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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 CD62LlowCD4+ 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. [ABSTRACT FROM AUTHOR]

In the original publication of the article, the authors found few errors and the corrections are given below. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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.)

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: 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: 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.