Applicable predictive factors extracted from peak flow trajectory for the prediction of asthma exacerbation.

BACKGROUND: Real-time asthma exacerbation prediction and acute asthma attack detection are essential for patients with severe asthma. Peak expiratory flow (PEF) exhibits a potential for use in long-term asthma self-monitoring. However, the method for processing PEF calculations remains to be clarified. OBJECTIVE: To develop clinically applicable novel exacerbation predictors calculated using PEF records. METHODS: Previously proposed exacerbation predictors, including the slope of PEF, percentage predicted PEF, percentage best PEF, the highest PEF over the lowest PEF within specific periods, and PEF coefficient of variation, in addition to a novel indicator delta PEF moving average (ΔMA), defined as the difference between 14-day and 3-day average PEF values, along with moving average (MA) adjusted for PEF reference (%ΔMA), were verified using the Hokkaido-based Investigative Cohort Analysis for Refractory Asthma data of 127 patients with severe asthma from whom 73,503 PEF observations were obtained. Receiver operating characteristic curves for all predictors were drawn, and the corresponding areas under the curve (AUCs) were computed. Regression analysis for MA and percentage MA were conducted. RESULTS: The most outstanding performance was shown by ΔMA and %ΔMA, with AUC values of 0.659 and 0.665 in the univariate model, respectively. When multivariate models were incorporated with random intercepts for individual participants, the AUC for ΔMA and %ΔMA increased to 0.907 and 0.919, respectively. CONCLUSION: The MA and percentage MA are valuable indicators that should be considered when deriving predictors from the PEF trajectory for monitoring exacerbations in patients with severe asthma. TRIAL REGISTRATION: The Hokkaido-based Investigative Cohort Analysis for Refractory Asthma was registered in the University Hospital Medical Information Network Clinical Trials Registry (UMIN ID: 000003254). https://center6.umin.ac.jp/cgi-open-bin/ctr_e/ctr_view.cgi?recptno=R000003917.

Computed tomography mucus plugs and airway tree structure in patients with chronic obstructive pulmonary disease: Associations with airflow limitation, health-related independence and mortality.

BACKGROUND AND OBJECTIVE: Mucus plugs and underlying airway tree structure can affect airflow limitation and prognosis in patients with chronic obstructive pulmonary disease (COPD), but their relative roles are unclear. This study used two COPD cohorts to examine whether mucus plugs on computed tomography (CT) were associated with airflow limitation and clinical outcomes independent of other airway structural changes and emphysema. METHODS: Based on visual CT assessment, patients with mucus plugs in 0, 1-2 and ≥3 lung segments were assigned to no-, low- and high-mucus groups. Loss of health-related independence and mortality were prospectively recorded for 3 and 10 years in the Kyoto-Himeji and Hokkaido cohorts, respectively. The percentages of the wall area of the central airways (WA%), total airway count (TAC) and emphysema were quantified on CT. RESULTS: Of 199 and 96 patients in the Kyoto-Himeji and Hokkaido cohorts, 34% and 30%, respectively, had high mucus scores. In both cohorts, TAC was lower in the high-mucus group than in the no-mucus group, whereas their emphysema severity did not differ. High mucus score and low TAC were independently associated with airflow limitation after adjustment for WA% and emphysema. In multivariable models adjusted for WA% and emphysema, TAC, rather than mucus score, was associated with a greater rate of loss of independence, whereas high mucus score, rather than TAC, was associated with increased mortality. CONCLUSION: Mucus plugs and lower airway branch count on CT had distinct roles in airflow limitation, health-related independence and mortality in patients with COPD.

Subtyping emphysematous COPD by respiratory volume change distributions on CT.

BACKGROUND: There is considerable heterogeneity among patients with emphysematous chronic obstructive pulmonary disease (COPD). We hypothesised that in addition to emphysema severity, ventilation distribution in emphysematous regions would be associated with clinical-physiological impairments in these patients. OBJECTIVE: To evaluate whether the discordance between respiratory volume change distributions (from expiration to inspiration) in emphysematous and non-emphysematous regions affects COPD outcomes using two cohorts. METHODS: Emphysema was quantified using a low attenuation volume percentage on inspiratory CT (iLAV%). Local respiratory volume changes were calculated using non-rigidly registered expiratory/inspiratory CT. The Ventilation Discordance Index (VDI) represented the log-transformed Wasserstein distance quantifying discordance between respiratory volume change distributions in emphysematous and non-emphysematous regions. RESULTS: Patients with COPD in the first cohort (n=221) were classified into minimal emphysema (iLAV% <10%; n=113) and established emphysema with high VDI and low VDI groups (n=46 and 62, respectively). Forced expiratory volume in 1 s (FEV1) was lower in the low VDI group than in the other groups, with no difference between the high VDI and minimal emphysema groups. Higher iLAV%, more severe airway disease and hyperventilated emphysematous regions in the upper-middle lobes were independently associated with lower VDI. The second cohort analyses (n=93) confirmed these findings and showed greater annual FEV1 decline and higher mortality in the low VDI group than in the high VDI group independent of iLAV% and airway disease on CT. CONCLUSION: Lower VDI is associated with severe airflow limitation and higher mortality independent of emphysema severity and airway morphological changes in patients with emphysematous COPD.

Apoptosis inhibitor of macrophage (AIM)/CD5L is involved in the pathogenesis of COPD.

BACKGROUND: Alveolar macrophages (AMs) and AM-produced matrix metalloprotease (MMP)-12 are known to play critical roles in the pathogenesis of chronic obstructive pulmonary disease (COPD). The apoptosis inhibitor of the macrophages (AIM)/CD5 molecule-like (CD5L) is a multifunctional protein secreted by the macrophages that mainly exists in the blood in a combined form with the immunoglobulin (Ig)M pentamer. Although AIM has both facilitative and suppressive roles in various diseases, its role in COPD remains unclear. METHODS: We investigated the role of AIM in COPD pathogenesis using porcine pancreas elastase (PPE)-induced and cigarette smoke-induced emphysema mouse models and an in vitro model using AMs. We also analyzed the differences in the blood AIM/IgM ratio among nonsmokers, healthy smokers, and patients with COPD and investigated the association between the blood AIM/IgM ratio and COPD exacerbations and mortality in patients with COPD. RESULTS: Emphysema formation, inflammation, and cell death in the lungs were attenuated in AIM-/- mice compared with wild-type (WT) mice in both PPE- and cigarette smoke-induced emphysema models. The PPE-induced increase in MMP-12 was attenuated in AIM-/- mice at both the mRNA and protein levels. According to in vitro experiments using AMs stimulated with cigarette smoke extract, the MMP-12 level was decreased in AIM-/- mice compared with WT mice. This decrease was reversed by the addition of recombinant AIM. Furthermore, an analysis of clinical samples showed that patients with COPD had a higher blood AIM/IgM ratio than healthy smokers. Additionally, the blood AIM/IgM ratio was positively associated with disease severity in patients with COPD. A higher AIM/IgM ratio was also associated with a shorter time to the first COPD exacerbation and higher all-cause and respiratory mortality. CONCLUSIONS: AIM facilitates the development of COPD by upregulating MMP-12. Additionally, a higher blood AIM/IgM ratio was associated with poor prognosis in patients with COPD. TRIAL REGISTRATION: This clinical study, which included nonsmokers, healthy smokers, and smokers with COPD, was approved by the Ethics Committee of the Hokkaido University Hospital (012-0075, date of registration: September 5, 2012). The Hokkaido COPD cohort study was approved by the Ethics Committee of the Hokkaido University School of Medicine (med02-001, date of registration: December 25, 2002).

Parenchymal destruction in asthma: Fixed airflow obstruction and lung function trajectory.

BACKGROUND: Fixed airflow obstruction (FAO) in asthma, particularly in nonsmokers, is generally believed to be caused by airway remodeling. However, parenchymal destruction may also contribute to FAO and longitudinal decline in forced expiratory volume in 1 second (FEV1). OBJECTIVES: To evaluate parenchymal destruction, we used emphysema indices, exponent D, and low-attenuation area percentage (LAA%) on computed tomography (CT), and test whether the parenchymal destruction and airway disease are independently associated with FAO and FEV1 decline in both smoking and nonsmoking asthma. METHODS: Exponent D, LAA%, wall area percentage at segmental airways, and airway fractal dimension (AFD) in those with asthma were measured on inspiratory CT and compared to those in patients with chronic obstructive pulmonary disease (COPD). RESULTS: Exponent D was lower and LAA% was higher in COPD (n = 42) and asthma with FAO (n = 101) than in asthma without FAO (n = 88). The decreased exponent D and increased LAA% were associated with FAO regardless of smoking status or asthma severity. In multivariable analysis, decreased exponent D and increased LAA% were associated with an increased odds ratio of FAO and decreased FEV1, irrespective of wall area percentage and airway fractal dimension. Moreover, decreased exponent D affected the longitudinal decline in FEV1 in those with severe asthma, independent of smoking status. CONCLUSIONS: Patients with asthma with FAO showed parenchymal destruction regardless of smoking status and asthma severity. Parenchymal destruction was associated with an accelerated FEV1 decline, suggesting the involvements of both airway and parenchyma in the pathophysiology of a subgroup of asthma.

Blood eosinophil count variability in chronic obstructive pulmonary disease and severe asthma.

BACKGROUND: Blood eosinophils are essential biomarkers that vary substantially over time in patients with COPD and asthma. However, no study has identified the changes and effects in the changes of the blood eosinophil counts over time in both diseases. This study aimed to demonstrate blood eosinophil variability in patients with COPD and severe asthma based on these backgrounds. METHODS: A total of 172 patients with COPD from the Hokkaido COPD cohort study and 96 patients with severe asthma from the Hokkaido Severe Asthma Cohort Study, whose blood eosinophil counts were measured annually over a 3-year period, were analyzed. The factors contributing to consistently high or low blood eosinophil counts were examined in each cohort. The stability of the eosinophil classification (<150, 150-299, ≥300 cells/µL) was compared based on the number of asthma-like features in patients with COPD and the smoking status in patients with severe asthma. RESULTS: Among all the patients, the most stable range of baseline blood eosinophil counts differed between the two diseases, with <150 cells/µL in COPD and ≥300 cells/µL in severe asthma. In COPD, the number of asthma-like features (bronchodilator reversibility, blood eosinophilia, and atopy) affects the blood eosinophil count variation patterns. In severe asthma, smoking status did not affect the blood eosinophil count variation patterns. CONCLUSIONS: We identified variations in the blood eosinophil counts and their contributing factors in patients with COPD and severe asthma.

Differential role of mucus plugs in asthma: Effects of smoking and association with airway inflammation.

BACKGROUND: The physiological importance of mucus plugs in computed tomography (CT) imaging is being increasingly recognized. However, whether airway inflammation and smoking affect the association between mucus plugs and clinical-physiological outcomes in asthma remains to be elucidated. The objective of this study is to examine how airway inflammation and/or smoking affect the correlation of CT-based mucus plug scores with exacerbation frequency and airflow limitation indices in asthma. METHODS: A total of 168 patients with asthma who underwent chest CT and sputum evaluation were enrolled and classified in eosinophilic asthma (EA; n = 103) and non-eosinophilic asthma (NEA; n = 65) groups based on sputum eosinophil percentage (cut-off: 3%). The mucus plug score was defined as the number of lung segments with mucus plugs seen on CT. RESULTS: More mucus plugs were detected on CT scans in the EA group than in the NEA group, regardless of smoking status. Mucus plug score and exacerbation frequency during one year after enrollment were significantly associated in the EA group but not in the NEA group after adjusting for demographics, blood eosinophil count, and fractional exhaled nitric oxide. Mucus plug score was associated with percentage of predicted forced expiratory volume in 1 s in non-smoking individuals in the EA and NEA group and in smoking individuals in the EA group but not in the NEA group after adjusting for demographics. CONCLUSIONS: The association of mucus plug score with exacerbation frequency and reduced lung function may vary due to airway inflammatory profile and smoking status in asthma.

Effects of obesity on CC16 and their potential role in overweight/obese asthma.

INTRODUCTION: Club cell secretory protein-16 (CC16) is a major anti-inflammatory protein expressed in the airway; however, the potential role of CC16 on overweight/obese asthma has not been assessed. In this study, we examined whether obesity reduces airway/circulatory CC16 levels using experimental and epidemiological studies. Then, we explored the mediatory role of CC16 in the relationship of overweight/obesity with clinical asthma measures. METHODS: Circulating CC16 levels were assessed by ELISA in three independent human populations, including two groups of healthy and general populations and asthma patients. The percentage of cells expressing club markers in obese vs. non-obese mice and human airways was determined by immunohistochemistry. A causal mediation analysis was conducted to determine whether circulatory CC16 acted as a mediator between overweight/obesity and clinical asthma measures. RESULTS: BMI was significantly and monotonously associated with reduced circulating CC16 levels in all populations. The percentage of CC16-expressing cells was reduced in the small airways of both mice and humans with obesity. Finally, mediation analysis revealed significant contributions of circulatory CC16 in the association between BMI and clinical asthma measures; 21.8% of its total effect in BMI's association with airway hyperresponsiveness of healthy subjects (p = 0.09), 26.4% with asthma severity (p = 0.030), and 23% with the required dose of inhaled corticosteroid (p = 0.042). In logistic regression analysis, 1-SD decrease in serum CC16 levels of asthma patients was associated with 87% increased odds for high dose ICS requirement (p < 0.001). CONCLUSIONS: We demonstrate that airway/circulating CC16, which is inversely associated with BMI, may mediate development and severity in overweight/obese asthma.

Further evidence for association of YKL-40 with severe asthma airway remodeling.

BACKGROUND: The chitinase-like protein YKL-40 is associated with airflow limitation on spirometry and airway remodeling in patients with asthma. It remains unclear whether YKL-40 is associated with morphologic changes in the airways and parenchyma or with future progression of airflow limitation in severe asthma. OBJECTIVE: To evaluate the association of circulating YKL-40 levels with morphologic changes in the airways and parenchyma and with longitudinal progression of airflow limitation. METHODS: The patients were participants in the Hokkaido Severe Asthma Cohort Study (n = 127), including smokers. This study consisted of 2 parts. In analysis 1, we analyzed associations between circulating YKL-40 levels and several asthma-related indices, including computed tomography-derived indices of proximal wall area percentage, the complexity of the airways (airway fractal dimension), and the parenchyma (exponent D) cross-sectionally (n = 97). In analysis 2, we evaluated the impact of circulating YKL-40 levels on forced expiratory volume in 1 second (FEV1) decline longitudinally for a 5-year follow-up (n = 103). RESULTS: Circulating YKL-40 levels were significantly associated with proximal wall area percentage and airway fractal dimension (r = 0.25, P = .01; r = -0.22, P = .04, respectively), but not with exponent D. The mean annual change in FEV1 was -33.7 (± 23.3) mL/y, and the circulating YKL-40 level was a significant independent factor associated with annual FEV1 decline (ß = -0.24, P = .02), even after controlling for exponent D (ß = -0.26, P = .01). CONCLUSION: These results provide further evidence for the association of YKL-40 with the pathogenesis of airway remodeling in severe asthma.

Association of longitudinal changes in quality of life with comorbidities and exacerbations in patients with severe asthma.

BACKGROUND: Quality of life (QoL) assessment is important in the management of severe asthma, and comorbidities and/or exacerbations may affect longitudinal QoL. However, there are few reports on the longitudinal assessment of QoL in patients with asthma over multiple years and its related factors. This study aimed to clarify the relationship of longitudinal changes in QoL with comorbidities and/or exacerbations during a prolonged observation period in patients with severe asthma. METHODS: A total of 105 subjects who participated in the Hokkaido-based Investigative Cohort Analysis for Refractory Asthma (Hi-CARAT) with a six-year follow-up were analyzed. QoL was assessed annually, using the Standardized Asthma Quality of Life Questionnaire, and the subjects were divided into three groups: (1) persistently good QoL, (2) persistently poor QoL, and (3) fluctuating QoL. Assessed comorbidities comprised depression, gastroesophageal reflux disease, and excessive daytime sleepiness (EDS), a key symptom of obstructive sleep apnea. RESULTS: Of 105 subjects with severe asthma, 53 (50%) were classified in the persistently good QoL group, 10 (10%) in the persistently poor QoL group, and 42 (40%) in the fluctuating QoL group. The persistently poor QoL group was associated with shorter time to hospitalization due to exacerbation and the presence of multiple comorbidities. In addition, the presence of EDS was an independent contributor to the fluctuating QoL group compared to the persistently good QoL group. CONCLUSIONS: The presence of multiple comorbidities and hospitalization due to exacerbation contribute to longitudinal changes in QoL in patients with severe asthma.

Multi-Institutional Prospective Cohort Study of Patients With Pulmonary Hypertension Associated With Respiratory Diseases.

BACKGROUND: There is limited evidence for pulmonary arterial hypertension (PAH)-targeted therapy in patients with pulmonary hypertension associated with respiratory disease (R-PH). Therefore, we conducted a multicenter prospective study of patients with R-PH to examine real-world characteristics of responders by evaluating demographics, treatment backgrounds, and prognosis.Methods and Results:Among the 281 patients with R-PH included in this study, there was a treatment-naïve cohort of 183 patients with normal pulmonary arterial wedge pressure and 1 of 4 major diseases (chronic obstructive pulmonary diseases, interstitial pneumonia [IP], IP with connective tissue disease, or combined pulmonary fibrosis with emphysema); 43% of patients had mild ventilatory impairment (MVI), whereas 52% had a severe form of PH. 68% received PAH-targeted therapies (mainly phosphodiesterase-5 inhibitors). Among patients with MVI, those treated initially (i.e., within 2 months of the first right heart catheterization) had better survival than patients not treated initially (3-year survival 70.6% vs. 34.2%; P=0.01); there was no significant difference in survival in the group with severe ventilatory impairment (49.6% vs. 32.1%; P=0.38). Responders to PAH-targeted therapy were more prevalent in the group with MVI. CONCLUSIONS: This first Japanese registry of R-PH showed that a high proportion of patients with MVI (PAH phenotype) had better survival if they received initial treatment with PAH-targeted therapies. Responders were predominant in the group with MVI.

One-year clinically important deterioration and long-term clinical course in Japanese patients with COPD: a multicenter observational cohort study.

BACKGROUND: Chronic obstructive pulmonary disease (COPD) is a heterogeneous disease with a complex progression of many clinical presentations, and clinically important deterioration (CID) has been proposed in the Western studies as a composite endpoint of disease progression. The aim of this study was to investigate the relationships between 1-year CID and the following long-term clinical outcomes in Japanese patients with COPD who have been reported to have different characteristics compared to the Westerners. METHODS: Among Japanese patients with COPD enrolled in the Hokkaido COPD cohort study, 259 patients who did not drop out within the first year were analyzed in this study. Two definitions of CID were used. Definition 1 comprised ≥ 100 mL decrease in forced expiratory volume in 1 s (FEV1), ≥ 4-unit increase in St George's Respiratory Questionnaire (SGRQ) score from baseline, or moderate or severe exacerbation. For Definition 2, the thresholds for the FEV1 and SGRQ score components were doubled. The presence of CID was evaluated within the first year from enrollment, and analyzed the association of the presence of CID with following 4-year risk of exacerbations and 9-year mortality. RESULTS: Patients with CID using Definition 1, but not any single CID component, during the first year had a significantly worse mortality compared with those without CID. Patients with CID using Definition 2 showed a similar trend on mortality, and had a shorter exacerbation-free survival compared with those without CID. CONCLUSIONS: Adoption of CID is a beneficial and useful way for the assessment of long-term disease progression and clinical outcomes even in Japanese population with COPD. The definition of CID might be optimized according to the characteristics of COPD population and the observation period for CID.

Determination of the cutoff values of Th2 markers for the prediction of future exacerbation in severe asthma: An analysis from the Hokkaido Severe Asthma Cohort Study.

BACKGROUND: We recently reported that severe asthma patients with frequent exacerbations showed high blood eosinophil counts (Eo) and fractions of exhaled nitric oxide (FeNO) compared with non-exacerbators. However, we did not determine exact cutoff values related to exacerbation. The aim of this study was to determine the cutoff values of Eo and FeNO that could be related to the exacerbation of severe asthma. We also aimed to confirm the clinical utility of Th2 markers related to exacerbation. METHODS: This study included 105 severe asthma patients who completed a three-year follow-up of a severe asthma cohort study, including smokers. Three Th2 markers were selected, viz., Eo, FeNO, and positive atopic status. Regarding Eo and FeNO, we determined the cutoff values for the definition of "positive" Th2 features using receiver operating characteristic curve analyses, based on the comparisons between frequent exacerbators and other patients. RESULTS: The cutoff values for positive Th2 features were Eo ≥ 250 cells/µL and FeNO ≥31 ppb. Sixteen patients (15.2%) had no Th2 features, 40 (38.1%) had one, 25 (23.8%) had two, and 24 (22.9%) had three. A high number of positive Th2 features was significantly associated with exacerbation frequencies over three years (p < 0.05). Similarly, compared to patients with one or no Th2 features, those with three Th2 features had a significantly higher probability of having more than one exacerbation (p < 0.05). CONCLUSIONS: The cutoff values determined in the current analysis were good predictors of future exacerbations in severe asthma patients.

Per cent low attenuation volume and fractal dimension of low attenuation clusters on CT predict different long-term outcomes in COPD.

BACKGROUND: Fractal dimension (D) characterises the size distribution of low attenuation clusters on CT and assesses the spatial heterogeneity of emphysema that per cent low attenuation volume (%LAV) cannot detect. This study tested the hypothesis that %LAV and D have different roles in predicting decline in FEV1, exacerbation and mortality in patients with COPD. METHODS: Chest inspiratory CT scans in the baseline and longitudinal follow-up records for FEV1, exacerbation and mortality prospectively collected over 10 years in the Hokkaido COPD Cohort Study were examined (n=96). The associations between CT measures and long-term outcomes were replicated in the Kyoto University cohort (n=130). RESULTS: In the Hokkaido COPD cohort, higher %LAV, but not D, was associated with a greater decline in FEV1 and 10-year mortality, whereas lower D, but not %LAV, was associated with shorter time to first exacerbation. Multivariable analysis for the Kyoto University cohort confirmed that lower D at baseline was independently associated with shorter time to first exacerbation and that higher LAV% was independently associated with increased mortality after adjusting for age, height, weight, FEV1 and smoking status. CONCLUSION: These well-established cohorts clarify the different prognostic roles of %LAV and D, whereby lower D is associated with a higher risk of exacerbation and higher %LAV is associated with a rapid decline in lung function and long-term mortality. Combination of %LAV and fractal D may identify COPD subgroups at high risk of a poor clinical outcome more sensitively.

Effects of Anaerobic Culturing on Pathogenicity and Virulence-Related Gene Expression in Pneumococcal Pneumonia.

BACKGROUND: The pathogenicity of Streptococcus pneumoniae under anaerobic conditions remains largely unknown. We examined the pathogenicity of S. pneumoniae cultured under anaerobic conditions in a murine model of pneumococcal pneumonia. METHODS: Mice were infected with S. pneumoniae grown under anaerobic or aerobic conditions. The pathogenic effects in vivo in the lower airway tract were then compared. The effect of anaerobic culture on lytA/ply transcript levels in vitro and in vivo were analyzed by quantitative real-time polymerase chain reaction. RESULTS: Mice inoculated with anaerobically cultured S. pneumoniae exhibited significantly lower survival rates and higher bacterial loads in the lungs and blood as compared to those infected with aerobically cultured S. pneumoniae. Aerobically cultured S. pneumoniae in the early log phase of growth was also able to induce severe pneumonia at levels equivalent to those of anaerobic S. pneumoniae. However, ply/gyrB transcript levels were significantly increased in the lungs of mice infected with anaerobically grown S. pneumoniae. In vitro, S. pneumoniae grown under anaerobic culture conditions demonstrated greater proliferation than S. pneumoniae grown under aerobic culture conditions, and bacterial concentrations were maintained for 24 hours without detectable upregulation of lytA messenger RNA. CONCLUSIONS: S. pneumoniae grown under anaerobic conditions had the potential to induce severe invasive bacteremic pneumococcal pneumonia in a manner different from that of S. pneumoniae grown under aerobic conditions.

Analysis of DLL3 and ASCL1 in Surgically Resected Small Cell Lung Cancer (HOT1702).

BACKGROUND: Delta-like protein 3 (DLL3) is a Notch ligand that has an important role in the tumorigenesis of small cell lung cancer (SCLC). Recently, rovalpituzumab tesirine (Rova-T), a DLL3-targeted antibody-drug conjugate, has been developed for treating SCLC. DLL3 is a transcriptional target of the achaete-scute homolog-1 (ASCL1) transcription factor, which is involved in pulmonary neuroendocrine cell development. However, the relationship between DLL3 and/or ASCL1 expression and the clinical features of SCLC remains unknown, especially for early-stage resected SCLC. This study aimed to investigate the expression of DLL3 and ASCL1 in resected SCLC samples using immunohistochemical analysis. MATERIALS AND METHODS: We collected 95 surgically resected SCLC samples, which were formalin fixed and paraffin embedded. Immunohistochemistry staining was performed to investigate the correlation between the expression of either DLL3 or ASCL1 and clinicopathological features of study patients. RESULTS: Seventy-seven (83%) of 93 immunohistochemically evaluable samples were positive for DLL3 (expression in ≥1% of tumor cells), and DLL3-high expression (≥75%) was observed in 44 samples (47%). Sixty-one (64%) of 95 samples were positive for ASCL1 (expression in ≥5% of tumor cells). A positive correlation was observed between DLL3 and ASCL1 expression. DLL3 and ASCL1 expression were not associated with survival in SCLC patients. DLL3 was more prevalent in patients with advanced clinical disease. CONCLUSION: DLL3 and ASCL1 were highly expressed in patients with surgically resected SCLC. DLL3 and ASCL1 may be targets for the treatment of SCLC. IMPLICATIONS FOR PRACTICE: This article examines the relationship between delta-like protein 3 (DLL3) and achaete-scute homolog-1 (ASCL1) protein expression with the clinical features of 95 surgically resected small cell lung cancer (SCLC). DLL3 is attracting attention because rovalpituzumab tesirine (Rova-T), a DLL3-targeted antibody-drug conjugate, was developed recently. DLL3 and ASCL1 were highly expressed in patients with surgically resected SCLC. DLL3 and ASCL1 may be targets for the treatment of early-stage SCLC, including with Rova-T.

A cis-eQTL allele regulating reduced expression of CHI3L1 is associated with late-onset adult asthma in Japanese cohorts.

BACKGROUND: The chitinase-like protein YKL-40 plays a major role in inhibiting the inflammasome. Deregulation of inflammasome activation is emerging as a key modulator of pathologic airway inflammation in patients with asthma. We determined whether cis-expression quantitative trait loci (eQTLs) of the gene that encodes YKL-40, chitinase 3-like 1 (CHI3L1), are involved in the onset of asthma or in specific asthma phenotypes. METHODS: This case-control study, which was conducted at the University of Tsukuba, Japan, included a total of 2709 adults from the Tsukuba genome-wide association study (GWAS) cohort (734 healthy volunteers and 237 asthma patients), the Tsukuba replication cohort (375 healthy adult volunteers and 381 adult asthma patients), and the Hokkaido replication cohort (554 healthy adult volunteers and 428 adult asthma patients). Among 34 cis-eQTLs in CHI3L1 in the lung, rs946261 was associated with adult asthma in these Japanese cohorts. The genetic impact of rs946261 on asthma was also examined according to the age at onset and adult asthma clusters. RESULTS: In the Tsukuba GWAS cohort, the C allele at rs946261 was significantly associated with reduced expression of CHI3L1 mRNA in the lung and with development of asthma (odds ratio (OR) 1.27; P = 0.036). The association was also observed following analysis of the three Japanese cohorts (OR 1.16; P = 0.013). A stronger association was found with late-onset asthma that developed at 41 years of age or later (OR 1.24; 95% confidence interval (CI) 1.07-1.45; P = 0.0058) and with a specific asthma phenotype characterized by late onset, less atopy, and mild airflow obstruction (OR 1.29; 95% CI 1.03-1.61; P = 0.027). CONCLUSIONS: The genotype consisting of the cis-eQTL allele that reduces expression of CHI3L1 was specifically associated with late-onset adult asthma. Given the important role of YKL-40 in many pathophysiological processes, including cell growth, migration, chemotaxis, reorganization, and tissue remodeling, it may be involved in an important pathogenic role in the establishment of inflammation and remodeling in asthmatic airways. Our findings may indicate the presence of a specific endotype related to exaggerated activation of YKL-40 in the pathogenesis of late-onset adult asthma.

An adult case of severe life-threatening Mycoplasma pneumoniae pneumonia due to a macrolide-resistant strain, Japan: a case report.

BACKGROUND: Until now, the prevalence of macrolide-resistant Mycoplasma pneumoniae (MP) infection among adult patients has been low, and severe MP pneumonia due to a macrolide-resistant strain has seldom been reported. Here, we describe a rare case of severe life-threatening MP pneumonia due to a macrolide-resistant strain in an adult, which was finally treated with fluoroquinolone and tetracycline after failed treatment with macrolide and corticosteroid. CASE PRESENTATION: A 39-year-old apparently healthy woman complained of fever and productive cough. Three days after onset, she was admitted to a local general hospital. On admission, her vital signs were stable except for high-grade fever. The patient's chest X-ray and chest computed tomography images revealed subsegmental consolidation in her right lower lobe. Treatment with ampicillin/sulbactam, and azithromycin were initiated under a clinical diagnosis of community-acquired pneumonia. After treatment initiation, her fever had not subsided, and the pulmonary lesion had extended to the entire lower lobe. Thus, treatment with prednisolone as steroid pulse therapy was initiated from clinical day 7. However, neither her symptoms nor her pulmonary lesion improved; therefore, she was transferred to our hospital for further examination and treatment. On admission (clinical day 14), her indirect hemagglutination titer for MP was elevated at 1:2560, and bronchoalveolar fluid examination yielded positive results for the mycoplasma antigen. Based on these clinical findings, we confirmed a case of severe life-threatening MP pneumonia. Since her respiratory condition was extremely severe, we initiated levofloxacin and tetracycline. Two days later (clinical day 16), her fever, malaise, and hypoxia resolved, and her pulmonary lesions had significantly improved. Further molecular identification yielded the DNA of MP from her bronchoalveolar fluid, and mutation of A2063G in the 23S rRNA gene was revealed. Based on these results and the clinical course, we confirmed our case as severe MP pneumonia due to a macrolide-resistant strain. CONCLUSION: More awareness is needed on the emergence of macrolide-resistant MP infection in adults, because severe infection could develop despite initial treatment with macrolide and steroid therapy, which are generally considered as standard therapy for MP.

Orchestrating Role of Apoptosis Inhibitor of Macrophage in the Resolution of Acute Lung Injury.

Appropriate resolution of inflammation is known to be essential in tissue homeostasis. In this study, we evaluated the significance of a macrophage-derived soluble protein, apoptosis inhibitor of macrophage (AIM), in LPS-induced lung injury in mice. After oropharyngeal administration of LPS, the level of free-form serum AIM increased on days 2-4, accompanied by the resolution of inflammation, which was observed in the cellular profile of bronchoalveolar lavage fluid. In an experiment using wild-type (WT) and AIM-/- mice, the resolution of inflammation was accelerated in AIM-/- mice when compared with the WT mice, which was reversed when recombinant AIM protein was administered. The changes in the histopathological findings and inflammatory mediators followed similar trends, and the ratio of apoptotic cells was increased in AIM-/- mice when compared with the WT mice. In vitro analysis showed that macrophage phagocytosis of apoptotic neutrophils was suppressed in the presence of AIM, indicating that anti-resolution property of AIM involves efferocytosis inhibition. In lipidomic analysis of lung tissues, the levels of several lipid mediators increased markedly when LPS was given to WT mice. However, in AIM-/- mice, the concentrations of these lipid mediators were not significantly upregulated by LPS. These data reflect the significant role of AIM in lipid metabolism; it may suppress lipid metabolites at baseline, and then produce an inflammatory/pathologic pattern in the event of LPS-induced lung injury. Taken together, AIM may play an orchestrating role in the resolution process of inflammation by altering the profile of pulmonary lipid mediators in mice.

[A Nutritional Supplement with a High Blend Ratio of ω-3 Fatty Acids(Prosure®) Reduces Severe Oral Mucositis and Body Weight Loss for Head and Neck Cancer Patients Treated with Chemoradiotherapy].

BACKGROUND: Oral mucositis and body weight loss are the most critical conditions known to lead to the discontinuation of chemoradiotherapy for head and neck cancer. We investigated the effect of a nutritional supplement with a high blend ratio of w-3 fatty acids(Prosure®)on body weight loss, oral mucositis, and the completion rate of chemoradiotherapy in patients with oropharyngeal and hypopharyngeal cancer. PATIENTS AND METHODS: The study group comprised patients with oropharyngeal and hypopharyngeal cancer who were treated with concomitant cisplatin and 70 Gy of radiotherapy. These patients received 2 packs of Prosure®per day during chemoradiotherapy. RESULTS: A total of 17 patients were included in this study. The reduction in body weight was significantly improved compared with that in the historical control group that did not receive Prosure®(7.3% vs 10.3%, p<0.01), and the rate of Grade 3-4 oral mucositis was significantly reduced for the patient groups that received Prosure®(CTCAE v3.0 GradeB3; 24% vs 58%, p<0.05). The completion rate of chemoradiotherapy was not significantly different between both groups(77% vs 60%, NS). CONCLUSIONS: A nutritional supplement with a high blend ratio of w-3 fatty acids(Prosure®)had effects on oral mucositis and body weight loss in head and neck cancer patients treated with chemoradiotherapy.