Search

// Sun Min Lim 1, 2 * , Hye Ryun Kim 1 * , Eun Kyung Cho 3 , Young Joo Min 4 , Jin Seok Ahn 5 , Myung-Ju Ahn 5 , Keunchil Park 5 , Byoung Chul Cho 1 , Ji-Hyun Lee 6 , Hye Cheol Jeong 6 , Eun Kyung Kim 6 , Joo-Hang Kim 2 1 Department of Internal Medicine, Division of Medical Oncology, Yonsei Cancer Center, Yonsei University College of Medicine, Seoul, Korea 2 Department of Internal Medicine, Division of Medical Oncology, CHA Bundang Medical Center, CHA University, Seongnam, Korea 3 Department of Internal Medicine, Gachon University Gil Medical Center, Incheon, Korea 4 Department of Oncology, Asan Medical Center, University of Ulsan college of Medicine, Seoul, Korea 5 Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea 6 Department of Internal Medicine, CHA Bundang Medical Center, CHA University, Seongnam, Korea * These authors have contributed equally to this work Correspondence to: Joo-Hang Kim, email: kim123@cha.ac.kr Keywords: primary resistance, epidermal growth factor, next-generation sequencing, tyrosine kinase inhibitor Received: March 01, 2016 Accepted: April 05, 2016 Published: April 21, 2016 ABSTRACT Background: Non-small-cell lung cancer (NSCLC) patients with activating epidermal growth factor receptor ( EGFR ) mutations may exhibit primary resistance to EGFR tyrosine kinase inhibitor (TKI). We aimed to examine genomic alterations associated with de novo resistance to gefitinib in a prospective study of NSCLC patients. Methods: One-hundred and fifty two patients with activating EGFR mutations were included in this study and 136 patients’ tumor sample were available for targeted sequencing of genomic alterations in 22 genes using the Colon and Lung Cancer panel (Ampliseq, Life Technologies). Results: All 132 patients with EGFR mutation were treated with gefitinib for their treatment of advanced NSCLC. Twenty patients showed primary resistance to EGFR TKI, and were classified as non-responders. A total of 543 somatic single-nucleotide variants (498 missense, 13 nonsense) and 32 frameshift insertions/deletions, with a median of 3 mutations per sample. TP53 was most commonly mutated (47%) and mutations in SMAD4 was also common (19%), as well as DDR2 (16%), PIK3CA (15%), STK11 (14%), and BRAF (7%). Genomic mutations in the PI3K/Akt/mTOR pathway were commonly found in non-responders (45%) compared to responders (27%), and they had significantly shorter progression-free survival and overall survival compared to patients without mutations (2.1 vs . 12.8 months, P =0.04, 15.7 vs. not reached, P

It is well known that oral corticosteroid and anti-tumor necrosis factor-α agents increase the risk of TB. However, little is known about whether inhaled corticosteroid (ICS) increases the risk of TB. We performed this study to assess the risk of pulmonary TB among ICS users, based on the presence of the radiologic sequelae of pulmonary TB.A retrospective cohort study was performed. Between January 1, 2000, and December 31, 2005, a total of 778 patients who had COPD were recruited. Among them, 162 patients were excluded according to the exclusion criteria. In total, 616 patients were followed until December 31, 2010. They were divided into four groups according to whether they used ICS and whether they had radiologic sequelae of prior pulmonary TB.A total of 20 patients developed pulmonary TB. Kaplan-Meier estimates showed an increased risk of pulmonary TB among the ICS users who had radiologic sequelae of prior pulmonary TB ( P , .001). Multivariate Cox regression showed that ICS use was an independent risk factor for the occurrence of pulmonary TB in patients who had a normal chest radiograph (hazard ratio, 9.079; 95% CI, 1.012-81.431; P 5 .049) and in patients who had radiologic sequelae of prior pulmonary TB (hazard ratio, 24.946; 95% CI, 3.090-201.365; P 5 .003).ICS use increases the risk of pulmonary TB in patients with COPD and the risk is greater in patients who have radiologic sequelae of prior pulmonary TB.

Purpose: Because evasion of tumor suppression is a critical step in cancer development, cancer cells have developed a variety of mechanisms to circumvent the influence of tumor suppressive pathways. Thus, genes that negatively regulate tumor suppressors could be considered novel types of oncogenes such as Bmi-1 repressing p16Ink4a and inhibiting p53 and were found to be frequently up-regulated in a variety of cancers. p38 mitogen-activated protein kinase (MAPK), which reportedly plays a crucial role as a tumor suppressor, is activated in number of lung adenocarcinomas, which is seemingly at odds with its role as a tumor suppressor. Methods: We examined 10 lung adenocarcinomas and corresponding normal tissues and determined the expression levels of a variety of tumor suppressor proteins through real-time polymerase chain reaction and immunohistochemistry and measured p38 MAPK activity by immunoblotting or immunohistochemistry analysis. In the in vitro cellular model, p38 activation by H-Ras and consequent senescence induction was achieved through retro-viral gene transduction. Similarly, the suppression of p16Ink4a by Bmi-1 after the introduction of H-Ras was achieved through transient transfection with cationic liposome. Results: We detected several lung adenocarcinomas that were positive for activated p38 MAPK but evidenced reduced levels of p16Ink4a expression. The suppression of p16Ink4a occurred in parallel with an increase in Bmi-1 and/or p16Ink4a promoter hypermethylation. Consistent with these observations, the H-Ras-stimulated induction of p16Ink4a was suppressed significantly through the coexpression of Bmi-1 in vitro. Discussion: These results demonstrate that the suppression of p16Ink4a by either the induction of Bmi-1 or the hypermethylation of p16Ink4 may be an important step in avoiding tumor surveillance by p38 MAPK during the development of lung cancer.

Small cell lung cancer (SCLC) is the leading cause of cancer death, with a high propensity for aggressiveness and metastasis even in an early stage. Thus, identification of biomarkers as early diagnostics and treatment is needed. In this study, we investigated differentially regulated proteins between human SCLC tissues and normal bronchial epithelium by proteomic analysis using two-dimensional electrophoresis (2-DE) and MALDI-TOF mass spectrometry. Seven proteins and protein isoforms, including, γ-actin, tubulin α-1B, laminin B1, coactosin-like protein-1 (COTL-1), ubiquitin carboxyl-terminal esterase L1, ubiquitin-conjugating enzyme E2-25K, and carbonic anhydrase 1, were up-regulated more than 2 fold in SCLC tissues. In particular, up-regulated COTL-1 expression was validated by Western blot analysis, immunohistochemistry, and reverse transcription quantitative polymerase chain reaction (RT-qPCR). Moreover, most SCLC tissues (93%; 28/30) were COTL-1-positive in immunohistochemistry, whereas only 16% (10/64) of nonsmall cell lung cancer (NSLC) tissues were. Taken together, this SCLC proteomic data may help in establishing a human SCLC proteome database. COTL-1 may be a biomarker or a therapeutic target in SCLC patients.

Myasthenia gravis (MG) is often complicated by respiratory failure, known as a myasthenic crisis. However, most of the patients who develop respiratory symptoms do so during the late course of disease and have other neurological signs and symptoms. However, in some patients respiratory failure is the initial presenting symptom. We report the case of a 68-year-old woman with MG who presented with isolated respiratory failure as her first presenting symptom. As illustrated by this case, it is important to consider neuromuscular disorders in cases of unexplained respiratory failure.

Summary Background A recently conducted randomized, phase III study that compared irinotecan plus cisplatin (IP) with etoposide plus cisplatin for the patients with extensive disease SCLC revealed a superior median survival rate and a superior 2-year survival rate for the IP combination therapy. Yet there have been few such reports on the patients suffering with limited disease SCLC (LD-SCLC). We conducted a phase II trial to evaluate the efficacy and toxicity of administering IP with concurrent radiotherapy for the patients with LD-SCLC. Patients and Methods Twenty chemotherapy-naive patients with LD-SCLC were enrolled in our study. The patients were treated with 40 mg/m2 irinotecan on days 1, 8 and 15 and with 60 mg/m2 cisplatin on day 1 every 4 weeks until a maximum of six cycles was delivered. Once-daily radiotherapy included the administration of 50.4 Gy in 28 fractions. After completion of the radiation therapy, the dose of irinotecan was increased to 60 mg/m2. Results The response rate was 85% (CR: 6; partial response, PR: 11). The median survival was 20.0 months (95% CI: 15.6–24.4 months) with 1-year and 2-year overall survival rates of 85 and 35%, respectively. The median progression free survival (PFS) was 12 months (95% CI: 6.2–18.1 months) with a 1-year PFS of 36%. The major hematologic toxicities of this regimen were neutropenia (60%), leukopenia (55%), anemia (20%) and thrombocytopenia (10%). The non-hematologic toxicities were nausea/vomiting (55%), diarrhea (35%) and dysphagia (15%). Conclusions Our data show that IP with concurrent radiotherapy is an effective and tolerable regimen for the treatment of LD-SCLC and these findings warrant further investigation.

Background Acute pulmonary thromboembolism (APTE) remains an important cause of morbidity and mortality in Western countries. In Korea, both the incidence and the mortality rate of APTE were thought to be low compared to Western countries. We performed the present study to investigate the current status of APTE in Korea. Methods Eight hundred and eight registry patients with APTE were analyzed with respect to clinical symptoms and signs, the presence of underlying diseases or predisposing factors, diagnostic methods, treatment and clinical course. Results The most common risk factors were prolonged immobilization (22.9%), deep venous thrombosis (22.0%), a recent operation (19.2%), and cancer (15.8%). The most common symptoms were dyspnea (78.6%), and chest pain (26.9%). The most common abnormality on chest radiography was effusion. The overall mortality rate at 3 months was 11.0%. Multivariate logistic regression analysis demonstrated that increased mortality risk was independently associated with the following baseline factors: onset in hospital (OR 1.88; 95% CI 1.03–3.42; p =0.03), lung cancer (OR 9.20; 95% CI 1.96–43.27; p =0.005), tachycardia (OR 3.50; 95% CI 1.86–6.60; p =0.0001), cardiogenic shock (OR 6.74; 95% CI 2.73–16.64; p =0.0001), and cyanosis (OR 3.45; 95% CI 1.27–9.44; p =0.01). Conclusions Some differences did exist for the risk factors, symptoms, chest X-ray findings, mortality rate and prognostic factors as compared with those for Western patients. These results can prove especially helpful in the diagnosis as well as for the treatment of patients with APTE.

Chronic obstructive pulmonary disease (COPD) is classified into emphysema and chronic bronchitis, which are thought to result from different pathophysiological pathways. Smoking-induced lung parenchymal destruction and inadequate repair are involved in the pathogenesis of emphysema. In addition, decreased expression of vascular endothelial growth factor and increased endothelial cell apoptosis in the lung may participate in emphysema pathogenesis. As stem cells, circulating endothelial progenitor cells (EPCs) may play a key role in the maintenance of vascular integrity by replacing and repairing the damaged endothelial cells in the tissues. To determine whether the lack of appropriate repair by circulating EPCs in cases of smoking-induced endothelial cell injury participates in emphysema pathogenesis, we determined the association between the colony-forming or migratory capacity of circulating EPCs and the presence of emphysema in 51 patients with COPD. The patients were divided into emphysema (n = 23) and non-emphysema groups (n = 28) based on high-resolution computed tomography. Twenty-two smokers with normal lung function and 14 normal non-smokers served as controls. Circulating EPCs isolated from patients with emphysema showed significantly lower colony-forming units (CFUs) than those from patients with non-emphysema group, smokers with normal lung function, and normal non-smokers. EPCs from patients with emphysema showed significantly lower migratory capacity than those from normal non-smoking controls (p < 0.05). On multivariate analysis, the EPC-CFU was independently associated with emphysema (OR 0.944, 95% CI = 0.903-0.987, p = 0.011). Thus, impaired functions of circulating EPCs may contribute to the development of emphysema.

Abnormal expression of let-7a microRNA (miRNA) in non-small cell lung cancer (NSCLC) cells and tissue has been previously reported. Our objective was to investigate whether let-7a miRNA is aberrantly expressed in the blood of NSCLC patients. Using real-time PCR (RT-PCR), we analyzed let-7a miRNA in archived whole blood from 65 participants, 35 of whom had NSCLC and 30 of whom did not. Using RT-PCR, we also investigated the expression of let-7a miRNA in NSCLC cell lines (A549 and HCC 1588), a normal human lung fibroblast cell line (WI-38) and in 40 human NSCLC tissues. The 2(-ddCt) of let-7a miRNA in the blood of normal subjects and those with NSCLC was 3242.49±355.28 and 747.85±177.74, respectively. The relative expression of let-7a miRNA in the A549 and HCC 1588 cancer cell lines was approximately 0.3 and 0.35, respectively, compared to WI-38 cells. The 2(-ddCt) of let-7a miRNA in the normal human lung tissues and human NSCLC tissues was 42.30±3.98 and 27.73±3.86, respectively. Let-7a miRNAs were under-expressed in the blood of NSCLC patients, as well as NSCLC cells and NSCLC tissues, compared to normal controls. The possibility of using let-7a miRNA as a serologic marker for lung cancer warrants further study.

Background Asthma is chronic airway inflammation that occurs together with reversible airway obstruction. T-lymphocytes play an important role in the pathogenesis of asthma. Proteomic technology has rapidly developed in the postgenomic era, and it is now widely accepted as a complementary technology to genetic profiling. We investigated the changes of proteins in T-lymphocytes of asthma patients by using standard proteome technology: two-dimensional polyacrylamide gel electrophoresis (2D-PAGE), matrix-assisted laser desorption ionization time-of-flight mass spectrometry (MALDI-TOF-MS), and a database search. Methods The proteins of CD3+ T-lymphocytes were isolated from whole blood of six steroid-naive asthmatic patients and of six healthy volunteers. 2D-PAGE was performed and the silver-stained protein spots were comparatively analyzed between the asthma and control groups using an image analyzer. Some differentially expressed spots were identified by MALDI-TOF-MS and database search. The messenger RNA expressions of some identified proteins were examined by real-time polymerase chain reaction (RT-PCR). Results Thirteen protein spots in the T-lymphocytes of the asthmatic patients were increased and 12 spots were decreased compared to those of the normal subjects. Among the identified proteins, the increased expression of the messenger RNA of phosphodiesterase 4C and thioredoxin-2 and the decreased expression of the messenger RNA of glutathione S-transferase M3 were confirmed by RT-PCR in the asthmatic patients. Conclusions Proteomic examination of the peripheral T-lymphocytes revealed some differentially expressed proteins in the asthmatic patients. The possibility of using the differentially expressed proteins as important biomarkers and therapeutic targets in asthma patients warrants further studies.