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Acute respiratory distress syndrome (ARDS) is characterized by dysregulated inflammation and increased permeability of lung microvascular cells. CD26/dipeptidyl peptidase-4 (DPP4) is a type II membrane protein that is expressed in several cell types and mediates multiple pleiotropic effects. We previously reported that DPP4 inhibition by sitagliptin attenuates lipopolysaccharide (LPS)-induced lung injury in mice. The current study characterized the functional role of CD26/DPP4 expression in LPS-induced lung injury in mice, isolated alveolar macrophages, and cultured lung endothelial cells. In LPS-induced lung injury, inflammatory responses [bronchoalveolar lavage fluid (BALF) neutrophil numbers and several proinflammatory cytokine levels] were attenuated in Dpp4 knockout (Dpp4 KO) mice. However, multiple assays of alveolar capillary permeability were similar between the Dpp4 KO and wild-type mice. TNF-α and IL-6 production was suppressed in alveolar macrophages isolated from Dpp4 KO mice. In contrast, in cultured mouse lung microvascular endothelial cells (MLMVECs), reduction in CD26/DPP4 expression by siRNA resulted in greater ICAM-1 and IL-6 expression after LPS stimulation. Moreover, the LPS-induced vascular monolayer permeability in vitro was higher in MLMVECs treated with Dpp4 siRNA, suggesting that CD26/DPP4 plays a protective role in endothelial barrier function. In summary, this study demonstrated that genetic deficiency of Dpp4 attenuates inflammatory responses but not permeability in LPS-induced lung injury in mice, potentially through differential functional roles of CD26/DPP4 expression in resident cellular components of the lung. CD26/DPP4 may be a potential therapeutic target for ARDS and warrants further exploration to precisely identify the multiple functional effects of CD26/DPP4 in ARDS pathophysiology.NEW & NOTEWORTHY We aimed to clarify the functional roles of CD26/DPP4 in ARDS pathophysiology using Dpp4-deficient mice and siRNA reduction techniques in cultured lung cells. Our results suggest that CD26/DPP4 expression plays a proinflammatory role in alveolar macrophages while also playing a protective role in the endothelial barrier. Dpp4 genetic deficiency attenuates inflammatory responses but not permeability in LPS-induced lung injury in mice, potentially through differential roles of CD26/DPP4 expression in the resident cellular components of the lung.
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Dipeptidil Peptidasa 4 , Lipopolisacáridos , Macrófagos Alveolares , Animales , Masculino , Ratones , Lesión Pulmonar Aguda/inducido químicamente , Lesión Pulmonar Aguda/metabolismo , Lesión Pulmonar Aguda/patología , Líquido del Lavado Bronquioalveolar , Permeabilidad Capilar , Células Cultivadas , Dipeptidil Peptidasa 4/metabolismo , Dipeptidil Peptidasa 4/genética , Células Endoteliales/metabolismo , Células Endoteliales/patología , Molécula 1 de Adhesión Intercelular/metabolismo , Molécula 1 de Adhesión Intercelular/genética , Interleucina-6/metabolismo , Interleucina-6/genética , Pulmón/patología , Pulmón/metabolismo , Lesión Pulmonar/inducido químicamente , Lesión Pulmonar/metabolismo , Lesión Pulmonar/patología , Macrófagos Alveolares/metabolismo , Macrófagos Alveolares/patología , Ratones Endogámicos C57BL , Ratones Noqueados , Síndrome de Dificultad Respiratoria/metabolismo , Síndrome de Dificultad Respiratoria/patología , Síndrome de Dificultad Respiratoria/inducido químicamente , Factor de Necrosis Tumoral alfa/metabolismoRESUMEN
PURPOSE: Auto-antibodies (auto-abs) to type I interferons (IFNs) have been identified in patients with life-threatening coronavirus disease 2019 (COVID-19), suggesting that the presence of auto-abs may be a risk factor for disease severity. We therefore investigated the mechanism underlying COVID-19 exacerbation induced by auto-abs to type I IFNs. METHODS: We evaluated plasma from 123 patients with COVID-19 to measure auto-abs to type I IFNs. We performed single-cell RNA sequencing (scRNA-seq) of peripheral blood mononuclear cells from the patients with auto-abs and conducted epitope mapping of the auto-abs. RESULTS: Three of 19 severe and 4 of 42 critical COVID-19 patients had neutralizing auto-abs to type I IFNs. Patients with auto-abs to type I IFNs showed no characteristic clinical features. scRNA-seq from 38 patients with COVID-19 revealed that IFN signaling in conventional dendritic cells and canonical monocytes was attenuated, and SARS-CoV-2-specific BCR repertoires were decreased in patients with auto-abs. Furthermore, auto-abs to IFN-α2 from COVID-19 patients with auto-abs recognized characteristic epitopes of IFN-α2, which binds to the receptor. CONCLUSION: Auto-abs to type I IFN found in COVID-19 patients inhibited IFN signaling in dendritic cells and monocytes by blocking the binding of type I IFN to its receptor. The failure to properly induce production of an antibody to SARS-CoV-2 may be a causative factor of COVID-19 severity.
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Autoanticuerpos , COVID-19 , Interferón Tipo I , Células Mieloides , Femenino , Humanos , Masculino , Autoanticuerpos/inmunología , Autoanticuerpos/sangre , COVID-19/inmunología , Células Dendríticas/inmunología , Interferón Tipo I/inmunología , Interferón Tipo I/metabolismo , Células Mieloides/inmunología , SARS-CoV-2/inmunología , Índice de Severidad de la Enfermedad , Transducción de Señal/inmunologíaRESUMEN
BACKGROUND: Endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) has been used to diagnose and stage lung cancer. Acquire™ Pulmonary and Expect™ Pulmonary dedicated EBUS-TBNA needles were introduced as the Franseen and Lancet needles, respectively. It is still unclear whether the Franseen or Lancet needles yield a higher quality specimen especially focusing on next-generation sequencing-based molecular testing. METHODS: A single-center, prospective study performed at the Chiba University Hospital randomly assigned patients to two groups: Group A, wherein the first and second EBUS-TBNA were performed using Lancet and Franseen needles, respectively, and Group B, wherein the first and second EBUS-TBNA were performed using Franseen and Lancet needles, respectively. Each specimen was compared and analyzed pathologically. The primary outcome was the histological tissue area except blood clot and the cellularity of each sample. We also examined the success rate of molecular testing. RESULTS: Twelve patients who underwent EBUS-TBNA between November 2022 and February 2023 were enrolled in this study. The tissue area of the specimens obtained by the Franseen and Lancet needles was 13.3 ± 6.4 mm2 and 10.6 ± 6.3 mm2, respectively (P = .355). The tumor cellularity in the specimens obtained using the Franseen and Lancet needles was 54.0 ± 30.3 and 46.2 ± 36.3%, respectively (P = .608). The success rate of molecular testing using the single-pass sample by Franseen needle was 85.7 and 57.1% by Lancet needle. No serious complications were reported. CONCLUSIONS: The Franseen needle tended to show a greater amount of specimen with higher tumor cellularity than the Lancet needle which may contribute higher success rate of molecular testing. Further studies must be conducted to validate the results of this study. KEY FINDINGS: What is known and what is new? What is the implication, and what should change now?
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BACKGROUND: Serum levels of stratifin (SFN), a member of the 14-3-3 protein family, increase in patients with drug-induced lung injury associated with diffuse alveolar damage. Therefore, we hypothesised that SFN levels would be higher in those experiencing acute exacerbation of interstitial lung disease (AE-ILD). A secondary analysis was also planned to determine whether SFN levels could discriminate survival in those with AE. METHODS: Thirty-two patients with clinically stable ILD (CS-ILD) and 22 patients with AE-ILD were examined to assess whether high serum SFN levels were associated with AE-ILD and whether SFN levels reflected disease severity or prognosis in patients with AE-ILD. RESULTS: Serum SFN levels were higher in the AE-ILD group than in the CS-ILD group (8.4 ± 7.6 vs. 1.3 ± 1.2 ng/mL, p < 0.001). The cut-off value of the serum SFN concentration for predicting 90-day and 1-year survival was 6.6 ng/mL. SFN levels were higher in patients who died within 90 days and 1 year than in patients who survived beyond these time points (13.5 ± 8.7 vs. 5.6 ± 5.3 ng/mL; p = 0.011 and 13.1 ± 7.5 vs. 3.1 ± 1.9 ng/mL; p < 0.001, respectively) in the AE-ILD group. When this cut-off value was used, the 90-day and 1-year survival rates were significantly better in the population below the cut-off value than in those above the cut-off value (p = 0.0017 vs. p < 0.0001). CONCLUSIONS: High serum SFN levels are associated with AE-ILD and can discriminate survival in patients with AE-ILD.
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Proteínas 14-3-3 , Progresión de la Enfermedad , Exorribonucleasas , Enfermedades Pulmonares Intersticiales , Índice de Severidad de la Enfermedad , Humanos , Masculino , Femenino , Anciano , Exorribonucleasas/sangre , Enfermedades Pulmonares Intersticiales/sangre , Enfermedades Pulmonares Intersticiales/mortalidad , Enfermedades Pulmonares Intersticiales/diagnóstico , Estudios Retrospectivos , Proteínas 14-3-3/sangre , Persona de Mediana Edad , Pronóstico , Biomarcadores/sangre , Anciano de 80 o más AñosRESUMEN
BACKGROUND: Pulmonary arterial hypertension is a serious medical condition. However, the condition is often misdiagnosed or a rather long delay occurs from symptom onset to diagnosis, associated with decreased 5-year survival. In this study, we developed and tested a deep-learning algorithm to detect pulmonary arterial hypertension using chest X-ray (CXR) images. METHODS: From the image archive of Chiba University Hospital, 259 CXR images from 145 patients with pulmonary arterial hypertension and 260 CXR images from 260 control patients were identified; of which 418 were used for training and 101 were used for testing. Using the testing dataset for each image, the algorithm outputted a numerical value from 0 to 1 (the probability of the pulmonary arterial hypertension score). The training process employed a binary cross-entropy loss function with stochastic gradient descent optimization (learning rate parameter, α = 0.01). In addition, using the same testing dataset, the algorithm's ability to identify pulmonary arterial hypertension was compared with that of experienced doctors. RESULTS: The area under the curve (AUC) of the receiver operating characteristic curve for the detection ability of the algorithm was 0.988. Using an AUC threshold of 0.69, the sensitivity and specificity of the algorithm were 0.933 and 0.982, respectively. The AUC of the algorithm's detection ability was superior to that of the doctors. CONCLUSION: The CXR image-derived deep-learning algorithm had superior pulmonary arterial hypertension detection capability compared with that of experienced doctors.
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Aprendizaje Profundo , Hipertensión Arterial Pulmonar , Humanos , Inteligencia Artificial , Hipertensión Arterial Pulmonar/diagnóstico por imagen , Rayos X , TóraxRESUMEN
Two anti-fibrotic drugs, pirfenidone (PFD) and nintedanib (NTD), are currently used to treat idiopathic pulmonary fibrosis (IPF). Peripheral blood mononuclear cells (PBMCs) are immunocompetent cells that could orchestrate cell-cell interactions associated with IPF pathogenesis. We employed RNA sequencing to examine the transcriptome signature in the bulk PBMCs of patients with IPF and the effects of anti-fibrotic drugs on these signatures. Differentially expressed genes (DEGs) between "patients with IPF and healthy controls" and "before and after anti-fibrotic treatment" were analyzed. Enrichment analysis suggested that fatty acid elongation interferes with TGF-ß/Smad signaling and the production of oxidative stress since treatment with NTD upregulates the fatty acid elongation enzymes ELOVL6. Treatment with PFD downregulates COL1A1, which produces wound-healing collagens because activated monocyte-derived macrophages participate in the production of collagen, type I, and alpha 1 during tissue damage. Plasminogen activator inhibitor-1 (PAI-1) regulates wound healing by inhibiting plasmin-mediated matrix metalloproteinase activation, and the inhibition of PAI-1 activity attenuates lung fibrosis. DEG analysis suggested that both the PFD and NTD upregulate SERPINE1, which regulates PAI-1 activity. This study embraces a novel approach by using RNA sequencing to examine PBMCs in IPF, potentially revealing systemic biomarkers or pathways that could be targeted for therapy.
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Fibrosis Pulmonar Idiopática , Inhibidor 1 de Activador Plasminogénico , Humanos , Leucocitos Mononucleares , Transcriptoma , Fibrosis Pulmonar Idiopática/tratamiento farmacológico , Fibrosis Pulmonar Idiopática/genética , Ácidos GrasosRESUMEN
Pulmonary hypertension (PH) with interstitial lung diseases (ILDs) often causes intractable conditions. CD26/Dipeptidyl peptidase-4 (DPP4) is expressed in lung constituent cells and may be related to the pathogenesis of various respiratory diseases. We aimed to clarify the functional roles of CD26/DPP4 in PH-ILD, paying particular attention to vascular smooth muscle cells (SMCs). Dpp4 knockout (Dpp4KO) and wild type (WT) mice were administered bleomycin (BLM) intraperitoneally to establish a PH-ILD model. The BLM-induced increase in the right ventricular systolic pressure and the right ventricular hypertrophy observed in WT mice were attenuated in Dpp4KO mice. The BLM-induced vascular muscularization in small pulmonary vessels in Dpp4KO mice was milder than that in WT mice. The viability of TGFß-stimulated human pulmonary artery SMCs (hPASMCs) was lowered due to the DPP4 knockdown with small interfering RNA. According to the results of the transcriptome analysis, upregulated genes in hPASMCs with TGFß treatment were related to pulmonary vascular SMC proliferation via the Notch, PI3K-Akt, and NFκB signaling pathways. Additionally, DPP4 knockdown in hPASMCs inhibited the pathways upregulated by TGFß treatment. These results suggest that genetic deficiency of Dpp4 protects against BLM-induced PH-ILD by alleviating vascular remodeling, potentially through the exertion of an antiproliferative effect via inhibition of the TGFß-related pathways in PASMCs.
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Hipertensión Pulmonar , Enfermedades Pulmonares Intersticiales , Osteocondrodisplasias , Humanos , Animales , Ratones , Hipertensión Pulmonar/inducido químicamente , Hipertensión Pulmonar/genética , Dipeptidil Peptidasa 4/genética , Fosfatidilinositol 3-Quinasas , Enfermedades Pulmonares Intersticiales/inducido químicamente , Enfermedades Pulmonares Intersticiales/genética , Bleomicina/toxicidad , Ratones Noqueados , Factor de Crecimiento Transformador beta/genéticaRESUMEN
Non-emphysematous chronic obstructive pulmonary disease (COPD), which is defined based on chest computed tomography findings, presented different transcriptome features of peripheral blood mononuclear cells (PBMCs) compared with emphysematous COPD. Enrichment analysis of transcriptomic data in COPD demonstrated that the "Hematopoietic cell lineage" pathway in Kyoto Encyclopedia of Genes and Genomes pathway analysis was highly upregulated, suggesting that cellular dynamic dysregulation in COPD lungs is affected by pathologically modified PBMCs. The differentially expressed genes (DEGs) upregulated in PBMCs reflected the disease state of non-emphysematous COPD. Upregulated DEGs such as XCL1, PRKCZ, TMEM102, CD200R1, and AQP1 activate T lymphocytes and eosinophils. Upregulating keratan sulfate biosynthesis and metabolic processes is associated with protection against the destruction of the distal airways. ITGA3 upregulation augments interactions with extracellular matrix proteins, and COL6A1 augments the profibrotic mast cell phenotype during alveolar collagen VI deposition. Upregulating HSPG2, PDGFRB, and PAK4 contributes to the thickening of the airway wall, and upregulating SERPINF1 expression explains the better-preserved vascular bed. Therefore, gene expression and pathway analysis in PBMCs in patients with non-emphysematous COPD represented type 2 immune responses and airway remodeling features. Therefore, these patients have asthmatic potential despite no clinical signs of asthma, in contrast to those with emphysematous COPD.
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Asma , Enfermedad Pulmonar Obstructiva Crónica , Humanos , Transcriptoma , Leucocitos Mononucleares , Enfermedad Pulmonar Obstructiva Crónica/genética , Genes Reguladores , Quinasas p21 ActivadasRESUMEN
BACKGROUND Hemoptysis due to airway hemorrhage is treated with hemostatic agents, bronchial artery embolization (BAE), or surgical resection. We present the case of a 65-year-old man with refractory hemoptysis associated with chronic progressive pulmonary aspergillosis (CPPA) who failed to respond to combined endobronchial occlusion (EBO) with endobronchial Watanabe spigot (EWS) and BAE. CASE REPORT A 63-year-old man was diagnosed with CPPA in the right upper lung and presented to our hospital 2 years later for hemoptysis at age 65. He developed severe hemoptysis during an outpatient visit, and was urgently admitted, intubated, and ventilated to prevent choking on blood clots. Chest computed tomography showed a large mass in the apical portion of the right lung, constituting apical pleural thickening and an encapsulated pleural effusion, and dilatation in the bronchial artery supplying the right upper lung lobe. Bronchoscopy revealed the right upper lobe B1-B3 as the bleeding source. The patient had recurrent hemoptysis that was not controlled by BAE or 6 EBO+EWS procedures, and he ultimately died of hypoxemia.In the literature review, EBO+EWS can effectively control hemoptysis in appropriate cases, without the need for BAE or surgical lung resection. It is less invasive, is associated with fewer adverse events than BAE or surgery, and can achieve temporary hemostasis for severe hemoptysis. CONCLUSIONS BAE and EBO+EWS were ineffective in controlling recurrent hemoptysis caused by CPPA in this case. However, a multidisciplinary approach such as attempting hemostasis with combined EBO+EWS and BAE may be a viable treatment option in severe cases of hemoptysis.
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Embolización Terapéutica , Aspergilosis Pulmonar , Enfermedades Vasculares , Anciano , Humanos , Masculino , Bronquios , Arterias Bronquiales , Embolización Terapéutica/métodos , Hemoptisis/etiología , Hemoptisis/terapia , Aspergilosis Pulmonar/complicaciones , Aspergilosis Pulmonar/terapia , Enfermedades Vasculares/terapiaRESUMEN
Background: The usefulness of lung ultrasound (LUS) has been demonstrated. However, it is unclear whether diagnostic techniques using LUS are accepted by all physicians. A simple simulation-based educational program may improve the LUS skills of beginners, but it has not been fully assessed. Objective: This prospective study was conducted to assess the educational outcomes of LUS training using a high-fidelity simulator. Methods: A simulator-based program for LUS was conducted. All clerkship students at the Department of Respirology at Chiba University Hospital participated in the program from December 2022 to April 2023. The participants watched a 30 minute teaching video on demand before a hands-on session lasting for 1 hour during the first week of the clinical clerkship. The readiness of the participants to learn LUS and the usefulness of the program were assessed using questionnaires administered before and after the program. The LUS skills were assessed using simulator-based tests during Weeks 1 and 4. Data on the accuracy and time required to answer the questions were collected during the tests. Results: Forty clerkship students participated in this study. Thirty-three (82.5%) had received other ultrasound education; however, only two (5.0%) had experience with LUS. Based on the questionnaire responses, the participants perceived LUS as useful (preprogram: 4.6 vs. postprogram: 4.8; P = 0.010; a 5-point Likert scale was used [1: not useful to 5: useful]). The simulator-based tests showed comparable accuracies at Weeks 1 and 4 for pneumothorax (Week 1: 47.5% vs. Week 4: 52.5%; P = 0.623), pulmonary edema (Week 1: 100% vs. Week 4: 100%; P = 1.000), and pleural effusion (Week 1: 37.5% vs. Week 4: 40.0%; P = 0.800). The time required for scanning was the same for each question. In addition, the test results did not differ with prior learning, previous knowledge, or experience during clinical clerkships on LUS. Conclusion: A short educational program consisting of on-demand learning and hands-on sessions with a high-fidelity simulator would be effective in equipping clerkship students with basic LUS skills. However, to increase its educational effectiveness to a practical degree, the program should be improved, and more opportunities for training using simulators should be provided.
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Radiation-induced organizing pneumonia is a rare complication of radiation therapy for thoracic cancer. Carbon-ion radiotherapy, an emerging treatment modality for early-stage lung cancer treatment, can also cause lung injuries. However, as cases of radiation-induced organizing pneumonia caused by carbon-ion radiotherapy for lung cancer have not been reported, its clinical features remain unclear. A 69-year-old woman was referred to our hospital 11 months after being diagnosed with early lung cancer due to refractory pneumonitis induced by carbon-ion radiotherapy. She had developed fever and dyspnea 4 months after undergoing carbon-ion radiotherapy and was subsequently diagnosed with radiation pneumonitis. The administration of oral prednisolone resulted in improvement. However, she relapsed each time the dose of prednisolone was tapered. She was diagnosed with radiation-induced organizing pneumonia caused by carbon-ion radiotherapy for lung cancer based on the clinical course and the results of the examination performed at our hospital. An improvement was observed after administering methylprednisolone (1000 mg/d) for 3 days. The dose of oral prednisolone was slowly tapered over a period of ≥6 months with no relapse. Organizing pneumonia caused by carbon-ion radiotherapy for lung cancer is treatable with corticosteroids; however, tapering the dose of corticosteroids may lead to relapse.
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Numerous SARS-CoV-2 variant strains with altered characteristics have emerged since the onset of the COVID-19 pandemic. Remdesivir (RDV), a ribonucleotide analogue inhibitor of viral RNA polymerase, has become a valuable therapeutic agent. However, immunosuppressed hosts may respond inadequately to RDV and develop chronic persistent infections. A patient with respiratory failure caused by interstitial pneumonia, who had undergone transplantation of the left lung, developed COVID-19 caused by Omicron BA.5 strain with persistent chronic viral shedding, showing viral fusogenicity. Genome-wide sequencing analyses revealed the occurrence of several viral mutations after RDV treatment, followed by dynamic changes in the viral populations. The C799F mutation in nsp12 was found to play a pivotal role in conferring RDV resistance, preventing RDV-triphosphate from entering the active site of RNA-dependent RNA polymerase. The occurrence of diverse mutations is a characteristic of SARS-CoV-2, which mutates frequently. Herein, we describe the clinical case of an immunosuppressed host in whom inadequate treatment resulted in highly diverse SARS-CoV-2 mutations that threatened the patient's health due to the development of drug-resistant variants.
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Adenosina Monofosfato/análogos & derivados , Alanina , Alanina/análogos & derivados , COVID-19 , ARN Polimerasa Dependiente de ARN de Coronavirus , Trasplante de Pulmón , Mutación , SARS-CoV-2 , Humanos , SARS-CoV-2/genética , COVID-19/virología , Alanina/uso terapéutico , Masculino , Antivirales/uso terapéutico , Huésped Inmunocomprometido , Adenosina Monofosfato/uso terapéutico , Farmacorresistencia Viral/genética , Persona de Mediana Edad , Tratamiento Farmacológico de COVID-19 , Enfermedades Pulmonares Intersticiales/genética , Enfermedades Pulmonares Intersticiales/virologíaRESUMEN
INTRODUCTION: Tube thoracostomy (TT) complications are common in respiratory medicine. However, the prevalence of complications and risk factors is unknown, and data on countermeasures are lacking. METHODS: This was a mixed-methods retrospective observational and qualitative study. This retrospective observational study included TT performed on patients admitted to the Department of Respiratory Medicine at our University Hospital between January 1, 2019, and August 31, 2022 (n=169). The primary endpoint was the incidence of TT-related complications. We reviewed the association between complications and patient- and medical-related factors as secondary endpoints. In this qualitative study, we theorized the background of physicians' susceptibility to TT-related complications based on the grounded theory approach. RESULTS: Complications were observed in 20 (11.8%) of the 169 procedures; however, they were unrelated to 30-day mortality. Poor activities of daily living (odds ratio 4.3, p=0.007) and regular administration of oral steroids (odds ratio 3.1, p=0.025) were identified as patient-related risk factors. Physicians undergoing training caused the most complications, and the absence of a senior physician at the procedure site (odds ratio 3.5, p=0.031) was identified as a medical risk factor. Based on this qualitative study, we developed a new model for TT complication rates consistent with the relationship between physicians' professional skills, professional identity, and work environments. CONCLUSIONS: Complications associated with TT are common. Therefore, it is necessary to implement measures similar to those identified in this study. Particularly, a supportive environment should be established for the training of physicians.
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In clinical clerkship (CC), medical students can practice evidence-based medicine (EBM) with their assigned patients. Although CC can be a valuable opportunity for EBM education, the impact of EBM training, including long-term behavioral changes, remains unclear. One hundred and nine fourth- and fifth-year medical students undergoing CC at a medical school in Japan attended a workplace-based learning program for EBM during CC (WB-EBM), which included the practice of the five steps of EBM. The program's effect on the students' attitudes toward EBM in CC was assessed through questionnaires. A total of 88 medical students participated in the program. Responses to the questionnaire indicated high satisfaction with the WB-EBM program. The most common theme in students' clinical problems with their assigned patients was the choice of treatment, followed by its effect. Based on the responses in the post-survey for the long-term effects of the program, the frequency of problem formulation and article reading tended to increase in the 'within six months' group comprising 18 students who participated in the WB-EBM program, compared with the control group comprising 34 students who did not. Additionally, the ability to self-assess problem formulation was significantly higher, compared with the control group. However, among 52 students who participated in the WB-EBM program more than six months later, EBM-related behavioral habits in CC and self-assessments of the five steps of EBM were not significantly different from those in the control group. The WB-EBM program was acceptable for medical students in CC. It motivated them to formulate clinical questions and enhanced their critical thinking. Moreover, the WB-EBM program can improve habits and self-evaluations about EBM. However, as its effects may not last more than six months, it may need to be repeated across departments throughout CC to change behavior in EBM practice.
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Prácticas Clínicas , Medicina Basada en la Evidencia , Estudiantes de Medicina , Lugar de Trabajo , Humanos , Prácticas Clínicas/organización & administración , Estudiantes de Medicina/psicología , Medicina Basada en la Evidencia/educación , Lugar de Trabajo/psicología , Femenino , Actitud del Personal de Salud , Japón , Masculino , Encuestas y CuestionariosRESUMEN
Hermansky-Pudlak syndrome (HPS) is a rare autosomal recessive disease that often causes progressive pulmonary fibrosis (HPS-PPF) in some genetic types with high mortality rates. No effective treatment for HPS-PPF other than lung transplantation has been established. Herein, we report a case of HPS type 1 with progressive pulmonary fibrosis treated with long-term nintedanib administration followed by lung transplantation. The resected lungs revealed diffuse interstitial lung lesions, including fibroblastic foci, suggesting the potential beneficial effects of anti-fibrotic drugs in HPS-PPF. Together with previous reports, the present case suggests that nintedanib might be a safe and effective drug for HPS-PPF.
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Albinismo , Trastornos Hemorrágicos , Síndrome de Hermanski-Pudlak , Indoles , Trasplante de Pulmón , Fibrosis Pulmonar , Humanos , Fibrosis Pulmonar/etiología , Fibrosis Pulmonar/complicaciones , Síndrome de Hermanski-Pudlak/complicaciones , Síndrome de Hermanski-Pudlak/tratamiento farmacológico , Síndrome de Hermanski-Pudlak/genética , Pulmón/patologíaRESUMEN
BACKGROUND: The Guidelines for the Management of Cough and Sputum (2019) of the Japanese Respiratory Society (JRS) were the first internationally published guidelines for the management of sputum. However, the data used to determine the causative diseases of bloody sputum and hemoptysis in these guidelines were not obtained in Japan. METHODS: A retrospective analysis was performed using the clinical information of patients with bloody sputum or hemoptysis who visited the department of respiratory medicine at a university or core hospital in Japan. RESULTS: Included in the study were 556 patients (median age, 73 years; age range, 21-98 years; 302 males (54.3%)). The main causative diseases were bronchiectasis (102 patients (18.3%)), lung cancer (97 patients (17.4%)), and non-tuberculous mycobacterial disease (89 patients (16%)). Sex and age differences were observed in the frequency of causative diseases of bloody sputum and hemoptysis. The most common cause was lung cancer in males (26%), bronchiectasis in females (29%), lung cancer in patients aged <65 years (19%), and bronchiectasis in those aged >65 years (20%). CONCLUSIONS: The present study is the first to investigate the causative diseases of bloody sputum and hemoptysis using data obtained in Japan. When investigating the causative diseases of bloody sputum and hemoptysis, it is important to take the sex and age of the patients into account.
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Bronquiectasia , Neoplasias Pulmonares , Neumología , Masculino , Femenino , Humanos , Anciano , Adulto Joven , Adulto , Persona de Mediana Edad , Anciano de 80 o más Años , Hemoptisis/epidemiología , Hemoptisis/etiología , Esputo/microbiología , Japón/epidemiología , Hospitales Universitarios , Estudios Retrospectivos , Tomografía Computarizada por Rayos X , Bronquiectasia/epidemiología , Bronquiectasia/complicaciones , Neoplasias Pulmonares/complicaciones , Neoplasias Pulmonares/epidemiologíaRESUMEN
INTRODUCTION: Programmed cell death ligand-1 (PD-L1) expression is a predictive biomarker for the efficacy of anti-programmed cell death receptor-1/PD-L1 antibodies in advanced non-small cell lung cancer (NSCLC). Although several assays have been approved for evaluating PD-L1 expression status, inter-assay discordance has been observed between some assays. The clinical significance of these discrepancies is still unclear. METHODS: We retrospectively reviewed treatment-naïve NSCLC patients whose PD-L1 expression was evaluated using both 22C3 and SP142 assays. Among those, efficacy analysis was performed for patients with PD-L1 tumor proportion score (TPS) ≥ 50 % (22C3), who had received first-line pembrolizumab monotherapy. Additionally, transcriptome analysis was conducted in the available tumors with TPS ≥ 50 % to investigate the distinct immune profiles that accompany inter-assay discordance. RESULTS: In total, 611 patients were eligible. Among 198 patients with TPS ≥ 50 %, 91 (46 %) had tumor cell score ≤ 1 (SP142, i.e., inter-assay discrepancy). In the 52 patients who received first-line pembrolizumab monotherapy, treatment efficacy was significantly lower in patients with the discrepancy than that in those without (objective response rate: 18 % vs. 83 %, p < 0.001; median progression-free survival [months]: 3.2 vs. 8.3, p < 0.001). Transcriptome analysis revealed significantly more CD274 splice variants with aberrant 3'-terminal sequences in tumors with the inter-assay discrepancy than in those without. CONCLUSION: The inter-assay discrepancy in the PD-L1 status of tumor cells between the 22C3 and SP142 assays, reflecting an imbalance in the CD274 splice variants, could be a biomarker for primary resistance against pembrolizumab monotherapy in high PD-L1-expressing NSCLCs.
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Anticuerpos Monoclonales Humanizados , Antígeno B7-H1 , Biomarcadores de Tumor , Carcinoma de Pulmón de Células no Pequeñas , Neoplasias Pulmonares , Humanos , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Carcinoma de Pulmón de Células no Pequeñas/genética , Carcinoma de Pulmón de Células no Pequeñas/patología , Anticuerpos Monoclonales Humanizados/uso terapéutico , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/patología , Neoplasias Pulmonares/genética , Masculino , Antígeno B7-H1/genética , Antígeno B7-H1/metabolismo , Femenino , Anciano , Persona de Mediana Edad , Estudios Retrospectivos , Biomarcadores de Tumor/metabolismo , Biomarcadores de Tumor/genética , Anciano de 80 o más Años , Antineoplásicos Inmunológicos/uso terapéutico , Adulto , Relevancia ClínicaRESUMEN
Inflammatory factors in the peripheral blood, such as the C-reactive protein level and neutrophil-to-lymphocyte ratio (NLR), are prognostic markers in multiple types of cancer, including non-small cell lung cancer (NSCLC). However, the association between inflammatory factors and prognosis based on histological types has not been adequately reported. In addition, the relationship between these factors and the immune condition of the tumor microenvironment (TME) is unclear. In this single center, retrospective study, we first investigated the relationship between preoperative inflammatory markers and clinical outcomes in 176 patients with NSCLC who underwent surgery. Lung adenocarcinoma (LUAD) showed no significant prognostic marker, whereas for lung squamous cell carcinoma (LUSC), a multivariate analysis showed that a high NLR was significantly associated with postoperative recurrence. In LUSC patients, the median time of postoperative recurrence-free survival in patients with a low NLR was longer than that in patients with a high NLR. We then compared the tumor-infiltrating lymphocyte (TIL) profile with inflammatory markers in peripheral blood and found that the NLR was negatively correlated with the frequencies of T cells and B cells in LUSC tissues. Thus, the NLR is a useful predictive biomarker for postoperative recurrence and may reflect the immune condition of the TME in LUSC.
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Carcinoma de Pulmón de Células no Pequeñas , Carcinoma de Células Escamosas , Neoplasias Pulmonares , Humanos , Carcinoma de Pulmón de Células no Pequeñas/diagnóstico , Carcinoma de Pulmón de Células no Pequeñas/cirugía , Pronóstico , Neoplasias Pulmonares/patología , Neutrófilos/patología , Estudios Retrospectivos , Microambiente Tumoral , Estadificación de Neoplasias , Linfocitos/patología , Carcinoma de Células Escamosas/patología , Células Epiteliales/patologíaRESUMEN
INTRODUCTION: To date, there is limited evidence on the effects of bronchodilators on respiratory dynamics in chronic obstructive pulmonary disease (COPD). Dynamic chest radiography (DCR) is a novel radiographic modality that provides real-time, objective and quantifiable kinetic data, including changes in the lung area (Rs), tracheal diameter, diaphragmatic kinetics and pulmonary ventilation during respiration, at a lower radiation dose than that used by fluoroscopic or CT imaging. However, the therapeutic effect of dual bronchodilators on respiratory kinetics, such as chest wall dynamics and respiratory muscle function, has not yet been prospectively evaluated using DCR. AIM: This study aims to evaluate the effects of bronchodilator therapy on respiratory kinetics in patients with COPD using DCR. METHODS AND ANALYSIS: This is an open-label, prospective, single-centre, non-controlled, comparative study. A total of 35 patients with COPD, aged 40-85 years, with a forced expiratory volume in the first second of 30-80%, will be enrolled. After a 2-4 weeks washout period, patients will receive tiotropium/olodaterol therapy for 6 weeks. Treatment effects will be evaluated based on DCR findings, pulmonary function test results and patient-related outcomes obtained before and after treatment. The primary endpoint is the change in Rs after therapy. The secondary endpoints include differences in other DCR parameters (diaphragmatic kinetics, tracheal diameter change and maximum pixel value change rate), pulmonary function test results and patient-related outcomes between pre-therapy and post-therapy values. All adverse events will be reported. ETHICS AND DISSEMINATION: Ethical approval for this study was obtained from the Ethics Committee of Chiba University Hospital. The results of this trial will be published in a peer-reviewed journal. TRIAL REGISTRATION NUMBER: jRCTs032210543.
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Benzoxazinas , Broncodilatadores , Combinación de Medicamentos , Enfermedad Pulmonar Obstructiva Crónica , Bromuro de Tiotropio , Humanos , Enfermedad Pulmonar Obstructiva Crónica/tratamiento farmacológico , Enfermedad Pulmonar Obstructiva Crónica/diagnóstico por imagen , Enfermedad Pulmonar Obstructiva Crónica/fisiopatología , Bromuro de Tiotropio/administración & dosificación , Bromuro de Tiotropio/uso terapéutico , Estudios Prospectivos , Broncodilatadores/uso terapéutico , Broncodilatadores/administración & dosificación , Anciano , Benzoxazinas/uso terapéutico , Benzoxazinas/administración & dosificación , Persona de Mediana Edad , Masculino , Anciano de 80 o más Años , Femenino , Adulto , Radiografía Torácica , Volumen Espiratorio Forzado/efectos de los fármacos , Pulmón/diagnóstico por imagen , Pulmón/fisiopatología , Pulmón/efectos de los fármacosRESUMEN
Pulmonary macrophage transplantation (PMT) is a gene and cell transplantation approach in development as therapy for hereditary pulmonary alveolar proteinosis (hPAP), a surfactant accumulation disorder caused by mutations in CSF2RA/B (and murine homologs). We conducted a toxicology study of PMT of Csf2ra gene-corrected macrophages (mGM-Rα+MÏs) or saline-control intervention in Csf2raKO or wild-type (WT) mice including single ascending dose and repeat ascending dose studies evaluating safety, tolerability, pharmacokinetics, and pharmacodynamics. Lentiviral-mediated Csf2ra cDNA transfer restored GM-CSF signaling in mGM-Rα+MÏs. Following PMT, mGM-Rα+MÏs engrafted, remained within the lungs, and did not undergo uncontrolled proliferation or result in bronchospasm, pulmonary function abnormalities, pulmonary or systemic inflammation, anti-transgene product antibodies, or pulmonary fibrosis. Aggressive male fighting caused a similarly low rate of serious adverse events in saline- and PMT-treated mice. Transient, minor pulmonary neutrophilia and exacerbation of pre-existing hPAP-related lymphocytosis were observed 14 days after PMT of the safety margin dose but not the target dose (5,000,000 or 500,000 mGM-Rα+MÏs, respectively) and only in Csf2raKO mice but not in WT mice. PMT reduced lung disease severity in Csf2raKO mice. Results indicate PMT of mGM-Rα+MÏs was safe, well tolerated, and therapeutically efficacious in Csf2raKO mice, and established a no adverse effect level and 10-fold safety margin.