Publications by authors named "Naozumi Hashimoto"

108 Publications

Amelanotic Malignant Melanoma with a BRAF V600E Mutation Mimicking Primary Lung Cancer.

Intern Med 2021 Aug 24. Epub 2021 Aug 24.

Department of Respiratory Medicine, Nagoya University Graduate School of Medicine, Japan.

Amelanotic melanoma is a rare type of melanoma that shows little or no melanin pigmentation. When tumor lesions are not detected in cutaneous sites, the presence of melanin is the hallmark sign of malignant melanoma. We herein report a case of amelanotic melanoma with a BRAF V600E mutation mimicking primary lung cancer that was finally diagnosed on an autopsy. The current case suggests important caveats for the differential diagnosis of patients with BRAF V600E mutation-positive poorly differentiated lung tumors. In terms of the pathological diagnosis, routine immunohistochemical staining may be useful, especially in patients with a poorly differentiated lung tumor without TTF-1 expression.
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http://dx.doi.org/10.2169/internalmedicine.6657-20DOI Listing
August 2021

Clinical course of liver injury induced by immune checkpoint inhibitors in patients with advanced malignancies.

Hepatol Int 2021 Aug 9. Epub 2021 Aug 9.

Department of Gastroenterology and Hepatology, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya, 466-8550, Japan.

Background: The clinical course of liver injury induced by immune checkpoint inhibitors (ICIs) varies among individuals, and there were few reports on the therapeutic effects of corticosteroids based on the patterns of liver injury.

Methods: We evaluated the characteristics and clinical course of immune-related liver injury in 1214 patients treated with ICIs for advanced malignancies except for hepatocellular carcinoma between August 2014 and May 2021.

Results: During the follow-up period (median, 252 days), 58 patients (4.8%) had an immune-related liver injury (≥ Grade 3). The liver-injury patterns were hepatocellular (n = 26, 44.8%), mixed (n = 11, 19.0%), or cholestatic (n = 21, 36.2%), and the median time to onset of liver injury was 39, 81, and 53 days, respectively; the hepatocellular pattern occurred earlier than the other types (p = 0.047). Corticosteroids were administered to 30 (51.7%) patients; while liver injury was improved in almost all patients with the hepatocellular pattern (n = 13/14, 92.9%), that failed to show improvement in over half of the patients with the non-hepatocellular patterns, and three patients with mixed patterns needed secondary immunosuppression with mycophenolate mofetil. Liver biopsies performed in 13 patients mainly showed lobular injury, endothelialitis, and spotty necrosis with infiltration of T cells positive for CD3 and CD8, but not CD4 or CD20.

Conclusion: The incidence pattern and therapeutic response to corticosteroids in immune-related liver injury differ according to the injury type. Although corticosteroids were effective for the hepatocellular pattern, an additional strategy for refractory non-hepatocellular patterns is needed.
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http://dx.doi.org/10.1007/s12072-021-10238-yDOI Listing
August 2021

Retrospective Analysis of the Efficacy of Early Antiretroviral Therapy in HIV-1-Infected Patients Coinfected with .

AIDS Res Hum Retroviruses 2021 Aug 3. Epub 2021 Aug 3.

Clinical Research Center, National Hospital Organization Nagoya Medical Center, Nagoya, Japan.

The early initiation of antiretroviral therapy (ART) in HIV-infected patients shortly after the initiation of treatment for pneumonia (PCP) has not been fully validated in a clinical setting. We retrospectively extracted all patients diagnosed with HIV-related PCP (HIV-PCP), including those with severe cases, who were treated with first-line ART in our hospital. The HIV-PCP patients were divided into two groups: an early ART group (patients who commenced ART within 21 days after the start of PCP treatment) and a deferred ART group (patients who started ART after 22 days). We compared the incidence of AIDS progression or death, the virological suppression rate, and changes in the CD4 cell count at 24 weeks after the initiation of ART between the two groups. In addition, we analyzed the incidences of immune reconstitution inflammatory syndrome and grade 3 or 4 laboratory and clinical adverse events within 24 weeks as safety outcomes. Ninety-one HIV-PCP patients (36 in the early ART group and 55 in the deferred group) were included in this study. We found no significant difference in the incidence of AIDS progression or death between the two groups. Virological outcomes tended to be better in the early ART group but were not significantly different. Increases in the CD4 cell counts at 24 weeks were comparable in both groups, suggesting that the safety was not significantly different. Analysis of the propensity-score matched cohort was performed to adjust for selection bias, and no significant difference was found in any outcome. Our results suggest that early ART introduction can be considered for untreated HIV-positive patients with PCP on the basis of efficacy and safety.
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http://dx.doi.org/10.1089/AID.2021.0025DOI Listing
August 2021

Size and surface modification of silica nanoparticles affect the severity of lung toxicity by modulating endosomal ROS generation in macrophages.

Part Fibre Toxicol 2021 06 17;18(1):21. Epub 2021 Jun 17.

Department of Respiratory Medicine, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya, 466-8550, Japan.

Background: As the application of silica nanomaterials continues to expand, increasing chances of its exposure to the human body and potential harm are anticipated. Although the toxicity of silica nanomaterials is assumed to be affected by their physio-chemical properties, including size and surface functionalization, its molecular mechanisms remain unclear. We hypothesized that analysis of intracellular localization of the particles and subsequent intracellular signaling could reveal a novel determinant of inflammatory response against silica particles with different physico-chemical properties.

Results: We employed a murine intratracheal instillation model of amorphous silica nanoparticles (NPs) exposure to compare their in vivo toxicities in the respiratory system. Pristine silica-NPs of 50 nm diameters (50 nm-plain) induced airway-centered lung injury with marked neutrophilic infiltration. By contrast, instillation of pristine silica particles of a larger diameter (3 μm; 3 μm-plain) significantly reduced the severity of lung injury and neutrophilic infiltration, possibly through attenuated induction of neutrophil chemotactic chemokines including MIP2. Ex vivo analysis of alveolar macrophages as well as in vitro assessment using RAW264.7 cells revealed a remarkably lower cellular uptake of 3 μm-plain particles compared with 50 nm-plain, which is assumed to be the underlying mechanism of attenuated immune response. The severity of lung injury and neutrophilic infiltration was also significantly reduced after intratracheal instillation of silica NPs with an amine surface modification (50 nm-NH) when compared with 50 nm-plain. Despite unchanged efficacy in cellular uptake, treatment with 50 nm-NH induced a significantly attenuated immune response in RAW264.7 cells. Assessment of intracellular redox signaling revealed increased reactive oxygen species (ROS) in endosomal compartments of RAW264.7 cells treated with 50 nm-plain when compared with vehicle-treated control. In contrast, augmentation of endosomal ROS signals in cells treated with 50 nm-NH was significantly lower. Moreover, selective inhibition of NADPH oxidase 2 (NOX2) was sufficient to inhibit endosomal ROS bursts and induction of chemokine expressions in cells treated with silica NPs, suggesting the central role of endosomal ROS generated by NOX2 in the regulation of the inflammatory response in macrophages that endocytosed silica NPs.

Conclusions: Our murine model suggested that the pulmonary toxicity of silica NPs depended on their physico-chemical properties through distinct mechanisms. Cellular uptake of larger particles by macrophages decreased, while surface amine modification modulated endosomal ROS signaling via NOX2, both of which are assumed to be involved in mitigating immune response in macrophages and resulting lung injury.
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http://dx.doi.org/10.1186/s12989-021-00415-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8210371PMC
June 2021

Oxytocin receptor is a promising therapeutic target of malignant mesothelioma.

Cancer Sci 2021 Sep 4;112(9):3520-3532. Epub 2021 Jul 4.

Department of Respiratory Medicine, Nagoya University Graduate School of Medicine, Nagoya, Japan.

Malignant mesothelioma (MM) is one of the most aggressive tumors. We conducted bioinformatics analysis using Cancer Cell Line Encyclopedia (CCLE) datasets to identify new molecular markers in MM. Overexpression of oxytocin receptor (OXTR), which is a G-protein-coupled receptor for the hormone and neurotransmitter oxytocin, mRNA was distinctively identified in MM cell lines. Therefore, we assessed the role of OXTR and its clinical relevance in MM. Kaplan-Meier and Cox regression analyses were applied to assess the association between overall survival and OXTR mRNA expression using The Cancer Genome Atlas (TCGA) datasets. The function of OXTR and the efficacy of its antagonists were investigated in vitro and in vivo using MM cell lines. Consistent with the findings from CCLE datasets analysis, OXTR mRNA expression was highly increased in MM tissues compared with other cancer types in the TCGA datasets, and MM cases with high OXTR expression showed poor overall survival. Moreover, OXTR knockdown dramatically decreased MM cell proliferation in cells with high OXTR expression via tumor cell cycle disturbance, whereas oxytocin treatment significantly increased MM cell growth. OXTR antagonists, which have high selectivity for OXTR, inhibited the growth of MM cell lines with high OXTR expression, and oral administration of the OXTR antagonist, cligosiban, significantly suppressed MM tumor progression in a xenograft model. Our findings suggest that OXTR plays a crucial role in MM cell proliferation and is a promising therapeutic target that may broaden potential therapeutic options and could be a prognostic biomarker of MM.
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http://dx.doi.org/10.1111/cas.15025DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8409407PMC
September 2021

Fibroblasts positive for meflin have anti-fibrotic property in pulmonary fibrosis.

Eur Respir J 2021 May 28. Epub 2021 May 28.

National Hospital Organization Nagoya Medical Center, Nagoya, Japan.

The prognosis of elderly individuals with idiopathic pulmonary fibrosis (IPF) remains poor. Fibroblastic foci, in which aggregates of proliferating fibroblasts and myofibroblasts are involved, are the pathological hallmark lesions in IPF to represent focal areas of active fibrogenesis. Fibroblast heterogeneity in fibrotic lesions hampers the discovery of the pathogenesis of pulmonary fibrosis. Therefore, to determine of the pathogenesis of IPF, identification of functional fibroblasts is warranted. This study was aimed to determine the role of fibroblasts positive for meflin, identified as a potential marker for mesenchymal stromal cells, during the development of pulmonary fibrosis. We characterised meflin-positive cells in a single cell atlas established by single-cell RNA sequencing (scRNA-seq)-based profiling of 243 472 cells from 32 IPF lungs and 29 normal lung samples. scRNA-seq combined with RNA hybridisation identified proliferating fibroblasts positive for meflin in fibroblastic foci, not dense fibrosis, of fibrotic lungs in IPF patients. We determined the role of fibroblasts positive for meflin using bleomycin (BLM)-induced pulmonary fibrosis. A BLM-induced lung fibrosis model for meflin-deficient mice showed that fibroblasts positive for meflin had anti-fibrotic property to prevent pulmonary fibrosis. Although transforming growth factor-β-induced fibrogenesis and cell senescence with senescence-associated secretory phenotype were exacerbated in fibroblasts the repression or lack of meflin, these were inhibited in meflin-deficient fibroblasts with meflin reconstitution. These findings provide evidence to show the biological importance of meflin expression on fibroblasts and myofibroblasts in the active fibrotic region of pulmonary fibrosis.
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http://dx.doi.org/10.1183/13993003.03397-2020DOI Listing
May 2021

The Importance of Appropriate Diagnosis in the Practical Management of Chronic Obstructive Pulmonary Disease.

Diagnostics (Basel) 2021 Mar 30;11(4). Epub 2021 Mar 30.

Department of Respiratory Medicine, Nagoya University Graduate School of Medicine, Nagoya 466-8550, Japan.

Chronic obstructive pulmonary disease (COPD) is projected to continue to contribute to an increase in the overall worldwide burden of disease until 2030. Therefore, an accurate assessment of the risk of airway obstruction in patients with COPD has become vitally important. Although the Global Initiative for Chronic Obstructive Lung Disease (GOLD), the American Thoracic Society (ATS) and European Respiratory Society (ERS), and the Japanese Respiratory Society (JRS) provide the criteria by which to diagnose COPD, many studies suggest that it is in fact underdiagnosed. Its prevalence increases, while the impact of COPD-related systemic comorbidities is also increasingly recognized in clinical aspects of COPD. Although a recent report suggests that spirometry should not be used to screen for airflow limitation in individuals without respiratory symptoms, the early detection of COPD in patients with no, or few, symptoms is an opportunity to provide appropriate management based on COPD guidelines. Clinical advances have been made in pharmacotherapeutic approaches to COPD. This article provides a current understanding of the importance of an appropriate diagnosis in the real-world management of COPD.
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http://dx.doi.org/10.3390/diagnostics11040618DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8067197PMC
March 2021

Efficacies of programmed cell death 1 ligand 1 blockade in non-small cell lung cancer patients with acquired resistance to prior programmed cell death 1 inhibitor and development of diabetic ketoacidosis caused by two different etiologies: a retrospective case series.

Endocr J 2021 May 1;68(5):613-620. Epub 2021 May 1.

Department of Respiratory Medicine, Nagoya University Graduate School of Medicine, Nagoya, Japan.

The programmed cell death 1 (PD-1)/programmed cell death 1 ligand 1 (PD-L1) axis is vital for immune resistance during tumor development, while PD-L1 inhibitors can also inhibit the PD-L1/B7-1 (CD80) interaction, indicating one of the molecular differences between PD-1 and PD-L1 inhibitors. However, the clinical benefits of PD-L1 inhibitors in patients previously treated with PD-1 inhibitors remain unknown. In this study, we retrospectively analyzed the clinical data of eight patients with non-small cell lung cancer who received the PD-L1 inhibitor atezolizumab and previously treated with the PD-1 inhibitor nivolumab. The median progression-free survival was 2.1 months (1.8-18.7 months), and 4 of 8 patients achieved at least stable disease. In two of these patients, atezolizumab treatment resulted in longer progression-free survival (PFS) compared with that of nivolumab. Conversely, one patient exhibited grade 4 diabetic ketoacidosis (DKA) within 2 weeks after the initial administration of atezolizumab. Another patient had developed type 1 diabetes mellitus (T1DM) during the prior nivolumab treatment and then developed DKA due to an infection after the initiation of atezolizumab. Both of them had high-risk human leukocyte antigen-DR/DQ types relevant to T1DM. These results demonstrate the potential efficacy of PD-L1 inhibitors to some tumors that have acquired resistance to PD-1 inhibitors and suggest that appropriate managements are required for not only a newly onset of T1DM but also blood glucose control after the development of T1DM during a reiteration of the PD-1/PD-L1 blockade.
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http://dx.doi.org/10.1507/endocrj.EJ20-0769DOI Listing
May 2021

Unusual presentation of recurrent follicular lymphoma as diffuse granular shadow.

Respirol Case Rep 2021 Mar 22;9(3):e00710. Epub 2021 Feb 22.

Department of Respiratory Medicine Nagoya University Graduate School of Medicine Nagoya Japan.

A 75-year-old man was diagnosed with advanced follicular lymphoma because of enlarged cervical lymph nodes. He received chemotherapy and was in complete remission for four years. However, after four years, he developed diffuse lymphadenopathy in the abdominal and iliac area suspected to be recurrent follicular lymphoma. At the time, he was asymptomatic and did not have any accompanying lung lesions. Due to his asymptomatic state, careful monitoring was chosen. Later, he developed diffuse granular shadow in the lung fields. A definite diagnosis was difficult to achieve without histological findings. Therefore, transbronchial lung biopsy of the lesions was performed. The pathology and immunohistochemistry of the lesions revealed recurrent follicular lymphoma. Although the frequency of recurrent follicular lymphoma presenting with diffuse granular shadow is uncommon, recurrent malignant lymphoma should be considered as a differential diagnosis in case with a history of malignant lymphoma.
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http://dx.doi.org/10.1002/rcr2.710DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7898273PMC
March 2021

Impact of post-capillary pulmonary hypertension on mortality in interstitial lung disease.

Respir Investig 2021 May 10;59(3):342-349. Epub 2021 Feb 10.

National Hospital Organization Nagoya Medical Center, Nagoya, Aichi, Japan.

Background: Pulmonary hypertension (PH) influences mortality in patients with interstitial lung disease (ILD). Almost all studies on patients with ILD, have focused on the clinical impact of pre-capillary PH on survival. Therefore, little is known about the influence of post-capillary PH. We aimed to assess the prevalence of post-capillary PH and its clinical impact on survival in patients with ILD, followed by comparison with pre-capillary PH.

Methods: This retrospective study enrolled 1152 patients with ILD who were diagnosed with PH using right heart catheterization between May 2007 and December 2015. We analyzed the demographics and composite outcomes (defined as death from any cause or lung transplantation) of patients with post-capillary PH and compared them with patients with pre-capillary PH.

Results: Thirty-two (20%) of the 157 patients with ILD-PH were diagnosed with post-capillary PH. Patients with post-capillary PH had significantly lower modified Medical Research Council scores, higher diffusion capacity for carbon monoxide, higher resting PaO, lower pulmonary vascular resistance (PVR), and higher lowest oxygen saturation during the 6-min walk test compared to those with pre-capillary PH. Cardiovascular diseases were associated with a higher risk of mortality in patients with post-capillary PH. Multivariate Cox proportional hazards analysis demonstrated no significant difference between the composite outcomes in pre-capillary and post-capillary PH, while PVR and the ILD Gender-Age-Physiology Index were significantly associated with the composite outcome.

Conclusions: We found that approximately one-fifth of patients with ILD-PH were diagnosed with post-capillary PH, and that PVR and not post-capillary PH was associated with mortality.
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http://dx.doi.org/10.1016/j.resinv.2020.12.010DOI Listing
May 2021

Long noncoding RNA TINCR is a novel regulator of human bronchial epithelial cell differentiation state.

Physiol Rep 2021 02;9(3):e14727

Pulmonary, Critical Care and Sleep Medicine Section, Department of Internal Medicine, Yale University School of Medicine, New Haven, CT, USA.

Long-noncoding RNAs (lncRNAs) have numerous biological functions controlling cell differentiation and tissue development. The knowledge about the role of lncRNAs in human lungs remains limited. Here we found the regulatory role of the terminal differentiation-induced lncRNA (TINCR) in bronchial cell differentiation. RNA in situ hybridization revealed that TINCR was mainly expressed in bronchial epithelial cells in normal human lung. We performed RNA sequencing analysis of normal human bronchial epithelial cells (NHBECs) with or without TINCR inhibition and found the differential expression of 603 genes, which were enriched for cell adhesion and migration, wound healing, extracellular matrix organization, tissue development and differentiation. To investigate the role of TINCR in the differentiation of NHBECs, we employed air-liquid interface culture and 3D organoid formation assay. TINCR was upregulated during differentiation, loss of TINCR significantly induced an early basal-like cell phenotype (TP63) and a ciliated cell differentiation (FOXJ1) in late phase and TINCR overexpression suppressed basal cell phenotype and the differentiation toward to ciliated cells. Critical regulators of differentiation such as SOX2 and NOTCH genes (NOTCH1, HES1, and JAG1) were significantly upregulated by TINCR inhibition and downregulated by TINCR overexpression. RNA immunoprecipitation assay revealed that TINCR was required for the direct bindings of Staufen1 protein to SOX2, HES1, and JAG1 mRNA. Loss of Staufen1 induced TP63, SOX2, NOTCH1, HES1, and JAG1 mRNA expressions, which TINCR overexpression suppressed partially. In conclusion, TINCR is a novel regular of bronchial cell differentiation, affecting downstream regulators such as SOX2 and NOTCH genes, potentially in coordination with Staufen1.
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http://dx.doi.org/10.14814/phy2.14727DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7851438PMC
February 2021

Bronchial wall thickening is associated with severity of chronic rhinosinusitis.

Respir Med 2020 Aug - Sep;170:106024. Epub 2020 May 22.

Department of Respiratory Medicine, Nagoya University Graduate School of Medicine, Nagoya, Japan.

Background: Though the relationship between chronic rhinosinusitis (CRS) and lower airway diseases is well recognized, the impact of CRS on bronchial wall structure has not been elucidated. Here, we evaluated the bronchial wall structure of CRS patients with or without diagnosed airway diseases by three-dimensional computed tomography (3D-CT).

Methods: Subjects who underwent both chest CT and sinus CT within a year were recruited from consecutive medical records. CRS was defined as a Lund-Mackay score (LMS) of over 5 points. Airway dimensions were measured using validated software. Standard blood tests and pulmonary function tests were performed, and their correlation with airway thickness was examined.

Results: One-hundred-seventy-two patients were recruited (93 CRS subjects and 79 non-CRS subjects). The bronchial walls of CRS subjects were significantly thicker than those of non-CRS subjects. CRS and asthma were related to bronchial wall thickening by multivariate linear regression analysis adjusted for age, smoking status, and chest symptoms. In addition, LMS was significantly correlated with bronchial wall thickening.

Conclusion: Airway walls in CRS subjects were thicker than those in non-CRS subjects and associated with the severity of CRS. These data indicate strong relationship between upper and lower airways regardless of chest symptoms or diagnosed airway diseases.
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http://dx.doi.org/10.1016/j.rmed.2020.106024DOI Listing
June 2021

Comparing incidences of infusion site reactions between brand-name and generic vinorelbine in patients with non-small cell lung cancer.

Br J Clin Pharmacol 2021 03 31;87(3):1318-1326. Epub 2020 Aug 31.

Department of Respiratory Medicine, Nagoya University Graduate School of Medicine, Nagoya, Japan.

Aim: This study aimed to compare the incidence of infusion site reactions (ISRs) induced by intravenous administration of brand-name and generic vinorelbine (VNR) for treating non-small cell lung cancer.

Method: This single-centre retrospective cohort study was conducted by medical chart review of VNR infusions. ISRs were defined as symptoms around the infusion site, including pain, redness and swelling. ISRs requiring treatment were defined as ISRs requiring treatments including steroid ointments, vein repuncture and local steroid injections.

Results: In all, 1973 VNR infusions were administered to 340 patients (brand-name 141 patients, generic 199 patients). ISRs and ISRs requiring treatment were observed in 161 and 100 patients, respectively. The ISR incidence per patient and per injection was significantly higher in generic VNR-treated patients than in brand-name VNR-treated patients (53.3% vs 39.0%, P = 0.0112 and 15.0% vs 9.9%, P = 0.0008, respectively). The frequency of ISRs requiring treatment was also significantly higher in the generic group (per patient 36.7% vs 19.2%, P = 0.0005; per injection 11.3% vs 5.5%, P < 0.0001). Multivariate analysis revealed that generic VNR was significantly associated with an increased risk of ISRs (per patient adjusted odds ratio [AOR] 1.775, P = 0.0155; per injection AOR 1.672, P = 0.004) and ISRs requiring treatment (per patient AOR 2.422, P = 0.0012; per injection AOR 2.286, P = 0.001).

Conclusion: Intravenous infusion of generic VNR was associated with an increased risk of ISRs. Further research is needed to elucidate the mechanism underlying the increased incidence of ISRs with generic VNR.
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http://dx.doi.org/10.1111/bcp.14516DOI Listing
March 2021

Clinical burden of immune checkpoint inhibitor-induced pneumonitis.

Respir Investig 2020 Sep 23;58(5):305-319. Epub 2020 Jul 23.

Department of Respiratory Medicine, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya 466-8550. Japan. Electronic address:

Immune checkpoint inhibitors (ICIs) have been a breakthrough in medical oncology. However, many patients experience a novel type of adverse drug reaction that has a unique clinical presentation, called immune-related adverse events (irAEs). A breakdown of self-tolerance and an exaggerated autoimmune reaction by the host are assumed to be the underlying mechanisms. Therefore, special attention to the optimal diagnosis and management is required. Among the various effects of irAE, pneumonitis has been recognized as an important manifestation because of its high morbidity and mortality. As the application of ICIs is expanding to a wider variety of tumor types, as well as its use with cytotoxic agents and radiation, clinicians are highly likely to encounter this complication. In this review, we will summarize the current understanding of the underlying mechanisms, incidence, risk factors, optimal diagnostic workup, and management of ICI-related pneumonitis (IRP). We will also review fundamental information on drug-induced lung toxicity in the oncology setting. In addition, research perspectives focused on better risk stratification and management to avoid serious complications in the future are presented.
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http://dx.doi.org/10.1016/j.resinv.2020.05.008DOI Listing
September 2020

Acute Exacerbation of Pleuroparenchymal Fibroelastosis Secondary to Allogenic Hematopoietic Stem Cell Transplantation.

Intern Med 2020 Nov 14;59(21):2737-2743. Epub 2020 Jul 14.

Department of Respiratory Medicine, Nagoya University Graduate School of Medicine, Japan.

In this article, we report a case with pleuroparenchymal fibroelastosis (PPFE) following hematopoietic stem cell transplantation (HSCT) that developed acute respiratory failure with new bilateral ground glass opacity, which could not be explained by either a pulmonary infection, drug toxicity or extraparenchymal causes. Although combination therapy with multiple immunosuppressants was transiently effective, the patient died from a recurrent exacerbation. Autopsied lungs demonstrated diffuse alveolar damage superimposed on PPFE. There was no evidence of any coexisting interstitial pneumonia with the usual interstitial pneumonia (UIP) pattern. Our case suggests that acute exacerbation can occur in patients with post-HSCT PPFE, even when a coexisting UIP pattern is absent.
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http://dx.doi.org/10.2169/internalmedicine.4995-20DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7691016PMC
November 2020

Primary Prophylaxis Indication for Docetaxel Induced Febrile Neutropenia in Elderly Patients with Non-Small Cell Lung Cancer.

Cancer Invest 2020 Aug 30;38(7):424-430. Epub 2020 Jul 30.

National Hospital Organization Nagoya Medical Center, Nagoya, Japan.

In advanced non-small cell lung cancer (NSCLC), the reported incidence of febrile neutropenia (FN) caused by docetaxel (DTX) is 10-20% in clinical trial data. However, FN incidence caused by DTX in real-world setting remains unclear. We evaluated FN incidence caused by DTX and identify risk factors of FN in real-world setting. One hundred and seventy-one NSCLC patients treated with DTX were retrospectively analyzed and 44 (26%) developed FN. Multivariate analysis identified higher age (≥65 years) and prior history of FN as independent risk factors for FN. Primary prophylaxis for FN might be recommended in elderly patients with/without prior history of FN.
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http://dx.doi.org/10.1080/07357907.2020.1793350DOI Listing
August 2020

Intractable diffuse pulmonary diseases: Manual for diagnosis and treatment.

Respir Investig 2021 Jan 2;59(1):8-33. Epub 2020 Jul 2.

National Hospital Organization Tokyo Medical Center, Tokyo, Japan. Electronic address:

This manual has been compiled by a joint production committee with the Diffuse Lung Disease Assembly of the Japanese Respiratory Society (JRS) to provide a practical manual for the epidemiology, diagnosis, and treatment of intractable diffuse pulmonary diseases. The contents are based upon the results of research into these diseases by the Diffuse Pulmonary Diseases Study Group (principal researcher: Sakae Homma) supported by the FY2014-FY2016 Health and Labor Sciences Research Grant on Intractable Diseases. This manual focuses on: 1) pulmonary alveolar microlithiasis, 2) bronchiolitis obliterans, and 3) Hermansky-Pudlak Syndrome with interstitial pneumonia. As these are rare/intractable diffuse lung diseases (2 and 3 were first recognized as specified intractable diseases in 2015), there have not been sufficient epidemiological studies made, and there has been little progress in formulating diagnostic criteria and severity scales; however, the results of Japan's first surveys and research into such details are presented herein. In addition, the manual provides treatment guidance and actual cases for each disease, aiming to assist in the establishment of future modalities. The manual was produced with the goal of enabling clinicians specialized in respiratory apparatus to handle these diseases in clinical settings and of further advancing future research and treatment.
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http://dx.doi.org/10.1016/j.resinv.2020.04.004DOI Listing
January 2021

Pituitary dysfunction induced by immune checkpoint inhibitors is associated with better overall survival in both malignant melanoma and non-small cell lung carcinoma: a prospective study.

J Immunother Cancer 2020 07;8(2)

Department of Endocrinology and Diabetes, Nagoya University Graduate School of Medicine, Nagoya, Japan

Background: Several immune-related adverse events (irAEs) are reported to be associated with therapeutic efficacy of immune checkpoint inhibitors, yet whether pituitary dysfunction, a life-threatening irAE, affects overall survival (OS) in patients with malignancies is unclear. This prospective study examined the association of pituitary dysfunction (pituitary-irAE) with OS of patients with non-small cell lung carcinoma (NSCLC) or malignant melanoma (MM).

Methods: A total of 174 patients (NSCLC, 108; MM, 66) treated with ipilimumab, nivolumab, pembrolizumab, or atezolizumab at Nagoya University Hospital were evaluated for OS and the development of pituitary-irAE. Kaplan-Meier curves of OS as a function of the development of pituitary-irAE were produced with the log-rank test as a primary endpoint.

Results: Pituitary-irAE was observed in 16 patients (4 (3.7%) with NSCLC, 12 (18.2%) with MM) having two different disease types: hypophysitis with deficiency of multiple anterior pituitary hormones accompanied by pituitary enlargement, and isolated adrenocorticotropic hormone (ACTH) deficiency without pituitary enlargement. Among these patients, 6 developed pituitary-irAE while being treated with ipilimumab (6/25 patients (24.0%) treated with ipilimumab) and 10 developed pituitary-irAE during treatment with nivolumab or pembrolizumab (10/167 (6.0%)). All 16 patients had ACTH deficiency and were treated with physiological doses of hydrocortisone. The development of pituitary-irAE was associated with better OS in patients with NSCLC (not reached vs 441 (95% CI not calculated) days, p<0.05) and MM (885 (95% CI 434 to 1336) vs 298 (95% CI 84 to 512) days, p<0.05).

Conclusions: In our study cohort, the incidence of pituitary-irAE was higher than previously reported and the development of pituitary-irAE predicted better prognosis for both NSCLC and MM when patients were treated with physiological doses of hydrocortisone.

Clinical Trials Registration: UMIN000019024.
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http://dx.doi.org/10.1136/jitc-2020-000779DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7328763PMC
July 2020

High-flow nasal cannula therapy for acute respiratory failure in patients with interstitial pneumonia: a retrospective observational study.

Nagoya J Med Sci 2020 May;82(2):301-313

Department of Respiratory Medicine, Nagoya University Graduate School of Medicine, Nagoya, Japan.

High-flow nasal cannula (HFNC) oxygen is a therapy that has demonstrated survival benefits in acute respiratory failure (ARF). However, the role of HFNC in ARF due to interstitial pneumonia (IP) is unknown. The aim of this study was to compare the effects of HFNC therapy and non-invasive positive pressure ventilation (NPPV) in ARF due to IP. This retrospective observational study included 32 patients with ARF due to IP who were treated with HFNC (n = 13) or NPPV (n = 19). The clinical characteristics, intubation rate and 30-day mortality were analyzed and compared between the HFNC group and the NPPV group. Predictors of 30-day mortality were evaluated using a logistic regression model. HFNC group showed higher mean arterial blood pressure (median 92 mmHg; HFNC group vs 74 mmHg; NPPV group) and lower APACHEII score (median 22; HFNC group vs 27; NPPV group) than NPPV group. There was no significant difference in the intubation rate at day 30 between the HFNC group and the NPPV group (8% vs 37%: p = 0.069); the mortality rate at 30 days was 23% and 63%, respectively. HFNC therapy was a significant determinant of 30-day mortality in univariate analysis, and was confirmed to be an independent significant determinant of 30-day mortality in multivariate analysis (odds ratio, 0.148; 95% confidence interval, 0.025-0.880; p = 0.036). Our findings suggest that HFNC therapy can be a possible option for respiratory management in ARF due to IP. The results observed here warrant further investigation of HFNC therapy in randomized control trials.
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http://dx.doi.org/10.18999/nagjms.82.2.301DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7276417PMC
May 2020

Involvement of heme oxygenase-1 in suppression of T cell activation by quercetin.

Immunopharmacol Immunotoxicol 2020 Aug 12;42(4):295-305. Epub 2020 May 12.

Department of Pathophysiological Laboratory Sciences, Nagoya University Graduate School of Medicine, Nagoya, Japan.

Aim: Acute rejection is still a major problem in transplantation and one of the most important causes of late graft loss. Cyclosporine and tacrolimus are widely used for suppression of T cell function to avoid graft rejection, but long-term use of these compounds is associated with serious toxicities. Quercetin, a flavonoid found in fruits and vegetables, has been demonstrated to exhibit cytoprotective effects through the induction of heme oxygenase (HO) -1, an enzyme involved in heme catabolism. We hypothesized that quercetin induces HO-1 in T cells and suppresses T cell function via HO-1. In the present study, we showed that quercetin suppressed the A23187-mediated expression of interleukin (IL) -2 in T cells.

Methods: Mouse splenocytes, enriched T cells, and EL4 cells, a mouse T cell line, were treated with quercetin, and then stimulated with A23187, a calcium ionophore, concanavalin A, or anti-CD3ε and anti-CD28 antibodies. Cell proliferation, expression of IL-2, calcium mobilization, apoptosis, cell cycle, and phosphorylation of extracellular signal-regulated kinase (ERK) were investigated.

Results: Quercetin induced HO-1, and this induction of HO-1 was implicated in the suppression of IL-2 production. Furthermore, the induction of HO-1 by quercetin suppressed the influx of calcium ions, a known trigger of IL-2 production. Additionally, quercetin suppressed T cell proliferation through promotion of cell cycle arrest via HO-1 induction, but quercetin did not induce apoptosis. To investigate the role of the signal transduction pathway in quercetin's effect on cell proliferation, we evaluated the phosphorylation of ERK in T cells. Quercetin suppressed the A23187-mediated stimulation of ERK, an effect that was mediated through HO-1. These results suggested that HO-1 is involved in the suppressive effects of quercetin on T cell activation and proliferation.

Conclusion: Our findings indicate that the quercetin may be a promising candidate for inducing HO-1 in T cells, thereby facilitating immunosuppressive effects.
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http://dx.doi.org/10.1080/08923973.2020.1759623DOI Listing
August 2020

Risk factors for pulmonary infection after diagnostic bronchoscopy in patients with lung cancer.

Nagoya J Med Sci 2020 Feb;82(1):69-77

Department of Respiratory Medicine, Nagoya University Graduate School of Medicine, Nagoya, Japan.

Pulmonary infection is a relatively rare but serious complication of flexible bronchoscopy. The aim of this study was to identify the risk factors for pulmonary infectious complications after diagnostic bronchoscopy in patients with lung cancer. We retrospectively analyzed the medical records of 636 patients who underwent bronchoscopic biopsy for lung cancer diagnosis between April 2011 and March 2016. We compared patients' characteristics, chest computed tomography and bronchoscopic findings, undertaken procedures, and final diagnoses between patients who developed the complication and those who did not. Pulmonary infection after the diagnostic bronchoscopy occurred in 19 patients (3.0%) and included pneumonia in 16 patients and lung abscess in 3. Patients with larger lesions, presence of endobronchial lesions, histology of small cell lung cancer, and advanced disease stage tended to develop pulmonary infectious complications more often. Our multivariate analysis revealed that a larger lesion size and the presence of endobronchial lesions were independently associated with post-bronchoscopy pulmonary infection. Although we found no mortality associated with the infections, two patients were left with significant performance status deterioration after the pulmonary infection and received no anticancer treatment. In conclusion, endobronchial lesions and a larger lesion size are independent risk factors for the incidence of infections following bronchoscopic biopsy in patients with lung cancer.
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http://dx.doi.org/10.18999/nagjms.82.1.69DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7103861PMC
February 2020

Omalizumab for Aspirin Hypersensitivity and Leukotriene Overproduction in Aspirin-exacerbated Respiratory Disease. A Randomized Controlled Trial.

Am J Respir Crit Care Med 2020 06;201(12):1488-1498

Clinical Research Center for Allergy and Rheumatology, National Hospital Organization Sagamihara National Hospital, Sagamihara, Japan.

Aspirin-exacerbated respiratory disease is characterized by severe asthma, nonsteroidal antiinflammatory drug hypersensitivity, nasal polyposis, and leukotriene overproduction. Systemic corticosteroid therapy does not completely suppress lifelong aspirin hypersensitivity. Omalizumab efficacy against aspirin-exacerbated respiratory disease has not been investigated in a randomized manner. To evaluate omalizumab efficacy against aspirin hypersensitivity, leukotriene E overproduction, and symptoms during an oral aspirin challenge in patients with aspirin-exacerbated respiratory disease using a randomized design. We performed a double-blind, randomized, crossover, placebo-controlled, single-center study at Sagamihara National Hospital between August 2015 and December 2016. Atopic patients (20-79 yr old) with aspirin-exacerbated respiratory disease diagnosed by systemic aspirin challenge were randomized (1:1) to a 3-month treatment with omalizumab or placebo, followed by a >18-week washout period (crossover design). The primary endpoint was the difference in area under logarithm level of urinary leukotriene E concentration versus time curve in the intent-to-treat population during an oral aspirin challenge. Sixteen patients completed the study and were included in the analysis. The area under the logarithm level of urinary leukotriene E concentration versus time curve during an oral aspirin challenge was significantly lower in the omalizumab phase (median [interquartile range], 51.1 [44.5-59.8]) than in the placebo phase (80.8 [interquartile range, 65.4-87.8]) ( < 0.001). Ten of 16 patients (62.5%) developed oral aspirin tolerance up to cumulative doses of 930 mg in the omalizumab phase ( < 0.001). Omalizumab treatment inhibited urinary leukotriene E overproduction and upper/lower respiratory tract symptoms during an oral aspirin challenge, resulting in aspirin tolerance in 62.5% of the patients with aspirin-exacerbated respiratory disease.
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http://dx.doi.org/10.1164/rccm.201906-1215OCDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7301746PMC
June 2020

Endobronchial ultrasound-guided transbronchial needle aspiration under non-invasive positive pressure for the diagnosis of lung metastasis due to renal cell carcinoma in a patient with respiratory failure.

Respir Med Case Rep 2020 24;29:101028. Epub 2020 Feb 24.

Department of Respiratory Medicine, Nagoya University Graduate School of Medicine, Japan.

A 65-year-old man with chronic respiratory failure caused by chronic obstructive pulmonary disease, had a pulmonary nodule adjacent to the inlet of right B1 and B3. The patient had undergone a surgery for right renal cell carcinoma and colon cancer 6 years prior. We attempted endobronchial ultrasound-guided transbronchial needle aspiration under non-invasive positive pressure ventilation for diagnosis, with rapid on-site cytology, which was performed without complications. The histological findings revealed lung metastasis involving renal cell carcinoma. Endobronchial ultrasound-guided transbronchial needle aspiration under non-invasive positive pressure ventilation is useful for diagnosing lesions that require access up to the segmental bronchus in patients with respiratory failure.
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http://dx.doi.org/10.1016/j.rmcr.2020.101028DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7047012PMC
February 2020

Potential Benefits of Bevacizumab Combined With Platinum-Based Chemotherapy in Advanced Non-Small-Cell Lung Cancer Patients With EGFR Mutation.

Clin Lung Cancer 2020 05 27;21(3):273-280.e4. Epub 2020 Jan 27.

Department of Respiratory Medicine, Nagoya University Graduate School of Medicine, Nagoya, Japan.

Background: Oncogenic EGFR signaling has been shown to upregulate vascular endothelial growth factor A (VEGFA) expression involved in tumor angiogenesis. However, the clinical benefits of bevacizumab plus cytotoxic chemotherapy for EGFR mutation-positive patients remain unclear. This study aimed to investigate VEGFA messenger RNA expression in patients with EGFR mutation, and to further compare the efficacy of bevacizumab combined with platinum-based chemotherapy between EGFR-mutant and wild-type patients.

Patients And Methods: Gene expression of various proangiogenic factors was analyzed in nonsquamous, non-small-cell lung cancer (NSCLC) patients using The Cancer Genome Atlas dataset. Additionally, clinical data of patients receiving carboplatin and pemetrexed (CPem; n = 104) or bevacizumab plus CPem (BevCPem; n = 55) at Nagoya University hospital were retrospectively assessed for progression-free survival and best overall response rate (ORR).

Results: Among various proangiogenic factors, only VEGFA expression was significantly higher in patients with advanced nonsquamous NSCLC with EGFR mutation compared to wild-type patients (P = .0476). Progression-free survival in the BevCPem group was significantly longer in patients with EGFR mutation than in wild-type patients (10.5 vs. 6.6 months; Wilcoxon P = .0278), while the difference in the CPem group was not significant (6.6 vs. 4.5 months; Wilcoxon P = .1822). The ORRs in the BevCPem group were 54.5% and 36.4% for EGFR-mutant and wild-type patients, respectively, and the ORRs in the CPem group were 35.5% and 28.8 % in EGFR-mutant and wild-type patients, respectively.

Conclusion: VEGFA messenger RNA expression was significantly increased in advanced nonsquamous NSCLC harboring EGFR mutation, and BevCPem provided better clinical benefits to patients with EGFR mutation than wild-type carriers.
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http://dx.doi.org/10.1016/j.cllc.2020.01.011DOI Listing
May 2020

Probable usual interstitial pneumonia pattern on chest CT: is it sufficient for a diagnosis of idiopathic pulmonary fibrosis?

Eur Respir J 2020 04 9;55(4). Epub 2020 Apr 9.

Dept of Respiratory Medicine, Nagoya University Graduate School of Medicine, Nagoya, Japan.

Recent studies have suggested that in patients with an idiopathic interstitial pneumonia (IIP), a probable usual interstitial pneumonia (UIP) pattern on chest computed tomography (CT) is sufficient to diagnose idiopathic pulmonary fibrosis (IPF) without histopathology.We retrospectively compared the prognosis and time to first acute exacerbation (AE) in IIP patients with a UIP and a probable UIP pattern on initial chest CT.One hundred and sixty IIP patients with a UIP pattern and 242 with a probable UIP pattern were identified. Probable UIP pattern was independently associated with longer survival time (adjusted hazard ratio 0.713, 95% CI 0.536-0.950; p=0.021) and time to first AE (adjusted hazard ratio 0.580, 95% CI 0.389-0.866; p=0.008). In subjects with a probable UIP pattern who underwent surgical lung biopsy, the probability of a histopathological UIP pattern was 83%. After multidisciplinary discussion and the inclusion of longitudinal behaviour, a diagnosis of IPF was made in 66% of cases. In IPF patients, survival time and time to first AE were not associated with CT pattern. Among subjects with a probable UIP pattern, compared to non-IPF patients, survival time and time to first AE were shorter in IPF patients.In conclusion, IIP patients with a probable UIP pattern on initial chest CT had a better prognosis and longer time to first AE than those with a UIP pattern. However, when baseline data and longitudinal behaviour provided a final diagnosis of IPF, CT pattern was not associated with these outcomes. This suggests diagnostic heterogeneity among patients with a probable UIP pattern.
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http://dx.doi.org/10.1183/13993003.02465-2018DOI Listing
April 2020

Anti-thyroid antibodies and thyroid echo pattern at baseline as risk factors for thyroid dysfunction induced by anti-programmed cell death-1 antibodies: a prospective study.

Br J Cancer 2020 03 3;122(6):771-777. Epub 2020 Feb 3.

Department of Clinical Oncology and Chemotherapy, Nagoya University Hospital, Nagoya, Japan.

Background: Anti-programmed cell death-1 (PD-1) antibodies can cause thyroid dysfunction. However, no predictive biomarkers enabling stratification of thyroid dysfunction risk have been identified.

Methods: A total of 209 patients treated with an anti-PD-1 antibody were evaluated for anti-thyroid antibodies at baseline and prospectively for thyroid function every 6 weeks for 24 weeks after treatment initiation, and then observed until the visits stopped. Thyroid ultrasonography was performed if the patient was positive for anti-thyroid antibodies at baseline.

Results: Of the 209 patients, 19 (9.1%) developed thyroid dysfunction (destructive thyroiditis or hypothyroidism). The cumulative incidence of thyroid dysfunction was significantly higher in patients who were positive vs. negative for anti-thyroid antibodies (15/44 [34.1%] vs. 4/165 [2.4%], p < 0.001). Forty-two patients positive for anti-thyroid antibodies at baseline were divided into two groups according to the presence of an irregular echo pattern. The cumulative incidence of thyroid dysfunction was significantly higher in those with an irregular vs. a regular echo pattern (13/23 [56.5%] vs. 1/19 [5.3%], p = 0.001). None of the patients developed thyroid dysfunction after the initial 24-week period.

Conclusions: The risk of thyroid dysfunction induced by anti-PD-1 antibodies can be predicted by evaluation of anti-thyroid antibodies and the thyroid echo pattern at baseline.

Trial Registration: UMIN000019024.
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http://dx.doi.org/10.1038/s41416-020-0736-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7078193PMC
March 2020

Thrombomodulin Alfa for Acute Exacerbation of Idiopathic Pulmonary Fibrosis. A Randomized, Double-Blind Placebo-controlled Trial.

Am J Respir Crit Care Med 2020 05;201(9):1110-1119

Department of Respiratory Medicine, Nagoya University Graduate School of Medicine, Aichi, Japan.

Acute exacerbation during the course of idiopathic pulmonary fibrosis causes a poor prognosis. Coagulation abnormalities and endothelial damage are involved in its pathogenesis. Thrombomodulin alfa, a recombinant human soluble thrombomodulin, has anticoagulant and antiinflammatory effects. Several clinical studies have shown that thrombomodulin alfa may improve survival of acute exacerbation. To determine the efficacy and safety of thrombomodulin alfa compared with placebo in acute exacerbation of idiopathic pulmonary fibrosis. This randomized, double-blind placebo-controlled phase 3 study conducted at 27 sites in Japan involved patients with an acute exacerbation of idiopathic pulmonary fibrosis. Subjects were randomized 1:1 to receive placebo or thrombomodulin alfa (380 U/kg/d for 14 d by intravenous drip infusion). All subjects were treated with high-dose corticosteroid therapy. The primary endpoint was the survival proportion on Day 90. Of the 82 randomized subjects, 77 completed the study and were included in the full analysis set (thrombomodulin alfa,  = 40; placebo,  = 37). The survival proportions on Day 90 were 72.5% (29 of 40) in the thrombomodulin alfa group and 89.2% (33 of 37) in the placebo group, a difference of -16.7 percentage points (95% confidence interval, -33.8 to 0.4%;  = 0.0863). In the safety population ( = 80), bleeding adverse events occurred in the thrombomodulin alfa group (10 of 42; 23.8%) and the placebo group (4 of 38; 10.5%). Thrombomodulin alfa did not improve the 90-day survival proportion. The present results suggest that the use of thrombomodulin alfa for the treatment of acute exacerbation of idiopathic pulmonary fibrosis not be recommended.Clinical trial registered with www.clinicaltrials.gov (NCT02739165).
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http://dx.doi.org/10.1164/rccm.201909-1818OCDOI Listing
May 2020

Diagnostic contribution of cytological examination to endobronchial ultrasound-guided transbronchial biopsy for lung malignancies.

Nagoya J Med Sci 2019 Nov;81(4):613-620

Department of Respiratory Medicine, Nagoya University Graduate School of Medicine, Nagoya, Japan.

Although endobronchial ultrasound guided transbronchial biopsy (TBB) with a guide sheath (EBUS-GS) is widely used for diagnosis of peripheral pulmonary lesions, the diagnostic contribution of cytology (bronchial brushing, bronchial washing and biopsy forceps rinse) has not been established. To determine the diagnostic contribution of cytological examination to EBUS-GS-TBB, we reviewed medical records of patients with lung malignancies who had undergone TBB with EBUS-GS (EBUS-GS group, =187) or TBB without EBUS-GS (conventional TBB [CTBB] group, =197) at Nagoya University Hospital. Although the mean size of target lesions was significantly larger in the CTBB group than the EBUS-GS group, the total diagnostic rate was equivalent between two groups (EBUS-GS: 73.3%, CTBB: 66.0%). In the EBUS-GS group, cytological procedures increased the diagnostic rate by 9.1% (17/137), compared with only 4.1% (8/130) in the CTBB group. Sensitivity of cytology among biopsy-negative patients was significantly higher in EBUS-GS group than CTBB group (=0.022). Furthermore, in the EBUS-GS group, among 17 patients whose malignant diagnoses could only be established cytologically, bronchial brushing contributed to the malignant diagnosis in 64.7% (11/17). These data may suggest that cytological examination, especially bronchial brushing, may be an important diagnostic contributor in EBUS-GS-TBB.
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http://dx.doi.org/10.18999/nagjms.81.4.613DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6892665PMC
November 2019
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