Serum Fibrinogen as a Biomarker for Disease Severity and Exacerbation in Patients with Non-Cystic Fibrosis Bronchiectasis.

Background: Serum biomarkers associated with severe non-cystic fibrosis (CF) bronchiectasis are currently lacking. We assessed the association of serum fibrinogen, adiponectin, and angiopoietin-2 levels with the severity and exacerbation of bronchiectasis. Methods: Serum levels of fibrinogen, adiponectin, and angiopoietin-2 were measured and compared in patients with stable non-CF bronchiectasis (n = 61) and healthy controls (n = 16). The correlations between the three biomarkers and the bronchiectasis severity index (BSI) or FACED scores were assessed. Univariate and multivariate linear regression analyses were performed to identify variables independently associated with BSI and FACED scores in patients with bronchiectasis. Additionally, the exacerbation-free survival was compared between groups of patients with high and low fibrinogen levels, while the predictors of exacerbation were analyzed using Cox proportional hazards regression. Results: Patients with non-CF bronchiectasis carried higher fibrinogen (3.00 ± 2.31 vs. 1.52 ± 0.74 µg/mL; p = 0.016) and adiponectin (12.3 ± 5.07 vs. 9.17 ± 5.30 µg/mL; p = 0.031) levels compared with healthy controls. The serum level of angiopoietin-2 was comparable between the two groups (1.49 ± 0.96 vs. 1.21 ± 0.79 ng/mL, p = 0.277). Correlations of adiponectin and angiopoietin-2 with BSI and FACED scores were not significant. However, there were significant correlations between fibrinogen and both BSI (r = 0.428) and FACED scores (r = 0.484). Multivariate linear regression analysis revealed that fibrinogen level was an independent variable associated with both BSI and FACED scores. A total of 31 (50.8%) out of 61 patients experienced exacerbation during the follow-up period of 25.4 months. Exacerbation-free survival was significantly longer in patients with low fibrinogen levels than in those with high fibrinogen (log-rank test, p = 0.034). High fibrinogen levels and Pseudomonas colonization were independent risk factors for future exacerbation (HR 2.308; p = 0.03 and HR 2.555; p = 0.02, respectively). Conclusions: Serum fibrinogen, but not adiponectin or angiopoietin-2, is a potential biomarker closely associated with the severity and exacerbation of non-CF bronchiectasis.

Impact of coexistent preserved ratio impaired spirometry on the survival of patients with lung cancer: Analysis of data from the Korean Association for Lung Cancer Registry.

BACKGROUND: Preserved ratio impaired spirometry (PRISm) is a common spirometric pattern that is associated with respiratory symptoms and higher mortality rates. However, the relationship between lung cancer and PRISm remains unclear. This study investigated the clinical characteristics of lung cancer patients with PRISm and the potential role of PRISm as a prognostic factor. METHODS: We retrospectively reviewed data collected from 2014 to 2015 in the Korean Association for Lung Cancer Registry. We classified all patients into three subgroups according to lung function as follows: normal lung function; PRISm (forced expiratory volume in 1 s [FEV1 ] < 80% predicted and FEV1 /forced vital capacity [FVC] ≥ 0.7); and chronic obstructive pulmonary disease (COPD; FEV1/FVC < 0.7). In non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC), the overall survival period was compared among the three subgroups. The prognostic factors were investigated using Cox regression analysis. RESULTS: Of the 3763 patients, 38.6%, 40.1%, and 21.3% had normal lung function, COPD, and PRISm, respectively. Patients with PRISm had poorer overall survival than those with COPD or normal lung function in NSCLC and SCLC (Mantel-Cox log-rank test, p < 0.05). In the risk-adjusted analysis, overall survival was independently associated with COPD (hazard ratio [HR] 1.209, p = 0.027) and PRISm (HR 1.628, p < 0.001) in NSCLC, but was only associated with PRISm (HR 1.629, p = 0.004) in SCLC. CONCLUSIONS: PRISm is a significant pattern of lung function in patients with lung cancer. At the time of lung cancer diagnosis, pre-existing PRISm should be considered a predictive factor of poor prognosis.

Serum hepatocyte growth factor as a predictor of disease severity and future exacerbations in patients with non-cystic fibrosis bronchiectasis.

BACKGROUND: Serum biomarkers associated with the severity of non-cystic fibrosis (CF) bronchiectasis are insufficient. This study determined the association of serum hepatocyte growth factor (HGF), osteopontin, and pentraxin-3 levels with disease severity and exacerbation in patients with non-CF bronchiectasis. METHODS: Serum levels of HGF, osteopontin, and pentraxin-3 were measured in patients with clinically stable non-CF bronchiectasis (n = 61). The correlation between the biomarkers and bronchiectasis severity index (BSI) and FACED score was assessed using univariate and multivariate linear regression analyses. Predictive variables associated with exacerbation were analyzed using a Cox proportional hazards model and the time to first exacerbation in high and low HGF groups during the observation period was compared using Kaplan-Meier survival curves. RESULTS: The BSI showed significant correlation with HGF (r = 0.423; p = 0.001) and pentraxin-3 (r = 0.316; p = 0.013). The FACED score was significantly correlated with HGF (r = 0.406; p = 0.001). Univariate and multivariate linear regression analysis revealed that serum level of HGF was independently associated with both scoring systems. The high HGF group showed a significantly shorter time to first exacerbation (Log-rank test, p = 0.014). Multivariate Cox proportional hazards regression analysis revealed that high serum HGF level and colonization with non-pseudomonas organisms were independent predictors of future exacerbations (HR 2.364; p = 0.024 and HR 2.438; p = 0.020, respectively). CONCLUSION: Serum level of HGF is a potential biomarker that is closely associated with disease severity and future risk of exacerbations in patients with non-CF bronchiectasis.

Serum albumin is a predictor of respiratory hospitalization in patients with bronchiectasis.

We evaluated serum albumin as an index for predicting respiratory hospitalization in patients with bronchiectasis. We retrospectively reviewed the medical records of 177 patients with bronchiectasis, categorized them into low and normal albumin groups, and compared their clinical characteristics. The prediction of respiratory hospitalization by factors such as serum albumin level, bronchiectasis severity index (BSI), and FACED score (an acronym derived from five variables of forced expiratory volume in 1 s; FEV1, age, chronic colonization of Pseudomonas aeruginosa, extent of bronchiectasis, and dyspnea) was assessed. There were 15 and 162 patients categorized in the low and normal albumin groups, respectively. The low albumin group had lower body mass index and forced expiratory volume in 1 s, and higher age, frequency of previous respiratory hospitalization, percentage of Pseudomonas colonization, number of affected lobes, BSI and FACED scores, and C-reactive protein (CRP) level, than the normal albumin group. The areas under the receiver operating characteristic curve of serum albumin level and BSI and FACED scores for predicting respiratory hospitalization were 0.732 (95% confidence interval (CI), 0.647-0.816), 0.873 (95% CI, 0.817-0.928), and 0.708 (95% CI, 0.618-0.799), respectively. Albumin level, CRP, modified Medical Research Council score, and chronic Pseudomonas aeruginosa (and other organisms) colonization were independent risk factors for respiratory hospitalization. Low serum albumin level was associated with worse clinical condition, higher severity scores, and respiratory hospitalization in patients with bronchiectasis.

Chronic cough is associated with depressive mood in women regardless of smoking status and lung function.

BACKGROUND: Chronic cough is a common respiratory symptom, and, if persistent, the patient's quality of life can worsen and result in a depressive mood, or vice versa. Although previous reports suggest a relationship between chronic cough and depression, we further investigated this relationship according to smoking status and lung function. METHODS: This observational study used cross-sectional data from the 6th Korean National Health and Nutrition Examination Survey (2014 and 2016). Propensity score matching using age, sex, smoking status, and lung function was performed for participants with and without chronic cough to reduce the confounding effects associated with depressive mood. Questionnaires recorded coughs persisting for >3 months and the Patient Health Questionnaire-9 (PHQ-9) assessed the severity of depressive mood. RESULTS: Among 12 494 participants who were >18 years old, 226 with chronic cough were matched with 226 with non-chronic cough. Overall, chronic cough participants showed higher PHQ-9 scores than the non-chronic cough participants (4.29 ± 5.23 vs. 2.63 ± 3.38, P < .001). When stratified by sex, the difference remained significant in women (5.69 ± 5.96 vs. 3.05 ± 3.97, P < .001) but not in men (3.18 ± 4.27 vs. 2.31 ± 3.65, P = .092). When stratified by lung function status, the difference remained significant for those with normal lung function (4.32 ± 5.32 vs. 2.78 ± 3.86, P = .003) and reduced lung function (4.19 ± 4.93 vs. 2.11 ± 3.55, P ≤ 0.001). Multivariate logistic regression analysis revealed that chronic cough was associated with PHQ-9 score (odds ratio [OR], 1.06; 95% confidence interval [CI], 1.014-1.27, P = .014), chronic obstructive pulmonary disease (OR, 4.87; 95% CI, 1.041-22.86, P = .044) and physician-diagnosed bronchial asthma (OR, 2.93; 95% CI, 1.162-7.435, P = .023). CONCLUSIONS: Depressive mood is significantly correlated with chronic cough in females.

A Nationwide Study of Severe Cutaneous Adverse Reactions Based on the Multicenter Registry in Korea.

BACKGROUND: Because severe cutaneous adverse reactions (SCARs), such as Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), and drug reaction with eosinophilia and systemic symptoms (DRESS) rarely occur, clinical data based on large-scale studies are still lacking. OBJECTIVE: To provide information on culprit drugs and clinical characteristics, including morbidity and mortality of SCARs based on a nationwide registry. METHODS: SCAR cases that occurred from 2010 to 2015 were recruited to the Korean SCAR registry from 34 tertiary referral hospitals. Demographics, causative drugs, causality, and clinical outcomes were collected by reviewing the medical record. RESULTS: A total of 745 SCAR cases (384 SJS/TEN cases and 361 DRESS cases) due to 149 drugs were registered. The main causative drugs were allopurinol (14.0%), carbamazepine (9.5%), vancomycin (4.7%), and antituberculous agents (6.3%). A strong preference for SJS/TEN was observed in carbonic anhydrase inhibitors (100%), nonsteroidal anti-inflammatory drugs (84%), and acetaminophen (83%), whereas dapsone (100%), antituberculous agents (81%), and glycopeptide antibacterials (78%) were more likely to cause DRESS. The mortality rate was 6.6% (SJS/TEN 8.9% and DRESS 4.2%). The median time to death was 19 days and 29 days in SJS/TEN and DRESS respectively, and 89.8% of deaths occurred within 60 days after the onset of the skin symptoms. CONCLUSION: Allopurinol, carbamazepine, vancomycin, and antituberculous agents were the leading causes of SCARs in Korea. Some drugs preferentially caused a specific phenotype. The mortality rate of SCARs was 6.6%, and most of the deaths occurred within 2 months.

Risk Factor and Mortality in Patients with Pulmonary Embolism Combined with Infectious Disease.

BACKGROUND: Infectious conditions may increase the risk of venous thromboembolism. The purpose of this study was to evaluate the risk factor for combined infectious disease and its influence on mortality in patients with pulmonary embolism (PE). METHODS: Patients with PE diagnosed based on spiral computed tomography findings of the chest were retrospectively analyzed. They were classified into two groups: patients who developed PE in the setting of infectious disease or those with PE without infection based on review of their medical charts. RESULTS: Of 258 patients with PE, 67 (25.9%) were considered as having PE combined with infectious disease. The sites of infections were the respiratory tract in 52 patients (77.6%), genitourinary tract in three patients (4.5%), and hepatobiliary tract in three patients (4.5%). Underlying lung disease (odds ratio [OR], 3.69; 95% confidence interval [CI], 1.926-7.081; p<0.001), bed-ridden state (OR, 2.84; 95% CI, 1.390-5.811; p=0.004), and malignant disease (OR, 1.867; 95% CI, 1.017-3.425; p=0.044) were associated with combined infectious disease in patients with PE. In-hospital mortality was higher in patients with PE combined with infectious disease than in those with PE without infection (24.6% vs. 11.0%, p=0.006). In the multivariate analysis, combined infectious disease (OR, 4.189; 95% CI, 1.692-10.372; p=0.002) were associated with non-survivors in patients with PE. CONCLUSION: A substantial portion of patients with PE has concomitant infectious disease and it may contribute a mortality in patients with PE.

Unique Clinical Characteristics and Prognosis of Allopurinol-Induced Severe Cutaneous Adverse Reactions.

BACKGROUND: Allopurinol is the most common cause of severe cutaneous adverse reactions (SCARs) in Korea due to the relatively high prevalence of the HLA-B*58:01 genotype (8%-13%). OBJECTIVE: We aimed to reveal the clinical characteristics and risk factors for death in allopurinol-induced SCARs in Korea. METHODS: We retrospectively reviewed the medical records of 106 subjects with allopurinol-induced SCARs and 639 subjects with other drug-induced SCARs who were enrolled in the Korean SCARs Registry (collected from 34 nationwide medical institutions) from January 2010 to December 2015. RESULTS: Subjects with allopurinol-induced Stevens-Johnson syndrome (SJS)/toxic epidermal necrolysis (TEN) were older and had more comorbidities, longer latent periods, longer disease durations, more deranged laboratory findings, and increased disease severity resulting in a higher mortality rate (17.6% vs 7.6%; P = .020) compared with the subjects with other drug-induced SCARs. There was no significant difference in age or mortality in drug reaction with eosinophilia and systemic symptoms (DRESS). Subjects with allopurinol-induced SJS/TEN were older and had shorter latent periods and a higher mortality rate (17.6% vs 3.7%; P = .044) than those with allopurinol-induced DRESS. In allopurinol-induced SJS/TEN, significant risk factors for death included chronic renal insufficiency, intensive care unit (ICU) admission, increased blood urea nitrogen levels on admission day, serum peak eosinophil counts, baseline and peak creatinine levels, baseline and peak alanine aminotransferase levels, and decreased lowest platelet counts. In allopurinol-induced DRESS, significant risk factors for death included ICU admission and increased glucose levels on admission day. CONCLUSIONS: Allopurinol-induced SCARs have unique characteristics and poor prognoses with important predictive factors of death.

Efficacy of the HLA-B∗58:01 Screening Test in Preventing Allopurinol-Induced Severe Cutaneous Adverse Reactions in Patients with Chronic Renal Insufficiency-A Prospective Study.

BACKGROUND: Thus far, human leukocyte antigen (HLA)-B∗58:01 has been recognized as the most important risk factor for allopurinol induced severe cutaneous adverse reactions (SCARs). OBJECTIVE: To determine the usefulness of prospective screening for the HLA-B∗58:01 allele to identify Korean individuals at risk for SCARs induced by allopurinol treatment. METHODS: We prospectively enrolled 542 patients with chronic renal insufficiency (CRI) from 10 hospitals nationwide and performed DNA genotyping to determine whether they carried the HLA-B∗58:01 allele. Of these, 503 HLA-B∗58:01-negative patients (92.8% of total) were treated with allopurinol, and 39 HLA-B∗58:01-positive patients (7.2%) were treated with febuxostat, an alternative drug. The patients then were followed up biweekly for 90 days using a telephone survey to monitor symptoms of adverse drug reactions, including SCARs. As a control, we used the historical incidence rate of allopurinol-induced SCARs in 4002 patients with CRI from the same hospitals who were enrolled retrospectively. RESULTS: Nineteen patients in the prospective cohort developed mild and transient adverse reactions but none showed allopurinol-induced SCARs. By contrast, we identified 38 patients with allopurinol-induced SCARs (0.95%) in the historical control. The difference in the incidence of allopurinol-induced SCARs between the prospective cohort and historical control was statistically significant (0% vs 0.95%, respectively; P = .029). CONCLUSIONS: The present study demonstrated the clinical usefulness of the HLA-B∗58:01 screening test before allopurinol administration to prevent allopurinol-induced SCARs in patients with CRI.

Quantitative severity of pulmonary emphysema as a prognostic factor for recurrence in patients with surgically resected non-small cell lung cancer.

BACKGROUND: Pulmonary emphysema is a major component of chronic obstructive pulmonary disease and lung cancer. However the prognostic significance of quantitative emphysema severity in patients with lung cancer is unclear. We analyzed whether numerical emphysema value is a prognostic factor for recurrence in patients with surgically resected non-small cell lung cancer. METHODS: We quantified emphysema severity of the whole lung and regional lobes in 45 patients (mean age 68.0 years) using an automated chest computed tomography-based program. Predictive factors for recurrence were investigated using a Cox proportional hazards model. Recurrence-free and overall survival was compared after dichotomization of patients according to whole lung emphysema severity. RESULTS: The mean percentage emphysema ratio of the whole lung was 1.21 ± 2.04. Regional lobar emphysema severity was highest in the right middle lobe (1.93 ± 0.36), followed by right upper (1.35 ± 2.50), left upper (1.34 ± 2.12), left lower (1.05 ± 2.52), and right lower (0.78 ± 2.28) lobes. The low severity group showed significantly longer overall survival compared to the high severity group (log-rank test, P = 0.018). Quantitative emphysema severity of the whole lung (hazard ratio 1.36; 95% confidence interval 1.0-1.73) and stage III (hazard ratio 6.17; 95% confidence interval 1.52-25.0) were independent predictors of recurrence after adjusting for age, gender, smoking status, and forced expiratory volume in one second. CONCLUSION: The severity of whole lung emphysema was independently associated with recurrence. Patients with non-small cell lung cancer and marginal pulmonary emphysema at lower severity survive longer after curative-intent surgery.

Impact of coexistent chronic obstructive pulmonary disease on the survival of patients with small cell lung cancer receiving chemotherapy.

BACKGROUND: While there is growing interest in the correlation between chronic obstructive pulmonary disease (COPD) and non-small cell lung cancer, very few studies have examined the interaction between COPD and small cell lung cancer (SCLC). Therefore, the aim of this study was to examine the impact of COPD on the survival of patients with SCLC. METHODS: The medical records of 110 patients with SCLC who received chemotherapy from July 2006 until April 2014 were retrospectively examined. The overall survival (OS) and progression-free survival (PFS) rates of spirometry-diagnosed COPD and non-COPD groups were compared. Predictors for poorer survival were analyzed using Cox proportional hazards regression. RESULTS: Of the 110 SCLC patients, 57 (51.8%) had coexistent COPD. The median OS for the COPD group was 11.6 months and for the non-COPD group was 11.2 months (log-rank test, P = 0.581), whereas the median PFS rates were 6.65 and 6.57 months, respectively (log-rank test, P = 0.559). Multivariate analysis identified Eastern Cooperative Oncology Group performance status ≥ 2 and extensive-stage SCLC as independent risk factors for shorter OS; however, coexisting COPD was not a predictor of survival. CONCLUSIONS: Although over half of the SCLC patients receiving chemotherapy had COPD, coexisting COPD had no impact on the survival of patients with SCLC.

Activation of p70S6 Kinase-1 in Mesenchymal Stem Cells Is Essential to Lung Tissue Repair.

All-trans retinoic acid (ATRA) or mesenchymal stem cells (MSCs) have been shown to promote lung tissue regeneration in animal models of emphysema. However, the reparative effects of the combination of the two and the role of p70S6 kinase-1 (p70S6k1) activation in the repair process have not been defined. Twenty-one days after intratracheal instillation of porcine pancreatic elastase (PPE), MSC and/or 10 days of ATRA treatment was initiated. Thirty-two days later, static lung compliance (Cst), mean linear intercepts (MLIs), and alveolar surface area (S) were measured. After PPE, mice demonstrated increased values of Cst and MLI, and decreased S values. Both ATRA and MSC transfer were individually effective in improving these outcomes while the combination of ATRA and MSCs was even more effective. The combination of p70S6k1-/- MSCs transfer followed by ATRA demonstrated only modest effects, and rapamycin treatment of recipients with wild-type (WT) MSCs and ATRA failed to show any effect. However, transfer of p70S6k1 over-expressing-MSCs together with ATRA resulted in further improvements over those seen following WT MSCs together with ATRA. ATRA activated p70S6k1 in MSCs in vitro, which was completely inhibited by rapamycin. Tracking of transferred MSCs following ATRA revealed enhanced accumulation and extended survival of MSCs in recipient lungs following PPE but not vehicle instillation. These data suggest that in MSCs, p70S6k1 activation plays a critical role in ATRA-enhanced lung tissue repair, mediated in part by prolonged survival of transferred MSCs. p70S6k1-activated MSCs may represent a novel therapeutic approach to reverse the lung damage seen in emphysema. Stem Cells Translational Medicine 2018;7:551-558.

Clinical importance of cross-sectional area of intercostal muscles in patients with chronic obstructive pulmonary disease.

INTRODUCTION: Limb muscle wasting is one of main systemic manifestation of chronic obstructive pulmonary disease (COPD). However, the change of respiratory muscle is unclear. OBJECTIVES: This study assessed the cross-sectional area (CSA) of the intercostal muscles (ICMs) in patients with COPD, using chest computed tomography (CT) and determined its association with the clinical characteristics of COPD. METHODS: They retrospectively reviewed 60 patients with stable COPD and compared them with 30 controls. CSA (mm2 ) of the ICM on chest CT was measured at the midline level of the lateral arch of the bilateral first rib with a 3-mm slice thickness by using CT histogram software. The association with the clinical characteristics of COPD and with the control groups was assessed. RESULTS: CSA of the ICM and the CSA/body mass index (BMI) were lower in the COPD group than in the control group. Patients with Global Initiative for Chronic Obstructive Lung Disease (GOLD) stage 4 had a significantly lower CSA of the ICM than patients with stage 1, 2, and 3. CSA of the ICM was positively associated with FEV1 , %FEV1 predicted, FEV1 /FVC ratio, and BMI and negatively associated with age. However, there were no associations with PaO2 , PaCO2 , smoking status, 6-minute walk test, frequency of acute exacerbation of COPD, and serum C-reactive protein level. CONCLUSION: Intercostal muscle atrophy occurs in COPD patients and is associated with severity of airway obstruction, BMI, and increasing age.

Serum Albumin and Disease Severity of Non-Cystic Fibrosis Bronchiectasis.

BACKGROUND: A clinical classification system has been developed to define the severity and predict the prognosis of subjects with non-cystic fibrosis (CF) bronchiectasis. We aimed to identify laboratory parameters that are correlated with the bronchiectasis severity index (BSI) and FACED score. METHODS: The medical records of 107 subjects with non-CF bronchiectasis for whom BSI and FACED scores could be calculated were retrospectively reviewed. The correlations between the laboratory parameters and BSI or FACED score were assessed, and multiple-linear regression analysis was performed to identify variables independently associated with BSI and FACED score. An additional subgroup analysis was performed according to sex. RESULTS: Among all of the enrolled subjects, 49 (45.8%) were male and 58 (54.2%) were female. The mean BSI and FACED scores were 9.43 ± 3.81 and 1.92 ± 1.59, respectively. The serum albumin level (r = -0.49), bilirubin level (r = -0.31), C-reactive protein level (r = 0.22), hemoglobin level (r = -0.2), and platelet/lymphocyte ratio (r = 0.31) were significantly correlated with BSI. Meanwhile, serum albumin (r = -0.37) and bilirubin level (r = -0.25) showed a significant correlation with the FACED score. Multiple-linear regression analysis showed that the serum bilirubin level was independently associated with BSI, and the serum albumin level was independently associated with both scoring systems. Subgroup analysis revealed that the level of uric acid was also a significant variable independently associated with the BSI in male bronchiectasis subjects. CONCLUSIONS: Several laboratory variables were identified as possible prognostic factors for non-CF bronchiectasis. Among them, the serum albumin level exhibited the strongest correlation and was identified as an independent variable associated with the BSI and FACED scores.

Comparing the clinical outcomes in stereotactic body radiotherapy for lung tumors between Ray-Tracing and Monte-Carlo algorithms.

PURPOSE: The purpose of this study was to compare the clinical outcomes between the groups using Ray-Tracing (RAT) and Monte-Carlo (MC) calculation algorithms for stereotactic body radiotherapy (SBRT) of lung tumors. MATERIALS AND METHODS: Thirty-five patients received SBRT with CyberKnife for 47 primary or metastatic lung tumors. RAT was used for 22 targets in 12 patients, and MC for 25 targets in 23 patients. Total dose of 48 to 60 Gy was prescribed in 3 to 5 fractions on median 80% isodose line. The response rate, local control rate, and toxicities were compared between RAT and MC groups. RESULTS: The response rate was lower in the RAT group (77.3%) compared to the MC group (100%) (p = 0.008). The response rates showed an association with the mean dose to the gross tumor volume, which the doses were re-calculated with MC algorithm in both groups. However, the local control rate and toxicities did not differ between the groups. CONCLUSIONS: The clinical outcome and toxicity of lung SBRT between the RAT and MC groups were similar except for the response rate when the same apparent doses were prescribed. The lower response rate in the RAT group, however, did not compromise the local control rates. As such, reducing the prescription dose for MC algorithm may be performed but done with caution.

Clarithromycin Attenuates Radiation-Induced Lung Injury in Mice.

Radiation-induced lung injury (RILI) is a common and unavoidable complication of thoracic radiotherapy. The current study was conducted to evaluate the ability of clarithromycin (CLA) to prevent radiation-induced pneumonitis, oxidative stress, and lung fibrosis in an animal model. C57BL/6J mice were assigned to control, irradiation only, irradiation plus CLA, and CLA only groups. Test mice received single thoracic exposures to radiation and/or oral CLA (100 mg/kg/day). Histopathologic findings and markers of inflammation, fibrosis, and oxidative stress were compared by group. On a microscopic level, CLA inhibited macrophage influx, alveolar fibrosis, parenchymal collapse, consolidation, and epithelial cell changes. The concentration of collagen in lung tissue was lower in irradiation plus CLA mice. Radiation-induced expression of tumor necrosis factor (TNF)-α, TNF receptor 1, acetylated nuclear factor kappa B, cyclooxygenase 2, vascular cell adhesion molecule 1, and matrix metallopeptidase 9 were also attenuated by CLA. Expression levels of nuclear factor erythroid 2-related factor 2 and heme oxygenase 1, transforming growth factor-ß1, connective tissue growth factor, and type I collagen in radiation-treated lungs were also attenuated by CLA. These findings indicate that CLA ameliorates the deleterious effects of thoracic irradiation in mice by reducing pulmonary inflammation, oxidative damage, and fibrosis.

Prognostic significance of the absolute monocyte counts in lung cancer patients with venous thromboembolism.

We investigated the clinical significance of the absolute monocyte count (AMC) as a predictor of the response to anticoagulation and survival in lung cancer patients with venous thromboembolism (VTE). We retrospectively reviewed 1707 patients with pathologically proven lung cancer who visited the hospital between July 2008 and May 2014. Among them, the clinical data of patients newly diagnosed with VTE and treated with anticoagulation were compared between the low and high AMC groups according to the median value of AMC (640/µL) at the time of VTE diagnosis. The incidence of VTE was 7.9 % during the study period. Most of the patients had non-small-cell lung cancer (82.1 %), stage IV (64.2 %), and pulmonary thromboembolism (76.1 %) and were incidentally diagnosed with VTE (76.9 %). The patients' characteristics and laboratory values were not significantly different between the low and high AMC groups. Among patients available for evaluation of the response to anticoagulation, the high AMC group was significantly more refractory to anticoagulation than the low AMC group (no response to anticoagulation, 21.7 vs. 6.8 %, respectively; p = 0.044). Additionally, the high AMC group showed worse overall survival (OS) than the low AMC group (median, 9.6 vs. 5.9 months; p = 0.038). On multivariate analysis, high AMC, low albumin, and advanced stage were independent poor prognostic factors for OS. High AMC is associated with refractoriness to anticoagulation and poor prognosis in lung cancer patients with VTE.

High-level expression of Hsp90ß is associated with poor survival in resectable non-small-cell lung cancer patients.

AIMS: The aim of this study was to investigate the expression of Hsp90ß and GRP94, and elucidate the clinical significance of their expression, in patients with resectable non-small-cell lung cancer (NSCLC). METHODS AND RESULTS: Surgical tissue specimens were obtained from 208 patients with NSCLC who underwent surgical resection. The expression levels of Hsp90ß and GRP94 were assessed with tissue microarrays and immunohistochemistry. No correlations were observed between Hsp90ß or GRP94 expression and several clinicopathological factors. The high-Hsp90ß group [median overall survival (OS) 20.4 months; 95% confidence interval (CI) 0.000-40.864] showed a significant decrease in OS as compared with the low-Hsp90ß group (median OS not reached; P = 0.003). In contrast to the Hsp90ß analysis, the GRP94 analysis did not show a difference in OS. Moreover, in subgroup analyses of patients with squamous cell carcinoma histology, OS (P = 0.012) and relapse-free survival (P = 0.044) were significantly worse in the high-Hsp90ß group than in the low-Hsp90ß group. Multivariate analysis suggested that old age [hazard ratio (HR) 1.568; 95% CI 1.019-2.412; P = 0.041], advanced disease (HR 2.066; 95% CI 1.218-3.502; P = 0.007) and high Hsp90ß expression (HR 1.802; 95% CI 1.061-3.060; P = 0.029) were independent poor prognostic factors for OS. CONCLUSIONS: Hsp90ß expression might be a useful marker of poor OS, although further large prospective studies are warranted to validate our findings.

Aged red garlic extract suppresses nitric oxide production in lipopolysaccharide-treated RAW 264.7 macrophages through inhibition of NF-κB.

Lipopolysaccharides (LPS) activate nuclear factor kappa B (NF-κB), a transcription factor that is involved in inflammatory response. The pathways that activate NF-κB can be modulated by phytochemicals derived from garlic. We recently demonstrated that aged red garlic extract (ARGE), a new formulation of garlic, decreases nitric oxide (NO) generation by upregulating of heme oxygenase-1 (HO-1) in RAW 264.7 cells activated by LPS. However, the effects of ARGE on LPS-induced NF-κB activation are unknown. This study was performed to evaluate whether ARGE regulates LPS-induced NO production by modulation of NF-κB activation in macrophages. The inhibition of NF-κB by Bay 11-7085, an inhibitor of NF-κB, decreased LPS-induced NO production. ARGE treatment markedly reduced LPS-induced NO production and NF-κB nuclear translocation. ARGE downregulated expression of inducible nitric oxide synthase (iNOS) and upregulated expression of HO-1, a cytoprotective and anti-inflammatory protein. However, Bay 11-7085 only reduced iNOS expression. The NO production and iNOS expressions upregulated by suppression of HO-1 were suppressed by treatment with ARGE and Bay 11-7085. These results show that ARGE reduces LPS-induced NO production in macrophages through inhibition of NF-κB nuclear translocation and HO-1 activation. Compared to Bay 11-7085, ARGE may enhance anti-inflammatory effects by controlling other anti-inflammatory signals as well as regulation of NF-κB.