Center for Lung Cancer

Goyang, South Korea

Center for Lung Cancer

Goyang, South Korea
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Kim Y.R.,Catholic University of Korea | Oh J.E.,Catholic University of Korea | Kim M.S.,Catholic University of Korea | Kang M.R.,Catholic University of Korea | And 4 more authors.
Journal of Pathology | Year: 2010

Nuclear factor erythroid-related factor 2 (NRF2) encodes a transcription factor that induces expression of cytoprotective proteins upon oxidative stress and oncogenic NRF2 mutations have been found in lung and head/neck cancers that inactivate KEAP1-mediated degradation of NRF2. The aim of this study was to catalogue NRF2 mutations in other human cancers. For this, we analysed 1145 cancer tissues from carcinomas from oesophagus, skin, uterine cervix, lung, larynx, breast, colon, stomach, liver, prostate, urinary bladder, ovary, uterine cervix, and kidney, and meningiomas, multiple myelomas, and acute leukaemias by single-strand conformation polymorphism (SSCP) assay. We detected NRF2 mutations in oesophagus (8/70; 11.4%), skin (1/17; 6.3%), lung (10/125; 8.0%), and larynx (3/23; 13.0%) cancers. Of note, all of the 22 mutations except one were found in squamous cell carcinomas (SCCs) (95.5%). The mutations were observed within or near DLG and ETGE motifs that are important in NRF2 and KEAP1 interaction. All of the oesophageal SCCs and skin SCCs with the NRF2 mutations showed increased NRF2 expression in the nuclei. However, none of the SCCs from oesophagus and skin harboured KEAP1 mutation. Our study demonstrated here that NRF2 mutation occurs not only in lung and head/neck cancers, but also in oesophageal and skin cancers. Our data suggest that the NRF2 mutation plays a role in the development of SCC and is a feature of SCC. Copyright © 2009 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.


Lee Y.,Center for Lung Cancer | Lee G.K.,Center for Lung Cancer | Yun T.,Center for Lung Cancer | Kim H.T.,Center for Lung Cancer | Lee J.S.,Center for Lung Cancer
Clinical Lung Cancer | Year: 2015

Background It has been reported that the presence of pretreatment EGFR T790M mutation may reduce the efficacy to EGFR tyrosine kinase inhibitors (TKI) in EGFR-mutant lung cancer. However, clinicopathologic features related to the likelihood of T790M mutation before treatment remains unknown. Patients and Methods DNA from 124 pretreatment tissue samples from patients with advanced non-small-cell lung cancer carrying sensitive EGFR mutations was genotyped for EGFR T790M mutation with mass spectrometry. We compared the characteristics of 24 T790M patients and 100 patients with no or a low-level T790M mutation. Results There were no differences in age, sex, histology, or initial stage between T790M and non/low T790M groups. However, there were significantly more never-smokers in the T790M group (P =.017). Brain metastasis was also more common in the T790M group (P =.036). The response rates to platinum, taxane, gemcitabine, and pemetrexed did not differ between the 2 groups. In the T790M group, the response rates were not significantly different among the 4 cytotoxic drugs (P =.809). The median time to progression during EGFR-TKI therapy was shorter in the T790M group than in the non/low T790M group (4.1 vs. 11.5 months, respectively; P <.001). The median overall survival from the start of first-line treatment of advanced disease was similar in both groups (31.5 vs. 36.0 months, respectively; P =.310). Conclusion The clinical features of EGFR T790M-mutant lung cancer were similar to those of sensitive EGFR-mutant lung cancer, except for the overrepresentation of never-smokers and brain metastasis. © 2015 Elsevier Inc. All rights reserved.


Hwangbo B.,Center for Lung Cancer | Lee G.-K.,Center for Lung Cancer | Lee H.S.,Center for Lung Cancer | Lim K.-Y.,Center for Lung Cancer | And 6 more authors.
Chest | Year: 2010

Objective: We performed this study to evaluate the role of transesophageal endoscopic ultrasound with bronchoscope-guided fine-needle aspiration (EUS-B-FNA) following endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) in the mediastinal staging of lung cancer. Methods: In this prospective study, we applied transbronchial and transesophageal ultrasonography using an ultrasound bronchoscope on patients with confirmed or strongly suspected potentially operable non-small cell lung cancer. Following EBUS-TBNA, EUS-B-FNA was used for mediastinal nodes that were inaccessible or difficult to access by EBUS-TBNA. The accessibility by EBUS-TBNA and EUS-B-FNA to mediastinal nodal stations having at least one node ≥5 mm was also checked. Results: In 150 patients, we performed EBUS-TBNA and EUS-B-FNA on 299 and 64 mediastinal nodal stations, respectively. Among 143 evaluable patients, EBUS-TBNA diagnosed mediastinal metastasis in 38 patients. EUS-B-FNA identified mediastinal metastasis in three additional patients. Surgery diagnosed mediastinal metastasis in four more patients. The sensitivity, negative predictive value, and diagnostic accuracy of EBUS-TBNA in the detection of mediastinal metastasis were 84.4%, 93.3%, and 95.1%, respectively. These values for the combined approach of EBUS-TBNA and EUS-B-FNA increased to 91.1%, 96.1%, and 97.2%, respectively, although the differences were not statistically significant (P = .332, P = .379, and P = .360, respectively). Among 473 mediastinal nodal stations having at least one node ≥5 mm that were evaluated, the proportion of accessible mediastinal nodal stations by EBUS-TBNA was 78.6%, and the proportion increased to 84.8% by combining EUS-B-FNA with EBUS-TBNA (P = .015). Conclusion: Following EBUS-TBNA in the mediastinal staging of potentially operable lung cancer, the accessibility to mediastinal nodal stations increased by adding EUS-B-FNA and an additional diagnostic gain might be obtained by EUS-B-FNA. Trial Registration:clinicaltrials.gov, NCT00741247. © 2010 American College of Chest Physicians.


Lee Y.,Center for Lung Cancer | Lee Y.,Research Institute and Hospital | Yoon K.-A.,Research Institute and Hospital | Joo J.,Biometric Research Branch | And 6 more authors.
Carcinogenesis | Year: 2013

The prognostic significance of inherited genetic variants in advanced-stage non-small cell lung cancer (NSCLC) patients remains unknown. In this study, we genotyped 271 817 singlenucleotide polymorphisms in 348 advanced NSCLC patients who received chemotherapy and analyzed their association with prognosis by using Cox proportional hazard regression model adjusted for known prognostic factors. Top candidate singlenucleotide polymorphisms (SNPs) were selected using the bootstrap re-sampling procedure. Median age of patient population was 56 years. Proportions of female, never smokers and adenocarcinoma were 64.9, 67.5 and 80.4%, respectively. We identified 17 top candidate SNPs related to prognosis using cut-off minimum P value of<5.0× 10-5 in at least 70% of 1000 bootstrap samples. These SNPs were located in the genomic regions of the FAM154A, ANKS1A, DLST, THSD7B, NCOA2, CDH8, SLC35D2, NALCN and EGF genes. The most significant SNP, rs1571228 (9p22.1:FAM154A), was significantly associated with overall survival in dominant model [AG+GG to AA, hazard ratio (HR) of death (95% CI)= 0.53 (0.42-0.67); P= 2.025× 10-7]. The SNP at 4q25:EGF, rs11098063, for which some genetic variations was previously reported to be associated with prognosis, also showed significant association with overall survival in additive model [CC versus CT versus TT, HR (95% CI)= 1.00 versus 0.61 (0.47-0.78) versus 0.39 (0.19-0.79); P= 9.582× 10-6]. Survival differences according to the genotype of these SNPs were independent of sex, smoking, histology and chemotherapy regimens. These results suggested the variants at multiple genetic loci might contribute to the risk of death in advanced NSCLC patients receiving chemotherapy. © The Author 2012. Published by Oxford University Press. All rights reserved.


Jang H.-J.,Center for Lung Cancer | Lee H.-S.,Center for Lung Cancer | Park S.Y.,Center for Lung Cancer | Zo J.I.,Center for Lung Cancer
Innovations: Technology and Techniques in Cardiothoracic and Vascular Surgery | Year: 2011

OBJECTIVE:: Robotic surgery has evolved in urology, gynecology, and general surgery and seems to be an oncologically sound surgical approach. Robotic surgery has been infrequently reported for pulmonary lobectomy. The aim of this study is to compare the outcomes of our early experience in performing robot-assisted lobectomy (RAL) with video-assisted thoracic surgery (VATS) for the treatment of non-small cell lung cancer. METHODS:: Between February and October 2009, 40 patients underwent RAL for resectable non-small cell lung cancer. The dissection and anatomic isolation of the hilar structures were performed using two arms of the da Vinci S system. A retrospective comparison with two VATS groups was performed, our initial 40 VATS patients (between January 2006 and February 2007) and our most recent 40 VATS patients (between June 2008 and September 2009). The entire experience with VATS lobectomy is 163 cases. RESULTS:: In the RAL group, the mean age was 64 years, and there were 23 male patients. Adenocarcinoma was diagnosed in 29 patients with a mean tumor size of 3.5 cm. There were no conversions to open thoracotomy. Among the patients in our initial and recent VATS lobectomy groups, the conversion rate was 3 (8%) and 2 (5%) patients, respectively. The operative time for the RAL (240 ± 62 minutes) and the initial VATS lobectomy groups (257 ± 57 minutes) were similar but was longer than the recent VATS lobectomy group (161 ± 39 minutes, P < 0.001). However, the rate of postoperative complications in the RAL group (n = 4, 10%) was significantly lower than that of the initial VATS group (n = 13, 32.5%, P = 0.027) and similar to that of the recent VATS group (n = 7, 17.5%, P = 0.755). Intraoperative bleeding was reduced in the RAL group compared with the initial VATS group (219 mL vs 374 mL P = 0.017), and the median length of postoperative stay was significantly shorter for the RAL group compared with the initial VATS group (6 vs 9 days, P < 0.001). CONCLUSIONS:: The outcomes of our early RAL experience was comparable to the our outcomes achieved with VATS lobectomy, whether performed early or late. © 2011 by Lippincott Williams & Wilkins.


Kang H.J.,Center for Lung Cancer | Hwangbo B.,Center for Lung Cancer
Tuberculosis and Respiratory Diseases | Year: 2013

Endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) is becoming a standard method for invasive mediastinal staging and for the diagnosis of paratracheal and peribronchial lesions. It is essential to understand the technical aspects of EBUS-TBNA to ensure safe and efficient procedures. In this review, we discuss the practical aspects to be considered during EBUS-TBNA, including anesthesia, manipulation of equipment, understanding mediastinal ultrasound images, target selection, number of aspirations needed per target, sample handling, and complications. Copyright ©2013 The Korean Academy of Tuberculosis and Respiratory Diseases. All rights reserved.


Lee Y.,Center for Lung Cancer | Kim S.H.,Center for Clinical Trials | Han J.-Y.,Center for Lung Cancer | Kim H.T.,Center for Lung Cancer | And 2 more authors.
Journal of Cancer Research and Clinical Oncology | Year: 2012

Purpose An inflammatory-immunological marker, neutrophil- to-lymphocyte ratio (NLR), was evaluated as a surrogate indicator for prognosis of advanced lung adenocarcinoma patients. Methods The subjects of this study were 199 never smokers with advanced lung adenocarcinoma, who were enrolled in a prospective randomized phase III study (First- SIGNAL) comparing gefitinib with gemcitabine plus cisplatin as first-line therapy. The values of NLR were assessed at two time points: at baseline (pretreatment) and on day 1 of the second cycle (posttreatment). Results A higher posttreatment NLR was associated with a worse tumor response (median posttreatment NLR, 1.56 for partial response, 1.64 for stable disease, and 2.70 for progressive disease; P<0.001). The risk of progression was higher when the posttreatment NLR was higher [hazard ratio (HR) = 1.23, 95 % confidence interval (CI) 1.15-1.31; P<0.001]. A high posttreatment NLR was associated with an increased risk of death (HR = 1.13, 95 % CI 1.06-1.21; P<0.001). These associations did not differ according to treatment arms. When total patients were divided into four groups according to the cutoff points of pre- and posttreatment NLRs, those with a high pretreatment NLR that declined substantially after treatment showed improved survival compared with those with a high pretreatment NLR that remained high even after treatment (median overall survival, 22.0 and 15.8 months, respectively; P<0.001). Conclusions A high posttreatment NLR is associated with poor prognosis. An early reduction in the NLR after effective treatment may indicate survival improvement in the patients with poor prognosis. © Springer-Verlag 2012.


Gwak H.-S.,National Cancer Center | Joo J.,Biometric Research Branch | Kim S.,Biometric Research Branch | Yoo H.,National Cancer Center | And 5 more authors.
Journal of Thoracic Oncology | Year: 2013

INTRODUCTION: Reports on the treatment result of leptomeningeal carcinomatosis (LMC) from a single primary cancer are rare and mixed treatment modalities make it even more difficult to interpret the results properly. Here, we report clinical outcomes of an intraventricular chemotherapy for LMC from non-small-cell lung cancer. METHODS: Medical records of 105 patients were retrieved and retrospectively analyzed to find the prognostic factors of patients' survival and symptom responses, including intracranial pressure (ICP) control. RESULTS: There were 44 men and 61 women, with a median age of 56 years (range, 31-75 years). Patients received a median five rounds of intraventricular chemotherapy (range, 1-49 rounds). The most common presenting symptom was headache (77%) with nausea or vomiting, which showed the highest response rate of 42%. Altered mentality (36%), cranial neuropathy (15%), and cauda equina symptoms (12%) revealed 10% or less of symptom response. Only eight patients (7.6%) showed negative conversion of cerebrospinal fluid cytology. Median overall survival was 3.0 months (range, 0.5-21.5 months). Age (≥60 years), poor Karnofsky performance score (< 70), and uncontrolled ICP were found to be unfavorable prognostic factors for patient survival. A greater amount of intraventricular chemotherapy, which was evaluated as time-dependent covariate, and concurrent systemic chemotherapy significantly improved overall survival in the multivariable analysis. CONCLUSION: Intraventricular chemotherapy for patients with LMC from non-small-cell lung cancer could palliate associated symptoms and prolong patients' survival. Careful selection of patients for intraventricular chemotherapy is recommended with aggressive ICP control and concurrent systemic chemotherapy. Copyright © 2013 by the International Association for the Study of Lung Cancer.


Lee Y.,Center for Lung Cancer | Shim H.S.,Yonsei University | Park M.S.,Yonsei University | Kim J.-H.,Yonsei University | And 4 more authors.
Clinical Cancer Research | Year: 2012

Purpose: This study aimed to search for predictors of epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKI) efficacy in previously treated patients with advanced squamous cell lung carcinoma in which EGFR mutations are very rare. Experimental Design: EGFR gene copy numbers were assessed by FISH and evaluated as predictors of EGFR-TKI efficacy in 71 patients with advanced squamous cell lung cancerwhoreceived gefitinib or erlotinib as a second-line or higher therapy. The tumors were classified into EGFR/FISH-positive (high polysomy/ gene amplification) and EGFR/FISH-negative (other) groups. Results: EGFR/FISH was positive in 19 (26.7%) patients. Only EGFR/FISH positive status was correlated with the EGFR-TKIs response (EGFR/FISH + vs. EGFR/FISH -, 26.3% vs. 2.0%; P = 0.005). In a multivariate analysis, the risk of progression was lower in EGFR/FISH-positive patients (HR of EGFR/FISH + vs. EGFR/ FISH -, 0.57; P = 0.057) or patients experiencing grade 2 or more rash (HR for rash grade 2 or more vs. less than 2, 0.54; P = 0.042), compared with EGFR/FISH-negative patients or those experiencing grade of less than 2 rash, respectively. When the combined criteria of EGFR/FISH and skin rash severity were analyzed, EGFR/FISH-negative patients with grade less than 2 rash had poorer clinical outcomes than patients with positive EGFR/FISH or grade 2 or more rash, apparent as a lower response rate (0.0% vs. 21.4%; P = 0.003) and a shorter median progression-free survival (1.13 months vs. 3.90 months; P = 0.0002). Conclusions: EGFR/FISH and skin rash severity may be used to identify which patients are likely to gain a benefit from EGFR-TKIs in this population. ©2012 AACR.


Park I.H.,Center for Lung Cancer | Kim J.Y.,Center for Lung Cancer | Jung J.I.,Center for Lung Cancer | Han J.-Y.,Center for Lung Cancer
Investigational New Drugs | Year: 2010

Lovastatin is a 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitor. Its inhibitory action on HMG-CoA reductase leads to depletion of isoprenoids, which inhibits post-translational modification of RAS. In this study, we investigated the effect of combining lovastatin with gefitinib on gefitinib-resistant human non-small cell lung cancer (NSCLC) cell lines with K-Ras mutations. Antitumor effects were measured by growth inhibition and 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. Effects on apoptosis were determined by flow cytometry, DNA fragmentation, and immunoblots. Protein levels of RAS, AKT/pAKT, and RAF/ERK1/2 in cancer cells were analyzed by immunoblot. Compared with gefitinib alone, a combination of gefitinib with lovastatin showed significantly enhanced cell growth inhibition and cytotoxicity in gefitinib-resistant A549 and NCI-H460 human NSCLC cells. In addition, lovastatin combination treatment significantly increased gefitinib-related apoptosis, as determined by fluorescence microscopy and flow cytometric analysis. These effects correlated with up-regulation of cleaved caspase-3, poly (ADP-ribose) polymerase (PARP), and Bax and down-regulation of Bcl-2. The combination of lovastatin and gefitinib effectively down-regulated RAS protein and suppressed the phosphorylation of RAF, ERK1/2, AKT, and EGFR in both cell lines. Taken together, these results suggest lovastatin can overcome gefitinib resistance, in NSCLC cells with K-Ras mutations, by down regulation of RAS protein, which leads to inhibition of both RAF/ERK and AKT pathways. © 2009 Springer Science+Business Media, LLC.

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