Sarcopenia correlates with systemic inflammation in COPD.

BACKGROUND: Muscle wasting and chronic inflammation are predominant features of patients with COPD. Systemic inflammation is associated with an accelerated decline in lung function. In this study, the prevalence of sarcopenia and the relationships between sarcopenia and systemic inflammations in patients with stable COPD were investigated. MATERIALS AND METHODS: In a cross-sectional design, muscle strength and muscle mass were measured by handgrip strength (HGS) and bioelectrical impedance analysis in 80 patients with stable COPD. Patients (≥40 years old) diagnosed with COPD were recruited from outpatient clinics, and then COPD stages were classified. Sarcopenia was defined as the presence of both low muscle strength (by HGS) and low muscle mass (skeletal muscle mass index [SMMI]). Levels of circulating inflammatory biomarkers (IL-6 and high-sensitivity TNFα [hsTNFα]) were measured. RESULTS: Sarcopenia was prevalent in 20 (25%) patients. Patients with sarcopenia were older, had lower body mass index, and a higher percentage of cardiovascular diseases. In addition, they had significantly higher modified Medical Research Council scores and lower 6-minute walk distance than those without sarcopenia. HGS was significantly correlated with age, modified Medical Research Council score, and COPD Assessment Test scores. Both HGS and SMMI had associations with IL-6 and hsTNFα (HGS, r=-0.35, P=0.002; SMMI, r=-0.246, P=0.044) level. In multivariate analysis, old age, lower body mass index, presence of cardiovascular comorbidities, and higher hsTNFα levels were significant determinants for sarcopenia in patients with stable COPD. CONCLUSION: Sarcopenia is very common in patients with stable COPD, and is associated with more severe dyspnea-scale scores and lower exercise tolerance. Systemic inflammation could be an important contributor to sarcopenia in the stable COPD population.

Compound EGFR mutation is frequently detected with co-mutations of actionable genes and associated with poor clinical outcome in lung adenocarcinoma.

Compound EGFR mutations, defined as double or multiple mutations in the EGFR tyrosine kinase domain, are frequently detected with advances in sequencing technology but its clinical significance is unclear. This study analyzed 61 cases of EGFR mutation positive lung adenocarcinoma using next-generation sequencing (NGS) based repeated deep sequencing panel of 16 genes that contain actionable mutations and investigated clinical implication of compound EGFR mutations. Compound EGFR mutation was detected in 15 (24.6%) of 61 cases of EGFR mutation-positive lung adenocarcinoma. The majority (12/15) of compound mutations are combination of the atypical mutation and typical mutations such as exon19 deletion, L858R or G719X substitutions, or exon 20 insertion whereas 3 were combinations of rare atypical mutations. The patients with compound mutation showed shorter overall survival than those with simple mutations (83.7 vs. 72.8 mo; P = 0.020, Breslow test). Among the 115 missense mutations discovered in the tested genes, a few number of actionable mutations were detected irrelevant to the subtype of EGFR mutations, including ALK rearrangement, BCL2L11 intron 2 deletion, KRAS c.35G>A, PIK3CA c.1633G>A which are possible target of crizotinib, BH3 mimetics, MEK inhibitors, and PI3K-tyrosine kinase inhibitors, respectively. 31 missense mutations were detected in the cases with simple mutations whereas 84 in those with compound mutation, showing that the cases with compound missense mutation have higher burden of missense mutations (P = 0.001, independent sample t-test). Compound EGFR mutations are detected at a high frequency using NGS-based repeated deep sequencing. Because patients with compound EGFR mutations showed poor clinical outcomes, they should be closely monitored during follow-up.

Genetic heterogeneity of actionable genes between primary and metastatic tumor in lung adenocarcinoma.

BACKGROUND: Biopsy for lung cancer diagnosis is usually done at a single site. But it is unclear that genetic information at one biopsy site represents that of other lesions and is sufficient for therapeutic decision making. METHODS: Non-synonymous mutations and insertions/deletions of 16 genes containing actionable mutations, and intron 2 deletion polymorphism of Bcl2-like11 were analyzed in 41 primary tumor and metastatic lymph node (L/N) matched, pStage IIA ~ IIIA non-small cell lung cancer (NSCLC) samples using a next generation sequencing based technique. RESULTS: A total of 249 mutations, including 213 non-synonymous mutations, 32 deletions, and four insertions were discovered. There was a higher chance of discovering non-synonymous mutations in the primary tumors than in the metastatic L/N (138 (64.8%) vs. 75 (35.2%)). In the primary tumors, 106 G > A:C > T transitions (76.8%) of 138 non-synonymous mutations were detected, whereas in the metastatic L/N, 44 (58.7%) of 75 were discovered. A total 24 (11.3%) out of 213 non-synonymous mutations were developed in the context of APOBEC signature. Of those, 21 (87.5%) was detected in the primary tumors and 4 (16.7%) was detected in the metastatic L/N. When the mutation profiles between primary tumor and metastatic L/N were compared, 13 (31.7%) of 41 cases showed discrepant mutation profile. There were no statistically significant differences in disease free survival and overall survival between groups showing identical mutation profiles and those with discrepancy between primary and metastatic L/N. CONCLUSIONS: Genetic heterogeneity between the primary and L/N metastatic lesions is not infrequent finding to consider when interpreting genomic data based on the result of one site inspection. A large prospective study may be needed to evaluate the impact of genetic heterogeneity on the clinical outcomes of NSCLC patients.

BCL2-like 11 intron 2 deletion polymorphism is not associated with non-small cell lung cancer risk and prognosis.

OBJECTIVES: BCL2-Like 11(BIM), which encodes a BH3-only protein, is a major pro-apoptotic molecule that facilitates cell death. We hypothesized that a BIM intron 2 deletion polymorphism increases lung cancer risk and predicts poor prognosis in non-small lung cancer (NSCLC) patients. MATERIALS AND METHODS: We prospectively recruited 450 lung cancer patients and 1:1 age, sex, and smoking status matched control subjects from February 2013 to April 2014 among patients treated at Severance, Gangnam Severance, and Chonnam Hwasoon Hospital. The presence of a 2903-bp genomic DNA deletion polymorphism of intron 2 of BIM was analyzed by PCR and validated by sequencing. Odds ratios were calculated by chi-square tests and survival analysis with Kaplan-Meier estimation. RESULTS AND CONCLUSION: Sixty-nine out of 450 (15.3%) lung cancer patients carried the BIM deletion polymorphism, while 66 out of 450 (14.7%) control subjects carried the BIM deletion polymorphism, with an odds ratio of for lung cancer of 1.054 (95% CI; 0.731-1.519). We categorized 406 NSCLC patients according to the presence of the polymorphism and found that there were no statistically significant differences in age, sex, histologic type, or stage between subjects with and without the deletion polymorphism. The BIM deletion polymorphism did not influence overall survival (OS) or progression free survival (PFS) in our sample (OS; 37.6 vs 34.4 months (P=0.759), PFS; 49.6 vs 26.0 months (P=0.434)). These findings indicate that the BIM deletion polymorphism is common in Korean NSCLC patients but does not significantly affect the intrinsic biologic function of BH3-only protein. Furthermore, the BIM deletion polymorphism did not predict clinical outcomes in patients with NSCLC.

Anastomotic Airway Complications after Lung Transplantation.

PURPOSE: Anastomotic airway complications are a major cause of morbidity and mortality after lung transplantation (LTx). In this study, the authors identified types and clinical outcomes of airway complications after LTx. MATERIALS AND METHODS: All bronchial anastomotic complications were analyzed in a total of 94 LTx cases involving 90 recipients who underwent surgery between July 2006 and May 2014. Fifteen LTx cases (14 recipients) with incomplete medical records for fiberoptic bronchoscopy (FBS) and three cases underwent heart-lung transplantation (HLT) were excluded. Postoperative FBS at 24-48 hours, 1, 3, 6, and 12 months, and then yearly after the transplantation were performed. RESULTS: A total of 76 LTx cases (75 recipients) were analyzed. The mean age of the recipients was 49.55 years (range, 18-71 years), and 38 (49.4%) were male. Twenty-one out of 76 cases (27.6%) experienced early anastomotic complications, and 12 (15.8%) presented late anastomotic complications. The early anastomotic airway complications presented in various forms: stenosis, 1 case; narrowing, 1; necrosis & dehiscence, 3; fistula, 4; granulation, 10; and infection, 2. Late complications almost entirely presented in the form of bronchial stenosis; five recipients showed stenosis at the anastomosis site, and one of them showed improvement after ballooning. Five others were found to have stenosis at the bronchus intermedius, distal to the anastomosis site. Three of these patients showed improvement after ballooning or bronchoplasty. CONCLUSION: By serial surveillance via FBS after LTx, we detected anastomotic airway complications in 42.9% of cases, which were successfully managed with improved clinical outcomes.

A rare case of primary thymic adenocarcinoma mimicking small cell lung cancer.

Primary thymic adenocarcinoma is a very rare malignancy of the anterior mediastinum with no standardized treatment. A 36-year-old male patient presented with hoarseness over the past 3 months. A chest computed tomography (CT) scan showed an infiltrative mass to the proximal vessels and aortic arch in left upper mediastinum (4.1×3.1×5.4 cm). Brain magnetic resonance imaging (MRI) showed focal lesions, suggesting metastasis in the left frontal lobe. A thoracoscopic biopsy of the mediastinal mass confirmed a primary thymic adenocarcinoma forming a glandular structure with atypia of tumor cells. The patient received four cycles of systemic chemotherapy, consisting of etoposide and cisplatin, with concurrent radiotherapy (6,000 cGy/30 fractions) to the mediastinal lesion and the metastatic brain lesion (4,200 cGy/12 fractions). A follow-up chest CT scan and brain MRI showed a decrease in the size of the left upper mediastinal mass and brain lesion. We report a rare case of the primary thymic adenocarcinoma with a literature review.

A case of locally advanced well-differentiated fetal adenocarcinoma of the lung treated with concurrent chemoradiation therapy.

Fetal adenocarcinoma is a rare adenocarcinoma subtype of pulmonary blastoma. A 48-year-old male patient is being referred to our hospital due to progressive dyspnea. A chest X-ray showed a lung mass of unknown origin that was obstructing the right main bronchus. After relieving the airway obstruction with stent insertion via bronchoscopy, a diagnosis of fetal adenocarcinoma is being confirmed through thoracoscopic biopsy. Due to the locally advanced state of the lung cancer, it seemed to be inoperable, and concurrent chemo-radiation therapy was being administered with docetaxel. The stent was removed after improvements in the airway obstruction followed by a lung mass shrinkage. Comparing to other contexts which describe fetal adenocarcinoma as lower grade malignancy with low-associated mortality, herein, we describe a case of locally-advanced fetal adenocarcinoma (T4N3M0). This is the first documented case being treated with concurrent chemoradiation therapy. The followed-up image studies represent a partial response and the patient is currently under further observations.

Notch1 destabilizes the adherens junction complex through upregulation of the Snail family of E-cadherin repressors in non-small cell lung cancer.

One of the critical steps driving cancer cell migration and metastasis is the repression of cell adhesion molecules resulting in loss of cell­to-cell adhesion. Although interactions between Notch1 and components of the adherens junction complex have been suggested, little is known concerning the consequence of their interactions. In this study, we investigated the interaction between the Notch1 and the E­cadherin/ß­catenin complex, its effect on the expression of adherens junction complex components and its influence on non-small cell lung cancer (NSCLC) cell proliferation. With progression of lung neoplastic lesions in LSL K-ras G12D mice, the expression of E­cadherin was inhibited whereas that of Notch1 was increased with frequent nuclear localization, suggesting an inverse relationship between E­cadherin and Notch1 expression with tumor progression. Transduction of the human Notch1 intracellular domain (N1ICD) into NSCLC cells inhibited expression of E­cadherin and ß­catenin and induced changes in the localization of adherens junction molecules. The loss of E­cadherin was mediated through upregulation of the Snail family of transcription factors, Snail and Slug. Experiments in which siRNA against E-cadherin was introduced into NSCLC cells revealed that N1ICD decreased the expression of ß­catenin in an E­cadherin­independent manner, leading to inhibition of markers of Wnt/ß­catenin signaling activation. Despite inhibition of Wnt/ß­catenin signaling in the N1ICD­transduced cells, cells transduced with N1ICD showed no difference in cell cycle progression when compared with that of the control vector-transduced cells. In conclusion, Notch1 inhibited the expression of E­cadherin through upregulation of the Snail family of transcriptional factors, resulting in inhibition of expression of ß­catenin and destabilization of adherens junctions.

Late respiratory infection after lung transplantation.

BACKGROUND: Aiming to improve outcome of lung transplantation (LTx) patients, we reviewed risk factors and treatment practices for the LTx recipients who experienced respiratory infection in the late post-LTx period (>1 month after LTx). METHODS: We analyzed the clinical data of 48 recipients and donors from 61 LTx, who experienced late respiratory infections. Late respiratory infections were classified according to the etiology, time of occurrence, and frequency of donor-to-host transmission or colonization of the recipient prior to transplantation. RESULTS: During the period of observation, 42 episodes of respiratory infections occurred. The organisms most frequently involved were gram (-) bacteria: Acinetobacter baumannii (n=13, 31.0%), Pseudomonas aeruginosa (n=7, 16.7%), and Klebsiella pneumoniae (n=4, 10.0%). Among the 42 episodes recorded, 14 occurred in the late post-LTx period. These were bacterial (n=6, 42.9%), fungal (n=2, 14.3%), viral (n=4, 28.5%), and mycobacterial (n=2, 14.3%) infections. Of 6 bacterial infections, 2 were from multidrug-resistant (MDR) A. baumannii and one from each of MDR P. aeruginosa, extended spectrum ß-lactamase (+) K. pneumoniae, methicillin-resistant Staphylococcus aureus and Streptococcus pneumoniae. Infection-related death occurred in 6 of the 14 episodes (43%). CONCLUSION: Although the frequency of respiratory infection decreased sharply in the late post-LTx period, respiratory infection was still a major cause of mortality. Gram (-) MDR bacteria were the agents most commonly identified in these infections.

Evaluation of characteristics for dye-sensitized solar cell with reflector applied.

Dye-sensitized solar cells have slightly lower photoelectric efficiency than silicon solar cells. Researchers have investigated various ways to address this problem. This study improved the efficiency of a dye-sensitized solar cell by re-driving it with a reflector, reusing discarded light after it was absorbed. The reflector increased efficiency by about 50%, by increasing the size of the pattern shape and increasing the distance of the reflector.

Development of a high-efficiency laminated dye-sensitized solar cell with a condenser lens.

Dye-sensitized solar cells have slightly lower photoelectric efficiency than silicon solar cells. Researchers have investigated various ways to address this problem. In this paper, we found that the optimized separation between the condenser lens and the cells was 8 mm. The cell efficiency increased from 2.5% to 8.3% compared to two isolated cells without a lens. If the efficiency of the basic cell can be increased sufficiently, it should be possible to commercialize the product.

A colorimetric chiral sensor based on chiral crown ether for the recognition of the two enantiomers of primary amino alcohols and amines.

A new colorimetric chiral sensor material consisting of three different functional sites such as chromophore (2,4-dinitrophenylazophenol dye), binding site (crown ether), and chiral barrier (3,3'-diphenyl-1,1'-binaphthyl group) was prepared and applied to the recognition of the two enantiomers of primary amino alcohols and amines. Among five primary amino alcohols and two primary amines tested, the two enantiomers of phenylalaninol show the highest difference in the absorption maximum wavelength (Δλ(max)=43.5 nm) and in the association constants (K(S)/K(R)=2.51) upon complexation with the colorimetric chiral sensor material and, consequently, the two enantiomers of phenylalaninol were clearly distinguished from each other by the color difference.