Publications by authors named "Takeshi Saraya"

132 Publications

Prospective nationwide multicentre cohort study of the clinical significance of autoimmune features in idiopathic interstitial pneumonias.

Thorax 2021 Jul 16. Epub 2021 Jul 16.

Respiratory Medicine, Shizuoka City Shimizu Hospital, Shizuoka, Japan.

Background: Some patients with idiopathic interstitial pneumonia (IIP) show autoimmune features. Interstitial pneumonia with autoimmune features (IPAF) was recently proposed as a research concept in these patients. However, retrospective studies reported conflicting results of its prognosis. Therefore, this study was conducted to prospectively evaluate the clinical significance of autoimmune features in patients with IIP.

Methods: This nationwide multicentre study prospectively enrolled consecutive patients with IIP. At the diagnosis, we systematically evaluated 63 features suggestive of connective tissue diseases using a checklist including symptoms/signs and autoantibodies, which contained most items of the IPAF criteria and followed up with the patients. Clinical phenotypes were included in a cluster analysis.

Results: In 376 patients with IIP enrolled, 70 patients (18.6%) met the IPAF criteria. The proportion of patients with IPAF was significantly lower in idiopathic pulmonary fibrosis (IPF) than in non-IPF (6.0% vs 24.3%, respectively). During a median observation period of 35 months, patients with IPAF more frequently developed systemic autoimmune diseases and had less frequent acute exacerbation of IIPs than patients with non-IPAF. IPAF diagnosis was significantly associated with better survival and was an independent positive prognostic factor in total and patients with non-IPF. Cluster analysis by similarity of clinical phenotypes identified a cluster in which there was a higher number of women, and patients had more autoimmune features and a better prognosis than other clusters.

Interpretation: These observations suggest that some patients with IIP show autoimmune features with distinct characteristics and favourable prognosis. However, we were not able to determine the appropriate therapies for these patients.
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http://dx.doi.org/10.1136/thoraxjnl-2020-216263DOI Listing
July 2021

A True Keloid in the Thorax.

Intern Med 2021 Jun 19. Epub 2021 Jun 19.

Department of Respiratory Medicine, Kyorin University School of Medicine, Japan.

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http://dx.doi.org/10.2169/internalmedicine.7240-21DOI Listing
June 2021

A simple method for discrimination of carcinomatous meningitis using CEA, total protein, and total cell count in the cerebrospinal fluid of primary lung cancer patients.

Medicine (Baltimore) 2021 Apr;100(14):e25367

Department of Respiratory Medicine, Kyorin University School of Medicine, 6-20-2 Shinkawa, Mitaka City 181-8611, Tokyo, Japan.

Abstract: Carcinomatous meningitis (CM) is a critical issue for physicians. However, no study has reported a simple and useful diagnostic or predictive marker for CM.This study aimed to elucidate the potential markers for diagnosing CM derived from cerebrospinal fluid (CSF).We retrospectively enrolled 78 lung cancer patients with suspected CM during the clinical course, including 42 CM and 36 non-CM patients. We compared the clinical and CSF findings, including carcinoembryonic antigen (CEA), between CM and non-CM patients, and explored the diagnostic markers for early identification of CM as well as the contributing factors for mortality.On CSF analysis, with cutoff values of CEA ≥5 ng/ml, total protein (TP) in CSF ≥45 g/dl, and total cell count (TCC) ≥7 cells/μL, the sensitivity, specificity, and area under the curve (AUC) for CM were 85.7%, 84.6%, and 0.887 (95% CI: 0.758-1.0, P < .001); 80.5%, 69.4%, and 0.755 (95% CI: 0.646-0.865, P < .001); and 56.1%, 100%, and 0.817 (95% CI: 0.722-0.912, P < .001), respectively. TP levels in CSF ≥the patients' age had a sensitivity, specificity, and an AUC of 48.8%, 77.8%, and 0.633 (95% CI: 0.722-0.912, P = .045) for CM, respectively. Among CM patients, patients with 'TP in CSF (>patients' age)" (n = 19, P = .008) showed significantly shorter 90-day survival probability than the residual patients (n = 20). None of the CSF parameters could predict the risk of mortality on Cox regression analysis.The cutoff value of CEA ≥5 ng/ml in CSF is a simple and useful method with a high diagnostic value for CM diagnosis, but not a suitable predicting factor for mortality. 'TP in CSF >patients' age" might be a novel factor for assessing short-term mortality.
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http://dx.doi.org/10.1097/MD.0000000000025367DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8036056PMC
April 2021

Immune-related adverse events with immune checkpoint inhibitors: Special reference to the effects on the lungs.

Medicine (Baltimore) 2021 Apr;100(14):e25275

Department of Respiratory Medicine, Kyorin University School of Medicine, Tokyo, Japan.

Abstract: Immune checkpoint inhibitors (ICIs) have emerged as evolutionary treatments for malignant diseases. Although ICIs can cause immune-related adverse events (irAEs) in various organs, precise timing after ICI initiation has been scarcely reported. Elucidating the effects of irAEs, such as time to onset, involvement of major organs, influence on progression-free survival (PFS), and overall survival (OS), are critical issues for physicians. Furthermore, lung-irAE as a whole is not well known.We conducted a retrospective study of 156 patients who were treated with ICIs and compared 82 irAE patients with 74 non-irAE patients.This study clearly demonstrated that the preferred period after induction of ICIs was significantly longer in lung-irAE than in other major organs (skin, digestive tract, and endocrine). The effect of irAEs on PFS and OS was evident PFS in the irAE group (n = 82) (median 128 days, interquartile range [IQR] 62-269 days, P = .002) was significantly longer than that in the non-irAE group (n = 74) (median 53 days, IQR 33-151 days). Similarly, OS was significantly longer in the irAE group (median 578 days, IQR 274-1027 days, P = .007) than in the non-irAE group (median 464 days, IQR: 209-842 days). However, this positive effect of irAEs in the lungs was not proportional to the extent of severity.Lung-irAEs can occur at a later phase than non-lung-irAEs and seemed not to prolong OS and PFS. However, further studies are needed to support these findings.
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http://dx.doi.org/10.1097/MD.0000000000025275DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8036099PMC
April 2021

Reusing N95 Respirators at Weekly Intervals During the COVID-19 Pandemic.

Cureus 2021 Feb 24;13(2):e13542. Epub 2021 Feb 24.

Respiratory Medicine, Kyorin University School of Medicine, Mitaka, JPN.

Objectives A surge in the demand for N95 filtering facepiece respirators (N95 respirators) due to the worldwide spread of coronavirus disease 2019 (COVID-19) has resulted in a global shortage of N95 respirators. This study was performed to evaluate the clinical validation of reusing N95 respirators following stringent fit test protocols. Methods After passing the first fit test, we prospectively enrolled healthcare workers who used N95 respirators for two hours per shift (duckbill-shaped HPR-R/HPR-S, dome-shaped Hi-Luck 350, and three-panel flat-fold respirators 9211) in settings such as bronchoscopy or respiratory specimen sampling. These procedures were repeated for up to three weeks, with the fit test performed every week. At each timing of the fit test, we used a fit-testing system for quantitatively evaluating particle leakage. Results A total of 41 participants were enrolled, including 24 doctors and 17 nurses, of whom 25 were women. The pass rate of successful reuse over three observational weeks using four fit tests was 85.4%, which was comparable among the three types of N95 respirators. Six (14.6%) participants failed the fit test, while no participants dropped out of protocol due to either N95 respirator damage or contamination. Among the six dropped out participants, four reused the duckbill-shaped type and two reused the three-panel flat-fold type. All participants using the cup-shaped type mask successfully completed the protocol. However, the passing rate of this study was not statistically different among the three types of N95 respirators. Conclusion This study shows that N95 respirators can be safely reused for a short period irrespective of their type, as quantitatively assessed by fit tests.
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http://dx.doi.org/10.7759/cureus.13542DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7998012PMC
February 2021

Successful Treatment of Mepolizumab- and Prednisolone-resistant Allergic Bronchopulmonary Aspergillosis with Dupilumab.

Intern Med 2021 Mar 1. Epub 2021 Mar 1.

Department of Respiratory Medicine, Kyorin University School of Medicine, Japan.

A 45-year-old man with allergic bronchopulmonary aspergillosis (ABPA) was treated with oral prednisolone (PSL) (30 mg/day), inhaled corticosteroids, and long-acting beta2-agonists. After confirmation of a PSL-dependent status (8 mg/day), subcutaneous injection with anti-interleukin (IL)-5 antibody (mepolizumab, 100 mg/month) was performed, and the PSL dose was tapered to 5 mg/day. However, ABPA recurred and proved refractory to oral itraconazole (200 mg/day). Alternative subcutaneous injection therapy with dupilumab (induction dose of 600 mg followed by a maintenance dose of 300 mg/2 weeks) enabled the successful withdrawal of oral PSL without clinical deterioration. This case demonstrates the potential utility of dupilumab for steroid-dependent ABPA via the synergistic suppression of IL-4 and IL-13 compared to monotherapy with anti-IL-5 antibody.
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http://dx.doi.org/10.2169/internalmedicine.6679-20DOI Listing
March 2021

Ruxolitinib inhibits poly(I:C) and type 2 cytokines-induced CCL5 production in bronchial epithelial cells: A potential therapeutic agent for severe eosinophilic asthma.

Immun Inflamm Dis 2021 Jun 3;9(2):363-373. Epub 2021 Feb 3.

Department of Respiratory Medicine, Kyorin University School of Medicine, Tokyo, Japan.

Rationale: Severe eosinophilic asthma is characterized by airway eosinophilia and corticosteroid-resistance, commonly overlapping with type 2 inflammation. It has been reported that chemokine (C-C motif) ligand 5 (CCL5) is involved in the exacerbation of asthma by RNA virus infections. Indeed, treatment with a virus-associated ligand and a T helper type 2 cell (Th2) cytokine can synergistically stimulate CCL5 production in bronchial epithelial cells. We aimed to evaluate the mechanisms underlying CCL5 production in this in vitro model and to assess the potential of Janus kinase 1 (JAK1) as a novel therapeutic target via the use of ruxolitinib.

Methods: We stimulated primary normal human bronchial epithelial (NHBE) cells and BEAS-2B cells with poly(I:C) along with interleukin-13 (IL-13) or IL-4, and assessed CCL5 production. We also evaluated the signals involved in virus- and Th2-cytokine-induced CCL5 production and explored a therapeutic agent that attenuates the CCL5 production.

Results: Poly(I:C) stimulated NHBE and BEAS-2B cells to produce CCL5. Poly(I:C) and IL-13 increased CCL5 production. Poly(I:C)-induced CCL5 production occurred via the TLR3-IRF3 and IFNAR/JAK1-phosphoinositide 3-kinase (PI3K) pathways, but not the IFNAR/JAK1-STATs pathway. In addition, IL-13 did not augment poly(I:C)-induced CCL5 production via the canonical IL-13R/IL-4R/JAK1-STAT6 pathway but likely via subsequent TLR3-IRF3-IFNAR/JAK1-PI3K pathways. JAK1 was identified to be a potential therapeutic target for severe eosinophilic asthma. The JAK1/2 inhibitor, ruxolitinib, was demonstrated to more effectively decrease CCL5 production in BEAS-2B cells than fluticasone propionate.

Conclusion: We have demonstrated that JAK1 is a possible therapeutic target for severe corticosteroid-resistant asthma with airway eosinophilia and persistent Th2-type inflammation, and that ruxolitinib has potential as an alternative pharmacotherapy.
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http://dx.doi.org/10.1002/iid3.397DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8127547PMC
June 2021

Wandering Pneumonia Mimicked by COVID-19.

Intern Med 2021 02 22;60(3):493-494. Epub 2020 Dec 22.

Department of Respiratory Medicine, Kyorin University School of Medicine, Japan.

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http://dx.doi.org/10.2169/internalmedicine.6476-20DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7925292PMC
February 2021

Keeping PPE barriers in COVID-19 wards while doing proper auscultation.

Antimicrob Resist Infect Control 2020 12 9;9(1):196. Epub 2020 Dec 9.

Faculty of Medicine, Hebrew University of Jerusalem, Jerusalem, Israel.

The emerging COVID-19 pandemic poses many difficulties to medical professionals. One of them is the need to use personal protective equipment (PPE) in order to protect themselves and their families, while not compromising their care. Physical examination is one of the cornerstones of medical assessment but parts of it are nearly impossible to do while wearing protective equipment. In this brief report we demonstrate a novel wireless stethoscope and its use for treating suspected and proven COVID-19 patients, as a representative to other infectious diseases.
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http://dx.doi.org/10.1186/s13756-020-00854-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7724452PMC
December 2020

Rapidly progressive respiratory failure with multiple halo signs on computed tomography in a patient with primary cardiac angiosarcoma derived from the right atrium: a case report.

BMC Pulm Med 2020 Dec 9;20(1):321. Epub 2020 Dec 9.

Department of Respiratory Medicine, Kyorin University School of Medicine, 6-20-2 Shinkawa, Mitaka City, Tokyo, 181-8611, Japan.

Background: Primary cardiac neoplasms are extremely rare, with an autopsy incidence of 0.0001-0.003%. Primary cardiac sarcoma is usually derived from the right atrium and it manifests as chest pain, arrhythmia, hemoptysis, dyspnea, and fatigue. The most common target organ for metastasis of primary angiosarcoma is the lungs, but the radiological-pathological correlation has been rarely reported.

Case Presentation: A 38-year-old healthy Japanese man was admitted to our hospital with persistent hemoptysis, exaggerated dyspnea, and two episodes of loss of consciousness in the past 3 months. Non-enhanced thoracic computed tomography (CT) revealed multiple scattered nodules with halo signs. Contrast-enhanced thoracic CT revealed a filling defect in the right atrium, which corresponded to the inhomogeneously enhancing tumor in the right atrium on enhanced electrocardiogram-gated cardiac CT. On day 2, acute respiratory failure occurred, and the patient was placed on mechanical ventilation. The patient was diagnosed with primary cardiac angiosarcoma based on the urgent transcatheter biopsied specimen of the right atrium mass and was treated with intravenous administration of doxorubicin. However, his respiratory status rapidly deteriorated, and he died on day 20. Postmortem biopsy showed that the multiple lung nodules with the halo signs corresponded to the intratumoral hemorrhagic necrosis and peripheral parenchymal hemorrhage in their background, suggesting the fragility of the lung tissue where the tumor had invaded, which caused hemoptysis. Furthermore, two episodes of loss of consciousness occurred probably due to a decreased cardiac output because of a massive tumor occupying the right atrium, recognized as an inhomogeneous centripetal enhancement on enhanced electrocardiogram-gated cardiac CT.

Conclusions: This case clearly demonstrated that primary cardiac angiosarcoma could expand in the right atrial cavity, which led to a decreased cardiac output resulting in repeated syncope, together with the fragility of lung tissue by tumor invasion, thereby generating a halo sign on thoracic CT.
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http://dx.doi.org/10.1186/s12890-020-01366-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7727232PMC
December 2020

Evidence of the Sequential Changes of Lung Sounds in COVID-19 Pneumonia Using a Novel Wireless Stethoscope with the Telemedicine System.

Intern Med 2020 Dec 2;59(24):3213-3216. Epub 2020 Nov 2.

Department of Respiratory Medicine, Kyorin University School of Medicine, Japan.

A 60-year-old woman was admitted to our hospital due to coronavirus disease 2019 (COVID-19) pneumonia with a chief complaint of persistent low-grade fever and dry cough for two weeks. Thoracic computed tomography demonstrated a crazy paving pattern in the bilateral lower lobes. In a COVID-19 ward, we used a novel wireless stethoscope with a telemedicine system and successfully recorded and shared the lung sounds in real-time between the red and green zones. The fine crackles at the posterior right lower lung fields changed from mid-to-late (day 1) to late inspiratory crackles (day 3), which disappeared at day 5 along with an improvement in both the clinical symptoms and thoracic CT findings.
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http://dx.doi.org/10.2169/internalmedicine.5565-20DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7807114PMC
December 2020

Detailed Molecular Interactions of Favipiravir with SARS-CoV-2, SARS-CoV, MERS-CoV, and Influenza Virus Polymerases In Silico.

Microorganisms 2020 Oct 20;8(10). Epub 2020 Oct 20.

Department of Microbiology, Yokohama City University School of Medicine, Yokohama, Kanagawa 236-0004, Japan.

Favipiravir was initially developed as an antiviral drug against influenza and is currently used in clinical trials against severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection (COVID-19). This agent is presumably involved in RNA chain termination during influenza virus replication, although the molecular interactions underlying its potential impact on the coronaviruses including SARS-CoV-2, SARS-CoV, and Middle East respiratory syndrome coronavirus (MERS-CoV) remain unclear. We performed in silico studies to elucidate detailed molecular interactions between favipiravir and the SARS-CoV-2, SARS-CoV, MERS-CoV, and influenza virus RNA-dependent RNA polymerases (RdRp). As a result, no interactions between favipiravir ribofuranosyl-5'-triphosphate (F-RTP), the active form of favipiravir, and the active sites of RdRps (PB1 proteins) from influenza A (H1N1)pdm09 virus were found, yet the agent bound to the tunnel of the replication genome of PB1 protein leading to the inhibition of replicated RNA passage. In contrast, F-RTP bound to the active sites of coronavirus RdRp in the presence of the agent and RdRp. Further, the agent bound to the replicated RNA terminus in the presence of agent, magnesium ions, nucleotide triphosphate, and RdRp proteins. These results suggest that favipiravir exhibits distinct mechanisms of action against influenza virus and various coronaviruses.
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http://dx.doi.org/10.3390/microorganisms8101610DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7589801PMC
October 2020

Novel predictive factors for patient discomfort and severe cough during bronchoscopy: A prospective questionnaire analysis.

PLoS One 2020 19;15(10):e0240485. Epub 2020 Oct 19.

Department of Respiratory Medicine, Kyorin University School of Medicine, Mitaka, Tokyo, Japan.

During bronchoscopy, discomfort is mainly caused by an unavoidable cough; however, there are no reports of any predictive factors for strong cough during bronchoscopy identified before the procedure. To clarify the factors underlying the discomfort status and predictive factors for strong cough during bronchoscopy, we prospectively evaluated patients who underwent bronchoscopy at Kyorin University Hospital between March 2018 and July 2019. Before and after bronchoscopy, the enrolled patients answered a questionnaire regarding the procedure. At the same time, bronchoscopists evaluated cough severity using a four-grade cough scale. We evaluated patient characteristics and predictive factors associated with bronchoscopy from the perspective of discomfort and strong cough. A total of 172 patients were ultimately enrolled in this study. On multivariate logistic regression analysis, comparison of the subjective data between the discomfort and comfort groups revealed that factors that were more common in the former group were younger age (OR = 0.96, p = 0.002), less experienced bronchoscopist (OR = 2.08, p = 0.047), and elevation of cough score per 1 point (OR = 1.69, p < 0.001). Furthermore, the predictive factors for strong cough prior to performing bronchoscopy were female sex (OR = 2.57, p = 0.009), EBUS-TBNA (OR = 2.95, p = 0.004), and prolonged examination time of more than 36 min (OR = 2.32, p = 0.022). Regarding patients' discomfort, younger age, less experienced bronchoscopist, and the elevation of cough score per 1 point were important factors for discomfort in bronchoscopy. On the other hand, female sex, EBUS-TBNA, and prolonged examination time were crucial factors for strong cough.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0240485PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7571709PMC
December 2020

Aggressive lung involvement in a patient with T-acute lymphoblastic leukaemia/lymphoblastic lymphoma: a tricky and rare case report.

Respirol Case Rep 2020 Aug 2;8(6):e00614. Epub 2020 Jul 2.

Department of Respiratory Medicine Kyorin University Tokyo Japan.

A 39-year-old man was admitted to our university hospital because of diffuse pulmonary infiltrates on chest X-ray. He had been diagnosed with T-acute lymphoblastic leukaemia/lymphoblastic lymphoma three years before and had been treated with chemotherapy and cord blood stem cell transplantation twice. Although he had neither blast cells in the peripheral blood nor leucocytosis, urgent bronchoscopy findings demonstrated blast cells invading both the alveolar spaces/alveolar septa and the vein walls. These pathological findings corresponded to ground-glass opacities and thickening of the interlobular septa on thoracic computed tomography (CT). In acute lymphoblastic leukaemia/lymphoblastic lymphoma patients presenting with infiltrates on thoracic CT, leukaemic pulmonary involvement should be considered in the differential diagnoses, even in the absence of hyperleucocytosis or blast cells in the blood, similar to pulmonary involvement in myeloid leukaemias.
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http://dx.doi.org/10.1002/rcr2.614DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7330916PMC
August 2020

Tuberculosis-associated chylothorax revealing an enlarged lymphatic duct due to tuberculosis lymphadenitis.

Respirol Case Rep 2020 Aug 18;8(6):e00600. Epub 2020 Jun 18.

Department of Respiratory Medicine Kyorin University School of Medicine Mitaka City Tokyo Japan.

A 77-year-old woman presented to our hospital with complaints of persistent cough and low-grade fever for two months. On radiological analysis, she had moderate right-sided pleural effusion with right hilar and subcarinal lymphadenopathies. Thoracentesis showed chylothorax of unknown cause. Bronchoscopy revealed a non-specific inflammatory process. However, thoracoscopic surgery demonstrated a curiously enlarged lymphatic duct with its proximal portion compressed by subcarinal lymphadenopathies, pathologically diagnosed as granulomatous lymphadenitis. Hence, tuberculous lymphadenitis was proven to be the cause of chylothorax. Interestingly, cauterization of the lymphatic duct decreased the total amount of right-sided pleural effusion along with a change in colour from milky yellow to red. These were in favour of tuberculosis (TB)-associated chylothorax with the advent of the TB pleuritis. All symptoms and pleural effusion disappeared after the initiation of anti-tuberculous drugs. The present case showed definite evidence of TB-associated chylothorax development mechanism via compression of the lymphatic duct by mediastinal lymphadenopathies.
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http://dx.doi.org/10.1002/rcr2.600DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7301284PMC
August 2020

An extremely rare case of nivolumab-associated macroscopic duodenitis with spontaneous regression.

Respirol Case Rep 2020 Jul 11;8(5):e00582. Epub 2020 May 11.

Department of Respiratory Medicine Kyorin University School of Medicine Tokyo Japan.

An 82-year-old man was presented to our hospital due to epigastric and right hypochondrial pain 17 weeks after the initiation of intravenous treatment with nivolumab for recurrent lung adenocarcinoma as multiple lung and sternal metastases. Urgent gastroscopy revealed macroscopic duodenitis such as severe erythema, oedema, black-coloured erosions, and ulcers located throughout the second portion of the duodenum, which was confirmed by abdominal computed tomography as circumferential thickening of the duodenal wall. Those lesions were pathologically considered as non-specific inflammation and spontaneously disappeared within a month, suggesting nivolumab-induced immune-related adverse events.
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http://dx.doi.org/10.1002/rcr2.582DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7214783PMC
July 2020

Molecular Evolution of the Fusion Protein () Gene in Human Respirovirus 3.

Front Microbiol 2019 15;10:3054. Epub 2020 Jan 15.

Department of Respiratory Medicine, School of Medicine, Kyorin University, Tokyo, Japan.

To elucidate the evolution of human respirovirus 3 (HRV3), we performed detailed genetic analyses of the gene (full-length) detected from hundreds of HRV3 strains obtained from various geographic regions. First, we performed time-scaled evolutionary analyses using the Bayesian Markov chain Monte Carlo method. Then, we performed analyses of phylodynamics, similarity, phylogenetic distance, selective pressure, and conformational B-cell epitope with the F-protein structural analyses. Time-scaled phylogenetic tree showed that the common ancestor of HRV3 and bovine respirovirus 3 diverged over 300 years ago and subdivided it into three major clusters and four subclusters during the most recent 100 years. The overall evolutionary rate was approximately 10 substitutions/site/year. Indigenous similarity was seen in the present strains, and the mean phylogenetic distance were 0.033. Many negative selection sites were seen in the ectodomain. The conformational epitopes did not correspond to the neutralizing antibody binding sites. These results suggest that the HRV3 gene is relatively conserved and restricted in this diversity to preserve the protein function, although these strains form many branches on the phylogenetic tree. Furthermore, HRV3 reinfection may be responsible for discordances between the conformational epitopes and the neutralizing antibody binding sites of the F protein. These findings contribute to a better understanding of HRV3 virology.
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http://dx.doi.org/10.3389/fmicb.2019.03054DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6974460PMC
January 2020

Molecular Evolution of the Protease Region in Norovirus Genogroup II.

Front Microbiol 2019 14;10:2991. Epub 2020 Jan 14.

Graduate School of Health Sciences, Gunma Paz University, Takasaki, Japan.

Noroviruses are a major cause of viral epidemic gastroenteritis in humans worldwide. The protease (Pro) encoded in open reading frame 1 (ORF1) is an essential enzyme for proteolysis of the viral polyprotein. Although there are some reports regarding the evolutionary analysis of norovirus GII-encoding genes, there are few reports focused on the region. We analyzed the molecular evolution of the region of norovirus GII using bioinformatics approaches. A time-scaled phylogenetic tree of the region constructed using a Bayesian Markov chain Monte Carlo method indicated that the common ancestor of GII diverged from GIV around 1680 CE [95% highest posterior density (HPD), 1607-1749]. The GII region emerged around 1752 CE (95%HPD, 1707-1794), forming three further lineages. The evolutionary rate of GII region was estimated at more than 10 substitutions/site/year. The distribution of the phylogenetic distances of each genotype differed, and showed genetic diversity. Mapping of the negative selection and substitution sites of the Pro structure showed that the substitution sites in the Pro protein were mostly produced under neutral selection in positions structurally adjacent to the active sites for proteolysis, whereas negative selection was observed in residues distant from the active sites. The phylodynamics of GII.P4, GII.P7, GII.P16, GII.P21, and GII.P31 indicated that their effective population sizes increased during the period from 2005 to 2016 and the increase in population size was almost consistent with the collection year of these genotypes. These results suggest that the region of the norovirus GII evolved rapidly, but under no positive selection, with a high genetic divergence, similar to that of the RNA-dependent RNA polymerase () region and the region of noroviruses.
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http://dx.doi.org/10.3389/fmicb.2019.02991DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6971112PMC
January 2020

Molecular evolution of the hemagglutinin-neuraminidase (HN) gene in human respirovirus 3.

Virus Res 2020 02 26;277:197824. Epub 2019 Nov 26.

Department of Respiratory Medicine, Kyorin University School of Medicine, Tokyo, Japan.

Human respirovirus 3 (HRV3) is a major causative agent of acute respiratory infections in humans. HRV3 can manifest as a recurrent infection, although exactly how is not known. In the present study, we conducted detailed molecular evolutionary analyses of the major antigen-coding hemagglutinin-neuraminidase (HN) gene of this virus detected/isolated in various countries. We performed analyses of time-scaled evolution, similarity, selective pressure, phylodynamics, and conformational epitope prediction by mapping to HN protein models. In this way, we estimated that a common ancestor of the HN gene of HRV3 and bovine respirovirus 3 diverged around 1815 and formed many lineages in the phylogenetic tree. The evolutionary rates of the HN gene were 1.1 × 10 substitutions/site/year, although the majority of these substitutions were synonymous. Some positive and many negative selection sites were predicted in the HN protein. Phylodynamic fluctuations of the gene were observed, and these were different in each lineage. Furthermore, most of the predicted B cell epitopes did not correspond to the neutralization-related mouse monoclonal antibody binding sites. The lack of a link between the conformational epitopes and neutralization sites may explain the naturally occurring HRV3 reinfection.
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http://dx.doi.org/10.1016/j.virusres.2019.197824DOI Listing
February 2020

Huge protruded subcutaneous emphysema by thoracic air leakage.

BMJ Case Rep 2019 Nov 28;12(11). Epub 2019 Nov 28.

Respiratory Medicine, Kyorin University School of Medicine, Mitaka, Japan.

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http://dx.doi.org/10.1136/bcr-2019-232151DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6887382PMC
November 2019

Pathological and Radiological Correlation in Prolonged Myeloperoxidase Anti-neutrophil Cytoplasmic Antibody-related Diffuse Alveolar Hemosiderosis.

Intern Med 2020 Feb 7;59(3):415-419. Epub 2019 Oct 7.

Department of Respiratory Medicine, Kyorin University School of Medicine, Japan.

A 60-year-old woman with a 20-year history of myeloperoxidase anti-neutrophil cytoplasmic antibody (MPO-ANCA)-associated vasculitis visited our hospital due to productive cough and a low-grade fever for several weeks. Thoracic computed tomography demonstrated scattered tiny nodules, patchy consolidation, ground glass opacities, and thickening interlobular septa. On video-assisted thoracic surgery, those abnormalities were found to correspond to the accumulation of hemosiderin-laden alveolar macrophages (AMs) in the alveolar spaces and alveolar septa due to MPO-ANCA vasculitis. The radiological findings persisted for a further two years, indicating the possibility of persistent vasculitis in the lung or evidence of incomplete clearance of hemosiderin-laden AMs.
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http://dx.doi.org/10.2169/internalmedicine.3107-19DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7028408PMC
February 2020

A novel diagnostic method for distinguishing parapneumonic effusion and empyema from other diseases by using the pleural lactate dehydrogenase to adenosine deaminase ratio and carcinoembryonic antigen levels.

Medicine (Baltimore) 2019 Mar;98(13):e15003

Division of Allergy/Pulmonary/Critical Care, Vanderbilt University Medical Center, Nashville, Tennessee.

Pleural effusions are a common medical problem not only for pulmonologists but also for general physicians, often needing thoracentesis for a definite diagnosis. However, thoracentesis cannot always reveal malignant cells or microbiological evidence.In this context, we prospectively enrolled a total of 289 patients with pleural effusions due to diverse etiologies: parapneumonic effusion (PPE) (63), empyema (22), tuberculous pleural effusion (TBPE) (54), malignant pleural effusion (MPE) (140), or chronic renal failure (CRF)/congestive heart failure (CHF) (10). The MPE group consisted of lung cancer (adenocarcinoma, n = 90; squamous cell carcinoma, n = 5; small cell carcinoma, n = 4), malignant lymphoma (n = 17), malignant mesothelioma (n = 11), malignant melanoma (n = 3), and metastasis from other organs (n = 10).This study demonstrated that the pleural lactate dehydrogenase (LDH)to adenosine deaminase (ADA) ratios differed significantly between patients with CHF/CRF, MPE, TBPE, empyema, and PPE. We discovered a simple method to differentiate pleural diseases based on the pleural LDH to ADA ratio and carcinoembryonic antigen (CEA). A pleural LDH to ADA ratio greater than 15.5 and a pleural CEA level of less than 5 ng/mL is indicative of PPE or empyema rather than TBPE, MPE, or transudative pleural effusion (CRF, CHF).This method has a sensitivity of 62.0%, a specificity of 91.0%, and an area under the receiver operating characteristic curve of 0.765 (95% confidence interval [CI]: 0678-0.852, P < .001), odds ratio of 16.6 (95% CI: 7.28-37.8, P < .001), a positive likelihood ratio (LR) of 6.8, and a negative LR of 0.02.
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http://dx.doi.org/10.1097/MD.0000000000015003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6456121PMC
March 2019

Lung adenocarcinoma and anti-transcriptional intermediary factor 1-gamma positive dermatomyositis complicated with spontaneous oesophageal rupture.

Respirol Case Rep 2019 Apr 4;7(3):e00403. Epub 2019 Feb 4.

Department of Respiratory Medicine Kyorin University School of Medicine Tokyo Japan.

A 58-year-old man presented with a two-month history of facial erythema and dry cough. Physical examination revealed typical cutaneous manifestations of dermatomyositis (DM), including heliotrope rash and shawl sign. A chest X-ray revealed a 4-cm mass in the right middle lung. After bronchoscopy and investigation of auto-antibodies, he was diagnosed with co-occurring transcriptional intermediary factor 1-gamma (TIF1-γ) positive DM and lung adenocarcinoma. He was administered oral prednisolone for subsequent muscle weakness, but developed TIF1-γ positive DM-associated oropharyngeal dysphagia complicated by spontaneous oesophageal rupture and died from progression of chemoresistant lung cancer.
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http://dx.doi.org/10.1002/rcr2.403DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6360367PMC
April 2019

Answer Found in a Blowing Sound: Amphoric Breathing Due to Cyst Formation in Pulmonary Adenocarcinoma.

Intern Med 2019 1;58(3):423-425. Epub 2019 Feb 1.

Department of Respiratory Medicine, Kyorin University School of Medicine, Japan.

A 51-year-old woman presented with dyspnea that had progressed over the previous year. On a physical examination, harsh, hollow breath sounds with a high-pitched timbre, termed "amphoric breathing", were identified during inspiration and expiration. Chest radiography and thoracic computed tomography performed over the previous three years revealed an enlarging cyst in the right lung arising from an area of consolidation. Pulmonary adenocarcinoma (T4 N0 M1a, stage IV) was diagnosed and considered a possible cause of the cyst, resulting in amphoric breathing.
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http://dx.doi.org/10.2169/internalmedicine.0623-17DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6395121PMC
March 2019

Multiple huge "cluster" and "galaxy" signs on chest radiography in a patient with pulmonary tuberculosis.

Respirol Case Rep 2019 Apr 25;7(3):e00398. Epub 2019 Jan 25.

Department of Respiratory Medicine Kyorin University School of Medicine Mitaka Japan.

A 62-year-old healthy man presented to our hospital due to a persistent fever of up to 38°C for one week. Thoracic computed tomography showed right pleural effusion with multiple large nodules up to 7 cm in diameter composed of numerous discrete small nodules like fireworks, the so-called "cluster" signs. Some of the large nodules had a hyper-dense portion centrally surrounded by partially discrete small nodules, not as densely assembled, suggestive of the "galaxy" sign. The repeated acid-fast sputum smears and both bronchial washings were all negative for , but the acid-fast culture of sputum taken soon after the first bronchoscopy, and pleural fluid, turned out to be positive for at six weeks after admission. The present case clearly demonstrates that the "galaxy" and "cluster" signs are red herring signs of the low rates of isolating , which should be differentiated from pulmonary sarcoidosis.
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http://dx.doi.org/10.1002/rcr2.398DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6346226PMC
April 2019

Bronchial epithelial cells produce CXCL1 in response to LPS and TNFα: A potential role in the pathogenesis of COPD.

Exp Lung Res 2018 09 24;44(7):323-331. Epub 2019 Jan 24.

a Department of Respiratory Medicine , Kyorin University School of Medicine , Mitaka , Japan.

Rationale: Neutrophilic airway inflammation plays a central role in chronic obstructive pulmonary disease (COPD). CXC chemokine ligand (CXCL)1 is a neutrophil chemokine involved in the pathogenesis of COPD. However, its clinical significance in COPD patients is poorly understood.

Aim Of The Study: To assess the production of CXCL1 by bronchial epithelial cells in response to lipopolysaccharide (LPS) and tumor necrosis factor (TNF)α.

Materials And Methods: We measured sputum CXCL1 and CXCL8 levels in patients with COPD, asthma, and asthma-COPD overlap (ACO), and compared them to those of patients with interstitial pneumonia (IP). Using primary human bronchial epithelial cells and BEAS-2B cells, CXCL1 protein release and mRNA expression were measured after LPS or TNFα stimulation. We evaluated signal transduction mechanisms for CXCL1 production using nuclear factor-κ B (NF-kB) and mitogen-activated protein kinase (MAPK) inhibitors, and examined the effects of anti-inflammatory agents on CXCL1 production in BEAS-2B cells.

Results: Sputum CXCL1 levels in COPD and ACO patients were higher than in IP patients, whereas sputum CXCL8 levels were not. Sputum CXCL1 levels were not affected by inhaled corticosteroid usage, whereas sputum CXCL8 levels tended to be affected. LPS and TNFα stimulated CXCL1 production and mRNA expression in bronchial epithelial cells. NF-kB and MAPK p38 were involved in LPS-induced CXCL1 production. Therapeutic anti-inflammatory agents minimally attenuated CXCL1 production and considerably inhibited CXCL8 production in BEAS-2B cells.

Conclusions: Sputum CXCL1 levels is a potentially better diagnostic marker for COPD than sputum CXCL8 levels, which is explained by that CXCL1 production in bronchial epithelial cells is less affected by therapeutic anti-inflammatory agents than CXCL8 production.
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http://dx.doi.org/10.1080/01902148.2018.1520936DOI Listing
September 2018

A 17-year-old woman with a solitary, mixed squamous cell and glandular papilloma of the bronchus.

Respirol Case Rep 2019 Feb 30;7(2):e00393. Epub 2018 Nov 30.

Department of Respiratory Medicine Kyorin University School of Medicine Tokyo Japan.

A 17-year-old woman was referred to our hospital due to cough on exertion and right chest pain over the previous two months, together with bloody sputum over the previous week. Chest X-ray demonstrated a nodule measuring 3 cm in diameter in the right middle lung field. On repeated bronchoscopy, the tumour was recognized as a rapidly growing intra-bronchial protruded tumour at the orifice of the right B8. Based on a tentative diagnosis of lung cancer, right lower lobectomy was performed. She was diagnosed with mixed squamous cell and glandular papilloma of the bronchus without smoking history and human papillomavirus infection. Solitary endobronchial papillomas are rare but should be considered a differential diagnosis for solitary lung nodule with the potential to develop into carcinoma.
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http://dx.doi.org/10.1002/rcr2.393DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6266232PMC
February 2019

Diagnostic clue for pleural metastasis of malignant melanoma.

J Gen Fam Med 2018 Nov 27;19(6):217-218. Epub 2018 Aug 27.

Department of Respiratory Medicine Kyorin University School of Medicine Mitaka, Tokyo Japan.

This case demonstrated the importance of recognition of melanin pigments in pleural effusion as a diagnostic tool for metastasis of malignant melanoma.
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http://dx.doi.org/10.1002/jgf2.200DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6238232PMC
November 2018

Amelanotic Malignant Melanoma with Dense Pleural Thickening Mimicking Malignant Mesothelioma.

Intern Med 2019 Apr 19;58(7):969-972. Epub 2018 Nov 19.

Division of Allergy, Pulmonary, and Critical Care Medicine, Vanderbilt University Medical Center, USA.

A 51-year-old man was diagnosed with stage IIC nodular malignant melanoma (T4bN0M0) of the right upper arm. The tumor was treatment-refractory, and left-sided pleural effusion emerged 1.5 years later. Aspiration of pleural fluid revealed abundant amelanotic, atypical cells that resembled epithelial malignant mesothelioma or lung adenocarcinoma cells; these cells were positive for melanoma-associated antigen recognized by T cells (MART-1)/Melan-A, HMB-45, and S-100 on immunocytochemistry. Thoracic computed tomography (CT) revealed marked diffuse pleural thickening in the left hemithorax that mimicked malignant mesothelioma; thus, the present report describes the unique cytological and radiological findings of this case.
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http://dx.doi.org/10.2169/internalmedicine.0867-18DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6478975PMC
April 2019

Serum sST2 levels predict severe exacerbation of asthma.

Respir Res 2018 Sep 3;19(1):169. Epub 2018 Sep 3.

Department of Respiratory Medicine, Kyorin University School of Medicine, 6-20-3 Sinkawa, Mitaka-city, Tokyo, 181-8612, Japan.

Background: Neutrophilic inflammation is associated with poorly controlled asthma. Serum levels of sST2, a soluble IL-33 receptor, increase in neutrophilic lung diseases. We hypothesized that high serum sST2 levels in stable asthmatics are a predictor for exacerbation within a short duration.

Methods: This prospective observational study evaluated the serum sST2 levels of 104 asthmatic patients who were treated by a lung disease specialist with follow-ups for 3 months.

Results: High serum sST2 levels (> 18 ng/ml) predicted severe asthma exacerbation within 3 months. Serum sST2 levels correlated positively with asthma severity (treatment step), airway HO levels, and serum IL-8 levels. High serum sST2 levels and blood neutrophilia (> 6000 /μl) were independent predictors of exacerbation. We defined a post-hoc exacerbation-risk score combining high serum sST2 level and blood neutrophilia, which stratified patients into four groups. The score predicted exacerbation-risk with an area under curve of 0.91 in the receiver operating characteristic curve analysis. Patients with the highest scores had the most severe phenotype, with 85.7% showing exacerbation, airflow limitation, and corticosteroid-insensitivity.

Conclusions: High serum sST2 levels predicted exacerbation within the general asthmatic population and, when combined with blood neutrophil levels, provided an exacerbation-risk score that was an accurate predictor of exacerbation occurring within 3 months.
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http://dx.doi.org/10.1186/s12931-018-0872-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6126416PMC
September 2018
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