SFTPB in serum extracellular vesicles as a biomarker of progressive pulmonary fibrosis.

Progressive pulmonary fibrosis (PPF), defined as the worsening of various interstitial lung diseases (ILDs), currently lacks useful biomarkers. To identify novel biomarkers for early detection of patients at risk of PPF, we performed a proteomic analysis of serum extracellular vesicles (EVs). Notably, the identified candidate biomarkers were enriched for lung-derived proteins participating in fibrosis-related pathways. Among them, pulmonary surfactant-associated protein B (SFTPB) in serum EVs could predict ILD progression better than the known biomarkers, serum KL-6 and SP-D, and it was identified as an independent prognostic factor from ILD-gender-age-physiology index. Subsequently, the utility of SFTPB for predicting ILD progression was evaluated further in 2 cohorts using serum EVs and serum, respectively, suggesting that SFTPB in serum EVs but not in serum was helpful. Among SFTPB forms, pro-SFTPB levels were increased in both serum EVs and lungs of patients with PPF compared with those of the control. Consistently, in a mouse model, the levels of pro-SFTPB, primarily originating from alveolar epithelial type 2 cells, were increased similarly in serum EVs and lungs, reflecting pro-fibrotic changes in the lungs, as supported by single-cell RNA sequencing. SFTPB, especially its pro-form, in serum EVs could serve as a biomarker for predicting ILD progression.

Galectin-10 in serum extracellular vesicles reflects asthma pathophysiology.

BACKGROUND: Novel biomarkers (BMs) are urgently needed for bronchial asthma (BA) with various phenotypes and endotypes. OBJECTIVE: We sought to identify novel BMs reflecting tissue pathology from serum extracellular vesicles (EVs). METHODS: We performed data-independent acquisition of serum EVs from 4 healthy controls, 4 noneosinophilic asthma (NEA) patients, and 4 eosinophilic asthma (EA) patients to identify novel BMs for BA. We confirmed EA-specific BMs via data-independent acquisition validation in 61 BA patients and 23 controls. To further validate these findings, we performed data-independent acquisition for 6 patients with chronic rhinosinusitis without nasal polyps and 7 patients with chronic rhinosinusitis with nasal polyps. RESULTS: We identified 3032 proteins, 23 of which exhibited differential expression in EA. Ingenuity pathway analysis revealed that protein signatures from each phenotype reflected disease characteristics. Validation revealed 5 EA-specific BMs, including galectin-10 (Gal10), eosinophil peroxidase, major basic protein, eosinophil-derived neurotoxin, and arachidonate 15-lipoxygenase. The potential of Gal10 in EVs was superior to that of eosinophils in terms of diagnostic capability and detection of airway obstruction. In rhinosinusitis patients, 1752 and 8413 proteins were identified from EVs and tissues, respectively. Among 11 BMs identified in EVs and tissues from patients with chronic rhinosinusitis with nasal polyps, 5 (including Gal10 and eosinophil peroxidase) showed significant correlations between EVs and tissues. Gal10 release from EVs was implicated in eosinophil extracellular trapped cell death in vitro and in vivo. CONCLUSION: Novel BMs such as Gal10 from serum EVs reflect disease pathophysiology in BA and may represent a new target for liquid biopsy approaches.

Single-cell Raman microscopy with machine learning highlights distinct biochemical features of neutrophil extracellular traps and necrosis.

The defining biology that distinguishes neutrophil extracellular traps (NETs) from other forms of cell death is unresolved, and techniques which unambiguously identify NETs remain elusive. Raman scattering measurement provides a holistic overview of cell molecular composition based on characteristic bond vibrations in components such as lipids and proteins. We collected Raman spectra from NETs and freeze/thaw necrotic cells using a custom built high-throughput platform which is able to rapidly measure spectra from single cells. Principal component analysis of Raman spectra from NETs clearly distinguished them from necrotic cells despite their similar morphology, demonstrating their fundamental molecular differences. In contrast, classical techniques used for NET analysis, immunofluorescence microscopy, extracellular DNA, and ELISA, could not differentiate these cells. Additionally, machine learning analysis of Raman spectra indicated subtle differences in lipopolysaccharide (LPS)-induced as opposed to phorbol myristate acetate (PMA)-induced NETs, demonstrating the molecular composition of NETs varies depending on the stimulant used. This study demonstrates the benefits of Raman microscopy in discriminating NETs from other types of cell death and by their pathway of induction.

Next-generation proteomics of serum extracellular vesicles combined with single-cell RNA sequencing identifies MACROH2A1 associated with refractory COVID-19.

BACKGROUND: The coronavirus disease 2019 (COVID-19) pandemic is widespread; however, accurate predictors of refractory cases have not yet been established. Circulating extracellular vesicles, involved in many pathological processes, are ideal resources for biomarker exploration. METHODS: To identify potential serum biomarkers and examine the proteins associated with the pathogenesis of refractory COVID-19, we conducted high-coverage proteomics on serum extracellular vesicles collected from 12 patients with COVID-19 at different disease severity levels and 4 healthy controls. Furthermore, single-cell RNA sequencing of peripheral blood mononuclear cells collected from 10 patients with COVID-19 and 5 healthy controls was performed. RESULTS: Among the 3046 extracellular vesicle proteins that were identified, expression of MACROH2A1 was significantly elevated in refractory cases compared to non-refractory cases; moreover, its expression was increased according to disease severity. In single-cell RNA sequencing of peripheral blood mononuclear cells, the expression of MACROH2A1 was localized to monocytes and elevated in critical cases. Consistently, single-nucleus RNA sequencing of lung tissues revealed that MACROH2A1 was highly expressed in monocytes and macrophages and was significantly elevated in fatal COVID-19. Moreover, molecular network analysis showed that pathways such as "estrogen signaling pathway," "p160 steroid receptor coactivator (SRC) signaling pathway," and "transcriptional regulation by STAT" were enriched in the transcriptome of monocytes in the peripheral blood mononuclear cells and lungs, and they were also commonly enriched in extracellular vesicle proteomics. CONCLUSIONS: Our findings highlight that MACROH2A1 in extracellular vesicles is a potential biomarker of refractory COVID-19 and may reflect the pathogenesis of COVID-19 in monocytes.

Identification of CD14 and lipopolysaccharide-binding protein as novel biomarkers for sarcoidosis using proteomics of serum extracellular vesicles.

Sarcoidosis is a complex, polygenic, inflammatory granulomatous multi-organ disease of unknown cause. The granulomatous inflammation in sarcoidosis is driven by the interplay between T cells and macrophages. Extracellular vesicles (EVs) play important roles in intercellular communication. We subjected serum EVs, isolated by size exclusion chromatography, from seven patients with sarcoidosis and five control subjects to non-targeted proteomics analysis. Non-targeted, label-free proteomics analysis detected 2292 proteins in serum EVs; 42 proteins were up-regulated in patients with sarcoidosis relative to control subjects; and 324 proteins were down-regulated. The protein signature of EVs from patients with sarcoidosis reflected disease characteristics such as antigen presentation and immunological disease. Candidate biomarkers were further verified by targeted proteomics analysis (selected reaction monitoring) in 46 patients and 10 control subjects. Notably, CD14 and lipopolysaccharide-binding protein (LBP) were validated by targeted proteomics analysis. Up-regulation of these proteins was further confirmed by immunoblotting, and their expression was strongly increased in macrophages of lung granulomatous lesions. Consistent with these findings, CD14 levels were increased in lipopolysaccharide-stimulated macrophages during multinucleation, concomitant with increased levels of CD14 and LBP in EVs. The area under the curve values of CD14 and LBP were 0.81 and 0.84, respectively, and further increased to 0.98 in combination with angiotensin-converting enzyme and soluble interleukin-2 receptor. These findings suggest that CD14 and LBP in serum EVs, which are associated with granulomatous pathogenesis, can improve the diagnostic accuracy in patients with sarcoidosis.

Cellular Adhesion Is a Controlling Factor in Neutrophil Extracellular Trap Formation Induced by Anti-Neutrophil Cytoplasmic Antibodies.

Anti-neutrophil cytoplasmic Ab (ANCA)-associated vasculitis (AAV) is a life-threatening condition characterized by improper activation of neutrophils and the release of neutrophil extracellular traps (NETs) in small vessels. This study aimed to explain the role of NETs in AAV pathogenesis by investigating a link between adhesion and NET release using human neutrophils. We leveraged an imaging flow cytometry-based assay and three-dimensional culture to demonstrate that neutrophil adhesion is essential for ANCA-induced NET formation. We confirmed this requirement for cell adhesion using standard microscopy on ultra-low attachment hydrogel surfaces and demonstrate that this depends on the focal adhesion kinase pathway as determined using inhibitors for multiple targets in this process. ANCA increased expression of ß2 integrins on neutrophils, and we confirmed that these integrins were required for NET formation using blocking Abs. Finally, inhibitors for oxidative burst prevented NET formation, and this oxidative burst was mediated by the focal adhesion pathway. Overall, our findings reveal a central role for neutrophil attachment in NET formation in response to ANCAs, helping to explain the restricted localization pattern of vessel damage, and suggesting that targeting neutrophil adhesion factors may be beneficial in preventing pathological damage from NETs during AAV.

Utility of radial endobronchial ultrasonography combined with transbronchial lung cryobiopsy in patients with diffuse parenchymal lung diseases: a multicentre prospective study.

BACKGROUND: Radial endobronchial ultrasonography (R-EBUS) has been used in conjunction with transbronchial lung cryobiopsy (TBLC) to diagnose diffuse parenchymal lung disease (DPLD) and to decrease the risk of bleeding complications. The diagnostic utility of different R-EBUS signs, however, remains unknown. OBJECTIVES: This study aimed to determine whether different R-EBUS signs could be used to more accurately diagnose DPLD and whether bronchial bleeding could be prevented with use of R-EBUS during TBLC. METHOD: Eighty-seven patients with DPLD were included in this multicentre prospective study, with 49 patients undergoing R-EBUS. R-EBUS signals were characterised as displaying either dense or blizzard signs. Pathological confidence of specimens obtained from TBLC was compared between patients with dense versus blizzard signs, and severity of bronchial bleeding was determined based on whether R-EBUS was performed or not. RESULTS: All patients with dense signs on R-EBUS showed consolidation on high-resolution CT (HRCT) imaging. Pathological confidence of lung specimens was significantly higher in patients with dense signs versus those with blizzard signs (p<0.01) and versus those who did not undergo R-EBUS (p<0.05). Patients who underwent TBLC with R-EBUS were more likely to experience no or mild bronchial bleeding than patients who did not undergo R-EBUS (p<0.01), with shorter procedure times (p<0.01). CONCLUSIONS: The dense R-EBUS sign corresponded with consolidation on HRCT. High-quality lung specimens may be obtainable when the dense sign is observed on R-EBUS, and R-EBUS combined with TBLC may reduce risk of bronchial bleeding and shorten procedure times.

Clinical impact of the radiological indeterminate for usual interstitial pneumonia pattern on the diagnosis of idiopathic pulmonary fibrosis.

BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is a fatal lung disease associated with significant morbidity and mortality. The international clinical practice guidelines for the diagnosis of IPF have recently been revised. METHODS: In this single-center retrospective study conducted between June 2006 and March 2018, 27 patients with a newly classified indeterminate for usual interstitial pneumonia (UIP) pattern on high-resolution computed tomography (HRCT) who had undergone surgical lung biopsy were enrolled at the Japanese Red Cross Medical Center. Clinical and pathological characteristics and prognosis were retrospectively analyzed from patient records. RESULTS: On the basis of multidisciplinary discussion (MDD), IPF was diagnosed in six patients (22%), unclassifiable interstitial pneumonia in 5 (19%), chronic hypersensitivity pneumonitis in 10 (37%), collagen vascular disease-associated interstitial lung disease in 5 (19%), and lymphoproliferative disorder in 1 (4%) patient. Ground-glass opacity, peribronchovascular distribution, upper or middle lobe distribution, mosaic attenuation, consolidation patterns, and honeycombing were found on HRCT. Histological UIP or probable UIP was observed in seven patients. The median survival time from the initial visit was 2770 days (92.3 months). There was a significant difference in survival time in the GAP stage and honeycombing on HRCT according to the log-rank test. CONCLUSIONS: Patients with an indeterminate for UIP pattern on HRCT were more likely to have non-IPF than IPF through pathological diagnosis and MDD. GAP stage and honeycombing on HRCT may be significant risk factors for all-cause mortality.

The 2014 autochthonous dengue fever outbreak in Tokyo: A case series study and assessment of the causes and preventive measures.

OBJECTIVE: In 2014, an autochthonous dengue fever outbreak occurred around the Yoyogi Park in Japan for the first time in 70 years. Despite no local cases reported since then, the risk of another outbreak remains high. This study reviews the autochthonous dengue fever cases of the outbreak, investigates its causes, and delineates preventive measures against autochthonous dengue epidemics. METHODS: We conducted a case series study of 15 patients who visited our institution during the 2014 outbreak. We collected and evaluated data on the surveillance of vector mosquitoes, weather, pest control, travelers' origins and destinations, and imported dengue fever cases using reports made by public institutions. RESULTS: All patients recovered with supportive treatments and none met the diagnostic criteria for severe dengue infection. Twelve patients with positive real-time polymerase chain reactions were confirmed as having dengue virus-1 infections. We found no obvious associations between the number of mosquitoes and the weather, or between the number of imported dengue fever cases and that of travelers. Insect growth regulator (IGR) against vector mosquitoes has been used since 2014 for pest control, but the number of larvae has not declined in the Yoyogi Park, although that of imagoes has been relatively suppressed. CONCLUSION: The 2014 outbreak emerged without particularly favorable climate conditions for vector mosquitoes. We found no obvious associations between the number of travelers or the imported dengue fever cases and the outbreak, but the increasing number of travelers may contribute to another outbreak. Pest control, including IGR, remains essential for infection control.

Prospective multicentre study on the safety and utility of transbronchial lung cryobiopsy with endobronchial balloon.

Transbronchial lung cryobiopsy (TBLC) has been increasingly utilised to diagnose diffuse parenchymal lung diseases (DPLDs) and lung cancers; however, TBLC protocols have not yet been standardised and the rate of complications associated with this procedure vary widely. Therefore, this prospective multicentre observational study investigated the safety and utility of the TBLC technique in patients with diffuse and localised respiratory diseases. This study was conducted at multiple medical centres in Japan between July 2018 and April 2019. The study's primary end-point was the rate of severe or serious adverse events associated with TBLC. Adverse events included bronchial bleeding, pneumothorax, pneumonia, respiratory failure, and an acute exacerbation of interstitial pneumonia. Adverse events were graded according to severity. During the TBLC procedure, an endobronchial balloon catheter for bronchial blockade was used in all patients. Pathological confidence and quality of specimens were categorised into three groups. A total of 112 patients were included. Neither severe nor serious adverse events were identified; therefore, the primary end-point was met. Nineteen patients (17%) experienced no bronchial bleeding. Mild or moderate bronchial bleeding was identified in 67% and 16% of patients, respectively. Mild pneumothoraces were identified in four patients (3.6%). The safety profile in patients aged ≥75 years was not significantly different from younger patients. Definite or probable pathological diagnoses were made in 84.9% of patients. This TBLC protocol with routine use of an endobronchial balloon had an acceptable safety profile and diagnostic yield in patients, including elderly ones, with diffuse and localised respiratory diseases.

Effectiveness and safety of benralizumab for severe asthma in clinical practice (J-BEST): a prospective study.

BACKGROUND: Benralizumab is a humanized, fucosylated, monoclonal antibody that targets the interleukin 5 (IL-5) α receptor. Several phase III trials have shown that benralizumab can significantly reduce the incidence of acute exacerbations and improve lung function in patients with severe asthma. However, there is a paucity of data from clinical practice. In this prospective study, we evaluated the effectiveness and safety of benralizumab for severe asthma in clinical practice. METHODS: This was a prospective, open-label, single-arm, single-center study in patients with severe asthma in clinical practice (UMIN000031951). Haematological, clinical, functional, and pharmacotherapeutic parameters were evaluated at baseline and at weeks 4 and 12 after initiation of benralizumab. RESULTS: Twenty-six patients were enrolled between May 2018 and March 2019. Both asthma quality of life questionnaire (AQLQ) score and asthma control test (ACT) score showed significant improvement over the study period. Forced expiratory volume in 1.0 second (FEV1) showed a significant increase at week 12 (baseline: 1.57 L; week 12: 1.75 L). Blood eosinophil and basophil counts were significantly decreased at week 12 compared to baseline. At week 12, the dose of regular oral corticosteroids (OCS) was significantly decreased from baseline as was the number of patients on need-based OCS. Benralizumab had no significant effect on fractional exhaled nitric oxide (FeNO) levels and total immunoglobulin E levels. Only one patient experienced mild headache during benralizumab therapy. CONCLUSIONS: In this study, benralizumab conferred clinically significant benefits in patients with severe asthma with no short-term severe adverse events.

Rapid and sustained effects of a single dose of benralizumab on chronic eosinophilic pneumonia.

Chronic eosinophilic pneumonia (CEP) is an eosinophilic inflammatory disease of unknown etiology, and oral corticosteroid (OCS) is commonly used for its treatment. Approximately half of CEP cases relapse secondary to reduction or termination of OCS. A 43-year-old woman visited our hospital because of a chronic cough and abnormal chest X-ray findings. She was diagnosed with CEP because of marked eosinophilia, as well as eosinophilic infiltrates in cryobiopsy samples. After initiation of OCS treatment, her symptoms disappeared with a decrease in peripheral blood eosinophil counts and the amelioration of abnormal infiltrative shadows on chest X-ray. However, symptoms reappeared after OCS termination, including a recurrence of eosinophilia and appearance of fresh abnormal shadows on chest X-ray. Because she refused readministration of OCS because of side effects such as appetite enhancement and moon face in last treatment course, we administered her a single dose of benralizumab. Her symptoms and peripheral eosinophil counts were markedly ameliorated 1 week after benralizumab administration. The marked amelioration in abnormal shadows on chest X-ray were maintained 2 weeks after benralizumab administration. She had no relapse of CEP for almost 6 months after benralizumab administration. Our experience with this case suggests that a single dose of benralizumab may be a treatment option for relapsed CEP cases or those with side effects of long-term OCS therapy.

Usefulness of Measurement of End-tidal CO2 Using a Portable Capnometer in Patients with Chronic Respiratory Failure Receiving Long-term Oxygen Therapy.

Objective Patients with chronic respiratory failure requiring long-term oxygen therapy (LTOT) are at a risk of CO2 retention because of excessive oxygen administration. The CapnoEye™ is a novel portable capnometer that can measure end-tidal CO2 (EtCO2) noninvasively. This retrospective study evaluated the usefulness of this device. Methods EtCO2 was measured using the CapnoEye™. The EtCO2 and partial pressure of venous carbon dioxide (PvCO2) were analyzed, and other clinical data were assessed. Patients Sixty-one consecutive patients with chronic respiratory failure receiving LTOT in the outpatient department at the Japanese Red Cross Medical Center between July 2017 and March 2018 were retrospectively reviewed. Results There was a significant correlation between EtCO2 and PvCO2 (r=0.63) in the total study population as well as in the COPD group (r=0.65) and ILD group (r=0.67). The PvCO2 and EtCO2 gradient was correlated with only the body mass index in a multivariate analysis (p=0.0235). The EtCO2 levels on the day of admission were significantly higher than those in the same patients when they were in a stable condition (p=0.0049). There was a significant correlation between ΔEtCO2 and ΔPvCO2 (r=0.4). A receiver-operating characteristic curve analysis revealed the optimal cut-off EtCO2 value for identifying hypercapnia to be 34 mmHg (p=0.0005). Conclusion The evaluation of EtCO2 by the CapnoEye™ was useful for predicting PvCO2. The body mass index was identified as a possible predictor of the PvCO2 and EtCO2 gradient. An increase in EtCO2 may indicate deterioration of the respiratory status in patients with chronic respiratory failure receiving LTOT.

Diagnostic usefulness of transbronchial lung cryobiopsy in two patients mildly affected with pulmonary lymphangioleiomyomatosis.

Transbronchial lung biopsy is a non-invasive technique used primarily for the pathological diagnosis of lymphangioleiomyomatosis (LAM). However, some cases, particularly those with early-stage lung lesions, are difficult to diagnose because of the specimen size and presence of artifacts. Herein, we present two cases of LAM with relatively mild cystic changes in the lungs and slight impairment seen in pulmonary function tests. Both patients were diagnosed pathologically through transbronchial lung cryobiopsy. These cases indicate that transbronchial lung cryobiopsy is a useful tool for diagnosing early-stage pulmonary LAM owing to its appropriate specimen size for detecting LAM cells and few crush artifacts.

Salvage Chemotherapy Following Osimertinib in Non-small Cell Lung Cancer Harboring Epidermal Growth Factor Receptor Mutation.

AIM: The current study reports the type of salvage chemotherapy following osimertinib and its treatment efficacy in patients with non-small-cell lung carcinoma (NSCLC) who acquire resistance to osimertinib. PATIENTS AND METHODS: In this retrospective cohort study, data from the medical charts of 40 patients with NSCLC treated with osimertinib were obtained, primarily focusing on 14 undergoing salvage chemotherapy including epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) or cytotoxic agents immediately following osimertinib. The treatment efficacy of salvage chemotherapy was evaluated. RESULTS: Five and nine patients received EGFR-TKI and cytotoxic agents following osimertinib, respectively. The overall response rate to EGFR-TKI treatment following osimertinib tended to be lower than that for cytotoxic agents (0% vs. 44.4%). The median progression-free-survival was significantly poorer in patients receiving EGFR-TKI treatment than in those receiving cytotoxic agents. CONCLUSION: Cytotoxic agent administration should be considered more frequently than EGFR-TKIs for patients with NSCLC resistant to osimertinib.

Efficacy and safety of semi-flexible thoracoscopic cryobiopsy in the diagnosis of elderly tuberculous pleurisy.

BACKGROUND: Thoracoscopic pleural biopsy is an efficient procedure in patients with undiagnosed exudative pleurisy. Rigid or flexible forceps have been widely used for this procedure. Recently, the use of cryo-techniques was reported in pleural biopsy during semi-rigid thoracoscopy; however, the feasibility and safety of pleural cryobiopsy in elderly patients have not yet been fully elucidated. CASE REPORTS: We describe two elderly patients who safely underwent semi-rigid thoracoscopic cryobiopsy and were diagnosed with tuberculous pleurisy. Both were >85 years of age, and chest auscultation revealed reduced breath sounds in the right lower zones. Laboratory investigations revealed an elevated level of C-reactive protein without leukocytosis in both patients. Computed tomography scan of the chest revealed right pleural effusion in both patients. Pleural fluid biochemical analysis results were indicative of an exudate. Sputum cultures demonstrated no bacterial growth and smears were negative for the presence of acid-fast bacilli. For definitive diagnosis, pleural biopsy was performed via thoracoscopic cryobiopsy. Specimens obtained from the cryoprobe demonstrated 200-300-µm caseating and non-caseating epitheloid cell granulomas with Langerhans type giant cells. Based on the above results, both patients were diagnosed with TB pleurisy. Anti-tuberculosis treatment resulted in good clinical outcome in both patients. CONCLUSION: Cryobiopsy is easier and more efficient than biopsy with conventional forceps. Our findings in these patients suggest that semi-rigid thoracoscopic cryobiopsy might be a useful alternative diagnostic method for undiagnosed pleural effusion in elderly patients.

Anti-MDA5 Antibody-positive Clinically Amyopathic Dermatomyositis Complicated by Unilateral Right-sided Interstitial Lung Disease.

We herein report a case of anti-MDA5 antibody-positive, clinically amyopathic dermatomyositis complicated by unilateral interstitial lung disease (ILD) in a 78-year-old man with a history of left lung tumor resection. He was admitted due to a persistent fever and abnormal right pulmonary opacity. A transbronchial lung cryobiopsy revealed pulmonary fibrosis, and combined immunosuppressive therapy was initiated. Findings from multiple evaluations, including dynamic breathing magnetic resonance imaging, supported decreased perfusion, ventilation, and mobility of the left lung as etiological factors of unilateral lung ILD. When patients present with laterality of such findings, clinicians should be aware that atypical imaging findings may be observed.

Hemophagocytic Lymphohistiocytosis in a Patient with Rheumatoid Arthritis on Pembrolizumab for Lung Adenocarcinoma.

Immune checkpoint inhibitors have changed the landscape of classic cancer treatment. However, their use is associated with the emergence of new adverse events. An elderly man with rheumatoid arthritis was started on pembrolizumab for newly diagnosed advanced lung cancer. He subsequently developed hemophagocytic lymphohistiocytosis (HLH), which is potentially fatal but has not been properly established as an immune checkpoint inhibition-induced event. We herein report the case of a patient with pembrolizumab-induced HLH.

Quantitative computed tomography measures of skeletal muscle mass in patients with idiopathic pulmonary fibrosis according to a multidisciplinary discussion diagnosis: A retrospective nationwide study in Japan.

BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is a progressive disease often accompanied by skeletal muscle wasting. We investigated whether skeletal muscle mass and muscle attenuation on computed tomography (CT) are predictors of mortality in IPF patients, using a nationwide cloud-based database and web-based multidisciplinary discussion (MDD) system. METHODS: IPF patients diagnosed using MDD from April 2009 to March 2014 were included. We analyzed the cross-sectional area (CSA) of the erector spinae muscle (ESMCSA) and the pectoralis muscle (PMCSA), muscle attenuation of the ESM (ESMMA), and PM (PMMA) on single-slice axial CT. Survival probability was assessed using the Kaplan-Meier method and compared by the log-rank test. Multivariate Cox proportional hazards models were used to evaluate the relationship among the ESMCSA, PMCSA, ESMMA, PMMA, clinical parameters, and prognosis. RESULTS: A total of 199 IPF patients were enrolled. Seventy-four patients died during the study period and the most frequent cause was acute exacerbation (13.1%). The group with the lowest quartile of ESMCSA had significantly worse survival than other groups (P = 0.009). Survival rates of the groups with the lowest quartile of PMCSA, lower ESMMA, and lower PMMA did not differ from those of other groups. According to multivariate analysis, ESMCSA < lower quartile was significantly associated with all-cause mortality (hazards ratio, 1.96; P = 0.030), whereas, ESMMA < median, PMCSA < lower quartile, and PMMA < median were not. CONCLUSIONS: Low ESMCSA on CT images may be a strong risk factor for all-cause mortality in IPF patients based on MDD diagnosis.

Diagnosis and outcome of resected solitary pulmonary nodules after liver transplantation.

OBJECTIVE: Solitary pulmonary nodules after liver transplantation are challenging clinical problems. Herein, we report the causes and clinical courses of resected solitary pulmonary nodules in patients who underwent liver transplantation. METHODS: We retrospectively obtained medical records of 68 patients who underwent liver transplantation between March 2009 and June 2016. This study mainly focused on patients with solitary pulmonary nodules observed on computed tomography scans during follow-ups that were conducted until their deaths or February 2019. RESULTS: Computed tomography scans revealed solitary pulmonary nodules in 7 of the 68 patients. Definitive diagnoses were obtained using video-assisted lung resection in all seven patients. None experienced major postoperative complications. The final pathologic diagnoses were primary lung cancer in three patients, pulmonary metastases from hepatocellular carcinoma in one patient, invasive pulmonary aspergillosis in one patient, post-transplant lymphoproliferative disorder in one patient, and hemorrhagic infarction in one patient. The three patients with lung cancer were subsequently treated with standard curative resection. CONCLUSIONS: Solitary pulmonary nodules present in several serious but potentially curable diseases, such as early-stage lung cancer. Patients who present with solitary pulmonary nodules after liver transplantation should be evaluated by standard diagnostic procedures, including surgical biopsy if necessary.