by health (at diagnosis: 32.0%; at 3 months: 27.3%) at both time points. The patients mentioning daily life, the issues related to how to spend daily life, showed significantly higher total scores and functional well-being subscale scores on the Functional Assessment of Cancer Therapy-Lung scale at both time points and lower depression scores at diagnosis and lower anxiety scores at 3 months on the Hospital Anxiety and Depression Scale. CONCLUSION: Family and daily life were highly valued by patients with advanced lung cancer at diagnosis. A better quality of life and better mood were associated with mentioning daily life, which should be taken into account in care planning to maintain patients' involvement in daily life even with incurable diseases.

Cigarette smoke inhibits engulfment of apoptotic cells by macrophages through inhibition of actin rearrangement.

Exposure to cigarette smoke (CS) was shown to impair the capacity of macrophages to clear bacteria and apoptotic cells. Here, we show that both the exposure of macrophages to cigarette smoke extract (CSE) in vitro and an acute single exposure to CS in vivo impair the macrophage clearance of apoptotic polymorphonuclear leukocytes (PMNs). Upon longer periods of exposure to smoke in vivo (4-12 weeks), the impaired capacity of macrophages to clear apoptotic cells persisted after the cessation of smoking, with slow recovery to normality observed 4 weeks later. With respect to the mechanism by which CS impairs the macrophage uptake of apoptotic PMNs, we did not detect altered surface expression of receptors associated with apoptotic cell clearance. We did observe the impaired phosphorylation of the guanine nucleotide exchange factor Vav1 and the downstream inhibition of Ras-related C3 botulinum toxin substrate 1 (Rac1) activation. Consistent with these findings, CS impaired the macrophage cytoskeletal changes observed after stimulation with apoptotic cells. A loss of actin occurred at the leading edge, manifested as impaired ruffling of the cell membrane and a decreased capacity to engulf apoptotic cells. The inability to clear PMNs would lead to a greater release of destructive PMN products, and would diminish the reparative phenotype induced by the macrophage clearance of apoptotic cells.

Comprehensive and long-term surveys of COVID-19 sequelae in Japan, an ambidirectional multicentre cohort study: study protocol.

INTRODUCTION: The rapid spread of COVID-19 posed a global burden. Substantial number of people died of the disease in the acute phase of infection. In addition, a significant proportion of patients have been reported to suffer from post-acute phase symptoms, sequelae of COVID-19, which may negatively influence the quality of daily living and/or socioeconomic circumstances of the patients. However, no previous study has comprehensively and objectively assessed the quality of life of patients by using existing international scales. Further, evidence of socioeconomic consequences among patients with COVID-19 is scarce. To address the multidimensional issues from sequelae of COVID-19, evidence from comprehensive surveys beyond clinical perspectives is critical that investigates health, and social determinants of disease progression as well as socioeconomic consequences at a large scale. METHODS AND ANALYSIS: In this study, we plan to conduct a nationwide and comprehensive survey for the sequelae of COVID-19 in a total of 1000 patients diagnosed at 27 hospitals throughout Japan. This study will evaluate not only the health-related status of patients from clinical perspectives but also the Health-related Quality of Life (HRQoL) scores, socioeconomic status and consequences to discuss the sequelae of the disease and the related risk factors. The primary endpoint is the frequency of long-term complications of COVID-19 infection. The secondary endpoints are risk factors for progression to sequelae of COVID-19 infection. The study will provide robust and important evidence as a resource to tackle the issues from the sequelae of COVID-19 from the multi-dimensional perspectives. ETHICS AND DISSEMINATION: This trial was approved by the Keio University School of Medicine Ethics Committee (20200243, UMIN000042299). The results of this study will be reported at a society meeting or published in a peer-reviewed journal.

Tracheal granular cell tumour presenting with throat discomfort.

Granular cell tumours (GCTs) are a rare form of neoplasm found throughout the body. Tracheobronchial involvement is less common. We describe a case of tracheal GCT in a 37-year-old Japanese woman presenting with throat discomfort. A tracheal tumour was found during laryngoscopy for undefined throat discomfort. Bronchoscopy demonstrated a white sub-epithelial solitary nodule on the tracheal wall, and pathological examination of the biopsy samples confirmed GCT. No therapeutic procedures were performed, and the tumour is currently under strict observation. Throat discomfort is a rare presentation of tracheal tumours, but an early inspection using laryngoscopy and bronchoscopy may be helpful in determining an accurate diagnosis.

Pattern of FDG-PET uptake in lipoid pneumonia simulating lung cancer.

Lipoid pneumonia presents with a variety of lung abnormalities, particularly mass forming lesions that mimic lung cancers. While 18F-fluorodeoxyglucose (FDG)-positron emission tomography (PET) is expected to discriminate both diseases, some previous reports showed pseudo-positive FDG uptake in lipoid pneumonia. Here, we report a case of pathologically proven chronic lipoid pneumonia in a 78-year-old Japanese man. Computed tomography (CT) showed multi-lobar mass-forming lesions with a fat-density. PET confirmed the spotty accumulation of FDG in the corresponding fat-density area on CT, suggesting lipoid pneumonia. We reviewed the literature and discussed the FDG uptake patterns in lipoid pneumonia.

A Histologically Complete Response to Immunotherapy Using Pembrolizumab in a Patient with Giant Cell Carcinoma of the Lung: An Additional Report and Literature Review.

We previously reported a case of giant cell carcinoma in the lung, in which the use of antiprogrammed death 1 (PD-1) immunotherapy resulted in substantial tumor reduction. In the present study, we describe an additional clinical course. A 69-year-old woman was diagnosed with giant cell carcinoma of the lung in clinical stage IVB (T2bN0M1c, BRA). The tumor expressed programmed death ligand 1 (PD-L1) in a high proportion. The patient received stereotactic radiotherapy for two sites of small brain metastases, followed by immunotherapy using anti-PD-1 antibodies (pembrolizumab). The treatment exerted a substantial tumor reduction through four cycles. However, treatment was withdrawn due to renal dysfunction. The primary lung tumor continued to regress for an additional four months without any further therapy, resulting in a clinical stage of T1aN0M0. Salvage thoracic surgery was then performed to remove the tumor residue in the lung. Microscopic examination of the sample revealed no residual cancer. The patient was free from recurrence at 16 months post surgery. We then comprehensively reviewed lung sarcomatoid carcinoma cases in the literature, in which anti-PD-1 antibodies were implemented. The current literature and our own findings suggest sarcomatoid carcinomas express high levels of tumoral PD-L1 and can be effectively treated with anti-PD-1 antibodies.

Pulmonary sclerosing pneumocytoma demonstrating intratumoral hematoma.

Pulmonary sclerosing pneumocytoma (PSP) is a rare benign neoplasm of the lung that shows a slow growing pattern. Corresponding contrast-enhancements on chest computed tomography (CT) vary widely in both patterns and degrees. However, gross intratumoral radiolucencies, attributable to cyst formation, necrosis, or intratumoral hematoma, were rarely reported in PSP cases. We herein report on a case involving a 61-year-old Japanese women with PSP demonstrating CT-defined intratumoral radiolucency. A chest CT scan revealed a solitary and well-circumscribed nodule that showed a substantial growth over a 7-year period. The tumor was composed of a solid portion visualized with contrast-enhancement and a central radiolucency on a chest CT scan. A positron emission tomography scan revealed high uptake of fluorodeoxyglucose on the solid portion of the tumor, but the radiolucent portion showed negative uptake. The examination of a tumor specimen obtained by a percutaneous core needle biopsy aided in determining a pathological diagnosis of PSP, and the patient subsequently received a right lower lobectomy of the lung. The portion of central radiolucency on the CT scan corresponding to the surgical specimen was pathologically proven to be gross hematoma.

Common functional polymorphisms in the cathepsin S promoter in Japanese subjects: possible contribution to pulmonary emphysema.

BACKGROUND AND OBJECTIVE: Cathepsin S is involved in the pathogenesis of COPD in murine models overexpressing interferon (IFN)-gamma and IL-13. It is widely accepted that genetic factors partly influence susceptibility to COPD; however, the association of genetic polymorphisms in the cathepsin S gene with COPD has not been reported previously. In this study, functional polymorphisms in the 5'-flanking region of the human cathepsin S gene were identified and their association with COPD phenotypes was investigated. METHODS: Genetic polymorphisms were detected by single strand conformation polymorphism analysis and direct sequencing. Genotypes and haplotypes were determined using amplification refractory mutation systems and single strand conformation polymorphism analysis. A promoter-reporter assay was used to compare transcriptional activities between the haplotypes on stimulation with IFN-gamma. Haplotype analysis was performed on 204 smoking and 104 non-smoking Japanese subjects. RESULTS: Four novel polymorphisms were detected in the 5'-flanking region and three major haplotypes were identified. The haplotypes were associated with distinct promoter activities on stimulation with IFN-gamma and there was a trend indicating that higher transcriptional activity was linked to less pulmonary emphysema. CONCLUSION: Novel functional polymorphisms were identified in the cathepsin S gene, which has a possible association with pulmonary emphysema in the Japanese population.