Four-year mortality and physical activity in Japanese patients with chronic obstructive pulmonary disease.

BACKGROUND: Physical activity (PA) is associated with the risk of mortality in patients with chronic obstructive pulmonary disease (COPD); however, evidence is limited to the Japanese population. This study aimed to evaluate the effects of PA on long-term mortality in Japanese patients with COPD. METHODS: We conducted a prospective observational study in a cohort of Japanese patients with COPD and assessed mortality during a 4-year follow-up period. The Cox proportional hazards model was used to evaluate the association between PA and mortality. RESULTS: Among 309 patients (294 men; median age, 76 years), 287 completed follow-ups while 45 died. The all-cause mortality rate was 27.5% in patients with low PA and 4.1% in those with high PA. Adjusted hazard ratios for all-cause mortality were associated with high PA. CONCLUSIONS: Higher PA levels are associated with a better prognosis across different settings and patient characteristics, even in Japanese patients with COPD. TRIAL REGISTRATION: The study was registered in the UMIN Clinical Trials Registry (UMIN000032112).

Physical activity and outcomes in Japanese patients with chronic obstructive pulmonary disease: From the Ishinomaki COPD Network registry.

BACKGROUND: Low physical activity levels are associated with an increased risk of exacerbations and all-cause mortality in patients with chronic obstructive pulmonary disease (COPD); however, evidence is limited in a population with a low frequency of exacerbations, such as the Japanese population. This study investigated the effects of physical activity on outcomes in Japanese patients with COPD. METHODS: We conducted a prospective observational study in a cohort of Japanese patients with COPD between April 2018 and July 2020. Characteristics, frequency of exacerbations, and mortality were assessed during the 1-year follow-up period. Logistic regression analysis evaluated the relationship between physical activity and outcomes. RESULTS: A total of 309 patients (294 males; median age, 75 years) with stable COPD were included, and 307 completed follow-up. Patients with lower levels of physical activity were older, and showed increased airflow obstruction, limited exercise capacity, increased dyspnea, depressive state, poor health status, muscle weakness, and more information needs for the disease. Patients with high levels of physical activity had a lower risk of exacerbation, including hospital admission, compared to those with low levels of activity (odds ratio [OR], 0.46; 95 % confidence interval [CI], 0.22-0.97; and OR, 0.21; 95 % CI, 0.09-0.50, respectively). High physical activity was associated with a reduced risk of all-cause mortality (OR, 0.07; 95 % CI, 0.01-0.55) and respiratory mortality (OR, 0.16; 95 % CI, 0.02-1.47). CONCLUSIONS: These findings showed that higher physical activity is associated with better clinical outcomes, even in a COPD population with a low frequency of exacerbations.

A case of metastatic endobronchial tumor from uterine leiomyosarcoma.

A 54-year-old woman presented with persistent productive cough, found to have an endobronchial tumor which obstructed the left upper lobe bronchus. Histopathological examination of a transbronchial biopsy of the endobronchial tumor suggested leiomyosarcoma. A positron emission tomography (PET)-CT revealed uterus tumor with moderate uptake of 18F-fluorodeoxyglucose, suggesting uterine malignancies. From the results of histological findings of the resected uterus and the biopsied bronchial specimen, she was diagnosed with uterine leiomyosarcoma and endobronchial metastasis. The systematic use of PET-CT could be useful for patients presenting with tumors that cause endobronchial metastasis of leiomyosarcomas.

Metabolic and Epigenetic Regulation of SMAD7 by STC1 Ameliorates Lung Fibrosis.

As shown in our previous studies, the intratracheal-administration of STC1 (stanniocalcin-1) ameliorates pulmonary fibrosis by reducing oxidative and endoplasmic reticulum stress through the uncoupling of respiration in a bleomycin-treated mouse model. However, the overall effect of STC1 on metabolism was not examined. Therefore, we first conducted a comprehensive metabolomics analysis to screen the overall metabolic changes induced by STC1 in an alveolar epithelial cell line using capillary electrophoresis time-of-flight mass spectrometry. The results were subsequently validated in multiple alveolar epithelial and fibroblast cell lines by performing precise analyses of each substance. STC1 stimulated glycolysis, acetyl-CoA synthesis, and the methionine and cysteine-glutathione pathways, which are closely related to the uncoupling of respiration, modulation of epigenetics, and reduction in oxidative stress. These results are consistent with our previous study. Subsequently, we focused on the inhibitory factor SMAD7, which exerts an antifibrotic effect and is susceptible to epigenetic regulation. STC1 upregulates SMAD7 in an uncoupling protein 2-dependent manner, induces demethylation of the SMAD7 promoter region and acetylation of the SMAD7 protein in human alveolar epithelial and fibroblast cell lines and a bleomycin-treated mouse model, and subsequently attenuates fibrosis. The antifibrotic effects of STC1 may partially depend on the regulation of SMAD7. In the evaluation using lung tissue from patients with idiopathic pulmonary fibrosis, SMAD7 expression and acetylation were high in the alveolar structure-preserving region and low in the fibrotic region. The intratracheal administration of STC1 may prevent the development of pulmonary fibrosis by regulating the metabolism-mediated epigenetic modification of SMAD7 in patients.

Exhaled nitric oxide: A biomarker for chronic obstructive pulmonary disease.

The fractional concentration of exhaled nitric oxide (FeNO) is recognized as a biomarker of type 2 inflammation in asthma, which is related to airway eosinophilia. We conducted a prospective observational study in a cohort of Japanese patients with chronic obstructive pulmonary disease (COPD) to evaluate the relationship between FeNO and clinical features and patient outcomes over a 3-year period. Participants were categorized into two groups based on FeNO levels (high and low), and the clinical features and outcomes were compared between the groups. Patients with high FeNO levels showed features of asthma and eosinophilic inflammation compared to those with low levels. However, high FeNO levels were not associated with worse outcomes (exacerbations, hospital admissions, all-cause and disease-specific mortality) compared to low levels. These results provide evidence that baseline FeNO is related to eosinophilic inflammation; however, is not a predictor of future exacerbations or prognosis in patients with stable COPD.

Clinical Characteristics and Outcomes of Patients with Asthma-COPD Overlap in Japanese Patients with COPD.

Purpose: Asthma-COPD overlap (ACO) has been reported as an association with a lower quality of life, frequent exacerbations, and higher mortality than those with COPD alone. However, clinical characteristics and outcomes of ACO remain controversial. Patients and Methods: We conducted a prospective observational study analyzing data of patients with stable COPD enrolled from the Ishinomaki COPD Network Registry. Patients with features of asthma who had a history of respiratory symptoms that vary over time and intensity, together with documented variable expiratory airflow limitation, were identified, and then defined as having ACO. The characteristics, frequency of exacerbations, and mortality during the 3-year follow-up were compared between patients with ACO and patients with COPD alone. Results: Among 387 patients with COPD, 41 (10.6%) were identified as having ACO. Patients with ACO tended to be younger, have higher BMI, have a shorter smoking history, and use more respiratory medications, especially inhaled corticosteroids. Inflammatory biomarkers including fractional exhaled nitric oxide, blood eosinophil count, total immunoglobulin E (IgE) level, and presence of antigen-specific IgE were significantly higher in patients with ACO than in those with COPD alone. Lung function, mMRC score, CAT score, and comorbidity index were not different between the groups. The annual rate of all exacerbations and severe exacerbations required hospital admission were not different between ACO and COPD alone (0.20 vs 0.14, 0.12 vs 0.10, events per person, respectively). Mortality was significantly higher in patients with COPD alone compared with those with ACO during the study period (P=0.037). Conclusion: The results of our study indicate that ACO is not associated with poor clinical features nor outcomes in an outpatient COPD cohort receiving appropriate treatment.

Clinical characteristics of Japanese patients with chronic obstructive pulmonary disease (COPD) with comorbid interstitial lung abnormalities: A cross-sectional study.

Smoking-related interstitial lung abnormalities are different from specific forms of fibrosing lung disease which might be associated with poor prognoses. Chronic obstructive pulmonary disease with comorbid interstitial lung abnormalities and that with pulmonary fibrosis are considered different diseases; however, they could share a common spectrum. We aimed to evaluate the clinical characteristics of Japanese patients with chronic obstructive pulmonary disease and comorbid interstitial lung abnormalities. In this prospective observational study, we analyzed data from the Ishinomaki COPD Network Registry. We evaluated the clinical characteristics of patients with chronic obstructive pulmonary disease with and without comorbid interstitial lung abnormalities by comparing the annualized rate of chronic obstructive pulmonary disease exacerbations per patient during the observational period. Among 463 patients with chronic obstructive pulmonary disease, 30 (6.5%) developed new interstitial lung abnormalities during the observational period. After 1-to-3 propensity score matching, we found that the annualized rate of chronic obstructive pulmonary disease exacerbations per patient during the observational period was 0.06 and 0.23 per year in the interstitial lung abnormality and control groups, respectively (P = 0.043). Our findings indicate slow progression of interstitial lung abnormality lesions in patients with pre-existing chronic obstructive pulmonary disease. Further, interstitial lung abnormality development did not significantly influence on chronic obstructive pulmonary disease exacerbation. We speculate that post-chronic obstructive pulmonary disease interstitial lung abnormalities might involve smoking-related interstitial fibrosis, which is different from specific forms of fibrosing lung disease associated with poor prognoses.

Association between sites and severity of eczema and the onset of cow's milk and egg allergy in children.

BACKGROUND: Cow's milk allergy (CMA) and egg allergy (EA) are common and can reduce quality of life in children. Infantile eczema is a well-established risk factor for the onset of food allergy via transdermal sensitization; however, various types of infantile eczema have not yet been evaluated. Therefore, we assessed the association between CMA and EA and the sites and the severity of infantile eczema. METHODS: This retrospective study was based on data from patients aged 2-19 years with atopic disease who were treated between July 2015 and March 2019 in a pediatric allergy clinic in Japan. Data regarding the history of IgE-mediated symptoms, eczema in the first year of life, parental history of atopic diseases, and infantile nutrition were collected. RESULTS: A total of 289 patients were included in the study, of which 81 and 111 children had IgE-mediated CMA and EA, respectively. The rates of CMA and EA were higher in the children with infantile eczema than in those without (30% vs. 9% and 42% vs. 21%). The rate of CMA was also higher in children with eczema on the face. Significant differences were noted in the rate of CMA among children with facial eczema of exudation (adjusted odds ratio 2.398; P = 0.017) and papules (adjusted odds ratio 2.787; P = 0.008), using multivariate analysis. CONCLUSION: The rate of IgE-mediated CMA was high among children with atopic disease having severe facial eczema during infancy.

Survival Analysis for Patients with ALK Rearrangement-Positive Non-Small Cell Lung Cancer and a Poor Performance Status Treated with Alectinib: Updated Results of Lung Oncology Group in Kyushu 1401.

LESSONS LEARNED: Alectinib confers a pronounced survival benefit in patients with ALK rearrangement-positive non-small cell lung cancer and a poor performance status. Survival benefit of alectinib for patients with a poor performance status was consistent regardless of the presence of central nervous system metastases. BACKGROUND: We previously reported a marked objective response rate (ORR) and safety for alectinib treatment in patients with ALK rearrangement-positive non-small cell lung cancer (NSCLC) and a poor performance status (PS) in the Lung Oncology Group in Kyushu (LOGiK) 1401 study. It remained unclear, however, whether alectinib might also confer a long-term survival benefit in such patients. METHODS: Eighteen patients with ALK rearrangement-positive advanced NSCLC and a PS of 2, 3, or 4 (n = 12, 5, and 1, respectively) were enrolled in LOGiK1401 between September 2014 and December 2015 and received alectinib. We have now updated the survival data for the study. RESULTS: The median follow-up time for all patients was 27.3 months. The median progression-free survival (PFS) was 16.2 months (95% confidence interval [CI], 7.1-30.8 months), and the median survival time (MST) and the 3-year overall survival rate were 30.3 months (95% CI, 11.5 months to not reached) and 43.8% (95% CI, 20.8-64.7%), respectively. This survival benefit was similarly manifest in patients with a PS of 2 (MST, 20.5 months) and those with a PS of ≥3 (MST, not reached). PFS did not differ between patients with or without central nervous system (CNS) metastases at baseline (median of 17.5 and 16.2 months, respectively, p = .886). CONCLUSION: Alectinib showed a pronounced survival benefit for patients with ALK rearrangement-positive NSCLC and a poor PS regardless of the presence of CNS metastases, a patient population for which chemotherapy is not indicated.

Clinical characteristics and outcomes in Japanese patients with COPD according to the 2017 GOLD classification: the Ishinomaki COPD Network Registry.

PURPOSE: The GOLD report provides a framework for classifying COPD in a way that reflects its clinical impact and allows treatment recommendations. The GOLD 2017 proposes a new classification whereby patients are grouped as A-D according to their symptoms and history of exacerbations. However, the clinical characteristics and outcomes in these patients are not well documented. PATIENTS AND METHODS: In this prospective observational study, we analyzed data from the Ishinomaki COPD Network Registry. All patients with stable COPD were classified into the four groups defined by GOLD 2017. The patient demographics, clinical characteristics, number of exacerbations, and mortality rate during 1 year of follow-up were compared between the groups. RESULTS: Four hundred and one patients with stable COPD were identified. There were 240 patients (59.9%) in group A, 122 (30.4%) in group B, 16 (4.0%) in group C, and 23 (5.7%) in group D. Patients in groups B, C, and D had ORs of 2.95, 3.92, and 5.45, respectively, for risk of exacerbation relative to group A. Groups C and D experienced exacerbations more frequently, including exacerbations leading to hospital admission, than groups A and B (both P<0.001) during the 1-year follow-up period. Patients with a high risk of exacerbation (groups C and D) had a lower body mass index, showed more symptoms, used more respiratory medications, and had more severe airflow limitation than patients at low risk of exacerbation (groups A and B). Mortality was not different between the high-risk and low-risk groups. CONCLUSION: The results of our study provide evidence that the GOLD 2017 classification identifies patients with COPD at risk of exacerbations, including those requiring hospitalization, but has a poor ability to predict mortality.

[ORAL AND SYSTEMIC SYMPTOMS IN CHILDREN WITH FRUIT ALLERGY].

BACKGROUND AND PURPOSE: The principal aim of this study was to clarify the clinical profile of pediatric patients with fruit allergies. SUBJECTS AND METHODS: We assigned 265 pediatric patients with fruit allergies who were receiving outpatient treatment at Aichi Children's Health and Medical Center and 32 who underwent kiwi or banana oral food chal- lenge (OFC) test to an oral symptom group or a systemic symptom group and retrospectively examined their clinical profiles and prognosis from their medical records. RESULTS: The most common cause of fruit allergy was kiwi (139 patients, 21% of all patients). Watermelon had the highest oral symptom induction rate (97%), whereas banana had the highest systemic reaction induction rate (46%). In the oral symptom group, the prevalence of hay fever was 54% and 66% of patients showed aller- gic reaction to multiple fruits. In contrast, in the systemic symptom group, the prevalence of pollen allergies was 24% and 77% of patients showed allergic reaction to a single fruit only. The results revealed that 65% of patients allergic to bananas had infant-onset allergy and seven among 20 patients were confirmed acquisition of tolerability by the OFC test. CONCLUSION: Our data suggest that there is a difference in the clinical profile and disease type between patients with oral symptoms and those with primarily systemic symptoms. It is important to differentiate between these patients for accurate diet guidance, safety management, and prognosis estimation.

Peripheral alveolar nitric oxide concentration reflects alveolar inflammation in autoimmune pulmonary alveolar proteinosis.

Nitric oxide and alveolar macrophage inflammation http://ow.ly/czCx30i12n8.

Relapsed Myasthenia Gravis after Nivolumab Treatment.

Nivolumab is a newly introduced promising therapy for treating lung cancer that restores the anti-tumor immunity by disrupting programmed cell death-1-mediated immuno-suppressive signaling. Although "new-onset" autoimmune diseases are well-known immune-related adverse events, whether or not nivolumab exacerbates "pre-existing" autoimmune disease remains unclear. We herein report a patient with "pre-existing" myasthenia gravis in whom nivolumab was administered that flared up after the treatment with nivolumab. Regardless of the disease stability, nivolumab has the potential to exacerbate an autoimmune disease, and we must pay close attention to each patient's medical history before administering this agent.

Surveillance of the use of adrenaline auto-injectors in Japanese children.

BACKGROUND: The appropriate usage of an adrenaline auto-injector (AAI, Epipen®) is a key aspect of patient and social education in the management of anaphylaxis. However, although AAIs are being prescribed increasingly frequently, there are few reports on their actual use. METHODS: The Anaphylaxis Working Group of the Japanese Society of Pediatric Allergy and Clinical Immunology requested that society members register cases in which AAIs were used. Two hundred and sixty-six cases were collected from March 2014 to March 2016. RESULTS: The cases included 240 events of immediate-type food allergies caused by cow's milk (n = 100), hen's egg (n = 42), wheat (n = 40), and peanuts (n = 11). Exercise-related events were reported in 19 cases; however, the diagnosis of food-dependent exercise-induced anaphylaxis with a specific causative food was only made in 4 cases (wheat, n = 2; fish, n = 1; squid, n = 1). The frequent reasons for the causative intake included programmed intake (n = 48), failure to check the food labeling (n = 43), and consuming an inappropriate food (n = 26). AAIs were used at schools or nurseries in 67 cases, with school or nursery staff members administering the AAI in 39 cases (58%). On arriving at the hospital, the symptom grade was improved in 71% of the cases, while grade 4 symptoms remained in 20% of the cases. No lethal cases or sequelae were reported. CONCLUSIONS: AAIs were used effectively, even by school teachers. The need to visit a hospital after the use of an AAI should be emphasized because additional treatment might be required.

Pathological features of explant lungs with fibrosis in autoimmune pulmonary alveolar proteinosis.

Association of fibrosis with autoimmune pulmonary alveolar proteinosis (aPAP) is rare. However, prognoses of such cases are poor and the process of the formation of fibrosis is still unknown. In this study, we report a case of aPAP with progressive fibrosis occurring in a 46-year-old woman. She had undergone several repetitions of whole lung lavage (WLL) for 7 years and granulocyte-macrophage colony-stimulating factor (GM-CSF) inhalation for 3 months; however, the progression of fibrosis was not hindered. Eventually, she was treated with bilateral lung transplantation. The computed tomography (CT) image suggested pulmonary fibrotic changes in her lung similar to usual interstitial pneumonia. However, the pathological analyses of explant lungs revealed that the fibrosis was not similar to ordinary interstitial pneumonias and suggested that the dysfunction of alveolar macrophage in removing the excess surfactant of alveolar spaces played an important role in the fibrogenesis in aPAP.

Alectinib for Patients with ALK Rearrangement-Positive Non-Small Cell Lung Cancer and a Poor Performance Status (Lung Oncology Group in Kyushu 1401).

INTRODUCTION: Alectinib has shown marked efficacy and safety in patients with anaplastic lymphoma receptor tyrosine kinase gene (ALK) rearrangement-positive NSCLC and a good performance status (PS). It has remained unclear whether alectinib might also be beneficial for such patients with a poor PS. METHODS: Eligible patients with advanced ALK rearrangement-positive NSCLC and a PS of 2 to 4 received alectinib orally at 300 mg twice daily. The primary end point of the study was objective response rate (ORR), and the most informative secondary end point was rate of PS improvement. RESULTS: Between September 2014 and December 2015, 18 patients were enrolled in this phase II study. Of those patients, 12, five, and one had a PS of 2, 3, or 4, respectively, whereas four patients had received prior crizotinib treatment. The ORR was 72.2% (90% confidence interval: 52.9-85.8%). The ORR did not differ significantly between patients with a PS of 2 and those with a PS of 3 or higher (58.3% and 100%, respectively [p = 0.114]). The PS improvement rate was 83.3% (90% confidence interval: 64.8-93.1%, p < 0.0001), with the frequency of improvement to a PS of 0 or 1 being 72.2%. The median progression-free survival was 10.1 months. Toxicity was mild, with the frequency of adverse events of grade 3 or higher being low. Neither dose reduction nor withdrawal of alectinib because of toxicity was necessary. CONCLUSIONS: Alectinib is a treatment option for patients with ALK rearrangement-positive NSCLC and a poor PS.

Mesenchymal stem cells correct inappropriate epithelial-mesenchyme relation in pulmonary fibrosis using stanniocalcin-1.

Current hypotheses suggest that aberrant wound healing has a critical role in the pathogenesis of idiopathic pulmonary fibrosis (IPF). In these hypotheses, continuous TGF-ß1 secretion by alveolar epithelial cells (AECs) in abnormal wound healing has a critical role in promoting fibroblast differentiation into myofibroblasts. Mesenchymal stem cells (MSCs) home to the injury site and reduce fibrosis by secreting multifunctional antifibrotic humoral factors in IPF. In this study, we show that MSCs can correct the inadequate-communication between epithelial and mesenchymal cells through STC1 (Stanniocalcin-1) secretion in a bleomycin-induced IPF model. Inhalation of recombinant STC1 shows the same effects as the injection of MSCs. Using STC1 plasmid, it was possible to enhance the ability of MSCs to ameliorate the fibrosis. MSCs secrete large amounts of STC1 in response to TGF-ß1 in comparison to AECs and fibroblasts. The antifibrotic effects of STC1 include reducing oxidative stress, endoplasmic reticulum (ER) stress, and TGF-ß1 production in AECs. The STC1 effects can be controlled by blocking uncoupling protein 2 (UCP2) and the secretion is affected by the PI3/AKT/mTORC1 inhibitors. Our findings suggest that STC1 tends to correct the inappropriate epithelial-mesenchymal relationships and that STC1 plasmid transfected to MSCs or STC1 inhalation could become promising treatments for IPF.

Myriad Functions of Stanniocalcin-1 (STC1) Cover Multiple Therapeutic Targets in the Complicated Pathogenesis of Idiopathic Pulmonary Fibrosis (IPF).

Idiopathic pulmonary fibrosis (IPF) is an intractable disease for which the pathological findings are characterized by temporal and spatial heterogeneity. The pathogenesis is composed of myriad factors, including repetitive injuries to epithelial cells, alterations in immunity, the formation of vascular leakage and coagulation, abnormal wound healing, fibrogenesis, and collagen accumulation. Therefore, the molecular target drugs that are used or attempted for treatment or clinical trials may not cover the myriad therapeutic targets of IPF. In addition, the complicated pathogenesis results in a lack of informative biomarkers to diagnose accurately the status of IPF. These facts point out the necessity of using a combination of drugs, that is, each single drug with molecular targets or a single drug with multiple therapeutic targets. In this review, we introduce a humoral factor, stanniocalcin-1 (STC1), which has myriad functions, including the maintenance of calcium homeostasis, the promotion of early wound healing, uncoupling respiration (aerobic glycolysis), reepithelialization in damaged tissues, the inhibition of vascular leakage, and the regulation of macrophage functions to keep epithelial and endothelial homeostasis, which may adequately cover the myriad therapeutic targets of IPF.

Angiogenesis inhibitor vasohibin-1 enhances stress resistance of endothelial cells via induction of SOD2 and SIRT1.

Vasohibin-1 (VASH1) is isolated as an endothelial cell (EC)-produced angiogenesis inhibitor. We questioned whether VASH1 plays any role besides angiogenesis inhibition, knocked-down or overexpressed VASH1 in ECs, and examined the changes of EC property. Knock-down of VASH1 induced premature senescence of ECs, and those ECs were easily killed by cellular stresses. In contrast, overexpression of VASH1 made ECs resistant to premature senescence and cell death caused by cellular stresses. The synthesis of VASH1 was regulated by HuR-mediated post-transcriptional regulation. We sought to define the underlying mechanism. VASH1 increased the expression of (superoxide dismutase 2) SOD2, an enzyme known to quench reactive oxygen species (ROS). Simultaneously, VASH1 augmented the synthesis of sirtuin 1 (SIRT1), an anti-aging protein, which improved stress tolerance. Paraquat generates ROS and causes organ damage when administered in vivo. More VASH1 (+/-) mice died due to acute lung injury caused by paraquat. Intratracheal administration of an adenovirus vector encoding human VASH1 augmented SOD2 and SIRT1 expression in the lungs and prevented acute lung injury caused by paraquat. Thus, VASH1 is a critical factor that improves the stress tolerance of ECs via the induction of SOD2 and SIRT1.