Publications by authors named "Takashi Ogura"

381 Publications

A proposed prognostic prediction score for pleuroparenchymal fibroelastosis.

Respir Res 2021 Jul 30;22(1):215. Epub 2021 Jul 30.

Department of Respiratory Medicine, Fukuoka University Chikushi Hospital, 1-1-1 Zokumyoin, Chikushino, Fukuoka, 818-8502, Japan.

Background: Clinical course of pleuroparenchymal fibroelastosis (PPFE) shows considerable variation among patients, but there is no established prognostic prediction model for PPFE.

Methods: The prediction model was developed using retrospective data from two cohorts: our single-center cohort and a nationwide multicenter cohort involving 21 institutions. Cox regression analyses were used to identify prognostic factors. The total score was defined as the weighted sum of values for the selected variables. The performance of the prediction models was evaluated by Harrell's concordance index (C-index). We also examined the usefulness of the gender-age-physiology (GAP) model for predicting the prognosis of PPFE patients.

Results: We examined 104 patients with PPFE (52 cases from each cohort). In a multivariate Cox analysis, a lower forced vital capacity (FVC [defined as FVC < 65%]; hazard ratio [HR], 2.23), a history of pneumothorax (HR, 3.27), the presence of a lower lobe interstitial lung disease (ILD) (HR, 2.31), and higher serum Krebs von den Lungen-6 (KL-6) levels (> 550 U/mL, HR, 2.56) were significantly associated with a poor prognosis. The total score was calculated as 1 × (FVC, < 65%) + 1 × (history of pneumothorax) + 1 × (presence of lower lobe ILD) + 1 × (KL-6, > 550 U/mL). PPFE patients were divided into three groups based on the prognostic score: stage I (0-1 points), stage II (2 points), and stage III (3-4 points). The survival rates were significantly different in each stage. The GAP stage was significantly associated with the prognosis of PPFE, but no difference was found between moderate (stage II) and severe (stage III) disease. Our new model for PPFE patients (PPFE Prognosis Score) showed better performance in the prediction of mortality in comparison to the GAP model (C-index of 0.713 vs. 0.649).

Conclusions: Our new model for PPFE patients could be useful for predicting their prognosis.
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http://dx.doi.org/10.1186/s12931-021-01810-zDOI Listing
July 2021

Effects of Heme Electronic Structure and Local Heme Environment on Catalytic Activity of a Peroxidase-Mimicking Heme-DNAzyme.

Inorg Chem 2021 Aug 22;60(15):11206-11213. Epub 2021 Jul 22.

Department of Chemistry, University of Tsukuba, Tsukuba 305-8571, Japan.

The catalytic cycle of a peroxidase-mimicking heme-DNAzyme involves an iron(IV)oxo porphyrin π-cation radical intermediate known as compound formed through heterolytic O-O bond cleavage of an Fe-bound hydroperoxo ligand (Fe-OOH) in compound , like that of a heme enzyme such as horseradish peroxidase (HRP). Peroxidase assaying of complexes composed of chemically modified hemes possessing various electron densities of the heme iron atom (ρ) and parallel-stranded tetrameric G-quadruplex DNAs of oligonucleotides d(TTAGGG), d(TTAGGGT), and d(TTAGGGA) was performed to elucidate the effects of the heme electronic structure and local heme environment on the catalytic activity of the heme-DNAzyme. The study revealed that the DNAzyme activity is enhanced through an increase in the ρ and general base catalysis of the adenine base adjacent to the heme, which are reminiscent of the "push" and "pull" mechanisms in the catalytic cycle of HRP, respectively, and that the activity of the heme-DNAzyme can be independently controlled through the heme electronic structure and local heme environment. These findings allow a deeper understanding of the structure-function relationship of the peroxidase-mimicking heme-DNAzyme.
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http://dx.doi.org/10.1021/acs.inorgchem.1c01179DOI Listing
August 2021

Patients with Terminal Interstitial Pneumonia Require Comparable or More Palliative Pharmacotherapy for Refractory Dyspnea than Patients with Terminal Lung Cancer.

Palliat Med Rep 2021 16;2(1):188-193. Epub 2021 Jun 16.

Department of Respiratory Medicine, Kanagawa Cardiovascular and Respiratory Center, Yokohama City, Japan.

Dyspnea is a severe symptom of terminal-stage interstitial pneumonia (IP). We commonly use continuous morphine or midazolam for terminal refractory dyspnea. We aimed to determine whether there is a difference in the use of continuous morphine and midazolam for terminal dyspnea between IP patients and lung cancer (LC) patients. This is a single-center retrospective study. We retrospectively examined the clinical records of IP and LC patients who had died in our hospital. These patients were divided into the IP and LC groups to compare the use of morphine and midazolam. Continuous morphine was administered to 50.0% of those in the IP group and 38.0% of those in the LC group for terminal dyspnea. There was no difference in the effect at six hours after morphine initiation between the two groups, but the concomitant use of continuous midazolam and morphine was more common in the IP group than in the LC group. The dose of continuous midazolam was significantly higher in the IP group than in the LC group, and the survival time after morphine initiation was significantly shorter in the IP group. The efficacy of continuous morphine administration for terminal dyspnea in IP patients was similar to that in LC patients for a short time after initiation, but just before death, more patients in the IP group required concomitant use of midazolam and morphine. Thus, IP patients require comparable or more palliative treatment than LC patients.
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http://dx.doi.org/10.1089/pmr.2021.0010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8244508PMC
June 2021

Asbestos exposure and tuberculous pleurisy as developmental causes of progressive unilateral upper-lung field pulmonary fibrosis radiologically consistent with pleuroparenchymal fibroelastosis.

Respir Investig 2021 Jun 22. Epub 2021 Jun 22.

Department of Respiratory Medicine, Kanagawa Cardiovascular and Respiratory Center, Yokohama, Japan.

Background: Unilateral upper-lung field pulmonary fibrosis (upper-PF), which is radiologically consistent with pleuroparenchymal fibroelastosis, develops after thoracic surgery. In most patients with unilateral upper-PF, aberrant intra-/extra thoracic air commonly emerges and an autopsy shows chronic pleuritis, which indicates that pleural involvement is associated with upper-PF development. If so, there may be patients with unilateral upper-PF who have a history of pleural involvement, including tuberculous pleurisy (TP) or asbestos exposure (AE). This study aimed to examine this supposition.

Methods: We examined the radiological reports of all consecutive patients from 2012 to 2018 to investigate whether there were patients having unilateral upper-PF and a history of TP or AE.

Results: Eight patients were included in the study. Five patients had a history of TP, and the remaining three had that of AE. All patients were men and had respiratory symptoms, and seven patients presented with restrictive ventilatory impairment. The interval between TP or last AE and upper-PF development was long, with a median of over 20 years. The upper-PF lesion was commonly located in the right lung, and aberrant intrathoracic air was observed in five patients during their clinical course. Additionally, the upper-PF lesion transformed into a cystic lesion in six patients, which resulted in Aspergillus infection in two patients. The prognosis was poor, with a median overall survival of 38 months.

Conclusions: Unilateral upper-PF developed even in patients with a history of pleural involvement. Our results indicate that pleural involvement plays an important role in the development of unilateral upper-PF.
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http://dx.doi.org/10.1016/j.resinv.2021.05.010DOI Listing
June 2021

Spontaneous regression following endobronchial ultrasound-guided transbronchial needle aspiration in lung cancer patients.

Respir Investig 2021 Jun 16. Epub 2021 Jun 16.

Department of Respiratory Medicine, Kanagawa Cardiovascular and Respiratory Center, Japan.

Spontaneous regression (SR) is defined as a complete or partial, temporary or permanent disappearance of a tumor without anticancer treatment, which potentially develops after surgery or biopsy for primary and metastatic tumors despite unknown incidence rate. Here, we report the incidence rate of SR after endobronchial ultrasound-guided transbronchial nodal needle aspiration (EBUS-TBNA) in lung cancer patients. Among 96 patients evaluable with chest CT before and after EBUS-TBNA, SR was found in three patients (3.1%). With regards to patient characteristics, two patients had small cell lung cancer (SCLC), and one patient had adenocarcinoma. All patients had stage 3 disease with a bulky N2 stage and a history of smoking. Two patients also had interstitial lung disease. Notably, SR was observed not only at the biopsied site, but also at the non-biopsied site. Our results indicate that SR can develop following EBUS-TBNA in a substantial proportion of lung cancer patients.
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http://dx.doi.org/10.1016/j.resinv.2021.05.003DOI Listing
June 2021

Imaging of COVID-19: An update of current evidences.

Diagn Interv Imaging 2021 May 25. Epub 2021 May 25.

Department of Diagnostic Radiology, Yokohama City University Graduate School of Medicine, 236-0004 Yokohama, Kanagawa, Japan.

Coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has been reported as a global emergency. As respiratory dysfunction is a major clinical presentation of COVID-19, chest computed tomography (CT) plays a central role in the diagnosis and management of patients with COVID-19. Recent advances in imaging approaches using artificial intelligence have been essential as a quantification and diagnostic tool to differentiate COVID-19 from other respiratory infectious diseases. Furthermore, cardiovascular involvement in patients with COVID-19 is not negligible and may result in rapid worsening of the disease and sudden death. Cardiac magnetic resonance imaging can accurately depict myocardial involvement in SARS-CoV-2 infection. This review summarizes the role of the radiology department in the management and the diagnosis of COVID-19, with a special emphasis on ultra-high-resolution CT findings, cardiovascular complications and the potential of artificial intelligence.
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http://dx.doi.org/10.1016/j.diii.2021.05.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8148573PMC
May 2021

Sustained Neutralizing Antibodies 6 Months Following Infection in 376 Japanese COVID-19 Survivors.

Front Microbiol 2021 7;12:661187. Epub 2021 May 7.

Department of Health Data Science, Yokohama City University Graduate School of Data Science, Yokohama, Japan.

There is scarce evidence regarding the long-term persistence of neutralizing antibodies among coronavirus disease 2019 (COVID-19) survivors. This study determined neutralizing antibody titers (NT) and antibodies against spike protein (SP) or nucleocapsid protein (NP) antigens approximately 6 months after the diagnosis of COVID-19. COVID-19 survivors in Japan were recruited. Serum samples and data related to patients' characteristics and COVID-19 history were collected. NT and titers of antibodies against NP and SP antigens were measured at 20-32 weeks after the first positive severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) test results. Factors associated with NT were identified using the multivariable linear regression and the correlations among NT and titers of immunoglobulin G (IgG) and total immunoglobulins (Igs) against NP and SP were assessed by Spearman's correlation. Among 376 participants (median [range] days after testing positive for SARS-CoV-2, 180 (147-224); median [range] years of age, 50 (20-78); 188 [50%] male), most tested positive for NT ( = 367, 98%), SP-IgG ( = 344, 91%), SP-total Ig ( = 369, 98%), NP-IgG ( = 314, 84%), and NP-total Ig ( = 365, 97%). Regression analysis indicated that higher BMI, fever, and the requirement of mechanical ventilation or extracorporeal membrane oxygenation were significantly associated with higher NT. Anti-SP antibodies correlated moderately with NT (Spearman's correlation: 0.63 for SP IgG; 0.57 for SP-total Ig), while the correlation was weak for anti-NP antibodies (0.37 for NP IgG; 0.32 for NP-total Ig). Most COVID-19 survivors had sustained neutralizing antibodies and tested positive for SP-total Ig and NP-total Ig approximately 6 months after infection.
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http://dx.doi.org/10.3389/fmicb.2021.661187DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8137897PMC
May 2021

Corticosteroids for hospitalized patients with mild to critically-ill COVID-19: a multicenter, retrospective, propensity score-matched study.

Sci Rep 2021 05 21;11(1):10727. Epub 2021 May 21.

Department of Emergency and Critical Care Medicine, Tokyo Bay Urayasu-Ichikawa Medical Center, 3-4-32 Todaijima, Urayasu-city, Chiba, 279-0001, Japan.

Corticosteroids use in coronavirus disease 2019 (COVID-19) is controversial, especially in mild to severe patients who do not require invasive/noninvasive ventilation. Moreover, many factors remain unclear regarding the appropriate use of corticosteroids for COVID-19. In this context, this multicenter, retrospective, propensity score-matched study was launched to evaluate the efficacy of systemic corticosteroid administration for hospitalized patients with COVID-19 ranging in the degree of severity from mild to critically-ill disease. This multicenter, retrospective study enrolled consecutive hospitalized COVID-19 patients diagnosed January-April 2020 across 30 institutions in Japan. Clinical outcomes were compared for COVID-19 patients who received or did not receive corticosteroids, after adjusting for propensity scores. The primary endpoint was the odds ratio (OR) for improvement on a 7-point ordinal score on Day 15. Of 1092 COVID-19 patients analyzed, 118 patients were assigned to either the corticosteroid and non-corticosteroid group, after propensity score matching. At baseline, most patients did not require invasive/noninvasive ventilation (85.6% corticosteroid group vs. 89.8% non-corticosteroid group). The odds of improvement in a 7-point ordinal score on Day 15 was significantly lower for the corticosteroid versus non-corticosteroid group (OR, 0.611; 95% confidence interval [CI], 0.388-0.962; p = 0.034). The time to improvement in radiological findings was significantly shorter in the corticosteroid versus non-corticosteroid group (hazard ratio [HR], 1.758; 95% CI, 1.323-2.337; p < 0.001), regardless of baseline clinical status. The duration of invasive mechanical ventilation was shorter in corticosteroid versus non-corticosteroid group (HR, 1.466; 95% CI, 0.841-2.554; p = 0.177). Of the 106 patients who received methylprednisolone, the duration of invasive mechanical ventilation was significantly shorter in the pulse/semi-pulse versus standard dose group (HR, 2.831; 95% CI, 1.347-5.950; p = 0.006). In conclusion, corticosteroids for hospitalized patients with COVID-19 did not improve clinical status on Day 15, but reduced the time to improvement in radiological findings for all patients regardless of disease severity and also reduced the duration of invasive mechanical ventilation in patients who required intubation.Trial registration: This study was registered in the University hospital Medical Information Network Clinical Trials Registry on April 21, 2020 (ID: UMIN000040211).
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http://dx.doi.org/10.1038/s41598-021-90246-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8140087PMC
May 2021

The Japanese Medical Science Federation COVID-19 Expert Opinion English Version.

JMA J 2021 Apr 8;4(2):148-162. Epub 2021 Apr 8.

Japanese Society of Respiratory Care Medicine.

In 2020, the COVID-19 pandemic has had unprecedented impacts on various aspects of the world. Each academic society has published a guide and/or guidelines on how to cope with COVID-19 separately. As the one and only nationwide association of academic societies that represent medical science in Japan, JMSF has decided to publish the expert opinion to help patients and care providers find specifically what they want. This expert opinion is a summary of recommendations by many academic societies and will be updated when necessary. Patients that each academic society targets differ even though they suffer from the same COVID-19, and recommendations can be different in a context-dependent manner. Readers are supposed to be flexible and adjustable when they use this expert opinion.
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http://dx.doi.org/10.31662/jmaj.2021-0002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8118966PMC
April 2021

Safety and tolerability of combination therapy with pirfenidone and nintedanib for idiopathic pulmonary fibrosis: A multicenter retrospective observational study in Japan.

Respir Investig 2021 May 13. Epub 2021 May 13.

Department of Respiratory Medicine, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo, 113-8510, Japan.

Background: Phase IV clinical trials in Western countries have reported that combined therapy with pirfenidone and nintedanib for idiopathic pulmonary fibrosis (IPF) has a manageable safety profile. However, data on the long-term safety and tolerability of this combination treatment in the real-world setting in Japan are limited.

Methods: The retrospective data of 46 patients with IPF who received combination therapy with pirfenidone and nintedanib were obtained from 16 institutes in Japan. Adverse events and adverse drug reactions (ADRs) were reported through a retrospective review of medical records.

Results: Nintedanib and pirfenidone were added to preceding treatment with antifibrotic drugs in 32 (69.6%) and 13 (28.3%) patients, respectively. In one patient (2.1%), the two drugs were concurrently initiated. The mean duration of monotherapy before initiating the combination was 26.3 months. In 26 of 38 patients (68.4%), the Gender-Age-Physiology index stage was II or III. Thirty-three patients (71.7%) had some ADRs, and 14 patients (30.4%) permanently discontinued either drug or both drugs owing to the development of ADRs during the observation period (mean: 59 weeks). The percentage of grade III or IV IPF according to the Japanese Respiratory Society severity classification was higher in patients who permanently discontinued either drug or both drugs than in those who continued both drugs (90.9% [10/11; 3 undetermined grade] vs. 61.1% [11/18; 1 undetermined grade]). Decreased appetite (18/46, 39.1%) and diarrhea (16/46, 34.8%) were frequently observed ADRs. Two patients (4.3%) had serious ADRs (liver toxicity and pneumothorax).

Conclusions: Real-world data imply that combination therapy with pirfenidone and nintedanib for IPF has a manageable safety/tolerability profile.
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http://dx.doi.org/10.1016/j.resinv.2021.04.005DOI Listing
May 2021

Serum Krebs von den Lungen-6 levels are associated with mortality and severity in patients with coronavirus disease 2019.

Respir Investig 2021 Apr 27. Epub 2021 Apr 27.

Department of Respiratory Medicine, Kanagawa Cardiovascular and Respiratory Center, Yokohama, Kanagawa, Japan. Electronic address:

Background: The serum Krebs von den Lungen-6 (KL-6) level is a predictive factor for acute respiratory distress syndrome (ARDS). The development of ARDS has been reported in patients with coronavirus disease 2019 (COVID-19). This study aimed to determine whether serum KL-6 levels are associated with mortality and severity in patients with COVID-19.

Methods: Among 361 Japanese patients with COVID-19 who were hospitalized at Kanagawa Cardiovascular and Respiratory Center between February 2020 and December 2020, 356 patients with data on serum KL-6 levels were enrolled and their medical records were retrospectively analyzed.

Results: A negative correlation was observed between KL-6 levels and the ratio of the arterial partial pressure of oxygen to the fraction of inspired oxygen on admission. The KL-6 levels on admission and the maximal KL-6 levels were higher in patients with severe disease (n = 60) than in those with nonsevere disease (n = 296). Furthermore, the maximal KL-6 levels were higher in nonsurvivors (n = 6) than in survivors (n = 350). In nonsurvivors, the KL-6 levels increased as the disease progressed. The optimal cutoff value of the maximal KL-6 level for discriminating between survivors and nonsurvivors was 684 U/mL, with a sensitivity of 83.3%, a specificity of 90.5%, and an area under the curve of 0.89.

Conclusions: The serum KL-6 level was associated with disease severity. Patients with KL-6 levels ≥684 U/mL had a significantly poorer outcome than those with KL-6 levels <684 U/mL.
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http://dx.doi.org/10.1016/j.resinv.2021.04.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8075813PMC
April 2021

Re: Immune checkpoint blockade for patients with lung cancer and idiopathic pulmonary fibrosis.

Eur J Cancer 2021 Jul 4;151:249-251. Epub 2021 May 4.

Department of Respiratory Medicine, Kanagawa Cardiovascular and Respiratory Center, 6-16-1, Tomioka-higashi, Kanazawa-ku, Yokohama-city, Kanagawa Prefecture, 236-0051, Japan.

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http://dx.doi.org/10.1016/j.ejca.2021.03.050DOI Listing
July 2021

Identification and Characteristics of Co-isolation of Multiple Nontuberculous Mycobacteria.

Intern Med 2021 Apr 26. Epub 2021 Apr 26.

Division of Pulmonary Medicine, Department of Respiratory Medicine, Kanagawa Cardiovascular and Respiratory Center, Japan.

Objective Although multiple non-tuberculous mycobacteria (NTM) species can be isolated from the same patient, little has been reported on co-isolation. We clarified the trends and characteristics of the co-isolation of multiple NTM species. Methods To collect data on multiple NTM isolation, we first extracted all patients who visited our hospital from 2006 through 2015 with a diagnosis of NTM lung diseases other than Mycobacterium avium complex (MAC) and then reviewed their medical records to evaluate the co-isolation of multiple NTM species. Results Of 213 patients with non-MAC lung disease, the most common NTM species was M. gordonae (32%), followed by M. kansasii (20%) and M. abscessus (14%). Non-MAC NTM lung disease tended to be associated with middle age with a low body mass index and male predominance. Multiple NTM species were isolated from 55 (26%) of the 213 patients. The clinical characteristics associated with multiple NTM species isolation included female predominance, never smokers and the absence of cavity lesions in the lungs. The highest co-isolation rate was observed in patients with M. gordonae isolation (30%), followed by M. furtuitum isolation (26%) and M. abscessus isolation (20%). Only MAC was isolated when co-isolated with M. abscessus. Among M. szulgai, M. peregrinum and M. terrae isolation, no other NTM species were detected. Conclusion Co-isolation of multiple NTM species was not uncommon, with 26% of patients with non-MAC NTM lung diseases showing co-isolation with multiple NTM species. Each NTM species had distinct characteristics in terms of co-isolation.
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http://dx.doi.org/10.2169/internalmedicine.5300-20DOI Listing
April 2021

Formation of Ni(II)-phenoxyl radical complexes by O: a mechanistic insight into the reaction of Ni(II)-phenol complexes with O.

Dalton Trans 2021 Apr;50(15):5161-5170

Graduate School of Science and Engineering, Ibaraki University, Mito 310-8512, Japan.

A reaction of Ni(ClO4)2·6H2O with a tripodal ligand having two di(tert-butyl)phenol moieties, H2tbuL, and 1 equivalent of triethylamine in CH2Cl2/CH3OH (1 : 1, v/v) under N2 gave a NiII-(phenol)(phenolate) complex, [Ni(HtbuL)(CH3OH)2]ClO4. The formation of the NiII-phenoxyl radical complex by O2 was observed in the reaction of this complex in the solid state. On the other hand, the NiII-phenoxyl radical complex [Ni(Me2NL)(CH3OH)2]ClO4 was obtained by the reaction of H2Me2NL having a p-(dimethylamino)phenol moiety with Ni(ClO4)2·6H2O in a similar procedure under O2, through the oxidation of the NiII-(phenol)(phenolate) complex. However, a direct redox reaction of the NiII ion could not be detected in the phenoxyl radical formation. The results of the reaction kinetics, XAS and X-ray structure analyses suggested that the O2 oxidation from the NiII-(phenol)(phenolate) complex to the NiII-phenoxyl radical complex occurs via the proton transfer-electron transfer (PT-ET) type mechanism of the phenol moiety weakly coordinated to the nickel ion.
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http://dx.doi.org/10.1039/d1dt00105aDOI Listing
April 2021

An observational study on nutrition status in gastric cancer patients receiving ramucirumab plus taxane: BALAST study.

Future Oncol 2021 Jul 25;17(19):2431-2438. Epub 2021 Mar 25.

Department of Clinical Oncology, St. Marianna University School of Medicine, Kawasaki, 216-8511, Japan.

Limited data are available regarding the efficacy of nutrition support in advanced gastric cancer (AGC) patients receiving a standard second-line combination chemotherapy. The BALAST study is conducted as a prospective, multicenter observational study to evaluate the efficacy of nutrition support for patients with AGC treated with ramucirumab plus taxane as second-line treatment. As part of the routine care, patients who are malnourished or at risk of malnutrition will receive nutrition support from dietitians. We will enroll a total of 26 patients to estimate weight control rate at 12 weeks as primary end point. This study will generate valuable data reinforcing the role of nutrition support therapy for AGC patients receiving second-line chemotherapy.
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http://dx.doi.org/10.2217/fon-2021-0076DOI Listing
July 2021

Impact of Body Weight Loss on Survival in Patients with Advanced Gastric Cancer Receiving Second-Line Treatment.

Nutr Cancer 2021 Mar 23:1-14. Epub 2021 Mar 23.

Department of Clinical Oncology, St. Marianna University School of Medicine, Kawasaki, Kanagawa, Japan.

Limited information is available regarding the impact of body weight loss (BWL) in patients with advanced gastric cancer (AGC) who receive second-line chemotherapy. We retrospectively reviewed data for consecutive AGC patients who received second-line treatment with taxane-based chemotherapy at our institution between January 2014 and September 2018. We calculated variables, including percent BWL per month during chemotherapy (%BWL/m), and analyzed the correlations between BWL and other clinicopathological parameters with survival. Forty-four AGC patients were registered (median age, 67.5 years; females,  = 16 [36.3%]; severe ascites,  = 12 [27.3%]). The median overall survival was significantly shorter among patients with a %BWL/m of 1% or more, compared with patients with less weight loss (6.3 mo, vs. 12.3 mo,  = 0.038). The %BWL/m (≥1% vs. <1%) was significantly correlated with survival in a univariate analysis (HR = 2.11,  = 0.04), and the survival period was shorter for patients with severe ascites (HR = 1.92; 95% CI, 0.90-3.90) and if their %BWL/m was 1% or more (HR = 2.01; 95% CI, 0.98-4.10) in a multivariate analysis. In conclusion, BWL during second-line chemotherapy was associated with a poor prognosis among patients with AGC.
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http://dx.doi.org/10.1080/01635581.2021.1902542DOI Listing
March 2021

Clinical characteristics of Japanese patients with moderate to severe COVID-19.

J Infect Chemother 2021 Jun 4;27(6):895-901. Epub 2021 Mar 4.

Department of Respiratory Medicine, Kanagawa Cardiovascular and Respiratory Center, Yokohama, Japan. Electronic address:

Introduction: Although several reports on the risk factors for severe disease of COVID-19 already exist, reports on effective early indicators are still limited, especially from Japan. This study was conducted to clarify the patient's characteristics whose disease progressed to severe status.

Methods: The medical records of all consecutive 300 Japanese patients hospitalized at our institution between February and November 2020 were retrospectively reviewed. The clinical characteristics were evaluated to compare between mild (no oxygen needed), moderate (oxygen needs of 1-4 L/min), and severe diseases (oxygen needs of 5 L/min or more).

Results: The median age was 68 years old, with 123 (41.0%) males and 177 (59.0%) females. Of these, 199 patients (66.3%), 55 patients (18.3%), 46 patients (15.3%) patients were in the mild disease, moderate disease, severe disease groups, respectively. Patients with severe disease were more likely to be older, have more comorbidities, and tended to have higher body mass index. In laboratory data, lymphocyte count, levels of C-reactive protein (CRP), LDH, and AST on admission were significantly associated with the severity. In multivariate analysis, age and CRP were the independent risk factors for severe disease (OR = 1.050, 1.130, respectively). The optimal cut-off value for age was 74 years old and that for CRP was 3.15 mg/dL.

Conclusions: Age and CRP were independently associated with disease severity of COVID-19 in multivariate analysis. Additionally, the numbers of underlying disease, lymphocyte count, and inflammatory markers such as LDH and D-dimer may also be related to disease severity.
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http://dx.doi.org/10.1016/j.jiac.2021.02.028DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7931728PMC
June 2021

A case of exogenous lipoid pneumonia diagnosed by transbronchial lung cryobiopsy.

Respir Investig 2021 Jul 5;59(4):555-558. Epub 2021 Mar 5.

Kanagawa Cardiovascular and Respiratory Center, Department of Respiratory Medicine, Tomioka-Higashi 6-16-1, Kanazawa-ku, Yokohama, 236-0051, Japan.

A 57-year-old man visited a referral physician due to abnormal chest shadows. Transbronchial lung biopsy (TBLB) failed to diagnose his condition. As antibiotics and systemic steroids did not improve the condition, he was referred to our hospital. A second TBLB in our hospital also failed to diagnose the disease. Transbronchial lung cryobiopsy (TBLC) was performed using radial endobronchial ultrasound with guide sheath (EBUS-GS), and the patient was diagnosed with lipoid pneumonia. Right upper lobe resection was performed, and lipoid pneumonia was confirmed from the surgical specimen. We report a case of lipoid pneumonia diagnosed by EBUS-GS TBLC.
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http://dx.doi.org/10.1016/j.resinv.2021.02.001DOI Listing
July 2021

Comparison of Clinical Characteristics and Outcomes between Idiopathic and Secondary Pleuroparenchymal Fibroelastosis.

J Clin Med 2021 Feb 18;10(4). Epub 2021 Feb 18.

Kanagawa Cardiovascular and Respiratory Center, Department of Respiratory Medicine, Yokohama 236-8651, Japan.

Background: Pleuroparenchymal fibroelastosis (PPFE) is a unique clinical, radiologic, and histopathologic entity for which several potential etiologies have been reported recently. However, there has been no comprehensive study of secondary PPFE.

Objective: Assessment of the clinical characteristics, outcomes, and prognostic factors of secondary and idiopathic PPFE.

Methods: We retrospectively reviewed the medical records of consecutive PPFE patients between January 1999 and December 2018. We identified 132 idiopathic PPFE patients and 32 secondary PPFE patients.

Results: The incidence of interstitial lung disease (ILD) pattern different from the usual interstitial pneumonia (UIP) pattern in the lower lobes was higher in secondary PPFE patients (38.5%) than in idiopathic PPFE patients (61.5%, = 0.02). The idiopathic and secondary PPFE groups did not differ significantly in terms of laboratory data, respiratory complications, and survival (median: 5.0 years vs. 4.1 years, = 0.95). The presence of UIP pattern was independently associated with increased mortality in multivariate analyses in idiopathic PPFE patients, but not in secondary PPFE patients.

Conclusions: The frequency and prognostic impact of UIP-pattern ILD differed between idiopathic and secondary PPFE patients. Lung transplantation should be considered in secondary PPFE patients with low diffusing capacity of the lungs for carbon monoxide (DLCO) regardless of lower-lobe ILD pattern.
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http://dx.doi.org/10.3390/jcm10040846DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7922642PMC
February 2021

Predictive factors for the long-term use of pirfenidone in patients with fibrosing interstitial lung disease.

Respir Investig 2021 Jul 19;59(4):414-420. Epub 2021 Feb 19.

Department of Respiratory Medicine, Kanagawa Cardiovascular and Respiratory Center, Yokohama, Japan. Electronic address:

Background: Pirfenidone is an anti-fibrotic agent approved for idiopathic pulmonary fibrosis (IPF), and long-term treatment data and the effect of continuation after disease progression have been reported. The efficacy and safety of pirfenidone in fibrosing interstitial lung disease (ILD) patients without IPF have been recently reported in clinical trials; therefore, the benefits of long-term treatment are also expected. This study aims to analyze the long-term treatment data of pirfenidone and clarify the predictive factors for long-term use of pirfenidone in non-IPF patients.

Methods: We retrospectively reviewed the records of consecutive fibrosing ILD patients who started using pirfenidone between 2008 and 2014.

Results: Of the 266 fibrosing ILD patients, 167 patients had IPF, and 99 had non-IPF. Despite the non-significant differences in body size and pulmonary function between IPF and non-IPF patients, the non-IPF patients had better overall survival than the IPF patients (median 4.06 years vs. 2.09 years, p < 0.0001). In addition, the non-IPF patients had a significantly longer time to treatment discontinuation than the IPF patients (median 2.20 years vs. 1.20 years, p = 0.002). Multivariate logistic regression analysis for ≥2 years of use of pirfenidone showed that the percent predicted forced vital capacity (%FVC) and age were predictive factors common to both IPF and non-IPF patients.

Conclusions: Our results indicate that non-IPF patients can continue using pirfenidone for longer durations than IPF patients. Initiation of pirfenidone for fibrosing ILD patients with higher %FVC and younger age would lead to long-term use of pirfenidone.
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http://dx.doi.org/10.1016/j.resinv.2021.01.002DOI Listing
July 2021

Development of an Automated Chemiluminescence Assay System for Quantitative Measurement of Multiple Anti-SARS-CoV-2 Antibodies.

Front Microbiol 2020 15;11:628281. Epub 2021 Jan 15.

Department of Microbiology, Yokohama City University Graduate School of Medicine, Yokohama, Japan.

Objectives: Serological tests for COVID-19 have been instrumental in studying the epidemiology of the disease. However, the performance of the currently available tests is plagued by the problem of variability. We have developed a high-throughput serological test capable of simultaneously detecting total immunoglobulins (Ig) and immunoglobulin G (IgG) against nucleocapsid protein (NP) and spike protein (SP) and report its performance in detecting COVID-19 in clinical samples.

Methods: We designed and prepared reagents for measuring NP-IgG, NP-Total Ig, SP-IgG, and SP-Total Ig (using N-terminally truncated NP (ΔN-NP) or receptor-binding domain (RBD) antigen) dedicated automated chemiluminescent enzyme immunoassay analyzer AIA-CL1200. After determining the basal thresholds based on 17 sera obtained from confirmed COVID-19 patients and 600 negative sera, the clinical validity of the assay was evaluated using independent 202 positive samples and 1,000 negative samples from healthy donors.

Results: All of the four test parameters showed 100% specificity individually (1,000/1,000; 95%CI, 99.63-100). The sensitivity of the assay increased proportionally to the elapsed time from symptoms onset, and all the tests achieved 100% sensitivity (153/153; 95%CI, 97.63-100) after 13 days from symptoms onset. NP-Total Ig was the earliest to attain maximal sensitivity among the other antibodies tested.

Conclusion: Our newly developed serological testing exhibited 100% sensitivity and specificity after 13 days from symptoms onset. Hence, it could be used as a reliable method for accurate detection of COVID-19 patients and to evaluate seroprevalence and possibly for surrogate assessment of herd immunity.
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http://dx.doi.org/10.3389/fmicb.2020.628281DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7843449PMC
January 2021

Pulmonary vascular enlargement and lesion extent on computed tomography are correlated with COVID-19 disease severity.

Jpn J Radiol 2021 May 27;39(5):451-458. Epub 2021 Jan 27.

Department of Respiratory Medicine, Kanagawa Cardiovascular and Respiratory Center, 6-16-1 Tomioka-higashi, Kanazawa-ku, Yokohama, Kanagawa, 236-8651, Japan.

Purpose: To assess the relationships among pulmonary vascular enlargement, computed tomography (CT) findings quantified with software, and coronavirus disease (COVID-19) severity.

Materials And Methods: Ultra-high-resolution (UHR) CT images of 87 patients (50 males, 37 females; median age, 63 years) with COVID-19 confirmed using real-time polymerase chain reaction were analyzed. The maximum subsegmental vascular diameter was measured on CT. Total CT lung volume (CTLV total) and lesion extent (ratio of lesion volume to CTLV total) of ground-glass opacities, reticulation, and consolidation were measured using software. Maximum pulmonary vascular diameter and lesion extent were analyzed using Spearman's correlation analysis. Logistic regression analysis was performed on CT results to predict disease severity. We also assessed changes in these measures on follow-up scans in 16 patients.

Results: All 23 patients with severe and critical illness had vascular enlargement (> 4 mm). Pulmonary vascular enlargement (odds ratio 3.05, p = 0.018) and CT lesion extent (odds ratio 1.07, p = 0.002) were independent predictors of disease severity after adjustment for age and comorbidities. On follow-up CT, vascular diameter and CT lesion volume decreased (p = 0.001, p = 0.002; respectively), but CTLV total did not change significantly.

Conclusion: Subsegmental vascular enlargement is a notable finding to predict acute COVID-19 disease severity.
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http://dx.doi.org/10.1007/s11604-020-01085-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7838849PMC
May 2021

Coronary artery disease and heart failure in patients with idiopathic pulmonary fibrosis.

Heart Vessels 2021 Aug 24;36(8):1151-1158. Epub 2021 Jan 24.

Respiratory Medicine, Kanagawa Cardiovascular and Respiratory Center, Yokohama, Kanagawa, Japan.

The aim of this study was to investigate the prevalence and prognostic value of coronary artery disease (CAD) and heart failure (HF) in patients with idiopathic pulmonary fibrosis (IPF). Thirteen hundred and fifty-eight patients with interstitial lung disease [851 (62%) males, mean age: 68 ± 10 years] were retrospectively analyzed. CAD was defined as (1) the presence of a clinical diagnosis of angina pectoris, (2) clinical diagnosis of a myocardial infarction, and (3) coronary angiography showing ≥ 1 vessel with a stenosis of > 75%. The definition of HF was made according to the modified Framingham criteria. Compared to the non-IPF group (n = 790), the IPF group (n = 568) had a significantly higher prevalence of CAD (9.3% vs. 4.4%, p < 0.001) and HF (8.2% vs. 3.7%, p < 0.001). During a median follow-up of 1.6 years, 152 deaths were identified. The patients with HF had a significantly worse prognosis than those without HF both in the non-IPF group and IPF group (both p < 0.05). However, the prognosis did not significantly differ between the patients with CAD and those without CAD both in the non-IPF group and IPF group. The presence of HF was an independent predictor of death in the IPF [hazard ratio (HR) 3.67, 95% confidence interval (CI) 1.57-8.56, p = 0.0025] and non-IPF (HR 5.07, 95% CI 1.44-17.86, p = 0.011) patients. The prevalence of CAD and HF was significantly higher in IPF than non-IPF patients. In addition, the presence of HF was a significant prognostic factor for both IPF and non-IPF patients. These results indicated that the importance of HF as a comorbidity for patients with ILD.
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http://dx.doi.org/10.1007/s00380-021-01787-1DOI Listing
August 2021

Effect of the Electron Density of the Heme Fe Atom on the Nature of Fe-O Bonding in Oxy Myoglobin.

Inorg Chem 2021 Jan 28;60(2):1021-1027. Epub 2020 Dec 28.

Department of Applied Chemistry, Faculty of Engineering, Sanyo-Onoda City University, Sanyo-Onoda, Yamaguchi 756-0884, Japan.

Mössbauer spectroscopy has been used to characterize oxygenated myoglobins (oxy Mbs) reconstituted with native and chemically modified Fe-enriched heme cofactors with different electron densities of the heme Fe atom (ρ) and to elucidate the effect of a change in the ρ on the nature of the bond between heme Fe and oxygen (O), i.e., the Fe-O bond, in the protein. Quadrupole splitting () was found to decrease with decreasing ρ, and the observed ρ-dependent confirmed an increase in the contribution of the ferric-superoxide (Fe-O) form to the resonance hybrid of the Fe-O fragment with decreasing ρ. These observations explicitly accounted for the lowering of O affinity of the protein due to an increase in the O dissociation rate and a decrease in the autoxidation reaction rate of oxy Mb through decreasing H affinity of the bound ligand with decreasing ρ. Therefore, the present study demonstrated the mechanism underlying the electronic control of O affinity and the autoxidation of the protein through the heme electronic structure. Carbon monoxide (CO) adducts of reconstituted Mbs (CO-Mbs) were similarly characterized, and we found that the resonance between the two canonical forms of the Fe-CO fragment was also affected by a change in ρ. Thus, the nature of the Fe-ligand bond in the protein was found to be affected by the ρ.
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http://dx.doi.org/10.1021/acs.inorgchem.0c03123DOI Listing
January 2021

A systematic review of corticosteroid treatment for noncritically ill patients with COVID-19.

Sci Rep 2020 12 1;10(1):20935. Epub 2020 Dec 1.

Department of Respiratory Medicine and Infectious Diseases, Oita University Faculty of Medicine, 1-1 Idaigaoka, Hasama-machi, Yufu, Oita, 879-5593, Japan.

The World Health Organization (WHO) has published guidance recommending systemic corticosteroids for the treatment of patients with severe or critical COVID-19 and no corticosteroids for those with nonsevere COVID-19. Although their recommendations for critical cases were based on the results from seven randomized controlled trials (RCTs), those for noncritical cases were based on the results from only one RCT, the Randomized Evaluation of COVID-19 Therapy (RECOVERY) trial. In search of additional evidence of corticosteroids' effect on COVID-19, we systematically reviewed controlled observational studies, besides RCTs, that assessed the impact of corticosteroid treatment on any type of mortality and/or other outcomes in noncritical patients. Of the 4037 titles and abstracts screened, we ultimately included the RECOVERY trial and five controlled observational studies using propensity score matching, (accessed on September 8, 2020). Two of the controlled observational studies assessed the association between corticosteroid treatment and in-hospital mortality, without finding statistical significance. Four of the controlled observational studies assessed corticosteroids' effect on other outcomes, demonstrating that they were associated with reduced risk of intubation in patients requiring oxygen and with longer hospitalization and viral shedding in mild or moderate cases. These results support the WHO recommendations not to use corticosteroids for nonsevere COVID-19.
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http://dx.doi.org/10.1038/s41598-020-78054-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7708623PMC
December 2020

Serum surfactant protein D as a predictive biomarker for the efficacy of pirfenidone in patients with idiopathic pulmonary fibrosis: a post-hoc analysis of the phase 3 trial in Japan.

Respir Res 2020 Nov 30;21(1):316. Epub 2020 Nov 30.

Department of Respiratory Medicine and Allergology, School of Medicine, Sapporo Medical University, South 1, West 16, Sapporo, 060-8543, Japan.

Background: Idiopathic pulmonary fibrosis (IPF) is a progressive, fatal disorder with a variable disease course. The recent advancement of antifibrotic therapy has increased the need for reliable and specific biomarkers. This study aimed to assess alveolar epithelial biomarkers as predictors for the efficacy of the antifibrotic drug pirfenidone.

Methods: We conducted a post-hoc analysis of the prospective, multicenter, randomized, placebo-controlled, phase 3 trial of pirfenidone in Japan (total, n = 267; pirfenidone, n = 163; placebo, n = 104). Logistic regression analysis was performed to extract parameters that predicted disease progression, defined by a ≥ 10% relative decline in vital capacity (VC) from baseline and/or death, at week 52. For assessment of serum surfactant protein (SP)-D, SP-A and Krebs von den Lungen (KL)-6, all patients were dichotomized by the median concentration of each biomarker at baseline to the high and low biomarker subgroups. Associations of these concentrations were examined with changes in VC at each time point from baseline up to week 52, along with progression-free survival (PFS). Additionally, the effect of pirfenidone treatment on serial longitudinal concentrations of these biomarkers were evaluated.

Results: In the multivariate logistic regression analysis, body mass index (BMI), %VC and SP-D in the pirfenidone group, and BMI and %VC in the placebo group were indicated as predictors of disease progression. Pirfenidone treatment reduced the decline in VC with statistical significance in the low SP-D and low SP-A subgroups over most of the treatment period, and also prolonged PFS in the low SP-D and low KL-6 subgroups. Furthermore, SP-D levels over time course were reduced in the pirfenidone group from as early as week 8 until the 52-week treatment period compared with the placebo group.

Conclusions: Serum SP-D was the most consistent biomarker for the efficacy of pirfenidone in the cohort trial of IPF. Serial measurements of SP-D might have a potential for application as a pharmacodynamic biomarker. Trial registration The clinical trial was registered with the Japan Pharmaceutical Information Center (JAPIC) on September 13, 2005 (registration No. JapicCTI-050121; http://Clinicaltrials.jp ).
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http://dx.doi.org/10.1186/s12931-020-01582-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7706186PMC
November 2020

Inferior mesenteric arteriovenous fistula during treatment with bevacizumab in colorectal cancer patient: A case report.

World J Gastrointest Oncol 2020 Nov;12(11):1364-1371

Department of Clinical Oncology, St. Marianna University School of Medicine, Kanagawa 216-8511, Japan.

Background: Fistula formation is a severe adverse event related to antiangiogenetic agents such as bevacizumab and inferior mesenteric arteriovenous fistula (IMAVF) is a result of acquired factor, especially colon surgery. However, IMAVF occurs very rarely and there are few reports in patients during chemotherapy. We report a case of a patient who developed IMAVF during treatment with bevacizumab in metastatic colorectal cancer (mCRC) after colon surgery.

Case Summary: An 81-year-old man was diagnosed with descending colon cancer and underwent left hemicolectomy without any complications. He was definitely diagnosed with high-risk stage 2 and received tegafur-uracil plus leucovorin as adjuvant chemotherapy. Three years and 6 mo after the operation, the cancer relapsed with peritoneal dissemination. The patient underwent CyberKnife radiosurgery targeting the recurrent tumor and received chemotherapy with S-1 plus bevacizumab. At 1 year after chemotherapy, he complained of severe diarrhea, which is suspected drug-induced colitis. As diarrhea worsened despite the termination of treatment, he underwent colonoscopy and computed tomography (CT) scans that revealed edematous change from sigmoid to rectosigmoid colon. CT scans also revealed an aneurysm adjacent to the inferior mesenteric vein and multidetector CT angiography showed the IMAVF. Elective angiography confirmed the diagnosis of an IMAVF and it was successfully treated by arterial embolization. The patient resumed chemotherapy with only S-1 6 mo after embolization.

Conclusion: Clinicians should keep in mind the probability of severe diarrhea arose from IMAVF in mCRC patients treated with bevacizumab.
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http://dx.doi.org/10.4251/wjgo.v12.i11.1364DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7667451PMC
November 2020

Efficacy and safety of nintedanib in Asian patients with systemic sclerosis-associated interstitial lung disease: Subgroup analysis of the SENSCIS trial.

Respir Investig 2021 Mar 19;59(2):252-259. Epub 2020 Nov 19.

Department of Allergy and Rheumatology, Nippon Medical School Graduate School of Medicine, Tokyo, Japan.

Background And Objective: In the SENSCIS trial in patients with systemic sclerosis-associated interstitial lung disease (SSc-ILD), nintedanib reduced the rate of decline in forced vital capacity (FVC) (mL/year) over 52 weeks by 44% in comparison with placebo, with manageable adverse events in most patients. We analyzed the efficacy and safety of nintedanib in patients of Asian race.

Methods: Patients with SSc-ILD were randomized to receive nintedanib or placebo. The outcomes over 52 weeks were analyzed in Asian versus non-Asian patients.

Results: Of the 288 patients in each treatment group, 62 (21.5%) in the nintedanib group and 81 (28.1%) in the placebo group were Asian; 90.2% of the Asian patients were enrolled in Asian countries. In the placebo group, the rate of FVC decline over 52 weeks was consistent between Asian and non-Asian patients (-99.9 and -90.6 mL/year, respectively). The effect of nintedanib on reducing the rate of FVC decline over 52 weeks was consistent between Asian (difference, 44.3 mL/year [95% CI: -32.8, 121.4]) and non-Asian patients (difference, 39.0 mL/year [95% CI: -5.1, 83.1]) (treatment-by-time-by-subgroup interaction, p = 0.91). Diarrhea was the most frequent adverse event and was reported in similar proportions of Asian and non-Asian patients in the nintedanib group (80.6% and 74.3%, respectively) and placebo group (28.4% and 32.9%, respectively).

Conclusions: In patients with SSc-ILD, nintedanib had a consistent benefit on slowing the progression of SSc-ILD in Asian and non-Asian patients, with a similar adverse event profile.

Trial Registration: ClinicalTrials.gov NCT02597933.
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http://dx.doi.org/10.1016/j.resinv.2020.10.005DOI Listing
March 2021
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