Publications by authors named "Naohiro Oda"

36 Publications

Exacerbation of pulmonary cryptococcosis associated with enhancement of Th2 response in the postpartum period.

J Infect Chemother 2021 Apr 8. Epub 2021 Apr 8.

Department of Medical Technology, Okayama University Graduate School of Health Sciences, Okayama, Japan; Department of Allergy and Respiratory Medicine, Okayama University Hospital, Okayama, Japan.

Cryptococcosis is an invasive mycosis that has become increasingly prevalent in immunocompromised patients. Pregnant women are also one of the risk populations for cryptococcosis. Reversal of Th2 to Th1 response following resolution of immunosuppression during the postpartum period can lead to overt clinical manifestations of a previously silent infection, resembling an immune reconstitution inflammatory syndrome. Here, we report a case of a 30-year-old woman who had an exacerbation of pulmonary cryptococcosis in the postpartum period mimicking an immune reconstitution inflammatory syndrome. In the present case, chest computed tomography showed multiple small nodules on the day of the delivery; however, pulmonary cryptococcosis, which was subclinical during pregnancy, rapidly worsened to mass-like consolidation at one month after the delivery. Pathohistological examination of the lung specimen showed lung parenchyma infiltration with histiocytes and numerous lymphocytes without granulomatous formations, and a small number of yeast-like organisms consistent with Cryptococcus without capillary involvement. Immunohistochemical staining showed predominance of CD3 cells and CD4 cells over CD8 cells. In addition, GATA3+ cells dominated over T-bet + cells. These data suggested exacerbation of pulmonary cryptococcosis associated with enhancement of Th2 response in the postpartum period.
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http://dx.doi.org/10.1016/j.jiac.2021.03.025DOI Listing
April 2021

The effects of antibiotics on the efficacy of immune checkpoint inhibitors in patients with non-small-cell lung cancer differ based on PD-L1 expression.

Eur J Cancer 2021 May 7;149:73-81. Epub 2021 Apr 7.

Department of Allergy and Respiratory Medicine, Okayama University Hospital, Japan.

Background: Immune checkpoint inhibitors (ICIs) are essential for treatment of various malignancies, including non-small-cell lung cancer (NSCLC). Recently, several studies have shown that the gut microbiome plays an important role in ICI treatment of solid cancers, and antibiotic (ATB) use had a negative impact on the outcomes of ICI treatment via dysbiosis in the gut. However, whether this is applicable to NSCLC remains unclear. The impact of ATBs based on PD-L1 expression also remains unclear.

Methods: We retrospectively reviewed the medical records of patients with NSCLC who received ICI monotherapy (anti-PD-1 or anti-PD-L1 antibody) at nine institutions from December 2015 to May 2018. Outcomes with use of ATBs during the 2 months before or a month after initiation of ICI treatment, including progression-free survival (PFS) and overall survival (OS), were investigated using the Kaplan-Meier method. Multivariate analysis was also conducted using a Cox proportional hazards model.

Results: A total of 531 patients were included in this study, among whom 98 (18.5%) received ATBs before or after ICI treatment. ATB use was significantly associated with a shorter median OS (11.7 months in the ATB group vs. 16.1 months in the non-ATB group; p = 0.028), whereas the difference in PFS was not significant (3.5 months in both the groups; p = 0.287). We next investigated the association based on PD-L1 expression in the 265 patients for whom PD-L1 expression was determined. There was no significant difference in the median OS or PFS between patients with NSCLC and PD-L1 expression <50% receiving ATBs and those not receiving ATBs (PFS: 3.3 vs. 2.8 months, p = 0.88; OS: 9.5 vs. 17.1 months, p = 0.24). Conversely, patients with NSCLC and PD-L1 expression ≥50% receiving ATBs showed significantly shorter median PFS and OS (PFS: 4.2 vs. 9.4 months, p = 0.012; OS: 11.9 vs. 28.4 months, p = 0.011). The impact of ATBs in patients with NSCLC and PD-L1 expression ≥50% was more significant than that in the entire cohort.

Conclusions: Our results indicate that the impact of ATB use on the efficacy of ICIs differed based on PD-L1 expression in patients with advanced NSCLC. A negative impact of ATB use was found in patients with NSCLC and PD-L1 expression ≥50% but not in those with PD-L1 expression <50%.
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http://dx.doi.org/10.1016/j.ejca.2021.02.040DOI Listing
May 2021

Dramatic Response to Carboplatin Plus Paclitaxel in Pancreatic Mucinous Cystadenocarcinoma with Liver Metastasis.

Intern Med 2021 Apr 5. Epub 2021 Apr 5.

Department of Allergy and Respiratory Medicine, Okayama University Hospital, Japan.

Mucinous cystic neoplasm (MCN) of the pancreas is a rare cystic tumor occurring in the pancreatic body and tail in young to middle-aged women that is pathologically characterized by an ovarian-like stroma. Chemotherapy for recurrent/advanced pancreatic MCN has been based on chemotherapy regimens for pancreatic ductal adenocarcinoma, but the prognosis is poor. We herein report a 37-year-old woman with pancreatic mucinous cystadenocarcinoma with liver metastasis that responded dramatically to carboplatin plus paclitaxel therapy (CBDCA + PTX). CBDCA + PTX may be a treatment option for recurrent/advanced pancreatic MCN with an ovarian-like stroma.
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http://dx.doi.org/10.2169/internalmedicine.6730-20DOI Listing
April 2021

Significance of PD-L1 expression in the cytological samples of non-small cell lung cancer patients treated with immune checkpoint inhibitors.

J Cancer Res Clin Oncol 2021 Mar 29. Epub 2021 Mar 29.

Department of Allergy and Respiratory Medicine, Okayama University Hospital, 2-5-1 Shikata-cho, Kita-ku, Okayama, Okayama, 700-8558, Japan.

Objectives: The programmed death-ligand 1 (PD-L1) tumor proportion score (TPS) in tumor tissue samples is an established clinical biomarker for non-small cell lung cancer (NSCLC). However, the significance of PD-L1 expression in other types of samples has not been fully investigated.

Patients And Methods: We conducted a multicenter retrospective cohort study of advanced NSCLC patients who received ICI treatment during the clinical course and investigated the effects of ICIs according to PD-L1 expression in cytology samples, including cell block and endobronchial ultrasound-guided (EBUS) transbronchial needle aspiration (TBNA) samples.

Results: A total of 264 patients were included in this study: PD-L1 expression was determined in cell block or TBNA specimens in 55 patients, and in tissue samples in 209 patients. Among the former patients, the median progression-free survival (PFS) of those with a TPS for PD-L1 ≥ 50% was significantly longer compared to that of those with a TPS < 50% (6.5 vs. 1.9 months, respectively, p = 0.008). When the cutoff value was set at 1%, the median PFS was 4.2 months in patients with a TPS ≥ 1% and 1.5 months in patients with a TPS < 1% (p < 0.001).

Conclusion: PD-L1 expression determined using cytology specimens predicts the efficacy of ICIs.
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http://dx.doi.org/10.1007/s00432-021-03615-5DOI Listing
March 2021

A phase II study of S-1 and cisplatin with concurrent thoracic radiotherapy followed by durvalumab for unresectable, locally advanced non-small-cell lung cancer in Japan (SAMURAI study).

Ther Adv Med Oncol 2021 27;13:1758835921998588. Epub 2021 Feb 27.

Department of Respiratory Medicine, Chugoku Central Hospital, Fukuyama-City, Hiroshima, Japan.

Background: Based on the results of the PACIFIC study, chemoradiotherapy followed by 1-year consolidation therapy with durvalumab was established as the standard of care for unresectable, locally advanced non-small-cell lung cancer (LA-NSCLC). However, some topics not foreseen in that design can be explored, including progression-free survival (PFS) and overall survival (OS) after the start of chemoradiotherapy, the proportion of patients who proceeded to consolidation therapy with durvalumab, and the optimal chemotherapeutic regimens. In Japan, the combination regimen of S-1 + cisplatin (SP), for which the results of multiple clinical studies have suggested a good balance of efficacy and tolerability, is frequently selected in clinical settings. However, the efficacy and safety of consolidation therapy with durvalumab following this SP regimen have not been evaluated. We therefore planned a multicenter, prospective, single-arm, phase II study.

Methods: In treatment-naïve LA-NSCLC, two cycles of combination chemotherapy with S-1 (80-120 mg/body, Days 1-14) + cisplatin (60 mg/m, Day 1) will be administered at an interval of 4 weeks, with concurrent thoracic radiotherapy (60 Gy). Responders will then receive durvalumab every 2 weeks for up to 1 year. The primary endpoint is 1-year PFS rate.

Discussion: Compared with the conventional standard regimen in Japan, the SP regimen is expected to be associated with lower incidences of pneumonitis, esophagitis, and febrile neutropenia, which complicate the initiation of consolidation therapy with durvalumab, and have higher antitumor efficacy during chemoradiotherapy. Therefore, SP-based chemoradiotherapy is expected to be successfully followed by consolidation therapy with durvalumab in more patients, resulting in prolonged PFS and OS. Toxicity and efficacy results of the SP regimen in this study will also provide information important to the future establishment of the concurrent combination of chemoradiotherapy and durvalumab.

Trial Registration: Japan Registry of Clinical Trials, jRCTs031190127, registered 1 November 2019, https://jrct.niph.go.jp/latest-detail/jRCTs031190127.
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http://dx.doi.org/10.1177/1758835921998588DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7917867PMC
February 2021

Pulmonary epithelioid haemangioendothelioma mimicking lung cancer.

BMJ Case Rep 2021 Feb 18;14(2). Epub 2021 Feb 18.

Allergy and Respiratory Medicine, Okayama University Hospital, Okayama, Japan.

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http://dx.doi.org/10.1136/bcr-2020-240152DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7896606PMC
February 2021

Legionella longbeachae pneumonia: A case report and literature review in Japan.

J Infect Chemother 2021 May 2;27(5):751-754. Epub 2021 Jan 2.

Department of Internal Medicine, Fukuyama City Hospital, Fukuyama, Japan.

Herein, we report the case of a 74-year-old man diagnosed with Legionella pneumonia detected by Loop-Mediated Isothermal Amplification (LAMP) method, which was suspected to have been transmitted from the potting soil. Legionella longbeachae was identified in the sputum culture. The patient was intubated and maintained on mechanical ventilation. Antimicrobial therapy with azithromycin was also administered. His symptoms were resolved and he was discharged after 26 days of hospitalization. Legionella longbeachae pneumonia rarely occurs in Japan, and published literature of Legionella longbeachae pneumonia cases in Japan was reviewed. Patients with severe pneumonia exposed to potting soils, but with negative urinary antigen test results, should be examined by LAMP method.
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http://dx.doi.org/10.1016/j.jiac.2020.12.010DOI Listing
May 2021

Detection of epidermal growth factor receptor mutations in exhaled breath condensate using droplet digital polymerase chain reaction.

Oncol Lett 2020 Dec 29;20(6):393. Epub 2020 Oct 29.

Department of Respiratory Medicine, Okayama University Hospital, Okayama 700-8558, Japan.

The detection of certain oncogenic driver mutations, including those of epidermal growth factor receptor (), is essential for determining treatment strategies for advanced non-small cell lung cancer (NSCLC). The current study assessed the feasibility of testing exhaled breath condensate (EBC) for mutations by droplet digital PCR (ddPCR). Samples were collected from 12 patients with NSCLC harboring EGFR mutations that were admitted to Okayama University Hospital between June 1, 2014 and December 31, 2017. A total of 21 EBC samples were collected using the RTube™ method and mutations (L858R, exon 19 deletions or T790M) were assessed through ddPCR analysis (EBC-ddPCR). A total of 3 healthy volunteer samples were also tested to determine a threshold value for each mutation. Various patient characteristics were determined, including sex (3 males and 9 females), age (range 54-81 years; median, 66 years), smoking history (10 had never smoked; 2 were former smokers), histology (12 patients exhibited adenocarcinoma), clinical stage (9 patients were stage IV; 3 exhibited post-operative recurrence) and mutation type (4 had L858R; 8 had exon 19 deletions; 8 had T790M). EBC-ddPCR demonstrated positive droplets in 8 of the 12 patients. The sensitivity and specificity of each mutation was as follows: 27.3 and 80.0% for L858R, 30.0 and 90.9% for Ex19del, and 22.2 and 100% for T790M. EBC-ddPCR analysis of mutations exhibited modest sensitivity and acceptable specificity. EBC-ddPCR is a minimally invasive and replicable procedure and may be a complementary method for testing in patients where blood or tissue sampling proves difficult.
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http://dx.doi.org/10.3892/ol.2020.12256DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7656106PMC
December 2020

Aspergillus Nodule with Hilar and Mediastinal Lymphadenopathy Mimicking Lung Cancer.

Am J Med 2021 03 8;134(3):339-340. Epub 2020 Nov 8.

Department of Internal Medicine, Fukuyama City Hospital, Fukuyama, Japan.

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http://dx.doi.org/10.1016/j.amjmed.2020.10.012DOI Listing
March 2021

Impact of previous thoracsic radiation therapy on the efficacy of immune checkpoint inhibitors in advanced non-smasll-cell lung cancer.

Jpn J Clin Oncol 2021 Feb;51(2):279-286

Department of Allergy and Respiratory Medicine, Okayama University Hospital, Okayama, Japan.

Objectives: Studies investigating the association between radiation therapy and the efficacy of immune checkpoint inhibitors in advanced non-small-cell lung cancer have provided inconsistent results, likely due to relatively small cohort sizes. This study investigated the effect of previous thoracic radiation therapy on the efficacy of immune checkpoint inhibitor therapy in a large non-small-cell lung cancer cohort.

Patients And Methods: We conducted a retrospective cohort study using data from 531 non-small-cell lung cancer patients who received monotherapy with programmed cell death protein 1/programmed death-ligand 1 inhibitors at nine institutions. The effects of thoracic radiation therapy on the efficacy of immune checkpoint inhibitors were investigated.

Results: A total of 531 non-small-cell lung cancer patients treated with immune checkpoint inhibitors were included in this study. The progression-free survival period was significantly longer in patients that had received thoracic radiation therapy before immune checkpoint inhibitor therapy compared to those without previous thoracic radiation therapy (median progression-free survival 5.0 vs. 3.0 months, P = 0.0013). A multivariate analysis showed that thoracic radiation therapy was an independent predictive factor of improved progression-free survival (hazard ratio of progression-free survival: 0.79, P = 0.049). In contrast, extra-thoracic radiation therapy was associated with inferior outcomes (median progression-free survival 3.0 vs. 4.2 months, P = 0.0008).

Conclusion: Previous thoracic radiation therapy, but not prior extra-thoracic radiation therapy, enhanced the efficacy of anti-programmed cell death protein 1/programmed death-ligand 1 therapy in non-small-cell lung cancer patients.
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http://dx.doi.org/10.1093/jjco/hyaa180DOI Listing
February 2021

Nintedanib can be used safely and effectively for idiopathic pulmonary fibrosis with predicted forced vital capacity ≤ 50%: A multi-center retrospective analysis.

PLoS One 2020 27;15(8):e0236935. Epub 2020 Aug 27.

Department of Hematology, Oncology, and Respiratory Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan.

Background: Nintedanib is a multi-kinase inhibitor approved for idiopathic pulmonary fibrosis (IPF); however, its efficacy and safety for patients with IPF and restricted pulmonary function remain unclear. Therefore, the objective of this study was to determine the efficacy and safety of nintedanib for patients with IPF and forced vital capacity (FVC) ≤ 50%.

Methods: This was a multi-center retrospective study performed by the Okayama Respiratory Disease Study Group. Patients were allocated into FVC ≤ 50% and FVC > 50% groups based on their predicted FVC. The primary endpoints were FVC changes from baseline after 6 and 12 months.

Results: 45 patients were eligible for the study. 18 patients had FVC ≤ 50%, and 27 patients had FVC > 50%. Overall, 31 and 19 patients underwent pulmonary function tests at 6 and 12 months after initiating nintedanib, respectively. FVC changes from baseline at 6 and 12 months after initiating nintedanib were comparable between the two groups. Adverse events were seen in all patients, and the rates of patients who discontinued nintedanib were also comparable (38.9% vs. 37.0%, p = 1.000). Multiple regression analysis showed that age and forced expiratory volume in 1 second (FEV1)/FVC were negatively correlated with changes in FVC at 6 months after initiating nintedanib.

Conclusions: Our data suggest that nintedanib can be a useful agent for IPF patients, including those with a low FVC, and that age and FEV1/FVC are predictive markers for changes in FVC following nintedanib treatment.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0236935PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7451511PMC
October 2020

Utility of immune checkpoint inhibitors in non-small-cell lung cancer patients with poor performance status.

Cancer Sci 2020 Oct 26;111(10):3739-3746. Epub 2020 Aug 26.

Department of Allergy and Respiratory Medicine, Okayama University Hospital, Okayama, Japan.

Most clinical trials of non-small-cell lung cancer (NSCLC) exclude patients with poor ECOG performance status (PS). Thus, the efficacy of immune checkpoint inhibitors (ICIs) in patients with poor PS remains unclear. Herein, we used data from a retrospective cohort to assess the potential clinical benefits of ICIs in NSCLC patients with poor PS. Data from NSCLC patients who received ICI monotherapy at 9 institutions between December 2015 and May 2018 were retrospectively analyzed. After excluding 4 patients who lacked PS data, a total of 527 ICI-treated patients, including 79 patients with PS 2 or higher, were used for our analyses. The progression-free survival (PFS) and overall survival (OS) of patients with PS 2 or higher were significantly shorter compared with those of PS 0-1 patients (median PFS, 4.1 vs 2.0 months; P < .001 and median OS, 17.4 vs 4.0 months; P < .001). Among NSCLC patients with programmed cell death protein-ligand 1 (PD-L1) expression of 50% or higher who were treated with pembrolizumab as first-line therapy, the median PFS times of patients with PS 2 and 0-1 were 7.3 and 8.1 months, respectively. There was no significant difference in PFS between patients with PS 2 and 0-1 (P = .321). Although poor PS was significantly associated with worse outcomes in NSCLC patients treated with ICIs, pembrolizumab as a first-line treatment in NSCLC patients expressing high levels of PD-L1 could provide a clinical benefit, even in patients with PS 2.
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http://dx.doi.org/10.1111/cas.14590DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7540975PMC
October 2020

Characteristics of patients with EGFR-mutant non-small-cell lung cancer who benefited from immune checkpoint inhibitors.

Cancer Immunol Immunother 2021 Jan 10;70(1):101-106. Epub 2020 Jul 10.

Department of Allergy and Respiratory Medicine, Okayama University Hospital, 2-5-1 Shikata-cho, Kita-ku, Okayama City, Okayama, 700-8558, Japan.

Objectives: Immune checkpoint inhibitors (ICIs) are less effective in non-small-cell lung cancer (NSCLC) patients with epidermal growth factor receptor (EGFR) mutations. However, a small percentage of patients with EGFR-mutant NSCLC do respond, and the characteristics of these patients are not known. Here, we identify the characteristics of patients who may respond to ICI therapy for EGFR-mutant NSCLC.

Patients And Methods: The medical records of NSCLC patients with EGFR mutations who received PD-1/PD-L1 antibody monotherapy at nine institutions were reviewed.

Results: In total, 58 patients with EGFR-mutant NSCLC were analyzed. Various clinical factors such as smoking history and EGFR mutation type were not associated with progression-free survival (PFS) of ICIs, while the PFS of prior EGFR tyrosine kinase inhibitors (TKIs) was inversely associated with that of ICIs. Patients who responded to prior EGFR TKIs for > 10 months exhibited a significantly shorter response to ICIs compared to those who had responded for ≤ 10 months (PFS of ICI: 1.6 vs. 1.9 months; hazard ratio: 2.54; 95% confidence interval 1.26-5.12; p = 0.009). However, patients who responded to ICIs for > 6 months responded to prior EGFR TKIs for significantly shorter periods compared to those who responded to ICIs for ≤ 6 months (PFS of prior EGFR TKI: 5.3 vs. 12.1 months; log-rank test: p = 0.0025).

Conclusion: The duration of response to prior EGFR TKIs could be a predictive marker of ICI therapy in EGFR-mutant NSCLC patients.
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http://dx.doi.org/10.1007/s00262-020-02662-0DOI Listing
January 2021

An Elderly Patient with Pulmonary Cryptococcosis with Mediastinal Lymphadenopathy Who Was Successfully Treated with Amphotericin B and Flucytosine.

Intern Med 2020 Oct 23;59(20):2547-2551. Epub 2020 Jun 23.

Department of Internal Medicine, Fukuyama City Hospital, Japan.

Pulmonary cryptococcosis develops not only in immunocompromised patients but also in immunocompetent patients. However, lymph node involvement is relatively rare in immunocompetent patients. We herein report the case of an 80-year-old man who was not in an apparent immunocompromised state but was diagnosed with pulmonary cryptococcosis with mediastinal lymphadenopathy. The patient was resistant to fluconazole and voriconazole monotherapy; thus, his lung lesions significantly worsened. He eventually responded well to a combination therapy of amphotericin B and flucytosine, which was administered according to the treatment strategy for disseminated diseases.
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http://dx.doi.org/10.2169/internalmedicine.4753-20DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7662044PMC
October 2020

Successful Treatment of Non-small-cell Lung Cancer with Atezolizumab Following Tubulointerstitial Nephritis Due to Pembrolizumab.

Intern Med 2020 Jul 9;59(13):1639-1642. Epub 2020 Apr 9.

General Internal Medicine 4, Kawasaki Medical School, Japan.

We herein report a 75-year-old man with non-small-cell lung cancer who developed tubulointerstitial nephritis due to pembrolizumab administration. He was successfully treated with atezolizumab following steroid administration. He was initially diagnosed with lung adenocarcinoma (T1bN3M1b, stage IV), with a programmed cell death-ligand 1 tumor proportion score of 25-49%. Although the tumor responded well to pembrolizumab, the drug was discontinued because of the diagnosis of tubulointerstitial nephritis on a renal biopsy. Tubulointerstitial nephritis was treated with 30 mg prednisolone, the dose of which was tapered to and maintained at 5 mg. Following lung cancer progression, atezolizumab was administered, and the tumor responded again. Its efficacy has been sustained for >15 months without recurrence of tubulointerstitial nephritis.
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http://dx.doi.org/10.2169/internalmedicine.4260-19DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7402961PMC
July 2020

Deterioration of high-resolution computed tomography findings predicts disease progression after initial decline in forced vital capacity in idiopathic pulmonary fibrosis patients treated with pirfenidone.

Respir Investig 2020 May 23;58(3):185-189. Epub 2020 Feb 23.

Department of Allergy and Respiratory Medicine, Okayama University Hospital, Okayama, Japan. Electronic address:

Background: Pirfenidone suppresses the decline of forced vital capacity (FVC) in patients with idiopathic pulmonary fibrosis (IPF). However, IPF progresses in some patients despite treatment. We analyzed patients with meaningful FVC declines during pirfenidone treatment and explored the factors predictive of disease progression after FVC decline.

Methods: This study was a retrospective, multicenter, observational study conducted by the Okayama Respiratory Disease Study Group. We defined initial decline in %FVC as 5% or greater per 6-month period during pirfenidone treatment. IPF patients who were treated with pirfenidone and experienced an initial decline from December 2008 to September 2017 were enrolled.

Results: We analyzed 21 patients with IPF. After the initial decline, 4 (19.0%) patients showed improvement in disease, 11 (52.4%) showed stable disease, and 6 (28.6%) showed progressive disease. There was no significant correlation between %FVC reduction on initial decline and subsequent %FVC change (p = 0.475). Deterioration of high-resolution computed tomography (HRCT) findings on initial decline was observed significantly more often in the progressive versus improved/stable disease groups (100% vs 20.0%, p = 0.009).

Conclusions: We revealed that deterioration of HRCT findings may predict disease progression after the initial decline in %FVC in IPF patients treated with pirfenidone.
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http://dx.doi.org/10.1016/j.resinv.2019.12.007DOI Listing
May 2020

The impact of body mass index on the efficacy of anti-PD-1/PD-L1 antibodies in patients with non-small cell lung cancer.

Lung Cancer 2020 01 18;139:140-145. Epub 2019 Nov 18.

Department of Allergy and Respiratory Medicine, Okayama University Hospital, Okayama, Japan.

Objectives: Body mass index (BMI) is reported to be associated with the efficacy of immune checkpoint inhibitors (ICIs) in solid tumors such as melanomas. However, it remains unclear whether such a relationship exists in non-small cell lung cancer (NSCLC) treated with programmed cell death protein 1 (PD-1)/ programmed death-ligand 1(PD-L1) inhibitors. The purpose of this study was to investigate the relationship between BMI and the efficacy of ICI treatment in patients with advanced NSCLC.

Materials And Methods: The medical records of NSCLC patients who received PD-1/PD-L1 antibody monotherapy at nine institutions between December 2015 and May 2018 were reviewed retrospectively. The effect of BMI was investigated in two cohorts. Cohort 1 included patients with NSCLCs with high PD-L1 expression (≥ 50 %) treated with pembrolizumab as first-line therapy, and cohort 2 included patients with NSCLCs treated with nivolumab/pembrolizumab/atezolizumab as second- or later-line treatment.

Results: A total of 513 from nine institutions were analyzed (84 in cohort 1, 429 in cohort 2). Using a BMI cut-off value of 22 kg/m2, which is an ideal BMI in our country (high BMI:22.0 and low BMI:22.0), there was no significant difference in the PFS or OS between the high and low BMI patients in cohort 1. However, in cohort 2, survival was significantly longer in patients with a high versus low BMI (PFS: 3.7 vs. 2.8 months, p = 0.036; OS: 15.4 vs. 13.5 months, p = 0.021).

Conclusion: BMI was significantly associated with the efficacy of ICIs in patients with NSCLC treated with second- or later-line PD-1/PD-L1 inhibitors in our cohort.
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http://dx.doi.org/10.1016/j.lungcan.2019.11.011DOI Listing
January 2020

A case of axillary lymphadenitis caused by in an immunocompetent patient.

Respir Med Case Rep 2019 14;28:100947. Epub 2019 Oct 14.

Department of Respiratory Medicine, Okayama University Hospital, Okayama, Japan.

Axillary lymphadenitis caused by non-tuberculous mycobacteria is rare and has been reported in immunocompromised hosts. Herein, we report the case of a 67-year-old man without immunodeficiency who developed right axillary lymphadenitis caused by and showed a small nodular shadow in the left pulmonary apex. Biopsy of the right axillary lymph node revealed several epithelioid granulomas, and the culture of the lymph node aspirate yielded . The lymph node lesion and left lung apex shadow resolved spontaneously after careful outpatient monitoring. This case suggests that axillary lymphadenitis could be caused by in an immunocompetent patient.
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http://dx.doi.org/10.1016/j.rmcr.2019.100947DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6818345PMC
October 2019

Legionella Pneumonia Following the Heavy Rain Event of July 2018 in Japan.

Intern Med 2019 Oct 27;58(19):2831-2834. Epub 2019 Jun 27.

Department of Internal Medicine, Fukuyama City Hospital, Japan.

We herein report the case of a 62-year-old man diagnosed with Legionella pneumonia while engaged in recovery work in a flooded area after the Heavy Rain Event of July 2018 in Japan. The patient was intubated and maintained on mechanical ventilation and continuous hemodiafiltration. He was also administered antimicrobial therapy with ciprofloxacin and azithromycin. After 53 days in the hospital, he was discharged. It is important to recognize the risk of Legionella infection and to take measures to prevent it during recovery work that involves exposure to water and soil after a flood disaster.
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http://dx.doi.org/10.2169/internalmedicine.2825-19DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6815902PMC
October 2019

Successful Treatment of Metastatic Urothelial Carcinoma after Accurate Diagnosis by Immunohistochemistry.

Acta Med Okayama 2019 Jun;73(3):279-284

Department of Hematology, Oncology and Respiratory Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama 700-8558, Japan.

Urothelial carcinoma usually presents with hematuria, but cases of multiple lymphadenopathy with elevated S-pancreas-1 antigen (SPan-1) levels have not been reported. A 62-year-old Japanese man with lymphadenopathies was diagnosed with an adenocarcinoma of unknown origin and transferred to our hospital for further diagnosis. Serum carbohydrate antigen 19-9 and SPan-1 levels were extremely elevated. Uroplakin III immunostaining was positive in the inguinal lymph node, and cystoscopy revealed the presence of invasive urothelial carcinoma. Treatment with cisplatin and gemcitabine promoted a complete metabolic response for > 4 years. The detection of uroplakin III and serum SPan-1 might help diagnose urothelial carcinoma.
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http://dx.doi.org/10.18926/AMO/56873DOI Listing
June 2019

Respiratory Failure due to Diaphragm Sarcoidosis Diagnosed by a Computed Tomography-guided Needle Biopsy.

Intern Med 2019 Jun 25;58(12):1771-1774. Epub 2019 Feb 25.

Department of Internal Medicine, Fukuyama City Hospital, Japan.

Sarcoidosis is a multisystem noncaseating granulomatous disorder of unknown etiology that can be found in almost any organ, but symptomatic respiratory muscle involvement is rare. We herein report the case of a 77-year-old woman with diaphragm sarcoidosis diagnosed by a computed tomography (CT)-guided needle biopsy that was successfully treated with a corticosteroid. The patient presented with dyspnea that lasted for two weeks and respiratory failure. CT revealed diffuse diaphragm thickening with contrast enhancement, which might be a characteristic imaging finding for diaphragm myopathy/myositis, including sarcoidosis. A CT-guided needle biopsy proved useful for the diagnosis of diaphragm sarcoidosis.
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http://dx.doi.org/10.2169/internalmedicine.2310-18DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6630132PMC
June 2019

A retinoid X receptor partial agonist attenuates pulmonary emphysema and airway inflammation.

Respir Res 2019 Jan 3;20(1). Epub 2019 Jan 3.

Department of Hematology, Oncology, Allergy and Respiratory Medicine, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, 2-5-1 Shikata-cho, Okayama, 700-8558, Japan.

Background: Retinoid X receptors (RXRs) are members of the nuclear receptor (NR) superfamily that mediate signalling by 9-cis retinoic acid, a vitamin A derivative. RXRs play key roles not only as homodimers but also as heterodimeric partners, e.g., for retinoic acid receptors, vitamin D receptors, and peroxisome proliferator-activated receptors. The NR family may also play important roles in the development of emphysema. However, the role of RXRs in the pathogenesis of emphysema is not well defined.

Methods: We developed a novel RXR partial agonist (NEt-4IB) and investigated its effect and mechanism compared to a full agonist (bexarotene) in a murine model of emphysema. For emphysema induction, BALB/c mice received intraperitoneal cigarette smoke extract (CSE) or intratracheal porcine pancreas elastase (PPE). Treatment with RXR agonists was initiated before or after emphysema induction.

Results: Treatment with NEt-4IB significantly suppressed the increase in static lung compliance and emphysematous changes in CSE-induced emphysema and PPE-induced established and progressive emphysema. NEt-4IB significantly suppressed PPE-induced neutrophilic airway inflammation and the levels of keratinocyte chemoattractant (KC), C-X-C motif ligand5 (CXCL5), interferon (IFN)-γ and IL-17. NEt-4IB also improved the matrix metalloproteinase-9 (MMP-9)/tissue inhibitor of metalloproteinase-1 (TIMP-1) imbalance and the reduced anti-oxidant activity in bronchoalveolar lavage (BAL) fluid. NEt-4IB suppressed PPE-induced vascular endothelial growth factor (VEGF) expression in the airway. Treatment with NEt-4IB and bexarotene significantly suppressed the increase in static lung compliance and emphysematous changes. However, adverse effects of RXR agonists, including hypertriglyceridemia and hepatomegaly, were observed in bexarotene-treated mice but not in NEt-4IB-treated mice.

Conclusion: These data suggest that RXRs play crucial roles in emphysema and airway inflammation, and novel partial RXR agonists could be potential therapeutic strategies for the treatment of PPE- and CSE-induced emphysema.
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http://dx.doi.org/10.1186/s12931-018-0963-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6318915PMC
January 2019

Requirement for neuropeptide Y in the development of type 2 responses and allergen-induced airway hyperresponsiveness and inflammation.

Am J Physiol Lung Cell Mol Physiol 2019 03 3;316(3):L407-L417. Epub 2019 Jan 3.

Department of Hematology, Oncology, Allergy, and Respiratory Medicine, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama , Japan.

Neuropeptide Y (NPY) is a neurotransmitter that is widely expressed in the brain and peripheral nervous system. Various immune cells express the NPY Y receptor. NPY modulates these cells via its Y receptor; however, involvement of NPY in the pathophysiology of bronchial asthma, particularly airway hyperresponsiveness (AHR), has not been defined. NPY-deficient and wild-type mice were intranasally sensitized and challenged to house dust mite (HDM) extract, and airway responses were monitored. After sensitization and challenge, NPY-deficient mice showed significantly lower AHR than wild-type mice, and numbers of eosinophils and levels of type 2 cytokines [interleukin (IL)-4, IL-5, and IL-13] in bronchoalveolar lavage fluid were significantly lower. Type 2 cytokine production from splenic mononuclear cells of HDM-sensitized mice was also significantly lower in NPY-deficient mice. Flow cytometry analysis showed that the number of CD4 T cells and CD11c antigen-presenting cells (APCs) was significantly lower in the lungs of NPY-deficient mice than in wild-type mice following sensitization and challenge. Significantly fewer CD11c APCs phagocytosed HDM in the mediastinal lymph nodes of NPY-deficient mice than in those of wild-type mice. Treatment with BIBO-3304, a NPY receptor antagonist, significantly suppressed development of HDM-induced AHR and inflammation in wild-type mice. These data identify an important contribution of NPY to allergen-induced AHR and inflammation through accumulation of dendritic cells in the airway and promotion of the type 2 immune response. Thus, manipulating NPY represents a novel therapeutic target to control allergic airway responses.
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http://dx.doi.org/10.1152/ajplung.00386.2018DOI Listing
March 2019

A phase II trial of EGFR-TKI readministration with afatinib in advanced non-small-cell lung cancer harboring a sensitive non-T790M EGFR mutation: Okayama Lung Cancer Study Group trial 1403.

Cancer Chemother Pharmacol 2018 12 1;82(6):1031-1038. Epub 2018 Oct 1.

Department of Allergy and Respiratory Medicine, Okayama University Hospital, Okayama, Japan.

Purpose: The aim of this study was to evaluate the efficacy of epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor (TKI) readministration using afatinib in patients with non-small-cell lung cancer (NSCLC) with a sensitive non-T790M EGFR mutation who had received cytotoxic chemotherapy after acquiring resistance to EGFR-TKIs.

Methods: Eligible patients had EGFR-mutant tumors resistant to first- or second-generation EGFR-TKIs and an EGFR-TKI-free period with cytotoxic agents. Confirmation of absence of the T790M mutation was required before registration. Afatinib (40 mg/body) was administered daily. The primary endpoint was progression-free survival (PFS). We assumed estimated and threshold PFS times of 3.3 and 1 months, with an α of 0.05 and β of 0.1, respectively.

Results: Twelve patients were enrolled from December 2014 to May 2017. The objective response rate and disease control rate were 17% and 84%, respectively. The median PFS time was 4.2 months (95% confidence interval [CI] 2.0-5.8), which met the pre-defined primary endpoint. The median overall survival was 11.6 months (95% CI 9.2-not reached). Grade 3 or worse adverse events included diarrhea (25%), elevated creatinine levels (8%), and hypokalemia (8%), without any treatment-related deaths.

Conclusion: EGFR-TKI readministration with afatinib for sensitive EGFR-mutant NSCLC without T790M after resistance to a first- or second-generation EGFR-TKI yielded modest activity with tolerable toxicity. It might be one of the treatment options in patients who do not possess T790M tumors, although further studies in this patient setting are warranted.
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http://dx.doi.org/10.1007/s00280-018-3694-5DOI Listing
December 2018

Severe asthma concomitant with allergic bronchopulmonary aspergillosis successfully treated with mepolizumab.

Allergol Int 2018 Oct 14;67(4):521-523. Epub 2018 Apr 14.

Department of Hematology, Oncology, and Respiratory Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan; Department of Allergy and Respiratory Medicine, Okayama Rosai Hospital, Okayama, Japan. Electronic address:

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http://dx.doi.org/10.1016/j.alit.2018.03.004DOI Listing
October 2018

Successful Long-term Management of Two Cases of Moderate Hemoptysis Due to Chronic Cavitary Pulmonary Aspergillosis with Bronchial Occlusion Using Silicone Spigots.

Intern Med 2018 Aug 30;57(16):2389-2393. Epub 2018 Mar 30.

Department of Respiratory Medicine, Japanese Red Cross Okayama Hospital, Japan.

Chronic pulmonary aspergillosis is a major cause of life-threatening hemoptysis. In symptomatic patients with simple aspergillomas, surgery is the main therapeutic method for preventing or treating life-threatening hemoptysis. However, the risks of both death and complications are higher in chronic cavitary pulmonary aspergillosis than in simple aspergilloma. We herein report two patients with persistent moderate hemoptysis due to chronic cavitary pulmonary aspergillosis who were not indicated for surgery, but were able to undergo successful long-term management with bronchial occlusion using silicone spigots. In diseases with a high recurrence rate of hemoptysis, the continuous placement of silicone spigots might therefore be effective to prevent rebleeding.
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http://dx.doi.org/10.2169/internalmedicine.0553-17DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6148162PMC
August 2018

Protective Effects of Bisoprolol against Acute Exacerbation in Moderate-to-Severe Chronic Obstructive Pulmonary Disease.

Acta Med Okayama 2017 Oct;71(5):453-457

Department of Allergy and Respiratory Medicine, Okayama University Hospital.

Although recent retrospective studies suggested that the use of β-blockers appears to help improve the mortality rate and decrease the rate of exacerbation in chronic obstructive pulmonary disease (COPD) patients with heart failure, the effects of β-blockers on COPD patients without heart failure have not been established. Based on previous reports, we have launched a multicenter, prospective, single-arm phase II study to evaluate the preventive effect of the cardioselective β-blocker bisoprolol in COPD exacerbation, in Japanese individuals with moderate-to-severe COPD who do not have heart failure but do have hypertension requiring the use of medication. The primary endpoint is the rate of mild-to-severe COPD exacerbation. The results of this study will clarify whether bisoprolol can prevent exacerbation in COPD patients without heart failure.
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http://dx.doi.org/10.18926/AMO/55446DOI Listing
October 2017

Long-term effects of beta-blocker use on lung function in Japanese patients with chronic obstructive pulmonary disease.

Int J Chron Obstruct Pulmon Dis 2017 10;12:1119-1124. Epub 2017 Apr 10.

Department of Allergy and Respiratory Medicine, Okayama University Hospital.

Background: Some recent studies have suggested that beta-blocker use in patients with chronic obstructive pulmonary disease (COPD) is associated with a reduction in the frequency of acute exacerbations. However, the long-term effects of beta-blocker use on lung function of COPD patients have hardly been evaluated.

Patients And Methods: We retrospectively reviewed 31 Japanese COPD patients taking beta-blockers for >1 year and 72 patients not taking them. The association between beta-blocker use and the annual change in forced expiratory volume in 1 second (FEV1) was assessed.

Results: At baseline, patient demographic characteristics were as follows: 97 males (mean age 67.0±8.2 years); 32 current smokers; and Global Initiative for Chronic Obstructive Lung disease (GOLD) stages I: n=26, II: n=52, III: n=19, and IV: n=6. Patients taking beta-blockers exhibited a significantly lower forced vital capacity (FVC), FEV1, and %FVC, and a more advanced GOLD stage. The mean duration of beta-blocker administration was 2.8±1.7 years. There were no differences in the annual change in FEV1 between patients who did and did not use beta-blockers (-7.6±93.5 mL/year vs -4.7±118.9 mL/year, =0.671). After controlling for relevant confounders in multivariate analyses, it was found that beta-blocker use was not significantly associated with the annual decline in FEV1 (β=-0.019; 95% confidence interval: -0.073 to 0.036; =0.503).

Conclusion: Long-term beta-blocker use in Japanese COPD patients might not affect the FEV1, one of the most important parameters of lung function in COPD patients.
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http://dx.doi.org/10.2147/COPD.S133071DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5391992PMC
March 2018

Pneumocystis Pneumonia Concomitant with Ectopic ACTH Syndrome Caused by a Large Cell Neuroendocrine Carcinoma of the Thymus.

Intern Med 2017 1;56(5):551-555. Epub 2017 Mar 1.

Department of Allergy and Respiratory Medicine, Okayama University Hospital, Japan.

We herein report the case of a 44-year-old man who was diagnosed with pneumocystis pneumonia (PCP) concomitant with ectopic adrenocorticotropic hormone (ACTH) syndrome, which had been caused by a large cell neuroendocrine carcinoma of the thymus. Chest computed tomography revealed ground-glass opacities in the lungs. PCP was diagnosed by a polymerase chain reaction with bronchoalveolar lavage. The levels of cortisol were slowly corrected with an adrenal enzyme inhibitor, and the exacerbation of PCP was successfully avoided. Our case indicates that in addition to prophylaxis, the early diagnosis of PCP and the slow correction of hypercortisolemia should be considered in order to prevent an exacerbation due to the reconstitution of the immune function in patients with ectopic ACTH syndrome.
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http://dx.doi.org/10.2169/internalmedicine.56.7655DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5399209PMC
April 2017

Effect of a retinoid X receptor partial agonist on airway inflammation and hyperresponsiveness in a murine model of asthma.

Respir Res 2017 01 23;18(1):23. Epub 2017 Jan 23.

Department of Hematology, Oncology, Allergy and Respiratory Medicine, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, 2-5-1 Shikata-cho, Kita-ku, Okayama, 700-8558, Japan.

Background: Retinoid X receptors (RXRs) are members of the nuclear receptor (NR) superfamily that mediate signaling by 9-cis retinoic acid, a vitamin A (retinol) derivative. RXRs play key roles not only as homodimers but also as heterodimeric partners-e.g., retinoic acid receptors (RARs), vitamin D receptors (VDRs), liver X receptors (LXRs), and peroxisome proliferator-activated receptors (PPARs). The NR family was recently associated with allergic diseases, but the role of RXRs in allergen-induced airway responses is not well defined. The goal of this study is to elucidate the role of RXRs in asthma pathogenesis and the potency of RXR partial agonist in the treatment of allergic airway inflammation and airway hyperresponsiveness using a murine model of asthma.

Methods: We investigated the effect of a novel RXR partial agonist (NEt-4IB) on the development of allergic airway inflammation and airway hyperresponsiveness (AHR) in a murine model of asthma. Balb/c mice were sensitized (days 0 and 14) and challenged (days 28-30) with ovalbumin (OVA), and airway inflammation and airway responses were monitored 48 h after the last OVA challenge. NEt-4IB was administered orally on days 25 to 32.

Results: Oral administration of NEt-4IB significantly suppressed AHR and inflammatory cell accumulation in the airways and attenuated the levels of TNF-α in the lung and IL-5, IL-13 and NO levels in bronchoalveolar lavage (BAL) fluid and the number of periodic acid Schiff (PAS)-positive goblet cells in lung tissue. Treatment with NEt-4IB also significantly suppressed NF-κB expression.

Conclusion: These data suggest that RXRs may be of crucial importance in the mechanism of allergic asthma and that the novel RXR partial agonist NEt-4IB may be a promising candidate for the treatment of allergic airway inflammation and airway hyperresponsiveness in a model of allergic asthma.
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http://dx.doi.org/10.1186/s12931-017-0507-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5260083PMC
January 2017