GSPE Protects against Bleomycin-Induced Pulmonary Fibrosis in Mice via Ameliorating Epithelial Apoptosis through Inhibition of Oxidative Stress.

Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive interstitial lung disease of unknown cause which leads to alveolar epithelial cell apoptosis followed by basement membrane disruption and accumulation of extracellular matrix, destroying the lung architecture. Oxidative stress is involved in the development of alveolar injury, inflammation, and fibrosis. Oxidative stress-mediated alveolar epithelial cell (AEC) apoptosis is suggested to be a key process in the pathogenesis of IPF. Therefore, the present study investigated whether grape seed proanthocyanidin extract (GSPE) could inhibit the development of pulmonary fibrosis via ameliorating epithelial apoptosis through the inhibition of oxidative stress. We found that GSPE significantly ameliorated the histological changes and the level of collagen deposition in bleomycin (BLM)-induced lungs. Moreover, GSPE attenuated lung inflammation by reducing the total number of cells in bronchoalveolar lavage (BAL) fluid and decreasing the expression of IL-6. We observed that the levels of H2O2 leading to oxidative stress were increased following BLM instillation, which significantly decreased with GSPE treatment both in vivo and in vitro. These findings showed that GSPE attenuated BLM-induced epithelial apoptosis in the mouse lung and A549 alveolar epithelial cell through the inhibition of oxidative stress. Furthermore, GSPE could attenuate mitochondrial-associated cell apoptosis via decreasing the Bax/Bcl-2 ratio. The present study demonstrates that GSPE could ameliorate bleomycin-induced pulmonary fibrosis in mice via inhibition of epithelial apoptosis through the inhibition of oxidative stress.

Histiocytic pleural effusion: the strong clue to malignancy.

BACKGROUND: There have been many studies on the clinical characteristics of neutrophilic, lymphocytic, and/or eosinophilic pleural effusion. While caring for patients with pleural effusion, we found that histiocytic pleural effusion (HisPE) was not uncommon. However, few studies have explored HisPE. The purpose of the present study was to determine the clinical characteristics and etiologies of HisPE. METHODS: In this retrospective study, HisPE was defined as pleural fluid white blood cells comprised of ≥ 50% histiocytes. Using a clinical data warehouse, patients with HisPE among all patients aged >18 years who underwent thoracentesis and pleural fluid analysis between January 2010 and December 2019 at Ulsan University Hospital were enrolled. A total of 295 (9.0%) of 3279 patients who underwent thoracentesis were identified as HisPE patients. Among them, 201 with exudative HisPE were included. Clinical characteristics and etiologies were extracted from medical records and analyzed. RESULTS: Among the 201 patients with exudative HisPE, the major causes were malignant pleural effusion (n = 102 [50.7%]), parapneumonic effusion (n = 9 [4.5%]), and tuberculous pleurisy (n = 9 [4.5%]). In the 102 patients with malignant pleural effusion, the main types of cancer were lung (n = 42 [41.2%]), breast (n = 16 [15.7%]), and stomach cancer (n = 11 [10.8%]). Among lung cancers, adenocarcinoma (n = 34 [81.0%]) was the most common histology. CONCLUSIONS: The leading cause of exudative HisPE was malignancy, particularly lung cancer. Physicians should consider the possibility of malignant disease if histiocytes are predominantly present in pleural effusion.

The association between hospital length of stay before rapid response system activation and clinical outcomes: a retrospective multicenter cohort study.

BACKGROUND: Rapid response system (RRS) is being increasingly adopted to improve patient safety in hospitals worldwide. However, predictors of survival outcome after RRS activation because of unexpected clinical deterioration are not well defined. We investigated whether hospital length of stay (LOS) before RRS activation can predict the clinical outcomes. METHODS: Using a nationwide multicenter RRS database, we identified patients for whom RRS was activated during hospitalization at 9 tertiary referral hospitals in South Korea between January 1, 2016, and December 31, 2017. All information on patient characteristics, RRS activation, and clinical outcomes were retrospectively collected by reviewing patient medical records at each center. Patients were categorized into two groups according to their hospital LOS before RRS activation: early deterioration (LOS < 5 days) and late deterioration (LOS ≥ 5 days). The primary outcome was 28-day mortality and multivariable logistic regression was used to compare the two groups. In addition, propensity score-matched analysis was used to minimize the effects of confounding factors. RESULTS: Among 11,612 patients, 5779 and 5883 patients belonged to the early and late deterioration groups, respectively. Patients in the late deterioration group were more likely to have malignant disease and to be more severely ill at the time of RRS activation. After adjusting for confounding factors, the late deterioration group had higher 28-day mortality (aOR 1.60, 95% CI 1.44-1.77). Other clinical outcomes (in-hospital mortality and hospital LOS after RRS activation) were worse in the late deterioration group as well, and similar results were found in the propensity score-matched analysis (aOR for 28-day mortality 1.66, 95% CI 1.45-1.91). CONCLUSIONS: Patients who stayed longer in the hospital before RRS activation had worse clinical outcomes. During the RRS team review of patients, hospital LOS before RRS activation should be considered as a predictor of future outcome.

Active tuberculosis risk associated with malignancies: an 18-year retrospective cohort study in Korea.

BACKGROUND: Active tuberculosis (TB) develops in approximately 10% of people with a latent tuberculosis infection (LTBI). TB guidelines recommend that LTBI screening and treatments target high-risk patients. Malignancies are not universally considered a high-risk factor for active TB. This study aimed to determine the degrees to which active TB risk was associated with various cancers in a Korean population. METHODS: This study involved patients aged ≥20 years who were diagnosed with cancer at Ulsan University Hospital (UUH) from January 2000 to December 2014 and individuals who visited UUH for health screening and were age- and sex-matched randomly with cases in a 1:2 ratio. Using retrospective cohort study, the development of bacteriologically confirmed TB (BCTB) within 3 years after enrollment was investigated. The relative risks of BCTB were estimated using incidence rate ratios (IRRs) and a Poisson regression analysis. RESULTS: During the study period, 380 of 34,783 cancer patients and 79 of 69,566 control subjects developed BCTB, yielding respective incidence rates of 535 and 37/100,000 person-years, respectively. In all cancer cases, the IRR of BCTB was 14.30, and especially high rates were associated with the following cancers: esophageal cancer (74.72), multiple myeloma (70.76), lung cancer (50.35), pancreatic cancer (46.04), leukemia (40.45), head and neck cancer (24.60), and lymphoma (22.67). CONCLUSIONS: The incidence of active TB was higher in cancer patients than in control subjects. In particular, lung cancer, esophageal cancer, pancreatic cancer, hematologic malignancy and head and neck cancer were identified as high-risk factors for active TB, as indicated by IRRs of 20-75. These findings suggest that patients with high-risk cancers should be targeted for LTBI screening and treatment.

Diagnosing peripheral lung lesions using endobronchial ultrasonography with guide sheath: A prospective registry study to assess the effect of virtual bronchoscopic navigation using a computed tomography workstation.

Bronchoscopy has a lower diagnostic yield for peripheral lung lesions (PLL). Endobronchial ultrasound guide sheath transbronchial lung biopsy (EBUS GS TBLB) has been used to overcome such limitation. Recent studies revealed that combined methods (e.g., EBUS GS TBLB plus electromagnetic navigation [EMN] or virtual bronchoscopic navigation [VBN]) further improve the diagnostic yield. However, those systems are associated with a high cost burden. Accordingly, we attempted to use VBN by computed tomography (CT) workstation (Aquarius iNtuition, TeraRecon) not dedicated only for VBN as an adjunctive tool for EBUS GS TBLB. We performed a prospective registry study to investigate whether VBN by CT workstation could improve the diagnostic yield of PLL.Between February 2017 and February 2018, 128 patients with PLL were divided into 2 groups (VBN and non-VBN [NVBN]). In NVBN group (n = 64), EBUS GS TBLB was performed using a hand-drawn bronchial map based on CT images. VBN group (n = 64) underwent EBUS GS TBLB using VBN images.VBN using CT workstation did not improve the diagnostic yield of EBUS GS TBLB for PLL (VBN vs NVBN, 72% vs 80%, P = .284). VBN slightly reduced procedure time (minute [mean ±â€ŠSD], 25.31 ±â€Š10.33 vs 25.81 ±â€Š9.22), navigation time (time to find the lesion) (9.10 ±â€Š7.88 vs 9.50 ±â€Š7.14), and fluoroscopy time (2.23 ±â€Š2.39 vs 2.86 ±â€Š4.61), while these differences were not statistically significant.The diagnostic yield of EBUS GS TBLB was not improved with VBN (compared with using a hand-drawn bronchial map). Although VBN slightly shortened the procedure-related times, which were not significantly different.

Circulating Tumor Cell Number Is Associated with Primary Tumor Volume in Patients with Lung Adenocarcinoma.

BACKGROUND: Circulating tumor cells (CTCs) are frequently detected in patients with advanced-stage malignant tumors and could act as a predictor of poor prognosis. However, there is a paucity of data on the relationship between CTC number and primary tumor volume in patients with lung cancer. Therefore, our study aimed to evaluate the relationship between CTC number and primary tumor volume in patients with lung adenocarcinoma. METHODS: We collected blood samples from 21 patients with treatment-naive lung adenocarcinoma and 73 healthy individuals. To count CTCs, we used a CTC enrichment method based on fluid-assisted separation technology. We compared CTC numbers between lung adenocarcinoma patients and healthy individuals using propensity score matching, and performed linear regression analysis to analyze the relationship between CTC number and primary tumor volume in lung adenocarcinoma patients. RESULTS: CTC positivity was significantly more common in lung adenocarcinoma patients than in healthy individuals (p<0.001). The median primary tumor volume in CTC-negative and CTC-positive patients was 10.0 cm³ and 64.8 cm³, respectively. Multiple linear regression analysis showed that the number of CTCs correlated with primary tumor volume in lung adenocarcinoma patients (ß=0.903, p=0.002). Further subgroup analysis showed a correlation between CTC number and primary tumor volume in patients with distant (p=0.024) and extra-thoracic (p=0.033) metastasis (not in patients with distant metastasis). CONCLUSION: Our study showed that CTC numbers may be associated with primary tumor volume in lung adenocarcinomas patients, especially in those with distant metastasis.

Risk factors for developing Mycobacterium kansasii lung disease: A case-control study in Korea.

Previous studies have suggested that development of Mycobacterium kansasii lung disease (MKLD) was associated with COPD, pneumoconiosis, aging, male, immunosuppression, alcohol, malignancy, and certain occupations such as mining and sandblasting. However, previous studies were outdated and used non-comparative statistical methods. We aimed to determine the current risk factors for developing MKLD in Korea by using appropriate statistical techniques.Eighty-six MKLD patients were identified through a search of the Ulsan University Hospital database between January 2010 and December 2014. These cases were matched with 172 controls who had normal respiratory systems in a health examination during the same period (matching variables, age and sex; case: control ratio of 1:2). Clinical and demographic characteristics were gathered by reviewing the medical record and telephone survey. Multivariate logistic regression analyses were performed to evaluate risk factors for developing MKLD.Multivariate analysis showed that occupation in heavy industries (adjusted odds ratio (aOR) 6.41, 95% confidence interval (CI) 2.19-18.74, P = .001) and low body mass index (BMI) (aOR [per kg/m] 0.73, 95% CI 0.63-0.85, P < .001) were independent risk factors for development of MKLD. Educational attainment more than high school was associated with a lower risk of MKLD development (aOR 0.22, 95% CI 0.08-0.63, P = .005).Employees in heavy industry and low BMI are independent risk factors for development of MKLD in Korea.

Mediastinal Bronchogenic Cysts: Demonstration of Fluid-Fluid Level in Bronchoscopic US Imaging.

We report the findings for 2 patients with a fluid-fluid level seen on endobronchial ultrasound (EBUS) images of bronchogenic cysts. The EBUS images demonstrated a well-circumscribed cyst with a fluid-fluid level showing an anechoic upper part and a relatively hyperechoic lower part. A fluid-fluid level on EBUS imaging of a bronchogenic cyst, which can help confirm the cystic nature of the lesion, has not been previously reported. EBUS-based confirmation of these cysts using fluid-fluid levels may help avoid unnecessary aspiration of the lesions.

Gynecomastia induced by H1-antihistamine (ebastine) in a patient with idiopathic anaphylaxis.

H1-antihistamine is generally a well-tolerated and safe drug. However, in resemblance with all other drugs, H1-antihistamines can also prompt adverse drug reactions (ADRs). We recently encountered the very unusual ADR of H1-antihistamine-induced gynecomastia. A 21-year-old man with idiopathic anaphylaxis was treated with ebastine (Ebastel), a second-generation H1-antihistamine, for the prevention of anaphylaxis. Three months later, the patient remained well without anaphylaxis, but had newly developed gynecomastia. Because anaphylaxis recurred after the cessation of H1-antihistamine, the preventive medication was changed to omalizumab. A few months later, his gynecomastia had entirely disappeared. Physicians should be aware of this exceptional ADR of H1-antihistamine.

Non-infected and Infected Bronchogenic Cyst: The Correlation of Image Findings with Cyst Content.

We hereby report a case on bronchogenic cyst which is initially non-infected, then becomes infected after bronchoscopic ultrasound (US)-guided transesophageal fine-needle aspiration (FNA). The non-infected bronchogenic cyst appears to be filled with relatively echogenic materials on US, and the aspirate is a whitish jelly-like fluid. Upon contrast-enhanced MRI of the infected bronchogenic cyst, a T1-weighted image shows low signal intensity and a T2-weighted image shows high signal intensity, with no enhancements of the cyst contents, but enhancements of the thickened cystic wall. The patient then undergo video-assisted thoracic surgery 14 days after the FNA. The cystic mass is known to be completely removed, and the aspirate is yellowish and purulent. To understand the image findings that pertain to the gross appearance of the cyst contents will help to diagnose bronchogenic cysts in the future.

A case of alveolar soft part sarcoma of the pleura.

Alveolar soft part sarcoma (ASPS) is a rare malignant soft-tissue neoplasm of unknown histogenesis. The two main sites of occurrence are the lower extremities in adults and the head and neck in children. We report the first case of pleural ASPS occurring in a 58-yr-old man who presented with progressive dyspnea. A computed tomographic scan of the thorax revealed a large enhancing pleural mass with pleural effusion in the left hemithorax. Wide excision of the pleural mass was performed. Histologically, the tumor consisted of organoid nests of large polygonal cells, the cytoplasm of which had eosinophilic and D-PAS positive granules. Immunohistochemical staining showed that the tumor cell nuclei were positive for transcription factor 3 (TFE3). The pleural ASPS with multiple bone metastases recurred 1 yr after surgery and the patient died of acute pulmonary embolism 1.5 yr after diagnosis.

Prospective phase II trial of a combination of gemcitabine and UFT as first-line treatment in elderly patients with advanced non-small cell lung cancer.

BACKGROUND: The standard regimen in elderly patients with non-small-cell lung cancer (NSCLC) is still uncertain. Gemcitabine is one of the most widely used drugs for the treatment of NSCLC, and several phase II trials specifically designed for elderly patients with advanced NSCLC have confirmed the role of gemcitabine in this setting. In addition, oral uracil-tegafur (UFT) was associated with a survival advantage in the adjuvant setting. Therefore, we performed a phase II study using the combination of gemcitabine and UFT as first-line therapy in elderly patients with advanced NSCLC. METHODS: Chemotherapy-naïve, elderly (≥ 70 years) patients who had histologically or cytologically confirmed with stage IIIB or IV NSCLC with a performance status of 1-2 were enrolled. Patients received gemcitabine (1250 mg/m(2) on days 1 and 8, respectively) and UFT (400mg/day on days 1-14) every 3 weeks for up to four cycles. Patients who had not progressed after four cycles continued UFT monotherapy until progression. Primary endpoint was overall response rate and secondary endpoints were overall survival, time to progression and safety profiles. RESULTS: Between March 2008 and November 2010, 48 patients were enrolled. The median age was 74.5 years (range: 70-84 years), and there were 29 males. The performance status was 1 in 41 and 2 in 7 patients. Thirty-one (64.6%) patients were stage IV and seventeen (35.4%) patients were stage IIIB. Thirty patients (62.5%) completed four cycles of chemotherapy. Response was evaluated in 44 patients. Partial response was achieved in twelve (25.0%) patients and stable disease in 23 (47.9%) patients. Disease control rate was 72.9%. The median survival time was 6.1 months (95% confidence interval [CI]; 5.1-7.0 months), the 1-year survival rate was 29.1% and the median time to progression was 4.6 months (95% CI; 3.7-5.5 months). Toxicities were mild and mostly hematological adverse events. Grade 3/4 neutropenia occurred in 8.3% of patients and one patients experienced febrile neutropenia. Grade 3/4 anemia and thrombocytopenia occurred in 2.1% and 2.1% of patients, respectively. Non-hematological toxicities were tolerable. CONCLUSIONS: The combination of gemcitabine and UFT was effective in disease control and well tolerated first-line regimen in elderly patients with advanced NSCLC.

A case of tuberculous arthritis following the use of etanercept.

Etanercept is a tumor necrosis factor (TNF) inhibitor that has been used for the treatment of chronic inflammatory diseases including rheumatoid arthritis, ankylosing spondylitis and psoriatic arthritis. Because of its immunosuppressive activity, opportunistic infections have been noted in treated patients, most notably caused by Mycobacterium tuberculosis. Tuberculosis may present in an extrapulmonary or disseminated form. Since TNF-alpha inhibitors have been used in Korea, a few cases of TNF-alpha inhibitor associated tuberculosis have been described. However, tuberculous arthritis has not been previously reported. We describe a case of tuberculous arthritis in a 57-year-old woman with rheumatoid arthritis who was treated with etanercept.

Prospective phase II trial of a combination of fixed dose rate infusion of gemcitabine with cisplatin and UFT as a first-line treatment in patients with advanced non-small-cell lung carcinoma.

PURPOSE: The standard chemotherapy for non-elderly patients with advanced non-small-cell lung cancer (NSCLC) is platinum-based doublet combination therapy. Preclinical and clinical evidence indicates that infusion at the fixed dose rate (FDR) of 10mg/(m(2)min) may be more effective than a standard 30-min infusion of gemcitabine. In addition, oral uracil-tegafur (UFT) was associated with a survival advantage in the adjuvant setting. Therefore, we performed a phase II study using the combination of gemcitabine, cisplatin and UFT as first-line therapy in patients with advanced NSCLC. PATIENTS AND METHODS: Eligible patients had histologically or cytologically confirmed stage IIIB or IV NSCLC with a performance status of 0-2 and were chemotherapy-naive. Gemcitabine (1,250 mg/m(2), 10mg/(m(2)min) on days 1 and 8, respectively) and cisplatin (75 mg/m(2) on day 1) were injected intravenously and UFT (400mg/day) was administered orally on days 1-14. Treatment was repeated every 3 weeks for up to six cycles. Primary endpoint was overall response rate and secondary endpoints were overall survival, time to progression and safety profile. RESULT: Thirty-seven patients were enrolled. The median age was 60 years (range: 44-72 years). The performance status was 0 in 4, 1 in 30, and 2 in 3 patients. Twenty-three patients completed six cycles. Complete response was achieved in one (3%) patient, partial response in 17 (46%) patients, and stable disease in 10 (27%) patients. The overall response rate was 48.6% on an intention-to-treat basis and 54.5% of patients in whom a response evaluation was possible (n=33). The median survival time was 14.7 months (95% confidence interval [CI] 11.2-18.2), the 1-year survival rate was 54% and the median time to progression was 5.4 months (95% CI 4.3-6.4). Toxicities were moderate and mostly hematological adverse events. Grade 3/4 neutropenia occurred in 37% of patients and four patients experienced febrile neutropenia. Grade 3/4 anemia and thrombocytopenia occurred in 19% and 5% of patients, respectively. Non-hematological toxicities were mild. CONCLUSION: The combination of gemcitabine, cisplatin and UFT is an active and well-tolerated first-line regimen in patients with advanced NSCLC.

A less intensive combination of paclitaxel and carboplatin in advanced non-small cell lung cancer patients who have aged 60 years or more and has a poor performance status.

BACKGROUND: The aim of this study was to evaluate the response, survival, and toxicities of a less intensive combination of paclitaxel and carboplatin, which is used in advanced non-small cell lung cancer (NSCLC) patients older than 60 years of age including those with a poor performance status. METHODS: Thirty patients received 135 mg/m2 of paclitaxel on day 1, and carboplatin was administered to the patients on day 1 every 4 weeks over an area under the concentration-time curve of 6. RESULTS: The response rate was 40%, the median overall survival was 9.1 months (95% CI, 4.2 to 14 months), and the 1 year survival rate was 31%. The median progression-free survival was 7.7 months (95% CI, 3.1 to 12.2 months). In addition, the toxicities were generally mild and reversible. CONCLUSION: This study demonstrates that a less intensive combination of paclitaxel/carboplatin is active and well tolerated in advanced NSCLC patients who are older than 60 years including those with a poor PS 3-4.

Hypothermia protects against endotoxin-induced acute lung injury in rats.

OBJECTIVE: Hypothermia in humans and animals is known to decrease the number and function of circulating neutrophils. Because an activation of circulating neutrophils and their sequestration into the lung are important pathogenetic phenomena in endotoxin-associated lung injury, we conjectured that hypothermia could prevent this type of lung injury. DESIGN AND SETTING: Animal study at a university-affiliated research institute. SUBJECTS: Thirty-six Sprague-Dawley rats. INTERVENTIONS: After anesthesia, the rats were randomly assigned to normothermia (37 degrees C, rectal temperature) or hypothermia (27 degrees C), which was induced by surface cooling. After 1 h of stable temperature, the rats were administered intratracheal doses of lipopolysaccharide (LPS; 3 mg/kg) (normothermia-LPS; hypothermia-LPS) or an equivalent volume of normal saline (normothermia-saline; hypothermia-saline). The rectal temperature was maintained within +/-1 degrees C of the target temperature for 6 h after the intratracheal treatment. MEASUREMENTS AND RESULTS: Compared with the normothermia-LPS group, the neutrophil count in bronchoalveolar lavage (BAL) fluid (p=0.002) and the myeloperoxidase activity of lung tissues (p=0.002) of the hypothermia-LPS group were both lower. Compared with the normothermia-LPS group, the BAL interleukin-1beta level of the hypothermia-LPS group was lower (p<0.001), whereas the BAL interleukin-10 level of the hypothermia-LPS group was higher (p=0.026). Compared with the normothermia-LPS group, the histologic scores for acute lung injury of the hypothermia-LPS group were lower (p=0.007). CONCLUSIONS: Hypothermia pretreatment decreased the pulmonary sequestration of neutrophils, induced a favorable balance between pro- and anti-inflammatory cytokines, and attenuated histologic injury in endotoxin-challenged rats.