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I.K. Park



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    MO10 - Molecular Pathology II (ID 127)

    • Event: WCLC 2013
    • Type: Mini Oral Abstract Session
    • Track: Pathology
    • Presentations: 1
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      MO10.11 - Genetic polymorphisms of TERT and TP63 genes are associated with exon 18 and exon 21 mutations of EGFR in adenocarcinoma of the lung. (ID 3046)

      17:15 - 17:20  |  Author(s): I.K. Park

      • Abstract
      • Presentation
      • Slides

      Background
      The presence of mutations of epidermal growth factor receptor (EGFR) is related to phenotypical characteristics such as ethnicity, gender and smoking status. Such observations led us to explore associations between genetic polymorphisms and EGFR mutational status.

      Methods
      We set up a set of samples from 677 primary pulmonary adenocarcinoma. We tested two genetic polymorphisms (rs2736100 and rs10937405), which were discovered previously as to be associated with the risk of lung adenocarcinoma. The association between EGFR mutational status and genetic polymorphisms were evaluated using logistic regression analysis.

      Results
      In 673 patients, four exons (18, 19, 20, 21) of EGFR were completely evaluated. Presence of EGFR mutations were found in 382 (56.8%) patients. In logistic regression analysis, female gender (aOR, 1.7 with 95% CI, 1.0-2.9) and smoking status (ex-smoker, aOR, 0.6 with 95% CI, 0.4-1.1; current smoker aOR, 0.4 with 95% CI, 0.2-0.8) were associated with presence of EGFR mutations. None of two single nucleotide polymorphism (SNP) sites showed significant association. In the analysis of individual type of EGFR mutations, however, we found a significant association between EGFR exon 18 mutations and a SNP rs27366100T/G located in TERT. The G/G genotype showed a 2.8-fold increase in the occurrence of the EGFR exon 18 mutations compared to T/T+G/T genotypes (aOR, 2.8 with 95% CI, 1.2-8.7). Additionally, C/T+T/T genotypes of rs10937405C/T SNP in TP63 showed frequnt occurrences of EGFR exon 21 mutations compared to CC genotype (aOR, 1.5 with 95% CI, 1.0-2.3).

      Conclusion
      Our findings suggest that the somatic mutations of EGFR may be closely associated with genetic polymorphisms. Further investigation of this field may enable us to identify patients who may get a benefit from EGFR inhibitors.

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    O09 - General Thoracic Surgery (ID 100)

    • Event: WCLC 2013
    • Type: Oral Abstract Session
    • Track: Surgery
    • Presentations: 1
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      O09.06 - Prognostic factors for long-term survival in non-small cell lung cancer patients with interstitial lung disease (ID 3453)

      17:10 - 17:20  |  Author(s): I.K. Park

      • Abstract
      • Presentation
      • Slides

      Background
      There is little information about prognosis after pulmonary resections for non-small cell lung cancer (NSCLC) in patients with interstitial lung disease (ILD). In this study, we examined the long-term outcome and the factors that affect long-term survival after resection for NSCLC in patients with ILD.

      Methods
      Between September 1996 and May 2011, 71 NSCLC patients were diagnosed as having ILD based on the CT and pathological findings. The extent of ILD on CT was scored visually at the level of 3 cm above the diaphragm as follows: minimal, <2 cm from the subpleura at the base of the lungs; moderate, >2 cm from the subpleura, but less than one-third of the lung area at the base of the lungs; severe, more than one-third of the lung area at the base of the lungs. Various clinical values such as gender, age, preoperative chemotherapy, severity of ILD on CT, preoperative pulmonary function test results, arterial blood gas studies, operative procedure, pathologic stage, cell type, and adjuvant treatment were evaluated using univariate and multivariate analysis.

      Results
      The mean age was 65.9 years, and the majority of patients were male(65:91.5%). In-hospital mortality was 9.9% (7/71). The causes of early mortality included pneumonia (n=4), acute respiratory distress syndrome (n=2), and acute exacerbation of ILD (n=1). The 5-year overall survival rate was 43.1% (stage I: 59.4%, stage II: 41.3%, stage III: 35.0%, respectively). In univariate analysis, the risk factors for long-term mortality were lower preoperative FEV~1~, FVC, severe ILD on CT, presence of pathologic pulmonary fibrosis, and non-squamous cell type. In multivariate analysis, severity of ILD on CT and non-squamous cell type remained as poor prognostic factors.Figure 1

      Conclusion
      Although patients with ILD undergoing pulmonary resection for NSCLC has resulted in a high in-hospital mortality, long-term survival can be expected in highly selected patients. NSCLC patients with severe ILD on CT findings and those with non-squamous cell type should be carefully selected for major pulmonary resection.

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    P1.19 - Poster Session 1 - Imaging (ID 179)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Imaging, Staging & Screening
    • Presentations: 1
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      P1.19-015 - Clinical application of thin section chest CT with computer-aided detection system for the detection of small metastatic nodules in pulmonary metastasectomy. (ID 3428)

      09:30 - 09:30  |  Author(s): I.K. Park

      • Abstract

      Background
      It is important to identify possible metastatic nodule prior to metastasectomy, in order to perform complete resection. Thin section chest CT (TSCT) can detect small metastatic nodules more accurately than conventional chest CT. Conventional CT is known to miss metastatic nodules that are manually palpable by up to 40%. Reported sensitivity of helical CT cannot exceed 90%, also. We adopted TSCT and applied computer-aided detection (CAD) system for the search of small metastatic nodules to improve the detection power of TSCT.

      Methods
      From March 2009 to February 2013, 333 patients were referred to thoracic surgeon for pulmonary metastasectomy. TSCT with CAD was performed in every candidate for pulmonary metastasectomy. Every nodule detected by TSCT and CAD was annotated by radiologists and the whole map and annotation numbers of nodules were reported before operation. Intraoperatively, bi-manual palpation in open metastasectomy and finger palpation in video assisted thoracoscopic surgery (VATS) were used to detect the nodules. Only operations with complete available data were included in the study and 251 operations from 239 patients were analyzed.

      Results
      A total of 1021 nodules were identified by TSCT with CAD, while 115 nodules (11.3%) were additionally detected by CAD. Among the annotated nodules, 742 nodules were palpable during operation. Including intraoperatively detected 49 nodules, a total of 824 nodules were resected. Of 527 pathologically proven malignant nodules, 518 (62.9%) nodules were metastatic lesions. Among metastatic lesions, 496 were detected by TSCT (95.8%), 9 by CAD (1.7%) and 13 by manual palpation (2.5%). Also, 11 metastatic nodules were no palpated during operation but resected according to the annotation on CT. The overall sensitivity of thin section chest CT with CAD was 97.5%. Though overall specificity of TSCT with CAD was very low as 12.1% because that of radiologist’s reading was 14.2%, specificity only for CAD was 45.6%.

      Conclusion
      TSCT could detect small subcentimetre nodules and CAD enabled detecting additional small nodules. With help of TSCT with CAD, even the metastatic nodules, which were not palpable during operation, could successfully be resected. Furthermore, TSCT with CAD could detect tiny nodules with rather high specificity compare to radiologist’s reading only. Although the number of true metastatic nodules was small and several metastatic nodules were undetected, the TSCT with CAD system increased the detection sensitivity and would be helpful in complete metastasectomy.

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    P3.07 - Poster Session 3 - Surgery (ID 193)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Surgery
    • Presentations: 1
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      P3.07-028 - Long-term result of robot-assisted esophagectomy for esophageal cancer: Technical feasibility and oncological reliability. (ID 2229)

      09:30 - 09:30  |  Author(s): I.K. Park

      • Abstract

      Background
      Whether robot-assisted esophagectomy is a technically feasible and oncologically reliable operation for esophageal cancer has not been proven. This study aimed to evaluate short-term and long-term outcomes of robot-assisted esophagectomy.

      Methods
      Robot-assisted esophagectomy was performed in prone position for cervical anastomosis or lateral position for intrathoracic anastomosis. Thoracic procedures were performed by totally robotic technique and abdominal procedures were performed by robot or laparotomy. Two field lymph node dissection was performed in all patients and dissection along both recurrent laryngeal nerves was performed in the patients with T1b or more stages. Retrospective review on short-term and long-term outcomes for robot-assisted esophagectomy was performed.

      Results
      Robot-assisted esophagectomy was performed in 46 patients between 2008 and 2013, which was 16% of total esophagectomy cases during the same period. There were 43 men and 3 women and mean age was 63.9 ± 8.2 years. Preoperative clinical stages were IA in 19 patients (41%), IB in 8 (17%), IIA in 6 (13%), IIB in 9 (20%), and IIIA in 4 (9%). Neoadjuvant chemoradiation was performed in 5 patients (11%). Abdominal procedures were performed by robot in 29 patients (63%) and by laparotomy in 16 (35%). R0 resection was accomplished in 45 patients (98%) and mean operation time including robot docking time were 512 ± 104 minutes. Total 2-field lymph node dissection along bilateral recurrent laryngeal nerve was performed in 32 patients (70%) and mean number of dissected lymph nodes were 29.1 ± 14.1. Cell types of esophageal cancer were squamous cell carcinoma in 45 patients (98%) and melanoma in 1 patient (2%). Pathologic stages were IA in 9 patients (20%), IB in 19 (41%), IIA in 2 (4%), IIB in 11 (24%), IIIA in 4 (9%), and IIIB in 1 (2%). There were one 30-day mortality (2%) and postoperative complication occurred in 15 patients (33%); respiratory complication in 5 patients (11%), anastomosis site leakage in 5 (11%), and vocal cord palsy requiring treatment in 3 (7%). Overall 5-year survival was 88% and 5-year freedom from recurrence was 73%. Locations of recurrence were regional in 4 patients (9%), distant in 4 (9%), and there was no local recurrence.

      Conclusion
      Robot-assisted esophagectomy was technically feasible and oncologically reliable surgery in this study. Further studies based on large series of data are necessary to prove advantages of robot-assisted esophagectomy.

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    P3.18 - Poster Session 3 - Pathology (ID 177)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Pathology
    • Presentations: 2
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      P3.18-016 - The usefulness of frozen section diagnosis as for the decision making milestone during the surgery for pulmonary ground glass nodules: embedding medium inflation technique (ID 2946)

      09:30 - 09:30  |  Author(s): I.K. Park

      • Abstract

      Background
      The appropriate intraoperative decision making of surgical resection for the pulmonary ground glass nodules (GGN) is often difficult. We aimed to evaluate the role of frozen section diagnosis (FSD) as for the intraoperative decision making milestone and compared its accuracy to that of preoperative CT based practice as an interim result.

      Methods
      We retrospectively reviewed FSD of 171 consecutive pulmonary GGN from February 2005 to June 2013 and compared the diagnostic accuracy. Initially, we used only conventional method (Group A) but recently, we adapted a embedding medium inflation method (Group B) for FSD. The qualities of FSD were compared with the final pathologic diagnoses of corresponding permanent paraffin sections. Also, we calculated the sensitivity, specificity, and predictive values of assessing the size of invasive portion in GGN between FSD using the inflation method and preoperative CT based practice.

      Results
      There were no differences in nodule sizes between two groups (1.45±0.6 versus 1.51±0.5, p=0.63). In group A, a correct differential diagnosis between malignancies and benign lesions were made in 138 nodules. Thirteen nodules were erroneously classified and reported as false-positive or false-negative frozen section diagnoses (Sensitivity 95.6%, Specificity 53.8%). Three nodules were under-diagnosed in FSD. One patient required a secondary operation because of false-negative frozen diagnosis at the time of initial surgery. In group B, all of 17 nodules were correctly classified by frozen section. There were no false-positive or false-negative diagnoses in terms of making a diagnosis of malignancy, resulting in 100%-sensitivity and -specificity. (Figure 1) Thirteen nodules were correctly classified as being either minimally invasive adenocarcinoma (MIA) or invasive adenocarcinoma. Three nodules were diagnosed as MIA by frozen section through measuring invasive tumor size (<5mm) concomitantly. With regards to the estimating the size of invasive components of GGN, FSD in group B was superior to measurement of solid component in GGO nodules on HRCT. (Table 1)Figure 1

      Conclusion
      The accuracy of FSD using the embedding medium inflation method in GGO nodules was outstanding compared to the conventional frozen method. Furthermore, this method can help surgeons plan the appropriate surgical treatment after wedge resection of a GGO nodule by providing accurate size estimation of the invasive components of the GGN.

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      P3.18-020 - The mutational profile of lung adenocarcinoma in Korean population (ID 3097)

      09:30 - 09:30  |  Author(s): I.K. Park

      • Abstract

      Background
      Recent development of molecular target agents encouraged us to investigate the presence of driver mutations in patients with non-small cell lung cancer. As the prevalence of individual driver mutation is different in each ethnic group, understanding of mutational profiles of a specific country is important for clinical practice as well as for decision-making process of health care. Hence, we investigated the genetic profile of lung adenocarcinoma in Korean population.

      Methods
      Among the patients who underwent surgical resection for lung adenocarcinoma between 2001 and 2011, we set up a total of 477 patients whose fresh frozen lung cancer tissues and paraffin blocks were available. We retrospectively searched medical records of the EGFR exons 18-21 mutation tests results. Then, we selected patients who did not harbor EGFR mutations or who had not tested for EGFR mutations. DNA was extracted from those patients’ samples, and EGFR exons 18-21 and KRAS mutation test were performed by Sanger sequencing method. Tissue microarray was made for all 477 patients, and the EML4-Alk fusion was tested by a break-apart FISH method. We also tested KIF5B-RET fusion by using a break-apart FISH method and also by inversion specific long-range PCR. We investigated any correlation between mutational status and clinical variables, such as age, gender, smoking status, stage, and long term survivals.

      Results
      Among 477 patients, 321 patients (67.3%) were harboring at least one of four driver mutations. The EGFR mutations were the most frequently detected (270, 56.6%), followed by KRAS mutations (37, 7.8%), and EML4-Alk fusion (19, 4.0%). We also found five patients who had KIF5B-RET fusion mutations (1.0%). There were 10 patients who had more than two driver mutations; EGFR and KRAS mutations in 4, EGFR and EML4-Alk fusion in 4, KRAS and EML4-Alk fusion in one, and EGFR and KIF5B-RET fusion in one patient. The presences of EGFR mutations were frequently observed in patients with female gender (p=0.000). Although the EGFR mutations were associated with longer overall survival in univariate analysis (log-rank test rank test p=0.007), the presence of EGFR mutation was not a prognostic factor in multivariate analysis (Cox’s regression test p=0.469). The mutational statuses were associated with neither the disease-free survival nor fthe reedom from recurrence.

      Conclusion
      Based on our work, we found as high as 67.3% of lung adenocarcinoma patients in Korean populations were harboring at least one driver mutation, which may get a benefit from target agents. We also found as high as 2% of patients harbored multiple driver mutations. As the target agent will eventually develop resistance, it is recommended to test each driver mutation thoroughly even if one driver mutation was detected. Furthermore, our observation suggests future molecular testing should be based on the next generation sequencing platform.

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    P3.19 - Poster Session 3 - Imaging (ID 181)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Imaging, Staging & Screening
    • Presentations: 1
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      P3.19-014 - CT Morphologic Patterns, Pathologic Subtypes, and Genetic Phenotypes: A Correlation Study in 600 Nodular Lung Adenocarcinomas (ID 2094)

      09:30 - 09:30  |  Author(s): I.K. Park

      • Abstract

      Background
      Genotype manifests itself as phenotype and that the one may inform the other. In terms of phenotype, imaging has the potential to assist in noninvasively characterizing the tumor, however, there are very few investigators who have pursued that potential connection between imaging features and the genetic characteristics of lung cancer. The purpose of this study was to retrospectively correlate the CT morphologic patterns of nodular lung adenocarcinomas (ADs) with pathological and molecular phenotypes in an East-Asian cohort of patients.

      Methods
      The institutional review board approved this retrospective study, and all patients provided informed consent. 600 primary lung ADs smaller than 3 cm in diameter that were surgically resected from 592 patients (M:F=257:335; mean age, 63) were included. CT morphologic pattern of ADs was evaluated by three board-certified thoracic radiologists and was classified into four patterns: pure GGN, GGO dominant part-solid nodule (PSN), solid dominant PSN, and pure solid nodule. EGFR mutation, ALK rearrangement, and KRAS mutation were evaluated using PCR-based direct DNA sequencing and FISH. Histologic subtype was classified according to IASLC/ATS/ERS classification of lung AD. The Fisher exact test and student t-test were used to assess statistical significance.

      Results
      Figure 1 In terms of CT morphologic patterns, 17.2%,15.2%, 31.8%, and 35.8% of tumors manifested as pure GGN, GGO dominant PSNs, solid dominant PSNs, and pure solid nodules, respectively. EGFR mutation was significantly more often found in ADs that manifested as subsolid nodules (69.9%, 269/385) than in ADs presented as pure solid nodules (46.7%, 100/214) (P<.0001). ALK rearrangement was more frequent in ADs that manifested as pure solid nodule (8.5%, 13/153) than in tumors presented as subsolid nodule (1.8%, 5/281) (P=.001). KRAS mutation showed no significant difference between subsolid nodules (6.6%, 8/121) and pure solid nodules (8.5%, 5/59) (P=.760). The ratio of subsolid nodule vs pure solid nodule was 72.7% vs 27.3% in ADs with EGFR mutation and was 27.8% vs 72.2% in ADs with ALK rearrangement. EGFR mutation was more frequent in minimally invasive ADs (P=.004) and lepidic predominant ADs (P=.018). ALK rearrangement was more frequent in solid predominant ADs (P=.002) and invasive mucinous ADs (P=.030). KRAS mutation was more frequent in invasive mucinous ADs (P=.001).

      Conclusion
      EGFR mutation was significantly more often found in ADs that manifested as subsolid nodules, and ALK rearrangement was more frequent in ADs that manifested as pure solid nodule.

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    P3.21 - Poster Session 3 - Diagnosis and Staging (ID 171)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Prevention & Epidemiology
    • Presentations: 1
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      P3.21-006 - The N-classification Based on the Number of Metastatic Lymph Node is Superior to Regional N-classification in Predicting Outcomes After Surgical Resection for Non-small Cell Lung Cancer. (ID 1764)

      09:30 - 09:30  |  Author(s): I.K. Park

      • Abstract

      Background
      In many cancers, the N-classification of current TNM stage is categorized by the number of positive lymph nodes. However, for non-small cell lung cancer (NSCLC), it is classified by the involvement of specific regional node groups. The aim of this study is to make a new N-classification grouping (nN stage) based upon the number of metastatic lymph nodes and to evaluate its prognostic significance in predicting outcome after resection of NSCLC.

      Methods
      Between January 2000 and April 2011, 2319 patients underwent surgery for NSCLC in our hospital. A total of 1982 patients was selected by excluding patients who received preoperative induction therapy or did not get curative resection and those with pN3 metastatic lymph nodes. Prospectively collected clinical information as well as pathologic variables were retrospectively analyzed. The recursive partitioning analysis was applied to define the most significant cut-off number of metastatic lymph nodes. We then analyzed overall and disease-free survival using the new nN stage grouping to test if it can provide more accurate classification compared to the conventional N stage grouping.

      Results
      Recursive partitioning analysis identified patients could be divided into three distinct groups according to the number of metastatic lymph nodes: nN0 (none), nN1 (1-7), nN2 (>7). Among 1982 patients, 1371 patients were nN0, 538 were nN1, and 73 were nN2. The 5-year overall survival rates were 79.8%, 62.1% and 36.1% for nN0, nN1, and nN2, respectively, and they were statistically different (p < 0.001, log-rank test). For conventional N stage, 1371 patients were pN0, 284 were pN1, and 327 were pN2. The 5-year survival rates were 79.8%, 63.8%, and 54.8% for pN0, pN1, and pN2 stages, respectively (p < 0.001, log-rank test). The chi-square value of nN stage was superior to that of pN stage (141.02 vs. 117.16). When we further analyzed those with pN2 patients, the nN1/pN2 group showed a significantly better survival rate than nN2/pN2 group (p < 0.001, log-rank test). Moreover, the overall survival of nN1/pN2 patients was not different from that of nN1/pN1 patients. (p = 0.074, log-rank test) Figure 1

      Conclusion
      The nN-classification seemed to predict long-term survival more accurately compared to conventional N stage grouping. Our result suggested the new N stage grouping based on the number of metastatic lymph node should be considered for the next revision of the TNM classification system for NSCLC.