Publications by authors named "Tomohisa Baba"

173 Publications

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

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

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

Cytoplasmic DNA accumulation preferentially triggers cell death of myeloid leukemia cells by interacting with intracellular DNA sensing pathway.

Cell Death Dis 2021 03 26;12(4):322. Epub 2021 Mar 26.

Division of Molecular Bioregulation, Cancer Research Institute, Kanazawa University, Kanazawa, Japan.

Accumulating evidence indicates the presence of cytoplasmic DNAs in various types of malignant cells, and its involvement in anti-cancer drug- or radiotherapy-mediated DNA damage response and replication stress. However, the pathophysiological roles of cytoplasmic DNAs in leukemias remain largely unknown. We observed that during hematopoietic stem cell transplantation (HSCT) in mouse myeloid leukemia models, double-stranded (ds)DNAs were constitutively secreted in the form of extracellular vesicles (EVs) from myeloid leukemia cells and were transferred to the donor cells to dampen their hematopoietic capabilities. Subsequent analysis of cytoplasmic DNA dynamics in leukemia cells revealed that autophagy regulated cytoplasmic dsDNA accumulation and subsequent redistribution into EVs. Moreover, accumulated cytoplasmic dsDNAs activated STING pathway, thereby reducing leukemia cell viability through reactive oxygen species (ROS) generation. Pharmaceutical inhibition of autophagosome formation induced cytoplasmic DNA accumulation, eventually triggering cytoplasmic DNA sensing pathways to exert cytotoxicity, preferentially in leukemia cells. Thus, manipulation of cytoplasmic dsDNA dynamics can be a novel and potent therapeutic strategy for myeloid leukemias.
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http://dx.doi.org/10.1038/s41419-021-03587-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7997981PMC
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

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

Expansion of senescent megakaryocyte-lineage cells maintains CML cell leukemogenesis.

Blood Adv 2020 12;4(24):6175-6188

Division of Molecular Bioregulation, Cancer Research Institute, Kanazawa University, Kanazawa, Ishikawa, Japan.

BCR-ABL, an oncogenic fusion gene, plays a central role in the pathogenesis of chronic myeloid leukemia (CML). Oncogenic signaling induces oncogene-induced senescence and senescence-associated secretory phenotype (SASP), which is characterized by enhanced production of various cytokines. BCR-ABL gene transduction confers senescent phenotype in vitro; however, the in vivo relevance of senescence has not been explored in this context. Transplantation of BCR-ABL-expressing hematopoietic stem/progenitor cells caused CML in mice with an increase in bone marrow BCR-ABL+CD41+CD150+ leukemic megakaryocyte-lineage (MgkL) cells, which exhibited enhanced senescence-associated β-galactosidase staining and increased expression of p16 and p21, key molecules that are crucially involved in senescence. Moreover, knockout of p16 and p21 genes reduced both BCR-ABL-induced abnormal megakaryopoiesis and the maintenance of CML cell leukemogenic capacity, as evidenced by attenuated leukemogenic capacity at secondary transplantation. The expression of transforming growth factor-β1 (TGF-β1), a representative SASP molecule, was enhanced in the leukemic MgkL cells, and TGF-β1 inhibition attenuated CML cell leukemogenic capacity both in vitro and in vivo. Furthermore, BCR-ABL-expressing MgkL cells displayed enhanced autophagic activity, and autophagy inhibition reduced bone marrow MgkL cell number and prolonged the survival of CML mice, which had transiently received the tyrosine kinase inhibitor, imatinib, earlier. Thus, BCR-ABL induced the expansion of senescent leukemic MgkL cells, which supported CML leukemogenesis by providing TGF-β1.
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http://dx.doi.org/10.1182/bloodadvances.2020003117DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7757005PMC
December 2020

Diverse Pathological Findings of Interstitial Lung Disease in a Patient with Dyskeratosis Congenita.

Intern Med 2021 Apr 16;60(8):1257-1263. Epub 2020 Nov 16.

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

A 42-year-old man with a history of surgery for tongue cancer was referred to our hospital due to an abnormal chest shadow. High-resolution computed tomography showed lower lobe reticulation. A physical examination revealed nail dystrophy, oral leukoplakia, and reticulated hypopigmentation. Lung biopsy revealed subpleural and perilobular fibrosis, suggestive of usual interstitial pneumonia. However, multiple pathological findings, including homogenous fibrosis and cell infiltration in the centrilobular region, which were compatible with nonspecific interstitial pneumonia, and bronchiolitis were also seen. Genetic testing showed a hemizygous missense mutation in the DKC1 gene, and the patient was diagnosed with dyskeratosis congenita. Although anti-fibrotic therapy was initiated, the patient's respiratory function has continued to decrease.
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http://dx.doi.org/10.2169/internalmedicine.5143-20DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8112977PMC
April 2021

Beneficial impact of weight loss on respiratory function in interstitial lung disease patients with obesity.

Respir Investig 2021 Mar 12;59(2):247-251. Epub 2020 Nov 12.

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

Background: Interstitial lung disease (ILD) patients commonly become obese or overweight due to deteriorated daily living activities and the adverse effects of prednisolone. This study aimed to clarify the effect of weight loss on pulmonary function test (PFT) in ILD patients with obesity.

Methods: Among all consecutive ILD patients with a body mass index (BMI) ≥ 27 kg/m who received nutrition education for improving obesity between June 2014 and December 2018, we retrospectively included patients who successfully decreased their body weight by over 2 kg and underwent follow-up PFT within 6 months. The results of PFT at baseline and follow-up and the level of Krebs von den Lungen-6 (KL-6) were compared.

Results: Eleven patients (5 men and 6 women; median BMI of 34.1 kg/m), were enrolled. For PFT at baseline, the percentages of forced vital capacity (%FVC), functional residual capacity (%FRC), and diffusing capacity of the lung for carbon monoxide (%DLCO) were 69.3%, 59.9%, and 54%, respectively. The median KL-6 was 1035 U/mL. The median interval from baseline to the follow-up PFTs was 41 days. Compared to the baseline results of PFT, %FVC, %FRC, and %DLCO significantly increased (p = 0.018, 0.0006, and 0.024, respectively), and the changes in body weight and FVC were strongly correlated (p = 0.0004). In addition, the median serum level of KL-6 at follow-up tended to decrease by 206.5 U/mL (p = 0.083).

Conclusion: In ILD patients with obesity, weight loss is important and potentially improves their disease course.
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http://dx.doi.org/10.1016/j.resinv.2020.10.002DOI Listing
March 2021

Treatment and relapse of interstitial lung disease in nivolumab-treated patients with non-small cell lung cancer.

Cancer Sci 2021 Apr 24;112(4):1506-1513. Epub 2021 Feb 24.

The Jikei University School of Medicine, Tokyo, Japan.

Nivolumab, a human monoclonal antibody against programmed death-1, is approved for the treatment of non-small cell lung cancer (NSCLC). Although nivolumab is generally well tolerated, it can cause interstitial lung disease (ILD), a rare but potentially fatal immune-related adverse event. Currently, there are limited data available on the treatment of nivolumab-induced ILD and its outcome. This retrospective cohort study based on a post-marketing study described the treatment of nivolumab-induced ILD and its outcome in NSCLC patients in Japan through the assessment of clinical and chest imaging findings by an expert central review committee. Treatment details for patients who experienced a relapse of ILD were also analyzed. Of the 238 patients identified as having nivolumab-induced ILD, 37 patients died of ILD. Corticosteroids were used in 207 (87.0%) patients. Of those, 172 (83.1%) patients responded well and survived and 35 (16.9%) died (most died during corticosteroid treatment). A total of nine patients experienced a relapse; at the time of relapse, four patients were taking nivolumab. Of those who were receiving corticosteroids at the time of relapse, three of four patients were taking low doses or had nearly completed dose tapering. All patients (except one, whose treatment was unknown) received corticosteroids for the treatment of relapse, but one patient died. Patients with NSCLC who experience nivolumab-induced ILD are treated effectively with corticosteroids, and providing extra care when ceasing or reducing the corticosteroid dose may prevent relapse of ILD.
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http://dx.doi.org/10.1111/cas.14715DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8019226PMC
April 2021

Radiographic features and poor prognostic factors of interstitial lung disease with nivolumab for non-small cell lung cancer.

Cancer Sci 2021 Apr 24;112(4):1495-1505. Epub 2021 Feb 24.

The Jikei University School of Medicine, Tokyo, Japan.

Nivolumab can cause interstitial lung disease (ILD), which may be fatal; however, mortality risk factors have not been identified. This postmarketing study evaluated the poor prognostic factors of ILD in nivolumab-treated patients with non-small cell lung cancer (NSCLC) in Japan. Clinical and chest imaging findings for each ILD case were assessed by an expert central review committee, and prognosis was evaluated by radiographic findings, including the presence/absence of peritumoral ground-glass opacity (peritumoral-GGO). Poor prognostic factors were identified by univariate and multivariate Cox regression analysis. Of the 238 patients with nivolumab-induced ILD, 37 died. The main radiographic patterns of ILD were cryptogenic organizing pneumonia/chronic eosinophilic pneumonia-like (53.4%), faint infiltration pattern/acute hypersensitivity pneumonia-like (20.2%), diffuse alveolar damage (DAD)-like (10.9%), and nonspecific interstitial pneumonia-like (6.3%). The main poor prognostic factors identified were DAD-like pattern (highest hazard ratio: 10.72), ≤60 days from the start of nivolumab treatment to the onset of ILD, pleural effusion before treatment, lesion distribution contralateral or bilateral to the tumor, and abnormal change in C-reactive protein (CRP) levels. Of the 37 deaths due to ILD, 17 had DAD-like radiographic pattern, three had peritumoral-GGO, and five had a change in radiographic pattern from non-DAD at the onset to DAD-like. Patients with NSCLC who develop ILD during nivolumab treatment should be managed carefully if they have poor prognostic factors such as DAD-like radiographic pattern, onset of ILD ≤60 days from nivolumab initiation, pleural effusion before nivolumab treatment, lesion distribution contralateral or bilateral to the tumor, and abnormal changes in CRP levels.
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http://dx.doi.org/10.1111/cas.14710DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8019215PMC
April 2021

Evaluation of lymphocytic infiltration in the bronchial glands of Sjögren's syndrome in transbronchial lung cryobiopsy.

BMC Pulm Med 2020 Oct 23;20(1):277. Epub 2020 Oct 23.

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

Background: Sjögren's syndrome (SS) is a systemic autoimmune disease characterized by deteriorated exocrine gland function with associated lymphocytic infiltration. However, there are few pathological studies on bronchial glands in SS. In this study, we aimed to clarify pathological features of bronchial glands in SS.

Methods: We retrospectively evaluated infiltration of lymphocytes in the bronchial glands incidentally collected by transbronchial lung cryobiopsy (TBLC), which were performed for the diagnosis of diffuse lung diseases. The degrees of lymphocyte infiltration in the bronchial glands were classified into four grades (grade 0-3). We compared the degrees of infiltration of SS with those of other diffuse lung diseases.

Results: TBLC for diagnosis of diffuse lung diseases were performed on 432 cases during the study period. The samples of 50 cases included bronchial glands. Of those, 20 cases were excluded due to insufficient size or influence of therapy. The remaining 30 cases included 17 of idiopathic interstitial pneumonias, 5 of chronic hypersensitivity pneumonia, 6 of connective tissue disease (SS; n = 4, systemic sclerosis; n = 1, dermatomyositis; n = 1) and 2 of other diseases. In SS, infiltration of lymphocytes was observed in all cases; grade 1 in one, grade 2 in one, and grade 3 in two cases. In contrast, 11 of 26 in other diseases showed no lymphocytes infiltration, with the remaining 15 of grade 1 infiltration. Grade 2 or more infiltration were found only in SS but not in other diseases.

Conclusion: Our results suggested that high-grade lymphocytic infiltration of bronchial glands is a distinct characteristics in SS.
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http://dx.doi.org/10.1186/s12890-020-01318-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7585306PMC
October 2020

COVID-19 Pneumonia Resembling an Acute Exacerbation of Interstitial Pneumonia.

Intern Med 2020 Dec 21;59(24):3207-3211. Epub 2020 Oct 21.

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

An 84-year-old man was admitted with hypoxemia and ground-glass opacities with traction bronchiectasis in both lungs and mild fibrosis on computed tomography. We first suspected that he had acute exacerbation of interstitial pneumonia and initiated methylprednisolone pulse therapy. On day 4, he was diagnosed with coronavirus disease 2019 (COVID-19) pneumonia. Although the ground-glass opacities were improved with corticosteroid treatment alone, the hypoxemia persisted, and the plasma D-dimer level increased. Anticoagulant therapy was initiated, and the hypoxemia was improved. COVID-19 pneumonia may result in radiological findings similar to those of acute exacerbation of interstitial pneumonia, and corticosteroids and anticoagulant therapy may lead to favorable outcomes.
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http://dx.doi.org/10.2169/internalmedicine.5630-20DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7807128PMC
December 2020

Involvement of a Transcription factor, , in Breast Cancer Metastasis to Bone.

Cancers (Basel) 2020 Oct 16;12(10). Epub 2020 Oct 16.

Division of Molecular Bioregulation, Cancer Research Institute, Kanazawa University, Kakuma-Machi, Kanazawa, Ishikawa 920-1192, Japan.

Patients with triple negative breast cancer (TNBC) is frequently complicated by bone metastasis, which deteriorates the life expectancy of this patient cohort. In order to develop a novel type of therapy for bone metastasis, we established 4T1.3 clone with a high capacity to metastasize to bone after orthotopic injection, from a murine TNBC cell line, 4T1.0. To elucidate the molecular mechanism underlying a high growth ability of 4T1.3 in a bone cavity, we searched for a novel candidate molecule with a focus on a transcription factor whose expression was selectively enhanced in a bone cavity. Comprehensive gene expression analysis detected enhanced mRNA expression in 4T1.3 grown in a bone cavity, compared with in vitro culture conditions. Moreover, gene transduction into 4T1.0 cells enhanced their capability to form intraosseous tumors. Moreover, shRNA treatment reduced tumor formation arising from intraosseous injection of 4T1.3 clone as well as another mouse TNBC-derived TS/A.3 clone with an augmented intraosseous tumor formation ability. Furthermore, NFE2 expression was associated with in vitro growth advantages of these TNBC cell lines under hypoxic condition, which mimics the bone microenvironment, as well as Wnt pathway activation. These observations suggest that NFE2 can potentially contribute to breast cancer cell survival in the bone microenvironment.
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http://dx.doi.org/10.3390/cancers12103003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7602858PMC
October 2020

Screening and diagnosis of acute and chronic bird-related hypersensitivity pneumonitis by serum IgG and IgA antibodies to bird antigens with ImmunoCAP®.

Allergol Int 2021 Apr 8;70(2):208-214. Epub 2020 Oct 8.

Department of Respiratory Medicine, Tokyo Medical and Dental University, Tokyo, Japan. Electronic address:

Background: Bird antigens are some of the most relevant antigens in hypersensitivity pneumonitis (HP). Possible sources of bird antigens are bird breeding, feather products and fertilizer with fowl droppings. For the screening and diagnosis of HP, the measurement of bird-specific antibodies should be standardized. The aim of this study was to clarify the utility of serum IgG (sIgG) and IgA (sIgA) antibodies to bird antigens in screening and diagnosing acute/chronic bird-related HP with ImmunoCAP® in multi-centre clinical research.

Methods: We executed a clinical performance test by conducting a multi-institutional study to measure the levels of sIgG/sIgA against pigeon, parrot and budgerigar antigens by the ImmunoCAP® system in 29 acute and 46 chronic bird-related HP patients.

Results: The levels of sIgG/sIgA against the bird antigens of the three species were significantly higher in subjects with acute bird-related HP and chronic bird-related HP with acute episodes (recurrent type) than in the control subjects. For sIgG, the optimal cutoff values by receiver operating characteristic (ROC) analysis were 24.6 mgA/L for pigeon, 14.0 mgA/L for parrot, and 8.7 mgA/L for budgerigar. By measuring multiple bird antigens and combining sIgG values of two species, the sensitivity and specificity for acute and recurrent-type chronic bird-related HP patients were 85-91% and 73-80%, respectively. For recurrent and insidious types of chronic bird-related HP, the sensitivity and specificity were 48-61% and 73-80%, respectively.

Conclusions: Measurement of the levels of sIgG/sIgA against pigeon, budgerigar and parrot antigens by ImmunoCAP® was useful for screening and diagnosis in bird-related HP.
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http://dx.doi.org/10.1016/j.alit.2020.09.003DOI Listing
April 2021

Pneumothorax in a COVID-19 Pneumonia Patient without Underlying Risk Factors.

Intern Med 2020 Nov 7;59(22):2921-2925. Epub 2020 Oct 7.

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

Coronavirus disease 2019 (COVID-19) has been recognized as a worldwide pandemic. However, the clinical course of COVID-19 remains poorly characterized. Although some cases of pneumothorax have been reported, they all had pulmonary complications or were managed with mechanical ventilation. We herein report a case of pneumothorax that developed even though the patient had no pulmonary underlying diseases and had never been managed with mechanical ventilation. In the present case, a lung bulla was found on chest computed tomography during treatment for COVID-19. We concluded that COVID-19 affected the formation of the lung bulla and induced the complication of pneumothorax.
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http://dx.doi.org/10.2169/internalmedicine.5731-20DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7725644PMC
November 2020

Inhalation challenge test using pigeon eggs for chronic hypersensitivity pneumonitis.

Clin Exp Allergy 2020 12 18;50(12):1381-1390. Epub 2020 Oct 18.

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

Background: Chronic hypersensitivity pneumonitis (CHP) remains a diagnostic challenge. The process of collecting and extracting serum and droppings from causative animals for the inhalation challenge test is complicated and the risk of inducing disease progression exists.

Objective: To investigate the utility and safety of an inhalation challenge test using pigeon eggs.

Methods: Pigeon eggs were pasteurized and mixed with a saline solution to produce an inhalation fluid. An inhalation challenge test was conducted on 19 patients with bird-related CHP and 17 patients with interstitial lung disease other than bird-related CHP. To identify antigens in pigeon eggs, the antigen-antibody responses of the pigeon eggs and serum from patients were evaluated using Western blotting.

Results: The mean changes in C-reactive protein, alveolar-arterial oxygen difference, erythrocyte sedimentation rate, and lactate dehydrogenase significantly increased by 0.32 mg/dL (P = .014), 7.8 Torr (P = .002), 1.4 mm/h (P = .012), and 5.4 U/mL (P = .0019), respectively, in bird-related CHP group compared to the control 24 hours after the inhalation challenge test. Furthermore, within 24 hours of the inhalation test, the mean forced vital capacity decreased by 2.3% in the bird-related CHP group compared with a decline of 0.05% in the control group (P = .035). Serum collected from seven bird-related CHP patients who underwent the inhalation challenge test and reacted to antigens with molecular weights of 37-75 KDa, and these molecular weights were consistent with egg albumin and globulin.

Conclusion: Since a mild response was observed after the inhalation challenge test using pigeon eggs, this test was an obvious candidate for diagnosing bird-related CHP.
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http://dx.doi.org/10.1111/cea.13752DOI Listing
December 2020

Real-World Evaluation of Factors for Interstitial Lung Disease Incidence and Radiologic Characteristics in Patients With EGFR T790M-positive NSCLC Treated With Osimertinib in Japan.

J Thorac Oncol 2020 12 11;15(12):1893-1906. Epub 2020 Sep 11.

Department of Thoracic Oncology, National Cancer Center Hospital, Chuo-ku, Tokyo, Japan.

Introduction: Using real-world Japanese postmarketing data, we characterized interstitial lung disease (ILD) development during the second- or later-line osimertinib treatment for EGFR mutation-positive NSCLC. Retrospective radiologic image evaluation of patients developing ILD was also performed.

Methods: Patients who had ILD events reported as an adverse drug reaction by their physicians and who were assessed as having developed ILD as assessed by an ILD expert committee in Japan were included.

Results: Among 3578 patients, 252 ILD events were reported in 245 patients (6.8%) by their attending physicians. The median (range) time to the first onset of ILD after osimertinib treatment initiation was 63.0 (5-410) days, and 29 patients with a fatal outcome were reported. The ILD expert committee assessed 231 of 3578 patients (6.5%) as having ILD. A previous history of nivolumab therapy (adjusted OR: 2.84; 95% confidence interval: 1.98-4.07) and a history or concurrence of ILD (3.51; 2.10-5.87) were identified as factors potentially associated with ILD onset during osimertinib treatment. In patients who had received a previous nivolumab treatment, the number and proportion of patients developing ILD were highest for patients who discontinued nivolumab treatment within the first month before initiating osimertinib; trends for decreasing incidence and proportion were observed, with an increasing duration between the end of nivolumab treatment and the initiation of osimertinib treatment.

Conclusions: The frequency of ILD was consistent with the known osimertinib safety profile in the Japanese population. A history or concurrence of ILD and history of previous nivolumab therapy are factors potentially associated with ILD onset during osimertinib treatment.
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http://dx.doi.org/10.1016/j.jtho.2020.08.025DOI Listing
December 2020

The potential utility of anterior upper lobe honeycomb-like lesion in interstitial lung disease associated with connective tissue disease.

Respir Med 2020 10 21;172:106125. Epub 2020 Aug 21.

Department of Respiratory Medicine, Saitama Red Cross Hospital, 1-5 Shintoshin, Chuo-ku, Saitama, 330-8553, Japan. Electronic address:

Background: Interstitial lung disease (ILD) is associated with high morbidity and mortality in patients with connective tissue disease (CTD). Because some patients with CTD overlap present with ILD first, with CTD diagnosed later, specific radiologic signs are needed to help differentiate each CTD or CTD-ILD from idiopathic ILD.

Objectives: To determine whether specific CT findings can help differentiate CTD as rheumatoid arthritis (RA), systemic sclerosis (SSc), or polymyositis/dermatomyositis (PM/DM).

Methods: We analyzed 143 consecutive ILD patients with RA, SSc, or PM/DM. We assessed diagnostic accuracy of CT findings of CTD-ILD, CT pattern, and signs including "anterior upper lobe honeycomb-like lesion" and "low attenuation area (LAA) within an interstitial abnormality" for each CTD-ILD. Prognostic predictors were determined using Cox regression models.

Results: Subjects were 78 patients with RA-ILD, 38 with SSc-ILD, 24 with PM/DM-ILD, and 3 with overlapping CTD-ILD. High frequency of anterior upper lobe honeycomb-like lesion suggests that CTD-ILD is due to RA-ILD (22%) rather than SSc-ILD (8%) or PM/DM-ILD (8%), whereas LAA within an interstitial abnormality suggests that CTD-ILD is due to SSc-ILD (26%) rather than RA-ILD (4%) or PM/DM-ILD (0%). Multivariate analysis showed that while not associated with survival, current or ex-smoker, honeycombing, and acute exacerbation were negative prognostic factors of mortality.

Conclusions: The tendency is high for RA-ILD, in which anterior upper lobe honeycomb-like lesion is a specific feature, to show UIP or NSIP/UIP pattern, combined emphysema, and honeycombing; SSc-ILD to show NSIP pattern and LAA within an interstitial abnormality; and PM/DM-ILD to show NSIP pattern and non-honeycombing.
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http://dx.doi.org/10.1016/j.rmed.2020.106125DOI Listing
October 2020

Inhaled Molgramostim Therapy in Autoimmune Pulmonary Alveolar Proteinosis.

N Engl J Med 2020 10 7;383(17):1635-1644. Epub 2020 Sep 7.

From the Translational Pulmonary Science Center, Cincinnati Children's Hospital Medical Center, Cincinnati (B.C.T.); National Hospital Organization Kinki-Chuo Chest Medical Center, Osaka (Y.I.), Aichi Medical University Hospital, Nagakute, Aichi (E.Y.), and Kanagawa Cardiovascular and Respiratory Center, Yokohama (T.B.) - all in Japan; Outpatients Clinic for Interstitial and Rare Lung Disease, Ruhrlandklinik University Hospital, Essen (F.B.), and Center for Interstitial and Rare Lung Diseases, Pulmonology, Thoraxklinik, Heidelberg University Hospital, and German Center for Lung Research, Heidelberg (M.K.) - all in Germany; the Departments of Critical Care and Respiratory Medicine, Royal Brompton Hospital, London (C.M.); Respiratory Diseases Department, Pontchaillou Hospital, IRSET UMR 1085, Rennes 1 University, Rennes, France (S.J.); the Department of Respiratory Diseases and Allergy, Aarhus University Hospital, Aarhus (E.B.), and Savara, Horsholm (C.G., I.T.) - both in Denmark; the Pneumology Unit, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy (I.C.); the 2nd Pulmonary Medicine Department, General University Hospital "Attikon," Medical School, National and Kapodistrian University of Athens, Athens (S.A.P.); University of Health Sciences Turkey, Yedikule Chest Diseases and Thoracic Surgery Education and Research Hospital, Istanbul (E.C.); Pulmonary Clinic of St. Petersburg Pavlov State Medical University, St. Petersburg, Russia (M.M.I.); Institute of Pulmonary and Allergy Medicine, Rabin Medical Center, Petah Tikva, Israel (M.R.K.); ILD Center of Excellence, Department of Pulmonology, St. Antonius Hospital, Nieuwegein, the Netherlands (M.V.); the University of Western Australia, Royal Perth Hospital, Perth, Australia (G.W.); and Savara, Austin, TX (T.J.).

Background: Autoimmune pulmonary alveolar proteinosis (aPAP) is a rare disease characterized by progressive surfactant accumulation and hypoxemia. It is caused by disruption of granulocyte-macrophage colony-stimulating factor (GM-CSF) signaling, which pulmonary alveolar macrophages require to clear surfactant. Recently, inhaled GM-CSF was shown to improve the partial pressure of arterial oxygen in patients with aPAP.

Methods: In a double-blind, placebo-controlled, three-group trial, we randomly assigned patients with aPAP to receive the recombinant GM-CSF molgramostim (300 μg once daily by inhalation), either continuously or intermittently (every other week), or matching placebo. The 24-week intervention period was followed by an open-label treatment-extension period. The primary end point was the change from baseline in the alveolar-arterial difference in oxygen concentration (A-aDo) at week 24.

Results: In total, 138 patients underwent randomization; 46 were assigned to receive continuous molgramostim, 45 to receive intermittent molgramostim, and 47 to receive placebo. Invalid A-aDo data for 4 patients (1 in each molgramostim group and 2 in the placebo group) who received nasal oxygen therapy during arterial blood gas measurement were replaced by means of imputation. For the primary end point - the change from baseline in the A-aDo at week 24 - improvement was greater among patients receiving continuous molgramostim than among those receiving placebo (-12.8 mm Hg vs. -6.6 mm Hg; estimated treatment difference, -6.2 mm Hg; P = 0.03 by comparison of least-squares means). Patients receiving continuous molgramostim also had greater improvement than those receiving placebo for secondary end points, including the change from baseline in the St. George's Respiratory Questionnaire total score at week 24 (-12.4 points vs. -5.1 points; estimated treatment difference, -7.4 points; P = 0.01 by comparison of least-squares means). For multiple end points, improvement was greater with continuous molgramostim than with intermittent molgramostim. The percentages of patients with adverse events and serious adverse events were similar in the three groups, except for the percentage of patients with chest pain, which was higher in the continuous-molgramostim group.

Conclusions: In patients with aPAP, daily administration of inhaled molgramostim resulted in greater improvements in pulmonary gas transfer and functional health status than placebo, with similar rates of adverse events. (Funded by Savara Pharmaceuticals; IMPALA ClinicalTrials.gov number, NCT02702180.).
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http://dx.doi.org/10.1056/NEJMoa1913590DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8083051PMC
October 2020

Outcome of early-stage combination treatment with favipiravir and methylprednisolone for severe COVID-19 pneumonia: A report of 11 cases.

Respir Investig 2020 Aug 28. Epub 2020 Aug 28.

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

Although the use of corticosteroids is not recommended in the World Health Organization statement for the treatment of coronavirus disease 2019 (COVID-19), steroid therapy may be indicated for critical cases in specific situations. Here, we report the successful treatment of 11 cases of severe COVID-19 pneumonia with favipiravir and methylprednisolone. All cases were severe and patients required oxygen administration or had a blood oxygen saturation ≤93% on room air. All were treated with favipiravir and methylprednisolone, and 10 of 11 patients responded well and required no further oxygen supplementation or ventilator management. This study shows the importance of the early-stage use of a combination of favipiravir and methylprednisolone in severe cases to achieve a favorable clinical outcome.
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http://dx.doi.org/10.1016/j.resinv.2020.08.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7455106PMC
August 2020

Tolerability and safety of nintedanib in elderly patients with idiopathic pulmonary fibrosis.

Respir Investig 2021 Jan 3;59(1):99-105. Epub 2020 Sep 3.

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

Background: In the phase III trial of nintedanib, only 10.8% of participants were aged ≥75 years. Here, we aimed to evaluate the tolerability and safety of nintedanib in elderly patients with idiopathic pulmonary fibrosis (IPF).

Methods: In total, 71 consecutive patients with (1) IPF, (2) age ≥75 years, and (3) newly prescribed nintedanib from September 2015 to April 2018 (elderly group) were retrospectively reviewed. Patient characteristics, treatment status, and adverse events (AEs) were compared between the elderly group and 126 patients with IPF, aged <75 years, with newly prescribed nintedanib during the same period (non-elderly group).

Results: In the elderly group, 32 patients (46.4%) discontinued nintedanib within 6 months. Body size was significantly smaller, the incidence rates of anorexia and nausea were significantly higher, and early termination within 6 months were more common in the elderly than in the non-elderly group. In elderly patients, a univariate logistic regression analysis showed that body mass index (BMI) and percentage forced vital capacity (FVC) were risk factors for early termination (p = 0.02 and 0.03, respectively). A low initial nintedanib dose did not reduce the incidence of AEs and early termination rate in the elderly group.

Conclusions: In elderly patients with IPF, the incidence of early nintedanib termination was higher, and anorexia and nausea were common AEs compared with those in non-elderly IPF patients. Treatment was frequently discontinued in elderly patients with low BMI and FVC, and chest physicians should be aware that nintedanib therapy may result in early termination in these patients.
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http://dx.doi.org/10.1016/j.resinv.2020.08.003DOI Listing
January 2021

Relationship of flow-volume curve pattern on pulmonary function test with clinical and radiological features in idiopathic pulmonary fibrosis.

BMC Pulm Med 2020 Aug 12;20(1):214. Epub 2020 Aug 12.

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

Background: The flow-volume (FV) curve pattern in the pulmonary function test (PFT) for obstructive lung diseases is widely recognized. However, there are few reports on FV curve pattern in idiopathic pulmonary fibrosis (IPF). In this study, we investigated the relationship between FV curve pattern and clinical or radiological features in IPF.

Methods: The FV curves on PFTs and chest high-resolution computed tomography (HRCT) images of 130 patients with IPF were retrospectively evaluated. The FV curves were divided into four groups based on the presence or absence of the convex and concave patterns: convex/concave, non-convex/concave, convex/non-concave, and non-convex/non-concave. Using a computer-aided system, CT honeycombing area (%HA) and subtracted low attenuation area (%sLAA) were quantitatively measured. To assess the distribution of CT findings, the lung area was divided into upper, lower, central, and peripheral areas. The relationships of FV curve patterns with patient characteristics, spirometry results, and quantitative CT findings were evaluated.

Results: The patients with convex pattern was identified in 93 (71.5%) and concave pattern in 72 (55.4%). Among the four groups, patients with the convex/non-concave pattern had significantly lower forced vital capacity (FVC) and higher %HA of the upper/peripheral lung area (p = 0.018, and p = 0.005, respectively). The convex/non-concave pattern was a significant predictor of mortality for IPF (hazard ratio, 2.19; p = 0.032).

Conclusions: Patients with convex/non-concave pattern in FV curve have lower FVC and poorer prognosis with distinct distribution of fibrosis. Hence, FV curve pattern might be a useful predictor of mortality in IPF.
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http://dx.doi.org/10.1186/s12890-020-01254-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7424671PMC
August 2020

Amyloidosis of the respiratory system: 16 patients with amyloidosis initially diagnosed by pulmonologists.

ERJ Open Res 2020 Jul 27;6(3). Epub 2020 Jul 27.

Dept of Respiratory Medicine, Saitama Cardiovascular and Respiratory Center, Saitama, Japan.

Background: diagnosis of amyloidosis of the respiratory system is rare. Few data are available regarding clinical presentation, precursor proteins, diagnostic procedures, comorbidities, complications, and outcome. We assessed clinical features of a series of patients with amyloidosis of the respiratory system in two Japanese centres.

Methods: Medical records of 16 patients with amyloidosis of the respiratory system were retrospectively analysed. Amyloid was diagnosed by polarisation microscopy using Congo red-stained tissue specimens and classified immunohistochemically.

Results: Median patient age was 71 years, and median follow-up period was 5 years. Immunoglobulin light-chain (AL)-λ amyloidosis was found in eight and AL-κ in five patients. Two patients harboured wild-type transthyretin and one harboured serum amyloid A-derived amyloid. Five different forms of amyloidosis of the respiratory system were observed: nodular pulmonary amyloidosis (seven patients), diffuse alveolar-septal amyloidosis (five), mediastinal lymph node amyloidosis (three), tracheobronchial amyloidosis (one), and pleural amyloidosis (one). One patient had diffuse alveolar-septal amyloidosis and mediastinal lymph node amyloidosis. Three of five patients with diffuse alveolar-septal amyloidosis were diagnosed by transbronchial lung biopsy as having concurrent diffuse alveolar haemorrhage or pneumocystis pneumonia. Two of three patients with mediastinal lymph node amyloidosis were diagnosed by endobronchial ultrasound-guided transbronchial needle aspiration.

Conclusions: Not only nodular pulmonary amyloidosis, diffuse alveolar-septal amyloidosis, and tracheobronchial amyloidosis but also mediastinal lymph node amyloidosis and pleural amyloidosis should be considered in the differential diagnosis of amyloidosis of the respiratory system. Useful diagnostic methods include transbronchial lung biopsy for diffuse alveolar-septal amyloidosis and endobronchial ultrasound-guided transbronchial needle aspiration for mediastinal lymph node amyloidosis.
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http://dx.doi.org/10.1183/23120541.00313-2019DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7383056PMC
July 2020

Small-cell lung carcinoma transformation of lung adenocarcinoma diagnosed by pericardial effusion: A case report.

Mol Clin Oncol 2020 Aug 3;13(2):129-132. Epub 2020 Jun 3.

Department of Respiratory Medicine, Kanagawa Cardiovascular and Respiratory Center, Yokohama, Kanagawa 236-0051, Japan.

The present report describes a case of a 68-year-old male patient with epidermal growth factor receptor (EGFR)-mutant non-small cell lung carcinoma (NSCLC). After cytotoxic chemotherapy of three regimens following 22 months of treatment with EGFR-tyrosine kinase inhibitors (EGFR-TKIs), including osimertinib, the patient underwent S-1 treatment. Despite a decrease in carcinoembryonic antigen 1 month after initiating S-1 treatment, the patient developed cardiac tamponade. The evaluation of pericardial effusion confirmed small-cell lung carcinoma (SCLC) transformation. Subsequently, a combination therapy of carboplatin and etoposide was administered, which led to a marked improvement in imaging. In patients with NSCLC who develop pericardial effusion after long-term EGFR-TKI therapy, including osimertinib treatment, it is important to investigate whether SCLC transformation occurs or not as a treatable entity.
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http://dx.doi.org/10.3892/mco.2020.2059DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7366234PMC
August 2020

Unilateral upper lung-field pulmonary fibrosis radiologically consistent with pleuroparenchymal fibroelastosis after thoracic surgery: Clinical and radiological courses with autopsy findings.

Respir Investig 2020 Jul 10. Epub 2020 Jul 10.

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

Background: Pleuroparenchymal fibroelastosis (PPFE) is a rare idiopathic interstitial pneumonia characterized by pleural and parenchymal involvements predominantly in the upper lobes. Unilateral upper-lung field pulmonary fibrosis (upper-PF) radiologically consistent with PPFE was recently reported in patients with a history of open thoracotomy and presented with impaired thoracic movements in the operated side with unknown mechanisms. This retrospective study aimed to elucidate the clinical and radiological courses and pathological findings of unilateral upper-PF.

Methods: All the consecutive patients diagnosed as having unilateral upper-PF between March 2012 and April 2018 were included. Radiological images and clinical courses before and after the diagnosis were thoroughly reviewed.

Results: Fourteen patients were included. Unilateral upper-PF was diagnosed after a median of 4.8 years from the open thoracotomy or video-assisted thoracic surgery for treating lung or esophageal cancer, or bronchiectasis. Before or at diagnosis, 12 (85.7%) of 14 patients developed aberrant intrathoracic/extrathoracic air suggestive of pleural fistula, although the degree was slight. Of note, the upper-PF lesion apparently deteriorated once aberrant air emerged in all the patients. After diagnosis, the upper-PF lesion transformed into cystic lesion in 9 patients, 4 of whom eventually developed pulmonary aspergillosis. The prognosis was poor, with a median overall survival of 49.3 months. The autopsy in one patient demonstrated findings consistent with PPFE and chronic pleuritis.

Conclusions: Unilateral upper-PF developed after thoracic surgeries and had many clinical, radiological, and pathological characteristics in common with idiopathic PPFE. Our results indicate that the commonly observed aberrant air may be correlated with disease development and progression.
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http://dx.doi.org/10.1016/j.resinv.2020.05.001DOI Listing
July 2020

Real-world use of osimertinib for epidermal growth factor receptor T790M-positive non-small cell lung cancer in Japan.

Jpn J Clin Oncol 2020 Aug;50(8):909-919

Department of Pulmonary Medicine and Oncology, Nippon Medical School, Tokyo, Japan.

Objective: Adverse drug reactions (ADRs) during real-world osimertinib use were investigated in Japan.

Methods: Patients with epidermal growth factor receptor (EGFR) T790M-positive non-small cell lung cancer treated with second-line or later oral osimertinib per the Japanese package insert (80 mg once daily) were included. Data were collected between 28 March 2016 and 31 August 2018.

Results: The median observation period in the safety analysis population (n = 3578) was 343.0 days. ADRs (defined as adverse events whose causality to osimertinib could not be denied by the attending physicians or manufacturer) were reported in 58.1% (2079/3578) of patients. ADRs of interstitial lung disease events were reported in 6.8% (245/3578; Grade ≥ 3, 2.9% [104/3578]) of patients, of whom 29 (11.8%) died (0.8% of patients overall). ADRs of QT interval prolonged, liver disorder and haematotoxicity were reported in 1.3% (45/3578; Grade ≥ 3, 0.1% [5/3578]), 5.9% (212/3578; Grade ≥ 3, 1.0% [35/3578]) and 11.4% (409/3578; Grade ≥ 3, 2.9% [104/3578]) of patients, respectively. In the efficacy analysis population (n = 3563), 119 (3.3%) patients had complete responses, 2373 (66.6%) had partial responses and 598 (16.8%) had stable disease. The objective response rate was 69.9%; disease control rate was 86.7%; and median progression-free survival (PFS) was 12.3 months. At 6 and 12 months, PFS rates were 77.4% (95% confidence interval [CI], 75.9-78.9) and 53.2% (95% CI, 51.3-55.1) and overall survival rates were 88.3% (95% CI, 87.2-89.4) and 75.4% (95% CI, 73.8-77.0), respectively.

Conclusions: These data support the currently established benefit-risk assessment of osimertinib in this patient population.
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http://dx.doi.org/10.1093/jjco/hyaa067DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7401719PMC
August 2020
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