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Background: Biomarkers that can accurately predict the efficacy of immune checkpoint inhibitors (ICIs) against programmed death 1 (PD-1) ligand in cancer immunotherapy are urgently needed. We have previously reported a novel formula that predicts the response to treatment with second-line nivolumab with high sensitivity and specificity in patients with non-small cell lung cancer (NSCLC) previously treated with chemotherapy. The formula was based on the percentages of CD62L low CD4 + T cells (effector T cells; %Teff) and CD4 + CD25 + FOXP3 + T cells (regulatory T cells; %Treg) in the peripheral blood before treatment estimated using the peripheral blood mononuclear cell (PBMC) method. Here, we investigated the applicability of the formula (K-index) to predict the response to treatment with another ICI to expand its clinical applicability. Furthermore, we developed a simpler assay method based on whole blood (WB) samples to overcome the limitations of the PBMC method, such as technical difficulties, in obtaining the K-index., Methods: The K-index was evaluated using the PBMC method in 59 patients with NSCLC who received first-line pembrolizumab treatment. We also assessed the K-index using the WB method and estimated the correlation between the measurements obtained using both methods in 76 patients with lung cancer., Results: This formula consistently predicted the response to first-line pembrolizumab therapy in patients with NSCLC. The WB method correlated well with the PBMC method to obtain %Teff, %Treg, and the formula value. The WB method showed high repeatability (coefficient of variation, < 10%). The data obtained using WB samples collected in tubes containing either heparin or EDTA-2K and stored at room temperature (18-24 °C) for one day after blood sampling did not differ. Additionally, the performance of the WB method was consistent in different flow cytometry instruments., Conclusions: The K-index successfully predicted the response to first-line therapy with pembrolizumab, as reported earlier for the second-line therapy with nivolumab in patients with NSCLC. The WB method established in this study can replace the cumbersome PBMC method in obtaining the K-index. Overall, this study suggests that the K-index can predict the response to anti-PD-1 therapy in various cancers, including NSCLC., (© 2022. The Author(s).)

CD4+ T-cell immunity helps clonal proliferation, migration, and cancer cell killing activity of CD8+ T cells and is essential in antitumor immune responses. To identify CD4+ T-cell clusters responsible for antitumor immunity, we simultaneously analyzed the naïve-effector state, Th polarization, and T-cell receptor clonotype based on single-cell RNA-sequencing data. Unsupervised clustering analysis uncovered the presence of a new CD4+ T-cell metacluster in the CD62Llow CD4+ T-cell subpopulation, which contained multicellular clonotypes associated with efficacy of programmed death-ligand 1 (PD-1) blockade therapy. The CD4+ T-cell metacluster consisted of CXCR3+CCR4-CCR6+ and CXCR3-CCR4-CCR6+ cells and was characterized by high expression of IL7 receptor and TCF7. The frequency of these cells in the peripheral blood significantly correlated with progression-free survival and overall survival of patients with lung cancer after PD-1 blockade therapy. In addition, the CD4+ metacluster in the peripheral blood correlated with CD4+ T-cell infiltration in the tumor microenvironment, whereas peripheral Th1 correlated with local CD8+ T-cell infiltration. Together, these findings suggest that CD62Llow CCR4-CCR6+ CD4+ T cells form a novel metacluster with predictive potential of the immune status and sensitivity to PD-1 blockade, which may pave the way for personalized antitumor immunotherapy strategies for patients., Significance: The identification of a new CD4+ T-cell metacluster that corresponds with immune status could guide effective tumor treatment by predicting response to immunotherapy using peripheral blood samples from patients., (©2022 The Authors; Published by the American Association for Cancer Research.)

The new 2018 classification of periodontal diseases is reported to be related to tooth loss due to periodontal disease (TLPD) during supportive periodontal therapy (SPT). However, few reports have evaluated this relationship for Asians or have analyzed the association of the new classification and TLPD by distinguishing between active periodontal therapy (APT) and SPT. In this study, we retrospectively applied the new classification to 607 Japanese periodontitis patients and examined the relationship between the new classification and annual TLPD rates per patient during the respective periods. TLPD rates were higher in patients in stage IV and/or grade C during both APT and SPT. TLPD during SPT was not associated with the presence or absence of TLPD during APT. Multivariate analysis revealed that stage IV and grade C as independent variables were significantly associated with the number of instances of TLPD not only during the total treatment period, but also during APT or SPT. Our results suggest that the new classification has a significantly strong association with TLPD during both APT and SPT, and that patients diagnosed with stage IV and/or grade C periodontitis had a higher risk of TLPD during both periods., (© 2022. The Author(s).)

Background: Chemoradiotherapy followed by durvalumab is the standard treatment for the patients with local advanced non-small cell lung cancer (NSCLC). There is a real-world data about the management of adverse events, such as pneumonitis, according to the different institutions. Here, we present the experience regarding the management of adverse events after the initiation of durvalumab as daily practice., Methods: From July 2018 to August 2019, 41 patients with locally advanced NSCLC, who underwent chemoradiotherapy followed by durvalumab, were retrospectively analyzed in the study using our medical records., Results: The median age of patients was 72 years (range: 51-80 years). A total of 33 patients were male and eight were female, and 40 patients (98%) received a total radiation dose of 60 Gy as concomitant chemoradiotherapy. The median V20 for the entire cohort was 18.9% (range: 3.5-29.9). Any adverse events during chemoradiotherapy and durvalumab were observed in 32 patients (78.0%), while three patients (7.3%) experienced grade 3 toxicities. In total, 25 (61.0%) patients experienced pneumonitis, four (9.8%) thyroid dysfunction, three (7.3%) myopathy, two (4.9%) rash or eruption, one (2.4%) bowel disease and one (2.4%) malaise. Grade 3 pneumonitis, thyroid dysfunction and myopathy were observed in one (2.4%), one (2.4%) and one (2.4%), respectively. A total of 22 (53.7%) patients were unable to continue durvalumab due to pneumonitis. However, durvalumab was finally readministered to six patients., Conclusions: The adherence to lung dose constraints such as V20 as well as close treatment monitoring are a prerequisite for the management of pneumonitis during maintenance therapy with durvalumab., (© 2020 The Authors. Thoracic Cancer published by China Lung Oncology Group and John Wiley & Sons Australia, Ltd.)

Background: Osimertinib is the most promising treatment option for patients with epidermal growth factor receptor (EGFR) mutation-positive non-small cell lung cancer (NSCLC) with acquired T790M resistance. However, recent studies have suggested that osimertinib could increase the frequency of serious adverse events (AEs) if administered immediately after immune checkpoint inhibitor (ICI) treatment., Methods: In this single-institution retrospective study conducted from May 2016 to January 2019, osimertinib was administered to 47 patients with pretreated advanced NSCLC harboring the EGFR mutation., Results: Of the 47 patients, 20 (42.6%) were men and 27 (57.4%) were women. The median age was 71 years (range 37-83 years). A total of 19 patients (40.4%) had a smoking history. Furthermore, seven patients (14.9%) received osimertinib immediately after nivolumab therapy, while 40 patients (85.1%) were treated with osimertinib after treatment with drugs other than nivolumab. The frequency of grade 3 or 4 hepatotoxicity was significantly higher in patients with nivolumab prior to osimertinib (4/7; 57.1%) than in those treated with drugs other than nivolumab prior to osimertinib (2/40; 5.0%) (P = 0.0026). Liver biopsies were performed in two patients who received osimertinib immediately after nivolumab. In both patients, CD-8-positive T cell infiltration was predominantly observed in the liver tissues., Conclusions: The use of osimertinib immediately after nivolumab significantly increased the frequency of grade 3 or higher hepatotoxicity in patients with advanced NSCLC harboring EGFR mutation acquired T790M resistance., (© 2020 The Authors. Thoracic Cancer published by China Lung Oncology Group and John Wiley & Sons Australia, Ltd.)

Accumulating evidence indicates that CD8 + T cells in the tumor microenvironment and systemic CD4 + T-cell immunity play an important role in mediating durable antitumor responses. We longitudinally examined T-cell immunity in the peripheral blood of patients with non-small lung cancer and found that responders had significantly ( P < 0.0001) higher percentages of effector, CD62L low CD4 + T cells prior to PD-1 blockade. Conversely, the percentage of CD25 + FOXP3 + CD4 + T cells was significantly ( P = 0.034) higher in nonresponders. We developed a formula, which demonstrated 85.7% sensitivity and 100% specificity, based on the percentages of CD62L low CD4 + T cells and CD25 + FOXP3 + cells to predict nonresponders. Mass cytometry analysis revealed that the CD62L low CD4 + T-cell subset expressed T-bet + , CD27 - , FOXP3 - , and CXCR3 + , indicative of a Th1 subpopulation. CD62L low CD4 + T cells significantly correlated with effector CD8 + T cells ( P = 0.0091) and with PD-1 expression on effector CD8 + T cells ( P = 0.0015). Gene expression analysis revealed that CCL19, CLEC-2A, IFNA, IL7, TGFBR3, CXCR3 , and HDAC9 were preferentially expressed in CD62L low CD4 + T cells derived from responders. Notably, long-term responders, who had >500-day progression-free survival, showed significantly higher numbers of CD62L low CD4 + T cells prior to PD-1 blockade therapy. Decreased CD62L low CD4 + T-cell percentages after therapy resulted in acquired resistance, with long-term survivors maintaining high CD62L low CD4 + T-cell percentages. These results pave the way for new treatment strategies for patients by monitoring CD4 + T-cell immune statuses in their peripheral blood., (©2019 American Association for Cancer Research.)

Background: After the cessation of immune checkpoint inhibitor (ICI) therapy due to an immune-related adverse event (irAE), it remains unclear whether retreatment with ICI is more effective than its discontinuation. To explore the clinical significance of its retreatment, patients with non-small cell lung cancer (NSCLC) who had treatment interruption of nivolumab due to irAEs were identified and the clinical differences between discontinuation and retreatment with nivolumab were retrospectively reviewed., Methods: 49 (26%) of 187 patients treated with nivolumab experienced the cessation of treatment due to a serious irAE. Retreatment was chosen in 21 patients (retreatment cohort), while 28 patients discontinued treatment (discontinuation cohort)., Results: The most common irAEs requiring treatment cessation in 49 patients included pneumonitis (59.2%), adrenal insufficiency (8.2%), liver dysfunction (8.2%) renal dysfunction (8.2%), colitis (6.1%), hypothyroidism (4.1%), and rash (2.0%). The frequency of grade 3 or 4 initial irAEs did not differ between the retreatment and discontinuation cohorts; however, the incidence of renal dysfunction and colitis was higher in the retreatment cohort than in the discontinuation cohort. Retreatment with nivolumab displayed an overall response rate of 15%, without a significant increase in irAEs. The median overall survival and progression-free survival did not differ significantly between the retreatment and discontinuation cohorts, irrespective of the efficacy of prior nivolumab., Conclusions: Retreatment exhibited a slightly higher efficacy without a significant increase in irAEs; however, the clinical significance of retreatment and discontinuation was similar in NSCLC patients that led to treatment interruption due to any irAE after initial nivolumab.

Background: Re-challenge of erlotinib after gefitinib failure is reported to yield some benefit in patients with non-small cell lung cancer (NSCLC) harboring epidermal growth factor receptor (EGFR) mutation. However, little is known about the re-challenge of afatinib after 1st generate on EGFR tyrosine kinase inhibitor (TKI) failure., Methods: From May 2015 to August 2018, 62 patients with advanced NSCLC harboring sensitive EGFR mutation received afatinib after gefitinib and/or erlotinib failure at our institution was included in our retrospective study., Results: The overall response rate (ORR) and disease control rate (DCR) of afatinib as re-challenge were 17.0% and 79.2%, respectively. The median time on treatment of 1st generation EGFR-TKI (1st TKI) was 14 months. By multivariate analysis, smoking, performance status (PS), and time on treatment of 1st TKI with more than 10 months were confirmed to be independent prognostic factors predicting a worse progression-free survival (PFS), and significant prognostic markers for overall survival (OS) were PS and time on treatment of 1st TKI with more than 10 months, especially in patients with exon 19 deletion., Conclusions: Re-challenge of afatinib was identified as one of the therapeutic options after 1st TKI failure in the patients with advanced NSCLC harboring EGFR mutation when the time of treatment by prior 1st TKI is more than 10 months.

Background: The aim of our study was to retrospectively assess the incidence of interstitial lung disease (ILD) related to EGFR-tyrosine kinase inhibitor (TKI) treatment immediately before and/or after the administration of a PD-1 antibody., Methods: We analyzed the data of 26 patients who underwent treatment with EGFR-TKIs immediately before and/or after the administration of an anti-PD-1 antibody., Results: Four out of the 26 patients developed ILD during EGFR-TKI treatment: three patients during the administration of osimertinib immediately after, and one during afatinib immediately before treatment with an anti-PD-1 antibody. Three of 12 patients who underwent EGFR-TKI therapy immediately after anti-PD-1 antibody treatment experienced osimertinib-induced ILD. ILD was not observed in the five patients administered an anti-PD-1 antibody followed by first or second-generation EGFR-TKIs., Conclusion: ILD was observed in the treatment sequence of an anti-PD-1 antibody followed by osimertinib, but not with first or second-generation EGFR-TKIs., (© 2019 The Authors. Thoracic Cancer published by China Lung Oncology Group and John Wiley & Sons Australia, Ltd.)

Background: It is unclear whether the chemotherapy response improves after exposure to immunotherapy. Antiangiogenic agents have been shown to stimulate the immune system and cause synergistic effects that stimulate tumor shrinkage. We conducted a retrospective study to evaluate improvement of the efficacy of ramucirumab plus docetaxel after the failure of nivolumab as a PD-1 inhibitor., Methods: From February 2016 to December 2017, 152 patients with non-small cell lung cancer (NSCLC) administered nivolumab in our institution were identified. We reviewed the records of 20 NSCLC patients administered ramucirumab plus docetaxel after nivolumab failure. The overall response rate (ORR), progression-free survival (PFS), and overall survival (OS) were investigated. Pegylated granulocyte colony-stimulating factor was prophylactically administered to 18 patients (90%) after the administration of ramucirumab plus docetaxel., Results: The median age of the patients was 70 (range: 55-77) years. Twelve patients were male and eight were female. The histology was adenocarcinoma in 16 patients, squamous cell carcinoma in three, and other in one. The ORR of ramucirumab plus docetaxel was 60%, and the PFS and OS were 169 and 343 days, respectively. Among the 20 patients, 12 achieved a partial response, giving an ORR of 60.0%. Six patients had stable disease and two had progressive disease. The disease control rate was 90%. Gastrointestinal adverse events were frequently observed in 19 patients., Conclusions: Ramucirumab plus docetaxel achieved a higher response rate when administered immediately after nivolumab failure compared to regimens without prior nivolumab administration., (© 2019 The Authors. Thoracic Cancer published by China Lung Oncology Group and John Wiley & Sons Australia, Ltd.)

Background: It remains unclear why radiation clinically provides a synergistic effect when combined with immune checkpoint inhibitors such as nivolumab. The purpose of our study was to retrospectively evaluate whether the therapeutic efficacy of nivolumab is improved as a result of a history of radiotherapy (RT) in patients with previously treated advanced non-small cell lung cancer (NSCLC)., Methods: From February 2016 to December 2017, 124 consecutive patients were administered nivolumab for pretreated advanced NSCLC. The patients were divided into RT and non-RT groups., Results: Sixty-six (53%) of the 124 patients had been administered RT before the initiation of nivolumab, 52 (42%) received extracranial RT, and 40 (32%) were treated with thoracic RT. The median number of nivolumab cycles was 4 (range: 1-43). The overall response rate (ORR) and disease control rate (DCR) of nivolumab in all patients were 28.0% and 58.4%, respectively. The ORR (36.4%) was significantly higher in patients who had received previous RT than in patients who had not received any RT (19%). The therapeutic efficacy of nivolumab was particularly noteworthy in patients with non-adenocarcinoma and squamous cell carcinoma histology administered extracranial RT, with ORRs of 48.3% and 52.6%, and DCRs of 87.1% and 84.2%, respectively., Conclusion: Previous RT was an independent prognostic marker of favorable prognosis after nivolumab administration and improved the response rate to nivolumab treatment. Previous RT was clinically identified to have a synergistic effect with nivolumab treatment, increasing the response rate and improving the outcome of patients with advanced NSCLC., (© 2019 The Authors. Thoracic Cancer published by China Lung Oncology Group and John Wiley & Sons Australia, Ltd.)

Background: Although small cell lung cancer (SCLC) is an aggressive cancer, few useful treatment options exist after relapse. Information concerning the efficacy and safety of carboplatin plus paclitaxel in patients with SCLC is limited., Methods: From April 2007 to October 2016, 318 patients with SCLC received chemotherapy at our institution. The medical records of patients treated with carboplatin and paclitaxel after first-line chemotherapy with platinum plus etoposide or irinotecan were retrospectively analyzed. The objectives were to investigate the frequency at which a carboplatin and paclitaxel regimen was administered to patients with SCLC in clinical practice, and to determine the response rate, progression-free survival (PFS), and tolerability of such agents., Results: A total of 24 (7.5%) patients (male, n = 21; female, n = 3; median age, 67 years; performance status, 0-1/≥2, 15/8 patients; limited/extensive disease, 6/15 patients; sensitive/refractory relapse, 3/21 patients) were treated with carboplatin plus paclitaxel. This regimen was chosen due to interstitial lung disease (ILD) (n = 17), radiation pneumonitis (n = 3), combination with palliative radiation therapy (n = 2), and the presence of other cancers (n = 2). The response rate was 33.3%, and the disease control rate was 62.5%. The median PFS and overall survival were 4.1 and 8.7 months, respectively. Grade 3/4 hematologic toxicities observed included neutropenia (54.2%), anemia (4.2%), and thrombocytopenia (8.3%). With the exception of grade 3 neuropathies (n = 2), non-hematologic toxicities were mild. No patients experienced an acute exacerbation of ILD., Conclusion: A combination of carboplatin plus paclitaxel as second-line chemotherapy is effective and feasible in patients with SCLC, especially in those with ILD., (Copyright © 2018 The Japanese Respiratory Society. Published by Elsevier B.V. All rights reserved.)

Background and Objective: Acute eosinophilic pneumonia (AEP) is characterized by a massive pulmonary infiltration of eosinophils. Mechanisms regulating the selective accumulation of eosinophils in AEP have not been fully established. The objective of this study was to evaluate the mechanisms of eosinophil accumulation in alveolar spaces through examination of bronchoalveolar lavage fluid (BALF) from AEP patients (AEP-BALF)., Methods: Eosinophils were isolated from the blood of healthy subjects and were placed on a human pulmonary microvascular endothelial cell monolayer cultured on Transwell filters (Coster, Cambridge, MA, USA). A saline control solution or BALF from patients with AEP, sarcoidosis or hypersensitivity pneumonitis was applied to the lower compartment, and the transendothelial migration of the eosinophils was evaluated. The concentrations of cytokines and chemokines in BALF were also measured., Results: Transmigration of eosinophils across endothelial cells was only induced by the AEP-BALF. This transmigration was blocked by anti-β 2 integrin mAb. The concentrations of eotaxin-2 and monocyte chemotactic protein (MCP)-4, which are CC chemokine receptor (CCR) 3 ligands, were elevated in the AEP-BALF, and anti-CCR3 mAb or anti-MCP-4 mAb inhibited the AEP-BALF-induced transmigration of eosinophils. Furthermore, the concentration of leukotriene (LT) B 4 was increased in the AEP-BALF, and an LTB 4 receptor antagonist partially suppressed the AEP-BALF-induced transmigration of eosinophils., Conclusion: These findings suggest that CCR3 ligands including eotaxin-2 and MCP-4, and LTB 4 play a role in the accumulation of eosinophils in AEP., (© 2017 Asian Pacific Society of Respirology.)

In the airways of severe asthmatics, an increase of neutrophils and eosinophils is often observed despite high-dose corticosteroid therapy. We previously reported that interleukin-8-stimulated neutrophils induced trans-basement membrane migration (TBM) of eosinophils, suggesting the link between neutrophils and eosinophils. Concentrations of lipopolysaccharide (LPS) in the airway increase in severe asthma. As neutrophils express Toll-like receptor (TLR)4 and can release chemoattractants for eosinophils, we investigated whether LPS-stimulated neutrophils modify eosinophil TBM. Neutrophils and eosinophils were isolated from peripheral blood of healthy volunteers and severe asthmatics. Eosinophil TBM was examined using a modified Boyden's chamber technique. Eosinophils were added to the upper compartment, and neutrophils and LPS were added to the lower compartment. Migrated eosinophils were measured by eosinophil peroxidase assays. LPS-stimulated neutrophils induced eosinophil TBM (about 10-fold increase), although LPS or neutrophils alone did not. A leukotriene B 4 receptor antagonist, a platelet-activating factor receptor antagonist or an anti-TLR4 antibody decreased eosinophil TBM enhanced by LPS-stimulated neutrophils by almost half. Neutrophils from severe asthmatics induced eosinophil TBM and lower concentrations of LPS augmented neutrophil-induced eosinophil TBM. These results suggest that the combination of neutrophils and LPS leads eosinophils to accumulate in the airways, possibly involved the pathogenesis of severe asthma., Competing Interests: Conflicts of Interest: None declared.

Background: Nontuberculous mycobacteria are well known to be a cause of hot tub lung, however, to our knowledge, there exists no case report of humidifier lung induced by mycobacteria., Case Presentation: A case of a nonimmunocompromised female patient with Mycobacterium gordonae-induced humidifier lung is described. She spontaneously recovered after discontinuing ultrasonic humidifier use. When subjected to a provocation test, she demonstrated acute respiratory distress with signs and symptoms, consistent with hypersensitivity pneumonitis. Before and after the provocation test, water in the humidifier reservoir revealed only Mycobacterium gordonae by the microbiologic analyses., Conclusion: To our knowledge, this is the first report of humidifier lung induced by nontuberculous mycobacteria. Although nontuberculous mycobacteria are well-known to be agents of hot tub lung or metal working fluid lung, physicians should also consider the pathogen as a cause of hypersensitivity lung reaction associated with humidifier use.

Background: ImmunoCAP® Rapid is a rapid test kit to measure the allergen-specific IgE to the eight major inhalation allergen (cat, mite, orchard grass, ragweed, wormwood, dog, cockroach, Japan cedar)., Methods: We performed ImmunoCAP® Rapid 83 patients with allergic disease (26 males, 57 females, median aged 43 years, 53 of asthma, 43 of allergic rhinitis) in our allergy center. ImmunoCAP® Rapid results were compared with those of skin prick test (SPT)., Results: Although total positive allergens of SPT were higher than that of ImmunoCAP® Rapid (26.5% vs 22.5%, p<0.05), there was no significantly difference of each positive allergen between two tests. The rate of ImmunoCAP® Rapid to Japan cedar was almost equivalent to SPT in all patients (68.7% vs 55.4%, p=0.07). In contrast, the rate of ImmunoCAP® Rapid to Japan cedar was higher than SPT in patients with rhinitis (90.4% vs 71.4%, p<0.05). Efficiency between ImmunoCAP® Rapid and SPT was 86.4%, sensitivity was 66.9%, and specificity was 93.4%. The reactivity of ImmunoCAP® Rapid to allergens significantly correlated with sizes of SPT (erythema: r=0.645, urticaria: r=0.657)., Conclusion: Although identification rate in the screening ImmunoCAP® Rapid slightly inferior to SPT, this test system was useful for diagnosis of Japan cedar and mite.

Background: Omalizumab, an anti-immunoglobulin E monoclonal antibody, has shown an inhibitory effect on airway inflammation, which may be associated with clinical improvement of severe asthma. This study evaluated changes in airway inflammation and cytokine release by the peripheral blood mononuclear cells (PBMCs) of Japanese patients with severe asthma after administration of omalizumab., Methods: Sixteen Japanese patients with severe asthma who were allergic to house-dust mites were enrolled in this study. Eight received omalizumab every 2 or 4 weeks for 16 weeks, and 8 control subjects were treated with conventional drug treatment. Changes in clinical scores for sputum eosinophils and levels of fraction of exhaled nitric oxide (FeNO) were measured at the time of enrollment and at week 16. Cytokines from PBMCs stimulated by house-dust mite (Dermatophagoides farinae) or ionomycin/phorbol myristate acetate (PMA) were measured at baseline and at week 16., Results: In the omalizumab-treated group, decreases in sputum eosinophils and FeNO were observed following treatment. Furthermore, the ex vivo production of interleukin (IL)-5 by PBMCs in response to both mite allergen and ionomycin/PMA decreased significantly. In contrast, interferon (IFN)-γ production was unchanged. There were no changes in any of the parameters observed in the control group., Conclusion: Omalizumab exerts inhibitory effects on airway inflammation in Japanese patients with severe allergic asthma. This treatment attenuates production of IL-5 by PBMCs stimulated with both a specific allergen and a nonspecific activator. Reduction of the Th2 inflammatory cascade likely contributes to clinical benefits; however, further studies are required to clarify these results due to the small sample size in this study., (Copyright © 2013 S. Karger AG, Basel.)

Background: Neutrophils are often increased in the airways of either chronic severe asthma or acute exacerbations. Neutrophils that have migrated in response to interleukin-8 (IL-8) may lead eosinophils to accumulate in the airways of patients with asthma and possibly aggravate the disease. In this study, we investigated whether formoterol modified the trans-basement membrane migration (TBM) of eosinophils stimulated with neutrophils and IL-8., Methods: Neutrophils and eosinophils were isolated from peripheral blood obtained from healthy donors. Eosinophil TBM was examined using a modified Boyden's chamber technique. Neutrophils were preincubated with or without formoterol (0.1 μM) at 37°C for 30 min. Eosinophils were added to the upper compartment of a chamber with a Matrigel-coated transwell insert. Medium containing preincubated neutrophils and IL-8 was added to the lower compartment of the chamber. After a 90-minute incubation, the eosinophils that had migrated into the lower chamber were calculated using eosinophil peroxidase assays., Results: A combination of neutrophils and IL-8 significantly induced the eosinophil TBM; formoterol alone had no effect. However, formoterol modestly but significantly attenuated the TBM of eosinophils stimulated with neutrophils and IL-8., Conclusion: These results suggest that formoterol may act as a therapeutic agent on enhanced eosinophilic inflammation in acute exacerbation or persistent, severe asthma. The effect of formoterol likely involves the inhibition of neutrophil activation., (Copyright © 2013 S. Karger AG, Basel.)

Objective: The authors experienced a case of prolonged cardiopulmonary resuscitation (CPR) on Mount Fuji (3776 m) that demanded strenuous work by the rescuers. The objective of this study was to provide information regarding the physiologic effects on the rescuers of performing CPR at moderate altitude., Methods: The effects of CPR at 2700 m and 3700 m above sea level on the physical condition of the rescuers were studied in 8 male volunteers., Results: Cardiopulmonary resuscitation for 5 minutes at 3700 m significantly reduced arterial blood oxygen saturation and increased rate-pressure products (P < .05). Scores on the Borg scale, a subjective score of fatigue, after CPR action at 2700 m (P < .05) and 3700 m (P < .01) were higher than the scores at sea level., Conclusions: Prolonged CPR at high altitude exerts a significant physical effect upon the condition of rescuers. A role for mechanical devices should be considered wherever possible., (Copyright © 2012 Wilderness Medical Society. Published by Elsevier Inc. All rights reserved.)

Background: Airway inflammation is a fundamental feature of bronchial asthma. We examined whether educational guidance using a text on pathophysiology and management of asthma modify airway inflammation of severe asthma., Methods: Eighteen severe persistent asthmatics were enrolled in this study. Evaluation on asthma control using Asthma Control Test (ACT), Asthma Health Questionnaire (AHQ)-Japan), FEV1, percentages of eosinophils and neutrophils in induced sputum were analyzed before and 4 weeks after patient education process., Results: Following educational guidance, ACT and FEV1 did not improve, but AHQ score significantly improved. Furthermore, percentage of eosinophils in sputum significantly reduced. On the contrary, the percentage of neutrophils in sputum was not changed. In accordance with this lack of the change in neutrophil numbers, neutrophil chemoattractants including IL-8 or CXCR3 in the induced sputum did not change before and after patient guidance., Conclusion: Educational guidance using a text on pathophysiology and management of asthma provides some effects on quality of life in asthmatic patients and eosinophilic inflammation, however, this procedure does not modify the control status of asthma and neutrophilic inflammation seen with severe asthma.

A case involved a 39-year-old female nurse in a health-care facility for elderly individuals requiring long-term care, who presented with insufficient control of bronchial asthma. Although she did not have tinea, she had opportunities for contact with patients who did. Careful interview of history suggested a relationship between asthma exacerbation and workplace, so we measured the specific IgE antibody to Trichophyton and confirmed a positive result. As occupational exposure to Trichophyton was considered as a cause of asthma exacerbations, avoidance of Trichophyton as well as anti-asthma treatment was conducted and symptoms improved. Identification and avoidance of specific allergens is essential for successful long-term management of asthma. However, measurement of specific IgE antibody to Trichophyton is not routinely performed, although this fungus could induce not only tinea, but also asthma. The possibility that occupational exposure to trichophyton could exacerbate asthma symptoms needs to be kept in mind, particularly in the case of nurses who may be in contact with elderly individuals with tinea.

Background: The interaction between allergic rhinitis and bronchial asthma is well known. However, there is little epidemiological data on the relationship between nasal diseases and asthma, especially in Japan., Methods: We administered a questionnaire to 126 patients to examine the frequency of associations between nasal and asthma symptoms in patients with both nasal disease and asthma. We also investigated in which type of patients the asthma symptoms were affected by changes in nasal symptoms., Results: Thirty-eight patients (30%) were aware that their asthma was worsened by exacerbated nasal disease, and nasal treatment improved asthma in 28 patients (22%). The influence of changes in nasal symptoms on asthma symptoms was stronger in patients lacking good asthma control. The relationship between nasal and asthma symptoms tended to be stronger in patients with sinusitis., Conclusion: About 30% of patients with nasal disease and asthma reported an association between their nasal and asthma symptoms. Nasal treatment is considered to be important for asthma control, especially in patients with asthma symptoms. These results suggested the important role of comprehensive allergy care in controlling both nasal disease and asthma.

Background: Most patients with asthma are currently controlled by pharmacotherapeutic means such as inhaled corticosteroid (ICS). However, whether ICS actually induces remission of asthma remains unknown. The present study evaluates changes in airway inflammation and hyperresponsiveness in adult patients with asthma after stopping ICS., Methods: We enrolled 11 patients with allergic asthma (7 males and 4 females; mean age, 52.3 years) who had been asymptomatic and had no exacerbation by low-dose ICS. Airway hyperresponsiveness (AHR) was assessed using methacholine challenge, and induced sputum was evaluated before and every 3 months after ICS cessation during the 1-year follow-up., Results: Among the 11 asthmatics, AHR increased in 10 (90.9%) and asthma clinically relapsed in 4 (36.4%) within 1 year of ICS cessation. AHR increased in all 7 asthmatics that were sensitized to Dermatophagoides farinae and asthma clinically relapsed in 4 (57.1%) of them. Furthermore, eosinophil numbers and IL-4 concentrations in the sputum significantly increased after ICS cessation., Conclusions: Remission with normal airway response to methacholine (no AHR) might be rare in adult patients with allergic asthma, and sensitization to house dust mites appears to play an important role in relapse. Therefore, ICS cessation should be carefully considered in patients sensitive to house dust mites. Serial determination of eosinophil counts or IL-4 concentrations in sputum might be appropriate for monitoring and preventing asthma relapse in adults., ((c) 2010 S. Karger AG, Basel.)

Electroconvulsive therapy induces hypermetabolism and elevates oxygen and energy demands, while more carbon dioxide is produced than usual. The purpose of the present study was to determine the elevated carbon dioxide exhalation and the adequate ventilation volume during electroconvulsive therapy. Carbon dioxide exhalation during an electrically induced seizure was continuously monitored by capnography and spirography in 15 patients with endogenous depression. A laryngeal mask airway was used to measure the airway gas flow. Data were collected during a total of 80 electroconvulsive therapy trials. The carbon dioxide exhalation at 1 min after electrical stimulation was higher than the control value (2.8 +/- 0.4 versus 2.3 +/- 0.3 ml.min(-1).kg(-1), mean +/- SD; P < 0.05). The ventilation volume was increased for 3 min after the electrical stimulation to maintain the end-tidal carbon dioxide partial pressure at 35-40 mmHg. The results showed that increasing the ventilation volume by approximately 20% may be necessary to compensate for the increased carbon dioxide exhalation during electroconvulsive therapy.

Purpose: Several ss-adrenergic-blocking drugs have been used during electroconvulsive therapy (ECT) to stabilize the hemodynamic alterations following electrical stimulation. The effects of two ultra-short acting ss-adrenergic-blocking drugs, esmolol and landiolol, on systemic and cerebral circulation were studied during ECT., Methods: In the first study (n = 15), dose-dependent hemodynamic changes were studied when landiolol was administered immediately after induction of anesthesia. In the second study (n = 12), effects of esmolol and landiolol on systemic and cerebral circulation were compared. Patients in Study 1 received three doses of landiolol, and patients in Study 2 received two types of ss-adrenergic-blocking drugs, in a randomized cross-over design in a series of ECT trials., Results: In the first study, 0.25 to 0.5 mg.kg(-1) landiolol induced a lower heart rate after the electrical stimulation compared to vehicle (P < 0.01). Landiolol did not have significant effects on blood pressure. In the second study, heart rate was stabilized by 1.0 mg.kg(-1) esmolol iv or 0.5 mg.kg(-1) landiolol iv. Increase in mean blood pressure was ameliorated by esmolol (P < 0.01), but not by landiolol. Mean cerebral blood flow velocity in the middle cerebral artery increased at one to two minutes after the electrical stimulation regardless of the use of ss-adrenergic-blocking drugs (P < 0.01). Muscular and electroencephalographic seizure durations were not significantly altered by the ss-adrenergic-blocking drugs., Conclusion: Landiolol suppresses heart rate elevation during ECT without affecting blood pressure. Cerebral blood flow velocity in the middle cerebral artery is not affected by the use of either esmolol or landiolol.

Autonomic nervous systems have important roles for survival of victims under hypobaric hypoxic condition. In the present study, we assessed the correlation between arterial oxygen saturation (Sp O 2 ) and heart rate variability (HRV) to identify the autonomic nervous responsiveness among trekkers at high altitude (n = 21). HRV was analyzed by the maximum entropy method. Sp O 2 among subjects at 3456 m (495 mm Hg) was 80% +/- 5% (mean +/- SD; range, 69%-93%). Sp O 2 and percentile entropy, and Sp O 2 and low-frequency variability, had positive correlation ( r = 0.455 and 0.518, respectively). Sp O 2 value among subjects with mountain sickness symptoms was not different from that among subjects without the symptoms. In conclusion, autonomic responses among high-altitude trekkers may be blunted under hypobaric hypoxic conditions. Deterioration of autonomic function measured by HRV might be more sensitive to hypoxia than clinical symptoms at high altitudes.

Background: The L-arginine-nitric oxide (NO) pathway plays an important role in the modulation of glomerular disease. We investigated whether beta-blocking agents, with and without an NO-generating function, had renoprotective effects in the 5/6 nephrectomized rats (Nx), an animal model of glomerulosclerosis., Methods: Nipradilol, a beta-blocker with an ONO(2) group (5, 10 or 15 mg/kg/day) and propranolol, a beta-blocker without this group (50 mg/kg/day) were administered for 12 weeks to Nx together with and without nitro-L-arginine methyl ester (L-NAME). We evaluated the effects of both drugs on proteinuria, hypertension, renal function, glomerulosclerosis and urinary excretion of NO metabolites (U(NOx)) and cyclic GMP (U(cGMP))., Results: Both drugs similarly attenuated the elevated blood pressure in Nx. However, nipradilol, at doses of 10 and 15 mg/kg/day, significantly decreased proteinuria and glomerulosclerosis, while propranolol did not. Nx showed reduced U(NOx) in comparison with the sham-operated rats. Nipradilol increased U(NOx) and U(cGMP) significantly and in a dose- dependent manner, whereas propranolol reduced them to levels lower than those in Nx. Nx receiving L-NAME reduced U(NOx). The addition of nipradilol increased U(NOx) and decreased urinary protein excretion and glomerulosclerosis, suggesting that the NO released from the drug contributed to its renoprotective effect., Conclusion: These findings indicate that nipradilol exerts its renoprotective effect through NO generation, and not by lowering blood pressure. The beta-adrenergic blocking action per se does not seem to be related to the renoprotective effect of these agents., (Copyright 2003 S. Karger AG, Basel)

Background: One of the key mechanisms leading to beta-adrenergic receptor-specific desensitization is the phosphorylation of agonist-occupied receptors by the specific beta-adrenergic receptor kinase (GRK2). The present study examines whether GRK2 is altered during septic shock in rats., Materials and Methods: Male Wistar rats (7 weeks) weighing between 250 and 300 g were anesthetized with pentobarbital (10 mg/kg ip). Escherichia coli endotoxin (10 mg/kg in 0.3 mL of saline) or saline (0.3 ml) was injected intravenously via the dorsal vein. Hemodynamic parameters and humoral mediators were measured at 2 h after the administration of endotoxin. The hearts were immediately excised to examine beta-adrenergic receptor density and GRK2 level. We also studied the inotropic response to isoproterenol at the same time in other animals., Results: Myocardial beta-adrenergic receptor density in the membrane fraction was decreased after an intravenous administration of 10 mg/kg LPS (LPS group: baseline value; 82 +/- 11 fmol/mg protein; 120 min after LPS; 58 +/- 11 fmol/mg protein, P < 0.05). GRK2 levels in the membrane and cytosolic fraction of the control group did not change. In the LPS group, GRK2 levels in the membrane fraction were increased at 60 and 120 min after the treatment (60 min; control, 4.5 +/- 0.4; pithed control, 4.4 +/- 0.6; LPS group, 6.2 +/- 0.3; pithed LPS group, 5.5 +/- 0.4; 120 min: control, 4.4 +/- 0.3; pithed control, 4.9 +/- 0.7; LPS group, 7.1 +/- 0.3; pithed LPS group, 5.9 +/- 0.4; densitometric unit, respectively: P < 0.05)., Conclusions: GRK2 levels in the membrane fraction are increased during septic shock in rats. GRK2 might play a role in the impairment of the beta-adrenergic receptor signal transduction system.

The number of alpine accidents has markedly increased among elderly trekkers in an aging society, Japan. We evaluated the physical condition of 176 trekkers by interview and physical examination on a popular middle altitude mountain. Heart rate, noninvasive blood pressure and arterial oxygen saturation (SpO2) were measured using a portable life monitor. It was revealed that more than 70% of the trekkers were over 50. Seventy-five percent of trekkers over 70 had some pre-existing medical problems. Systolic and diastolic blood pressure before the start of trekking, increased with age. However, such age-dependent differences were not apparent at the summit hut. SpO2 values decreased slightly but significantly with age. In conclusion, many elderly people enjoy nonchallenging middle altitude trekking in an aging society. Alpine accidents caused by health problems tend to arise more frequently in this population. Alpine rescue teams should be well-prepared for the alpine accidents of elderly trekkers., (Copyright 2002, Elsevier Science (USA). All rights reserved.))

Unlabelled: Propofol anesthesia increases the seizure threshold of patients receiving electroconvulsive therapy. Excessive neuronal suppression could result in an unacceptably short seizure. We sought to identify the correlation between the pre-ictal bispectral index (BIS) score and seizure duration in patients receiving electroconvulsive therapy under propofol anesthesia. BIS was monitored in 38 psychotically depressed patients. Anesthesia was induced by a bolus injection of 1 mg/kg of propofol. The duration of muscular and electroencephalographic seizure was measured during the therapy. The BIS immediately before the electrical shock was 54 +/- 13. Both muscular and electroencephalographic seizure durations had a positive correlation with pre-ictal BIS (r = 0.68 and 0.73, respectively; P < 0.01). After the electrically induced seizure, BIS decreased to 30 +/- 8, reflecting post-ictal suppression. BIS scores when the patients had awakened after the seizure had a wide variation (range, 29-81; mean, 45; SD, 13). In conclusion, seizure duration has a positive correlation with BIS immediately before electrical shock; however, BIS may not be an accurate predictor of awakening after electrical shock., Implications: Pre-ictal bispectral index had a positive correlation with seizure duration and could be useful to prevent an unacceptably short seizure in electroconvulsive therapy under propofol anesthesia.

Objectives: Many travelers who are not specially trained for activities at high altitude are at risk of physical problems, including cardiovascular disorders, when exposed to high-altitude environments. In the present study, we investigated how actual acute exposure to altitudes of 2700 and 3700 m affected the autonomic nervous control of heart rate in untrained office workers., Methods: Physiological parameters (heart rate, respiratory rate, arterial blood oxygen saturation, and end-expiratory carbon dioxide tension) were measured at sea level, 2700 m, and 3700 m. The power of heart rate variability was quantified by determining the areas of the spectrum in 2 component widths: low frequency (LF; 0.04-0.15 Hz) and high frequency (HF; 0.15-0.5 Hz). The ratio of LF power to HF power (LF:HF), which is considered to be an index of cardiac sympathetic tone, was also assessed., Results: Both HF and LF heart rate variability decreased according to the elevation of altitude. High- and low-frequency powers at 3700 m were significantly lower than those at sea level (P < .01 for HF, P < .05 for LF). The LF:HF ratio at 2700 m was not significantly different from that at sea level. However, it was significantly increased at 3700 m (P < .01)., Conclusions: At 2700 and 3700 m, the activity of the autonomic nervous system measured by heart rate variability was decreased in untrained office workers. The sympathetic nervous system was dominant to the parasympathetic at 3700 m. These alterations in the autonomic nervous system might play some role in physical fitness at high altitudes.