A Rare Case of Overlapping Durvalumab-induced Myositis, Takotsubo-like Morphological Changes Caused by Myocarditis, and Myasthenia Gravis.

Immune checkpoint inhibitors can cause a range of immune-related adverse events, including myositis, Takotsubo cardiomyopathy, and myasthenia gravis. We herein report a rare case of a 78-year-old man with concurrent durvalumab-induced myositis, Takotsubo-like morphological changes caused by myocarditis, and myasthenia gravis. The patient initially required invasive ventilation and exhibited symptoms of myasthenia gravis after treatment with high-dose steroids. However, he subsequently achieved successful recovery after the administration of intravenous immunoglobulin, plasmapheresis, and high-dose steroids. We advocate vigilant neurological monitoring of patients with immune checkpoint inhibitor-induced myositis, including the assessment of ptosis and other relevant signs, so that prompt treatment can be initiated at the time of emergence or progression of immune checkpoint inhibitor-induced myasthenia gravis.

A Novel Filtration Membrane for Clustered Circulating Tumor Cell Extraction: A Prospective Feasibility Study.

BACKGROUND/AIM: Circulating tumor cells (CTCs) have garnered attention as biomarkers for therapeutic response and prognosis in malignant neoplasms. Nonetheless, existing literature predominantly relies on surrogate markers of tumor cells or focuses on single-cell CTC, failing to adequately address the challenge of detecting cluster-forming CTCs, which bear considerable prognostic implications. This prospective study aims to validate the efficacy of a novel filtration membrane, namely Soft Micro Pore Filter (S-MPF®), for rare cell recovery in detecting CTCs through the analysis of clinical samples. PATIENTS AND METHODS: Patients with confirmed lung cancer or highly suspected lung cancer based on specific criteria (solid tumor size >2.0 cm, serum carcinoembryonic level >7.5 ng/ml, maximum standard uptake value derived from fluorodeoxyglucose-position emission tomography >2.9) were included in the study. CTCs were extracted from preoperative peripheral arterial blood samples using S-MPF®, and the validity of the filtration system was positively verified. RESULTS: Out of the 25 enrolled patients, 23 had lung cancer. CTC positivity was observed in 17 cases (73.9%), whereas cluster CTC positivity was observed in 16 cases (69.6%), with a median count of two clusters. Single CTC positivity was observed in 11 cases (52.1%), with a median count of one cell. CONCLUSION: The utilization of the newly developed S-MPF® filtration membrane exhibited a high rate of CTC identification, demonstrating its suitability for clinical applications.

Serum Free Radical Scavenging Capacity Profiles of Patients with Chronic Obstructive Pulmonary Disease.

Background: Oxidative stress is an important mechanism for the development and progression of chronic obstructive pulmonary disease (COPD). It may also contribute to systemic manifestation in patients with COPD. Reactive oxygen species (ROS) including free radicals play a crucial role in oxidative stress in COPD. The aims of this study were to determine serum scavenging capacity profile against multiple free radicals and to evaluate its correlation with pathophysiology, exacerbations, and prognosis in patients with COPD. Methods: Serum scavenging capacity profile against multiple free radicals comprising hydroxyl radical (•OH), superoxide radical (O2 -•), alkoxy radical (RO•), methyl radical (•CH3), alkylperoxyl radical (ROO•), and singlet oxygen (1O2) was assessed using the multiple free-radical scavenging method in 37 patients with COPD (mean age, 71 years; mean forced expiratory volume in 1 s, 55.2% predicted). The severity of emphysema was evaluated by Goddard classification on chest computed tomography. Exacerbations were recorded prospectively for 1 year and the overall mortality was assessed 5 years after the initial assessment. Results: •OH scavenging capacity was significantly decreased (p < 0.05) and O2 -• and •CH3 scavenging capacity tended to decrease in patients with COPD compared to that in healthy controls. On the other hand, ROO• scavenging capacity tended to increase. In addition, RO• scavenging capacity was associated with severity of emphysema (p < 0.05) and exacerbation frequency (p < 0.02). There was a difference in the profile of the scavenging capacity between survived and deceased patients with COPD for 5 years after initial assessment. Conclusion: Characteristic profile of free radical scavenging capacity can provide insight into the pathophysiology and prognosis of patients with COPD.

Primary pulmonary diffuse large B-cell lymphoma presenting multiple nodules mimicking metastasis: A case report.

Primary pulmonary diffuse large B-cell lymphoma is a rare entity. We describe a case of pulmonary lymphoma with multiple nodules mimicking metastases in a treated patient with rheumatoid arthritis. A 73-year-old man was diagnosed with rheumatoid arthritis at the age of 30. He was treated with leflunomide. He was followed up for a nontuberculous mycobacterial infection. He underwent percutaneous coronary intervention for acute myocardial infarction at the age of 70. In April 2022, routine follow-up revealed new-onset multiple nodules on chest computed tomography (CT). A position emission tomography/CT scan with 18F-fluorodeoxyglucose showed a low-high maximum standardized uptake value by multiple nodules. Pathologic examination of a video-assisted thoracic surgical biopsy revealed pulmonary diffuse large B-cell lymphoma. Systemic chemotherapy with rituximab, cyclophosphamide, vincristine, and prednisolone reduced and eliminated multiple nodules. Pulmonary lymphoma should be considered as a differential diagnosis in the case of multiple nodules on a chest CT.

Verification of A New Filter for Isolation of Circulating Tumor Cells by Only Blood Filtration.

BACKGROUND/AIM: Since circulating tumor cells (CTCs) are precursors of metastatic lesions, extracting CTCs from whole blood is useful in obtaining information for cancer treatment. One of the CTC isolation methods is the size selection method; however, since the conventional methods are expensive and cumbersome, we developed an affordable and simple filter, whose usefulness is verified in this study. MATERIALS AND METHODS: The new filter [hereafter, soft micropore filter (S-MPF)] is made up of a polyethylene film with a thickness of 15 µm and conical pores having a diameter of 8-10 µm, which are opened uniformly (opening rate, 20%). This filter can filter whole blood by free-falling under gravity. The possibilities of the filter's usage for model CTC isolation, immunostaining, short-term cell culture, and gene mutation detection in extracted model CTCs were verified. RESULTS: S-MPF was able to extract model CTCs with an isolation rate of up to 15%. These model CTCs were detected by cytology, immunostaining, and culture by short-term incubation of filtered cells. Furthermore, genetic mutations were identified in the cultured cells. In addition, CTC isolation from the peripheral blood of patients with lung cancer was demonstrated by setting the volume of collected blood to 15 ml to prevent a low recovery rate. CONCLUSION: The S-MPF can be used to extract model CTCs quickly and easily. Moreover, cytological diagnosis, immunostaining, short-term culture, and gene mutation search are possible with this filter. Given its proven applicability in clinical samples, this filter can be used in clinical settings.

Successful management of recurrent allergic bronchopulmonary aspergillosis after changing from mepolizumab to dupilumab: A case report.

An 81-year-old woman presented to our hospital due to an abnormal shadow on a chest X-ray and a 4-week-old persistent cough. Laboratory examination revealed increased serum eosinophils and immunoglobulin E. The Asthma Control Test (ACT) score and forced expiratory volume in 1 sec indicated airway obstruction. Chest computed tomography (CT) revealed mucoid impaction in the dilated left-lingular lobar bronchus. She was diagnosed with bronchial asthma and treated with a high-dose inhaled corticosteroid/long-acting ß2 agonist. Two months later, her mucoid impaction in the CT image worsened; moreover, bronchoscopy revealed the white mucus plug with Charcot-Leyden crystals and filamentous fungi. The patient was diagnosed with Allergic bronchopulmonary aspergillosis (ABPA) and treatment with 30 mg/day prednisolone was started. Both the blood eosinophil count and the chest image improved almost substantially, and the steroid was discontinued after a year. Sixteen months after cessation of prednisolone treatment, peripheral eosinophilia and mucoid impaction in the left B3b recurred. For the treatment of bronchial asthma and recurrent ABPA, administration of mepolizumab was initiated. Subsequently, although her peripheral eosinophils count decreased, chest CT showed expansion of the mucoid impaction and IgE increased despite mepolizumab treatment. Alternative subcutaneous injection therapy with dupilumab improved chest image, serum IgE level, and her ACT score. After changing from mepolizumab to dupilumab, her ABPA, asthma, and pulmonary function improved remarkably. This case illustrates the potential utility of dupilumab for ABPA without re-administration of oral prednisolone. Additional research is needed to identify an effective therapy for ABPA with asthma.

Improvement of peripheral neuropathy in a patient with antineutrophil cytoplasmic antibody-negative eosinophilic granulomatosis with polyangiitis by additional mepolizumab.

BACKGROUND: Eosinophilic granulomatosis with polyangiitis (EGPA) is a vasculitis characterized by abnormally high eosinophils and frequent peripheral neuropathy. Mepolizumab is an approved therapy for EGPA, but its efficacy against peripheral neuropathy remains unknown. CASE PRESENTATION: A 41-year-old woman was admitted in the hospital with dyspnea and neuropathy. Ground glass opacity and infiltrative shadow in the bilateral lungs were evident on chest computed tomography images. Eosinophils were increased in serum, in bronchoalveolar lavage fluid (BALF), and in transbronchial lung biopsy, and bacteria were not detected in BALF. EGPA resulting in severe eosinophilic asthma, sinusitis, pulmonary infiltrates, and peripheral neuropathy was diagnosed. Prednisolone (50 mg/day) caused remission of eosinophilic pneumonia and sinusitis, but not peripheral neuropathy. During prednisolone tapering (7 mg/day, 10 months after treatment), eosinophils were increased, and peripheral neuropathy relapsed. The humanized anti-IL-5 antibody mepolizumab (300 mg) was initially administered, followed by prednisolone. Mepolizumab caused sustained peripheral neuropathy remission and effective prednisolone tapering. CONCLUSIONS: Introduction of mepolizumab combined with prednisolone may improve peripheral neuropathy.

Fractal dimension in CT low attenuation areas is predictive of long-term oxygen therapy initiation in COPD patients: Results from two observational cohort studies.

BACKGROUND: Some chronic obstructive pulmonary disease (COPD) patients develop hypoxemia with disease progression, with some even requiring long-term oxygen therapy (LTOT). Lung function, especially diffusing capacity, and the annual decline in PaO2, are reported to be predictive factors of chronic respiratory failure. However, the association between lung morphometry evaluated using computed tomography (CT) images and LTOT initiation is unknown. METHODS: We retrospectively evaluated the relationship between clinical indices, including pulmonary function, body mass index (BMI), and CT parameters, at baseline and LTOT initiation in two prospective COPD cohorts. In the Nara Medical University cohort (n = 76), the low attenuation area (LAA) and its fractal dimension (fractal D) were adapted as the indices for parenchymal destruction in CT images. The association between these CT measurements and LTOT initiation was replicated in the Kyoto University cohort (n = 130). RESULTS: In the Nara Medical University cohort, lower BMI (hazard ratio [HR]:0.70, p = 0.006), lower % diffusing capacity (%DLCO) (HR: 0.92, p = 0.006), lower %DLCO/VA (HR, 0.90, p = 0.008), higher RV/TLC (HR, 1.26, p = 0.012), higher LAA% (HR: 1.18, p = 0.001), and lower fractal D (HR: 3.27 × 10-8, p < 0.001) were associated with LTOT initiation. Multivariate analysis in the Kyoto University cohort confirmed that lower %DLCO and lower fractal D were independently associated with LTOT initiation, whereas LAA% was not. CONCLUSION: Fractal D, which is the index for morphometric complexity of LAA in CT analysis, is predictive of LTOT initiation in COPD patients.

Human Adipose-Derived Mesenchymal Stem Cells Ameliorate Elastase-Induced Emphysema in Mice by Mesenchymal-Epithelial Transition.

PURPOSE: Chronic obstructive pulmonary disease (COPD) is a worldwide problem because of its high prevalence and mortality. However, there is no fundamental treatment to ameliorate their pathological change in COPD lung. Recently, adipose-derived mesenchymal stem cells (ADSCs) have attracted attention in the field of regenerative medicine to repair damaged organs. Moreover, their utility in treating respiratory diseases has been reported in some animal models. However, the detailed mechanism by which ADSCs improve chronic respiratory diseases, including COPD, remains to be elucidated. We examined whether human ADSCs (hADSCs) ameliorated elastase-induced emphysema and whether hADSCs differentiated into alveolar epithelial cells in a murine model of COPD. METHODS: Female SCID-beige mice (6 weeks old) were divided into the following four groups according to whether they received an intratracheal injection of phosphate-buffered saline or porcine pancreatic elastase, and whether they received an intravenous injection of saline or hADSCs 3 days after intratracheal injection; Control group, hADSC group, Elastase group, and Elastase-hADSC group. We evaluated the lung function, assessed histological changes, and compared gene expression between hADSCs isolated from the lung of Elastase-hADSC group and naïve hADSCs 28 days after saline or elastase administration. RESULTS: hADSCs improved the pathogenesis of COPD, including the mean linear intercept and forced expiratory volume, in an elastase-induced emphysema model in mice. Furthermore, hADSCs were observed in the lungs of elastase-treated mice at 25 days after administration. These cells expressed genes related to mesenchymal-epithelial transition and surface markers of alveolar epithelial cells, such as TTF-1, ß-catenin, and E-cadherin. CONCLUSION: hADSCs have the potential to improve the pathogenesis of COPD by differentiating into alveolar epithelial cells by mesenchymal-epithelial transition.

Resting Breathing Instability During Wakefulness as a Predictor of Clinical Outcome in COPD.

BACKGROUND: Dyspnea is a common symptom in patients with COPD. It causes physical inactivity and impaired health-related quality of life. Although optimal breathing methods alleviate dyspnea, it is unclear whether breathing instability has a clinical impact on patients with COPD. This study aimed to investigate whether resting breathing instability during wakefulness was associated with dyspnea assessed by the modified Medical Research Council (mMRC) dsypnea scale and whether breathing instability can be a novel predictor of clinical outcomes. METHODS: Forty-four subjects with stable COPD were enrolled (mean age, 71.0 y). Resting breathing was monitored for 15 min by using respiratory inductance plethysmography. Breathing instability was evaluated with the coefficient of variation for breath-by-breath respiratory duration and tidal volume ([Formula: see text]) by using an artifact-free respiratory signal for 5 min. Pulmonary function testing and blood gas analysis were performed (mean FEV1 percent of predicted, 68.5%). Questionnaires with regard to dyspnea and health-related quality of life were also completed. Exacerbations were recorded prospectively for 1 year after the initial assessment. RESULTS: The coefficients of variation for [Formula: see text] were significantly higher in the subjects with an mMRC dyspnea scale score ≥ 2 versus those with an mMRC dyspnea scale score < 2 (26.4 ± 7.4% vs 20.3 ± 6.4%, P = .006) . The coefficients of variation for respiratory duration and VT were not associated with age, body mass index, and pulmonary function variables. In multivariate analysis, FEV1 percent of predicted and coefficient of variation for [Formula: see text] remained significant predictors for an mMRC dyspnea scale score ≥ 2 (P = .004 and P = .01, respectively). Coefficient of variation values were also correlated with several health-related quality of life domains. The exacerbation frequency was associated with the coefficient of variation for [Formula: see text]. CONCLUSIONS: Resting breathing pattern during wakefulness is a novel assessment tool for severity of dyspnea, which can be one of the predictors for exacerbation in patients with COPD.

[Intrathoracic washing with urokinase was effective for empyema with atelectasis].

A 60-year-old man had a medical examination because of fever in the emergency hospital and had a diagnosis of pneumonia and was treated, but he was admitted to our hospital 2 days later because there was not the improvement of his symptom. The chest computed tomography(CT)image showed multilocular pleural effusions and lower lobe atelectasis with the air bronchogram on the left side. We diagnosed the case as empyema and inserted a catheter, but drainage was very few and injected 60,000 urokinase units for 3 days from the next day. We removed a drain 2 days after the 3rd infusion, and the pleural thickening became mild, and atelectasis was gradually improved in the chest CT image, and the inflammatory reaction was reduced, too. The intrathoracic washing with urokinase was thought to be effective for empyema with atelectasis.