Publications by authors named "Wan-Seop Kim"

84 Publications

Fatty acid synthetase expression in triple-negative breast cancer.

J Pathol Transl Med 2022 Mar 21;56(2):73-80. Epub 2022 Jan 21.

Department of Pathology, Konkuk University Medical Center, Konkuk University School of Medicine, Seoul, Korea.

Background: Triple-negative breast cancer (TNBC) has a relatively poor prognosis. Research has identified potential metabolic targets, including fatty acid metabolism, in TNBC. The absence of effective target therapies for TNBC led to exploration of the role of fatty acid synthetase (FASN) as a potential target for TNBC therapy. Here, we analyzed the expression of FASN, a representative lipid metabolism-related protein, and investigated the association between FASN expression and Ki-67 and the programmed death ligand 1 (PD-L1) biomarkers in TNBC.

Methods: Immunohistochemical expression of FASN was analyzed in 166 patients with TNBC. For analytical purposes, patients with 0-1+ FASN staining were grouped as low-grade FASN and patients with 2-3+ FASN staining as high-grade FASN.

Results: FASN expression was observed in 47.1% of TNBC patients. Low and high expression of FASN was identified in 75.9% and 24.1%, respectively, and no statistically significant difference was found in T category, N category, American Joint Committee on Cancer stage, or recurrence rate between the low and high-FASN expression groups. Ki-67 proliferation level was significantly different between the low and high-FASN expression groups. FASN expression was significantly related to Ki-67 as the level increased. There was no significant difference in PD-L1 positivity between the low- and high-FASN expression groups.

Conclusions: We identified FASN expression in 166 TNBC patients. The Ki-67 proliferation index was positively correlated with FASN level, indicating higher proliferation activity as FASN increases. However, there was no statistical association with PD-L1 SP142, the currently FDA-approved assay, or FASN expression level.
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http://dx.doi.org/10.4132/jptm.2021.10.27DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8935000PMC
March 2022

Targeted Next-Generation Sequencing Analysis Predicts the Recurrence in Resected Lung Adenocarcinoma Harboring Mutations.

Cancers (Basel) 2021 Jul 20;13(14). Epub 2021 Jul 20.

Precision Medicine Lung Cancer Center, Konkuk University Medical Center, Seoul 05030, Korea.

Targeted NGS, widely applied to identify driver oncogenes in advanced lung adenocarcinoma, may also be applied to resected early stage cancers. We investigated resected -mutated lung adenocarcinoma mutation profiles to evaluate prognostic impacts. Tissues from 131 patients who had complete resection of stage I-IIIA -mutated lung adenocarcinoma were analyzed by targeted NGS for 207 cancer-related genes. Recurrence free survival (RFS) was estimated according to genetic alterations using the Kaplan-Meier method and Cox proportional regression analysis. The relapse rate was 25.2% (33/131). Five-year RFS of stages IA, IB, II, and IIIA were 82%, 75%, 35%, and 0%, respectively ( < 0.001). RFS decreased with the number of co-mutations ( = 0.025). Among co-mutations, the mutation was associated with short RFS in a multivariate analysis (hazard ratio: 5.4, 95% confidence interval: 2.1-14.4; = 0.001). mutations were associated with short RFS in stage IB-IIIA ( = 0.01). RFS was shorter with exon 19 deletion (19-del) than with mutation 21-L858R in stage IB-IIIA tumors ( = 0.008). Among 19-del subtypes, pL747_P753delinS (6/56, 8.9%) had shorter RFS than pE746_A750del (39/56, 69.6%), the most frequent subtype ( = 0.004).
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http://dx.doi.org/10.3390/cancers13143632DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8306820PMC
July 2021

Programmed Death Ligand 1 Immunohistochemistry in Triple-Negative Breast Cancer: Evaluation of Inter-Pathologist Concordance and Inter-Assay Variability.

J Breast Cancer 2021 Jun 26;24(3):266-279. Epub 2021 May 26.

Department of Pathology, Seoul National University Bundang Hospital, Seoul National University College of Medicine, Seongnam, Korea.

Purpose: The programmed death ligand 1 (PD-L1) SP142 assay with a 1% immune cell (IC) cutoff is approved for the selection of advanced triple-negative breast cancer (TNBC) patients for atezolizumab treatment. We aimed to evaluate the interobserver concordance of PD-L1 scoring and inter-assay variability of various PD-L1 assays in TNBC.

Methods: Thirty patients with primary TNBC were selected, and SP142, SP263, 22C3, and E1L3N assays were performed. PD-L1 staining in ICs and tumor cells (TCs) was scored by 10 pathologists who were blinded to the assay. The interobserver concordance among pathologists and the inter-assay variability of the four PD-L1 assays were analyzed. For SP142, the intraobserver concordance among the six pathologists was analyzed after training.

Results: The adjusted means of PD-L1 IC scoring ranged from 6.2% to 12.9% for the four assays; the intraclass correlations showed moderate (0.584-0.649) reader concordance. The PD-L1 IC scoring with a 1% cutoff resulted in identical scoring in 40.0%-66.7% of cases and a poor to moderate agreement (Fleiss κ statistic [FKS] = 0.345-0.534) for the four assays. The SP142 assay had the widest range of positive rate (56.5%-100.0%), lowest number of cases with identical scoring, and lowest FKS at 1% cutoff. Pairwise comparison of adjusted means showed significantly decreased PD-L1 staining in SP142 compared with the other assays in both ICs and TCs. As for the intraobserver concordance in the SP142 assay, the overall percent agreement was 87.8% with a 1% IC cutoff. After training, the proportion of cases with identical scoring at a 1% IC cutoff increased to 70.0%; the FKS also increased to 0.610.

Conclusion: The concordance of PD-L1 IC scoring among pathologists was low, at the 1% cutoff for the SP142 assay without training. SP142 showed the lowest PD-L1 expression in both IC and TC.
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http://dx.doi.org/10.4048/jbc.2021.24.e29DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8250096PMC
June 2021

Molecular biomarker testing for non-small cell lung cancer: consensus statement of the Korean Cardiopulmonary Pathology Study Group.

J Pathol Transl Med 2021 May 11;55(3):181-191. Epub 2021 May 11.

Department of Pathology, Pusan National University Hospital, Pusan National University School of Medicine, Busan, Korea.

Molecular biomarker testing is the standard of care for non-small cell lung cancer (NSCLC) patients. In 2017, the Korean Cardiopulmonary Pathology Study Group and the Korean Molecular Pathology Study Group co-published a molecular testing guideline which contained almost all known genetic changes that aid in treatment decisions or predict prognosis in patients with NSCLC. Since then there have been significant changes in targeted therapies as well as molecular testing including newly approved targeted drugs and liquid biopsy. In order to reflect these changes, the Korean Cardiopulmonary Pathology Study Group developed a consensus statement on molecular biomarker testing. This consensus statement was crafted to provide guidance on what genes should be tested, as well as methodology, samples, patient selection, reporting and quality control.
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http://dx.doi.org/10.4132/jptm.2021.03.23DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8141968PMC
May 2021

Genomic profiling of extracellular vesicle-derived DNA from bronchoalveolar lavage fluid of patients with lung adenocarcinoma.

Transl Lung Cancer Res 2021 Jan;10(1):104-116

Precision Medicine Lung Cancer Center, Konkuk University Medical Center, Seoul, Korea.

Background: Extracellular vesicles (EVs) are membrane-bound and nanometer-sized particles released from most types of cells, containing double-stranded DNA reflecting mutational status of the parental tumor cells. Furthermore, epidermal growth factor receptor (EGFR) genotyping using EV-derived DNA (EV DNA) in bronchoalveolar lavage fluid (BALF) showed almost 100% sensitivity in patients with advanced non-small cell lung cancer (NSCLC).

Methods: We assessed the technical performance of DNA derived from BALF-EV (BALF EV DNA) in targeted next-generation sequencing (NGS) for detection and quantification of mutations compared with the matching tissue DNA in 20 lung adenocarcinomas.

Results: DNA yields, tumor purity, and depth of coverage were higher using the tissue DNA than using the BALF EV DNA. However, estimated library size was not significantly different between the two samples, and BALF EV DNA yielded longer fragments than tissue DNA. Overall mutation concordance between the two samples were 56% for nonsynonymous somatic mutations and increased to 81% for clinically significant mutations. By-variant sensitivity for clinically significant somatic mutations increased from 62% to 83% in the NGS of BALF EV DNA. Allele frequencies of EGFR and TP53 were higher in tissue DNA (10-25%) than in BALF EV DNA (<5%). Tumor mutation burden of BALF EV DNA correlated with that of tissue DNA.

Conclusions: Our findings demonstrate, for the first time, that BALF EV DNA in patients with NSCLC can be a reliable DNA source for targeted NGS for the identification of actionable genetic alterations and that this approach has high clinical feasibility and utility.
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http://dx.doi.org/10.21037/tlcr-20-888DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7867756PMC
January 2021

Comprehensive Analysis of Cardiac Xeno-Graft Unveils Rejection Mechanisms.

Int J Mol Sci 2021 Jan 13;22(2). Epub 2021 Jan 13.

Departments of Surgery, Konkuk University Medical Center, Konkuk University School of Medicine, Seoul 05030, Korea.

Porcine heart xenotransplantation is a potential treatment for patients with end-stage heart failure. To understand molecular mechanisms of graft rejection after heart transplantation, we transplanted a 31-day-old (GTKO) porcine heart to a five-year-old cynomolgus monkey. Histological and transcriptome analyses were conducted on xenografted cardiac tissue at rejection (nine days after transplantation). The recipient monkey's blood parameters were analyzed on days -7, -3, 1, 4, and 7. Validation was conducted by quantitative real-time PCR (qPCR) with selected genes. A non-transplanted GTKO porcine heart from an age-matched litter was used as a control. The recipient monkey showed systemic inflammatory responses, and the rejected cardiac graft indicated myocardial infarction and cardiac fibrosis. The transplanted heart exhibited a total of 3748 differentially expressed genes compared to the non-transplanted heart transcriptome, with 2443 upregulated and 1305 downregulated genes. Key biological pathways involved at the terminal stage of graft rejection were cardiomyopathies, extracellular interactions, and ion channel activities. The results of qPCR evaluation were in agreement with the transcriptome data. Transcriptome analysis of porcine cardiac tissue at graft rejection reveals dysregulation of the key molecules and signaling pathways, which play relevant roles on structural and functional integrities of the heart.
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http://dx.doi.org/10.3390/ijms22020751DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7828557PMC
January 2021

ASO Author Reflections: CTNNB1 and Fusion Genes as Predictors for Recurrence in Resected Early-Stage Lung Adenocarcinoma.

Ann Surg Oncol 2021 Jul 5;28(7):3994-3995. Epub 2020 Nov 5.

Precision Medicine Lung Cancer Center, Konkuk University Medical Center, Seoul, Republic of Korea.

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http://dx.doi.org/10.1245/s10434-020-09323-7DOI Listing
July 2021

Targeted Next-Generation Sequencing Analysis for Recurrence in Early-Stage Lung Adenocarcinoma.

Ann Surg Oncol 2021 Jul 2;28(7):3983-3993. Epub 2020 Nov 2.

Precision Medicine Lung Cancer Center, Konkuk University Medical Center, Seoul, Republic of Korea.

Background: Despite surgical resection, early lung adenocarcinoma has a recurrence rate of 20-50%. No clear predictive markers for recurrence of early lung adenocarcinoma are available. Targeted next-generation sequencing (NGS) is rarely used to identify recurrence-related genes. We aimed to identify genetic alterations that can predict recurrence, by comparing the molecular profiles of patient groups with and without recurrence.

Methods: Tissues from 230 patients with resected stage I-II lung adenocarcinoma (median follow-up: 49 months) were analyzed via targeted NGS for 207 cancer-related genes. The recurrence-free survival according to the number and type of mutation was estimated using the Kaplan-Meier method. Independent predictive biomarkers related to recurrence were identified using the Cox proportional hazards model.

Results: Recurrence was observed in 64 patients (27.8%). In multivariate analysis adjusted for age, sex, smoking history, stage, surgical mode, and visceral pleural invasion, the CTNNB1 mutation and fusion genes (ALK, ROS1, RET) were negative prognostic factors for recurrence in early-stage lung adenocarcinoma (HR 4.47, p = 0.001; HR 2.73, p = 0.009). EGFR mutation was a favorable factor (HR 0.51, p = 0.016), but the CTNNB1/EGFR co-mutations were negative predictors (HR 19.2, p < 0.001). TP53 mutation was a negative predictor compared with EGFR mutation for recurrence (HR 5.24, p = 0.02).

Conclusions: Targeted NGS can provide valuable information to predict recurrence and identify patients at high recurrence risk, facilitating selection of the treatment strategy among close monitoring and adjuvant-targeted therapy. Larger datasets are required to validate these findings.
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http://dx.doi.org/10.1245/s10434-020-09276-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8184531PMC
July 2021

Liquid biopsy using extracellular vesicle-derived DNA in lung adenocarcinoma.

J Pathol Transl Med 2020 Nov 8;54(6):453-461. Epub 2020 Oct 8.

Precision Medicine Lung Cancer Center, Konkuk University Medical Center, Seoul, Korea.

Blood liquid biopsy has emerged as a way of overcoming the clinical limitations of repeat biopsy by testing for the presence of acquired resistance mutations to therapeutic agents. Despite its merits of repeatability and non-invasiveness, this method is currently only used as a supplemental test due to a relatively low sensitivity rate of 50%-60%, and cannot replace tissue biopsy. The circulating tumor DNAs used in blood liquid biopsies are passive products of fragmented DNA with a short half-life released following tumor cell death; the low sensitivity seen with liquid blood biopsy results from this instability, which makes increasing the sensitivity of this test fundamentally difficult. Extracellular vesicles (EVs) are ideal carriers of cancer biomarkers, as cancer cells secret an abundance of EVs, and the contents of tumor cell-originated EVs reflect the molecular and genetic composition of parental cells. In addition, EV-derived DNAs (EV DNAs) consist of large-sized genomic DNAs and tumor-specific oncogenic mutant DNAs. For these reasons, liquid biopsy using EV DNA has the potential to overcome issues arising from tissue shortages associated with small biopsies, which are often seen in lung cancer patients, and the biopsy product can be used in other diagnostic methods, such as epidermal growth factor receptor (EGFR) mutation testing and next-generation sequencing (NGS). A higher sensitivity can be achieved when EV DNAs obtained from bronchoalveolar lavage fluid (BALF) are used rather than those from blood. BALF, when obtained close to the tumor site, is a promising liquid biopsy tool, as it enables the gathering of both cellular and non-cellular fractions of the tumor microenvironment, and provides increased diagnostic sensitivity when compared to blood.
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http://dx.doi.org/10.4132/jptm.2020.08.13DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7674759PMC
November 2020

Concordance of Programmed Death-Ligand 1 Expression between SP142 and 22C3/SP263 Assays in Triple-Negative Breast Cancer.

J Breast Cancer 2020 Jun 1;23(3):303-313. Epub 2020 Jun 1.

Department of Pathology, Konkuk University School of Medicine, Seoul, Korea.

Purpose: Triple-negative breast cancer (TNBC) represents a major clinical challenge due to its aggressive and metastatic behavior and the lack of available targeted therapies. Therefore, therapeutic strategies are needed to improve TNBC patient management. Recently, atezolizumab and nab-paclitaxel chemotherapy has been approved by the Food and Drug Administration for the first-line treatment of patients with locally advanced and metastatic TNBC. The programmed death-ligand 1 (PD-L1) immunohistochemical SP142 assay was also approved as a companion diagnostic device for selecting TNBC patients for atezolizumab treatment. This study aimed to evaluate and compare the analytical performance of the PD-L1 22C3/SP263 assays in comparison with the SP142 assay for ≥ 1% immune cells (ICs).

Methods: Immunohistochemical expression for the PD-L1 22C3/SP263 assays, in comparison with the SP142 assay, was analyzed for the ≥ 1% ICs in 95 TNBCs.

Results: At the 1% cut-off value, the proportions of positive cases were 52.6% for the SP142 assay in infiltrating ICs and 50.5% and 52.6% for the 22C3 and SP263 assays in tumor cells, respectively. The PD-L1 SP263 assay had the highest while the PD-L1 22C3 assay had the lowest total positive expression rate at all cut-off values. The concordance rate between the assays was highest at a 1% cut-off value and decreased when the cut-off value increased. The concordance rate between the SP142 and SP263 assays at 1% cut-off was high, while in comparison, the concordance rate between the SP142 and 22C3 assays at 1% cut-off was relatively lower.

Conclusion: This study demonstrates that although the 22C3 assay at a 1% cut-off value compared with the PD-L1 SP142 assay at the clinically relevant cut-off shows comparable but not interchangeable analytical performance, the analytical performance of the SP263 assay at a 1% cut-off value shows interchangeable performance with the PD-L1 SP142 assay at the clinically relevant cut-off.
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http://dx.doi.org/10.4048/jbc.2020.23.e37DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7311361PMC
June 2020

Current status and future perspectives of liquid biopsy in non-small cell lung cancer.

J Pathol Transl Med 2020 May 15;54(3):204-212. Epub 2020 Apr 15.

Department of Pathology, Konkuk University Medical Center, Konkuk University School of Medicine, Seoul, Korea.

With advances in target therapy, molecular analysis of tumors is routinely required for treatment decisions in patients with advanced non-small cell lung cancer (NSCLC). Liquid biopsy refers to the sampling and analysis of circulating cell-free tumor DNA (ctDNA) in various body fluids, primarily blood. Because the technique is minimally invasive, liquid biopsies are the future in cancer management. Epidermal growth factor receptor (EGFR) ctDNA tests have been performed in routine clinical practice in advanced NSCLC patients to guide tyrosine kinase inhibitor treatment. In the near future, liquid biopsy will be a crucial prognostic, predictive, and diagnostic method in NSCLC. Here we present the current status and future perspectives of liquid biopsy in NSCLC.
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http://dx.doi.org/10.4132/jptm.2020.02.27DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7253954PMC
May 2020

High polymerase ε expression associated with increased CD8+T cells improves survival in patients with non-small cell lung cancer.

PLoS One 2020 20;15(5):e0233066. Epub 2020 May 20.

Macrogen Inc., Seoul, Republic of Korea.

DNA replicase polymerase ε (POLE) is critical in proofreading and correcting errors of DNA replication. Low POLE expression plays a pivotal role in accumulation of mutations and onset of cancer, contributing to development and growth of tumor cells. The aim of this study is to reveal the survival, alternative genes and antitumoral immune activities in non-small cell lung cancer (NSCLC) patients with low POLE expression and provide treatment strategies that can increase their survival rates. This study investigated the clinicopathologic parameters, various tumor-infiltrating lymphocytes (TILs), endogenous retrovirus, molecular interactions and in vitro drug screen according to POLE mutation/expression in 168 and 1,019 NSCLC patients from the Konkuk University Medical Center (KUMC) and the Cancer Genome Atlas, respectively. We identified mutations of 75 genes in the sequencing panels, with POLE frame shift p.V1446fs being the most frequent (56.8%) in KUMC based on 170 targeted sequencing panels. Mutant and high expression of POLE correlated with favorable prognosis with increased TILs and tumor mutation burden, compared with wild type and low expression of POLE. We found specific molecular interactions associated with cell cycle and antigen presentation. An in vitro drug screen identified dasatinib that inhibited growth of the NSCLC cell line with low POLE expression. POLE could contribute to the future development of anticancer drugs for patients with NSCLC.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0233066PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7239475PMC
July 2020

Risk factors for primary lung cancer among never-smoking women in South Korea: a retrospective nationwide population-based cohort study.

Korean J Intern Med 2020 05 19;35(3):692-702. Epub 2020 Feb 19.

Department of Occupational and Environmental Medicine, Seoul St. Mary's Hospital, of Medicine, The Catholic University of Korea, Seoul, Korea.

Background/aims: We performed a large-scale, retrospective, nationwide, cohort study to investigate the risk factors for lung cancer among never-smoking Korean females.

Methods: The study data were collected from a general health examination and questionnaire survey of eligible populations conducted between January 1, 2003 and December 31, 2004; the data were acquired from the tailored big data distribution service of the National Health Insurance Service. After a 1-year clearance period, 5,860,922 of 6,318,878 never-smoking female participants with no previous history of lung cancer were investigated. After a median follow-up of 11.4 years, 43,473 (0.74%) participants were defined as "newly diagnosed lung cancer".

Results: After adjusting for all variables at baseline, the variables older age, lower body mass index (BMI), less exercise, frequent alcohol drinking, meat-based diet, rural residence, and previous history of cancer were associated with a higher incidence of lung cancer. Low BMI (< 18.5 kg/m2: hazard ratio [HR], 1.33; 95% confidence interval [CI], 1.27 to 1.40) was a significant independent risk factor; as BMI decreased, HR increased. Negative associations between BMI and lung-cancer development were also observed after controlling for age (p for trend < 0.001). Drinking alcohol one to two times a week (HR, 1.25; 95% CI, 1.21 to 1.28) and eating a meat-based diet (HR, 1.08; 95% CI, 1.01 to 1.15) were associated with lung-cancer incidence.

Conclusion: Modifiable baseline characteristics, such as BMI, exercise, alcohol consumption, and diet, are risk factors for lung-cancer development among never- smoking females. Thus, lifestyle modifications may help prevent lung cancer.
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http://dx.doi.org/10.3904/kjim.2019.283DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7214358PMC
May 2020

Extracellular vesicle-based EGFR genotyping in bronchoalveolar lavage fluid from treatment-naive non-small cell lung cancer patients.

Transl Lung Cancer Res 2019 Dec;8(6):1051-1060

Precision Medicine Lung Cancer Center, Konkuk University Medical Center, Seoul, Republic of Korea.

Background: Extracellular vesicles (EV) have been proven to contain double-stranded DNA reflecting the mutational status of the parental tumor cells in non-small cell lung cancer (NSCLC), which can be translated into clinically useful EV-based liquid biopsy for Epidermal growth factor receptor (EGFR) genotyping using bronchoalveolar lavage fluid (BALF) obtained from tumor site.

Methods: Patients subjected for an initial lung cancer work-up underwent bronchoscopy and BALF was obtained from tumor site. After isolating EVs from BALF by ultracentrifugation, EV-derived DNA (EV DNA) was extracted for subsequent EGFR genotyping performed through peptide nucleic acid (PNA)-mediated Real-Time PCR. The sensitivity, specificity, and concordance rate of BALF EV-based EGFR genotyping were calculated in comparison to tissue genotyping.

Results: The average sensitivity and specificity of BALF EV-based EGFR genotyping were 76% and 87%, respectively, while the sensitivity significantly increased as the stage progressed. Especially, in stage IV, BALF EV-based EGFR typing identified all tissue-proven EGFR mutant cases (n=31) and detected 6 additional mutant cases. The concordance rate was 79% in stage I, 100% in stage II, 74% in stage III, and 92% in stage IV. As TNM stage advanced, especially in the presence of metastasis, concordance rate significantly increased (P<0.05).

Conclusions: The use of BALF for the collection of EV DNA in lung cancer patients resulted in a highly accurate diagnosis. The establishment of a fast and reliable method to identify target genes using EV DNA illustrated that it can overcome the problems of low sensitivity and instability in using cell-free DNA (cfDNA).
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http://dx.doi.org/10.21037/tlcr.2019.12.16DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6976373PMC
December 2019

Tannic Acid Promotes TRAIL-Induced Extrinsic Apoptosis by Regulating Mitochondrial ROS in Human Embryonic Carcinoma Cells.

Cells 2020 01 23;9(2). Epub 2020 Jan 23.

Department of Pathology, School of Medicine, Institute of Biomedical Science and Technology, Konkuk University, Seoul 05029, Korea.

Human embryonic carcinoma (EC; NCCIT) cells have self-renewal ability and pluripotency. Cancer stem cell markers are highly expressed in NCCIT cells, imparting them with the pluripotent nature to differentiate into other cancer types, including breast cancer. As one of the main cancer stem cell pathways, Wnt/β-catenin is also overexpressed in NCCIT cells. Thus, inhibition of these pathways defines the ability of a drug to target cancer stem cells. Tannic acid (TA) is a natural polyphenol present in foods, fruits, and vegetables that has anti-cancer activity. Through Western blotting and PCR, we demonstrate that TA inhibits cancer stem cell markers and the Wnt/β-catenin signaling pathway in NCCIT cells and through a fluorescence-activated cell sorting analysis we demonstrated that TA induces sub-G1 cell cycle arrest and apoptosis. The mechanism underlying this is the induction of mitochondrial reactive oxygen species (ROS) (mROS), which then induce the tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-mediated extrinsic apoptosis pathway instead of intrinsic mitochondrial apoptosis pathway. Moreover, ribonucleic acid sequencing data with TA in NCCIT cells show an elevation in TRAIL-induced extrinsic apoptosis, which we confirm by Western blotting and real-time PCR. The induction of human TRAIL also proves that TA can induce extrinsic apoptosis in NCCIT cells by regulating mROS.
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http://dx.doi.org/10.3390/cells9020282DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7072125PMC
January 2020

Effect of Prostaglandin E Injected Into Donors in a Heterotopic Heart Transplant Model of Sprague Dawley Rats.

Transplant Proc 2019 Oct;51(8):2808-2813

Department of Surgery, Konkuk University Hospital, Seoul, Republic of Korea. Electronic address:

Introduction: Prostaglandin E (PGE) administered to patients in the immediate post-transplant period has been known to reduce ischemic reperfusion injuries (IRIs), but the effect on IRI of PGE administered to the donor is unknown. The purpose of this study was to determine the effect on IRI of PGE injected into donor rats during heterotopic heart transplantation.

Methods: Genetically identical male Sprague Dawley rats with a body weight of 300-320 g at 8-9 weeks of age were used for the study. Experimental methods were the same in the control (G, n = 6) and experimental groups (G, n = 6), but only the donor rats in the experimental group received an intramuscular injection of PGE (5 μg/kg) prior to the donor surgery. On day 1 the animals were sacrificed with the removal of the transplanted heart. Histologic analysis was performed in the hematoxylin-eosin-stained slides to assess interstitial edema and neutrophil infiltration by a pathologist.

Results: Median times of the donor organ procurement, cold ischemia, and warm ischemia were 37, 69, and 35 minutes, respectively, in the G group and 38, 76.5, and 33 minutes respectively in G group; there were no statistical differences. Heartbeats were observed in the transplanted graft in 2 of the G group and 2 of G group immediately after heart transplantation, but in all transplanted grafts on day 1 after surgery. Histologic scores for neutrophil infiltration showed significantly lower in the G group than in the G group.

Conclusion: PGE administration to donors in a rat heart transplantation model may significantly reduce IRI.
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http://dx.doi.org/10.1016/j.transproceed.2019.01.198DOI Listing
October 2019

High prevalence of the MLH1 V384D germline mutation in patients with HER2-positive luminal B breast cancer.

Sci Rep 2019 07 29;9(1):10966. Epub 2019 Jul 29.

Department of Pathology, Konkuk University Medical Center, Konkuk University School of Medicine, Seoul, Korea.

HER2-positive luminal B breast cancer (BC), a subset of the luminal B subtype, is ER-positive and HER2-positive BC which is approximately 10% of all BC. However, HER2-positive luminal B BC has received less attention and is less represented in previous molecular analyses than other subtypes. Hence, it is important to elucidate the molecular biology of HER2-positive luminal B BC to stratify patients in a way that allows them to receive their respective optimal treatment. We performed molecular profiling using targeted next-generation sequencing on 94 HER2-positive luminal B BC to identify its molecular characteristics. A total of 134 somatic nonsynonymous mutations, including 131 nonsynonymous single nucleotide variants and three coding insertions/deletions were identified in 30 genes of 75 samples. PIK3CA was most frequently mutated (38/94, 40.4%), followed by TP53 (31/94, 33.0%), and others were detected at lower frequencies. Recurrent germline mutations of MLH1 V384D were found in 13.8% (13/94), with a significantly high TP53 mutations rate. The frequency of MLH1 V384D germline mutation in individuals with HER2-positive luminal B BC was significantly higher than that observed in the controls. All 13 cases were classified as microsatellite stable tumors. Tumor mutation burdens (TMB) were not significantly different between MLH1 V384D carrier and wild type. The concordant results of microsatellite instability (MSI) and TMB suggest that the haploinsufficiency of MLH1 plays a role as a tumor predisposition factor rather than a direct oncogenic driver. Our study identified, for the first time, that MLH1 V384D germline variant is frequently detected in HER2-positive luminal B BC. MLH1 V384D germline variant may not only contribute to gastrointestinal cancer predisposition but may also contribute to BC in East Asians.
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http://dx.doi.org/10.1038/s41598-019-47439-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6662670PMC
July 2019

Comprehensive analysis for diagnosis of preoperative non-invasive follicular thyroid neoplasm with papillary-like nuclear features.

PLoS One 2019 5;14(7):e0218046. Epub 2019 Jul 5.

Department of Pathology, Konkuk University Medical Center, Konkuk University School of Medicine, Seoul, Republic of Korea.

Objective: The current paradigm in the treatment of patients with non-invasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP) is a diagnostic lobectomy rather than complete thyroidectomy and postoperative radioiodine treatment. Consequently, preoperative diagnosis of NIFTP is considered to be important.

Methods: We performed the comprehensive analysis for diagnosis of preoperative 20 NIFTPs in comparison with 41 invasive encapsulated follicular papillary thyroid carcinomas (I-EFVPTCs) using the Korean Thyroid Imaging Reporting and Data System (K-TIRADS), Bethesda System for Reporting Thyroid Cytopathology (TBSRTC), and molecular analysis for BRAF and RAS mutations.

Results: K-TIRADS 3 was identified as the most common sonographic diagnosis in both NIFTP and I-EFVPTC. Unlike I-EFVPTC, K-TIRADS 5 was not identified in NIFTP. AUS/FLUS was the most common cytopathological diagnosis and none of the cases were classified as malignant category in both groups, although the difference in distribution was not significant between the groups. BRAF mutation was not found in NIFTP but was present in 9.8% of cases in I-EFVPTC. The frequency of RAS mutation in I-EFVPTCs was twice as high as that of NIFTP. Wild-type BRAF and RAS in NIFTP was significantly higher than I-EFVPTC.

Conclusion: The existence of overlapping features between the groups was evident, hence conclusive distinction between radiology, cytology and molecular analysis could not be achieved. Apparently, the diagnosis of NIFTP based on comprehensive analysis was not confirmable but could perceive or at least favor the diagnosis of NIFTP.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0218046PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6611592PMC
February 2020

Provisional Guideline Recommendation for EGFR Gene Mutation Testing in Liquid Samples of Lung Cancer Patients: A Proposal by the Korean Cardiopulmonary Pathology Study Group.

J Pathol Transl Med 2019 May 28;53(3):153-158. Epub 2019 Feb 28.

Department of Pathology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea.

Liquid biopsy for detection of mutation from circulating tumor DNA is a new technology which is attractive in that it is non-invasive. Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKI) is an effective first line drug for advanced non-small cell lung cancer patients who harbor activating EGFR mutation. During the course of treatment, resistance against TKI arises which can be contributed to EGFR T790M mutation in about 50-60% of patients. Third generation TKI may overcome the resistance. In patients who cannot undergo tissue biopsy due to variable reasons, liquid biopsy is an excellent alternative for the detection of EGFR T790M mutation. However, this relatively novel method requires standardization and vigorous quality insurance. Thus, a standard set of guideline recommendations for liquid biopsy for EGFR mutation testing suitable for the Korean medical community is necessary. In this article, we propose a set of provisional guideline recommendations that was discussed and approved by the Cardiopulmonary Pathology Study Group of the Korean Society of Pathologists.
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http://dx.doi.org/10.4132/jptm.2019.02.22DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6527939PMC
May 2019

Liquid biopsy using the supernatant of a pleural effusion for EGFR genotyping in pulmonary adenocarcinoma patients: a comparison between cell-free DNA and extracellular vesicle-derived DNA.

BMC Cancer 2018 Dec 10;18(1):1236. Epub 2018 Dec 10.

Department of Pulmonary, Lung Cancer Center, Konkuk University Medical Center and Medicine, Konkuk University School of Medicine, 120-1 Hwayang-dong, Gwangjin-Gu, Seoul, 05030, Republic of Korea.

Background: EGFR genotyping in pulmonary adenocarcinoma patients who develop pleural effusions is mostly performed using cytology or cell block slides with low sensitivity. Liquid biopsy using the supernatant of pleural effusions may be more effective because they contain many components released by cancer cells. Extracellular vesicles (EVs) are known to carry oncogenic double-stranded DNA that is considered a notable biomarker. Here, we investigate the efficiency of liquid biopsy using cell-free DNA (cfDNA) and extracellular vesicle-derived DNA (EV-derived DNA) from the supernatant of pleural effusions for EGFR genotyping in patients with pulmonary adenocarcinoma.

Methods: Fifty pleural effusion samples from patients with pulmonary adenocarcinoma were evaluated. The supernatant, after removing the cell pellet by centrifugation, was used for liquid biopsy, and EVs were isolated from the pleural effusion by ultracentrifugation. EV-derived DNA and cfDNA were extracted separately, and EGFR genotyping was performed by the PNA clamping method.

Results: Among 32 patients who were EGFR-tyrosine kinase inhibitor (TKI) naïve with a known tissue EGFR genotype, liquid biopsy using EV-derived DNA from the pleural effusion supernatant showed 100% matching results with tissue EGFR genotyping in 19 EGFR mutant cases and detected three additional EGFR mutations in patients with wild-type (WT) tissue. Liquid biopsy using cfDNA from pleural effusion supernatants missed two cases of tissue-based EGFR mutations and found two additional EGFR mutation cases. In 18 patients who acquired resistance to EGFR-TKI, EGFR genotyping using EV-derived DNA from the pleural effusion supernatant detected the T790 M mutation in 13 of 18 (72.2%) patients, and this mutation was detected in 11 (61.1%) patients using cfDNA. By contrast, only three patients were found to present the T790 M mutation when using cell block or cytology slides.

Conclusions: Liquid biopsy using the supernatant of pleural effusions showed significantly improved results for EGFR genotyping compared to those using conventional cell block or cytology samples. Liquid biopsy using EV-derived DNA is promising for EGFR genotyping, including T790 M detection in pulmonary adenocarcinoma patients who develop pleural effusions.
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http://dx.doi.org/10.1186/s12885-018-5138-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6288853PMC
December 2018

Role of MEL-18 Amplification in Anti-HER2 Therapy of Breast Cancer.

J Natl Cancer Inst 2019 Jun;111(6):609-619

Department of Pathology, College of Medicine.

Background: Resistance to HER2-targeted therapy with trastuzumab still remains a major challenge in HER2-amplified tumors. Here we investigated the potential role of MEL-18, a polycomb group gene, as a novel prognostic marker for trastuzumab resistance in HER2-positive (HER2+) breast cancer.

Methods: The genetic alteration of MEL-18 and its clinical relevance were examined in multiple breast cancer cohorts including METABRIC (n = 1,980), TCGA (n = 825), and our clinical specimens (n = 213, trastuzumab-treated HER2+ cases). MEL-18 amplification was validated by fluorescence in situ hybridization (FISH) analysis. The MEL-18 effect on trastuzumab response was confirmed by in vitro cell viability assays and an in vivo xenograft experiment (n = 7 per group). Gene expression microarray and receptor tyrosine kinase array were performed to identify the trastuzumab resistance mechanism by MEL-18 loss. All statistical tests were two-sided.

Results: MEL-18 was exclusively amplified in approximately 30-50% of HER2+ breast tumors and was associated with a favorable clinical outcome (disease-free survival: P = .02 in HER2+ cases, METABRIC; P = .04 in patients receiving trastuzumab). In MEL-18-amplified HER2+ breast cancer, MEL-18 depletion induced trastuzumab resistance by increasing ADAM sheddase-mediated ErbB ligand production and receptor heterodimerization. MEL-18 epigenetically silenced ADAM10/17 expression in cooperation with polycomb-repressive complex (PRC) 1 and PRC2. Combination treatment with an ADAM10/17 inhibitor and trastuzumab could overcome MEL-18 loss-mediated trastuzumab resistance in vivo (BT474/shMEL-18 xenograft: trastuzumab, mean [SD] tumor volume = 406.1 [50.1] mm3, vs trastuzumab + GW280264 30 mg/kg, mean [SD] tumor volume = 68.4 [15.6] mm3, P < .001). Consistently, trastuzumab-treated patients harboring concomitant MEL-18 amplification and low ADAM17 expression showed prolonged relapse-free survival (P = .02 in our cohort, n = 213).

Conclusion: MEL-18 serves to prevent ligand-dependent ErbB heterodimerization and trastuzumab resistance, suggesting MEL-18 amplification as a novel biomarker for HER2+ breast cancer.
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http://dx.doi.org/10.1093/jnci/djy151DOI Listing
June 2019

Cumulative smoking dose affects the clinical outcomes of EGFR-mutated lung adenocarcinoma patients treated with EGFR-TKIs: a retrospective study.

BMC Cancer 2018 Jul 28;18(1):768. Epub 2018 Jul 28.

Lung Cancer Center, Konkuk University Medical Center, 120-1 Hwayang-dong, Gwangjin-Gu, Seoul, 05030, Republic of Korea.

Background: Although lung adenocarcinoma with activating epidermal growth factor receptor (EGFR) mutations is common in never smokers, one-third of the patients are ever-smokers. We aimed to investigate the effect of cumulative smoking dose(CSD) on clinical outcomes, including progression-free survival (PFS) and overall survival (OS), in patients with EGFR-mutated lung adenocarcinoma receiving EGFR-tyrosine kinase inhibitors (TKIs).

Methods: We retrospectively analyzed 142 patients with EGFR-mutation positive advanced or recurrent lung adenocarcinoma who were administered gefitinib, erlotinib, afatinib, and osimertinib. These patients were classified based on their CSD as never smokers, light smokers (≤10 pack-years [PYs]), moderate smokers (11-30 PYs), and heavy smokers (> 30 PYs). PFS and OS were analyzed according to smoking subgroups via Kaplan-Meier curves.

Results: Among the 142 patients, 91 (64.1%), 12 (8.5%), 22 (15.5%), and 17 (12%) were never, light, moderate, and heavy smokers, respectively. CSD was inversely associated with median PFS in a statistically significant dose-dependent manner (11.8 months (mo), 11.0 mo, 7.4 mo, and 3.9 mo; p < 0.001). Statistically significant negative association was observed between CSD and median OS (33.6 mo, 26.3 mo, 20 mo, and 8.9 mo; p < 0.001). In the multivariate analysis adjusted for age, sex, performance status, stage, and timing of EGFR-TKIs, CSD was an independent predictive factor for disease progression (hazard ratio [HR], 4.00; 95% confidence interval [CI], 1.95-8.23; p = 0.012) and OS (HR, 3.9; 95% CI, 1.84-8.28; p < 0.001).

Conclusion: CSD is an important predictive and prognostic factor in patients with EGFR-mutated lung adenocarcinoma, and associated smoking-related gene signatures might affect the outcomes.
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http://dx.doi.org/10.1186/s12885-018-4691-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6064083PMC
July 2018

A Case of Concurrent De Novo C797S and L858R EGFR Mutation Detected in Stage IA Non-Small Cell Lung Cancer Patient.

J Thorac Oncol 2017 11;12(11):e179-e181

Department of Pathology, Konkuk University School of Medicine, Seoul, Republic of Korea.

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http://dx.doi.org/10.1016/j.jtho.2017.07.016DOI Listing
November 2017

Current Cytology Practices in Korea: A Nationwide Survey by the Korean Society for Cytopathology.

J Pathol Transl Med 2017 Nov 27;51(6):579-587. Epub 2017 Sep 27.

Department of Pathology, Inje University Busan Paik Hospital, Inje University College of Medicine, Busan, Korea.

Background: Limited data are available on the current status of cytology practices in Korea. This nationwide study presents Korean cytology statistics from 2015.

Methods: A nationwide survey was conducted in 2016 as a part of the mandatory quality-control program by the Korean Society for Cytopathology. The questionnaire was sent to 208 medical institutions performing cytopathologic examinations in Korea. Individual institutions were asked to submit their annual cytology statistical reports and gynecologic cytology-histology correlation data for 2015.

Results: Responses were obtained from 206 medical institutions including 83 university hospitals, 87 general hospitals, and 36 commercial laboratories. A total of 8,284,952 cytologic examinations were performed in 2015, primarily in commercial laboratories (74.9%). The most common cytology specimens were gynecologic samples (81.3%). Conventional smears and liquid-based cytology were performed in 6,190,526 (74.7%) and 2,094,426 (25.3%) cases, respectively. The overall diagnostic concordance rate between cytologic and histologic diagnoses of uterine cervical samples was 70.5%. Discordant cases were classified into three categories: category A (minimal clinical impact, 17.4%), category B (moderate clinical impact, 10.2%), and category C (major clinical impact, 1.9%). The ratio of atypical squamous cells of undetermined significance to squamous intraepithelial lesion was 1.6 in university hospitals, 2.9 in general hospitals, and 4.9 in commercial laboratories.

Conclusions: This survey reveals the current status and trend of cytology practices in Korea. The results of this study can serve as basic data for the establishment of nationwide cytopathology policies and quality improvement guidelines in Korean medical institutions.
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http://dx.doi.org/10.4132/jptm.2017.08.11DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5700880PMC
November 2017

Asymmetric Electron-Hole Decoherence in Ion-Gated Epitaxial Graphene.

Sci Rep 2017 09 21;7(1):12130. Epub 2017 Sep 21.

Center for Electricity and Magnetism, Korea Research Institute of Standards and Science, Daejeon, 34113, Republic of Korea.

We report on asymmetric electron-hole decoherence in epitaxial graphene gated by an ionic liquid. The observed negative magnetoresistance near zero magnetic field for different gate voltages, analyzed in the framework of weak localization, gives rise to distinct electron-hole decoherence. The hole decoherence rate increases prominently with decreasing negative gate voltage while the electron decoherence rate does not exhibit any substantial gate dependence. Quantitatively, the hole decoherence rate is as large as the electron decoherence rate by a factor of two. We discuss possible microscopic origins including spin-exchange scattering consistent with our experimental observations.
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http://dx.doi.org/10.1038/s41598-017-12425-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5608950PMC
September 2017

F-18 fluorodeoxyglucose positron emission tomography for differential diagnosis and prognosis prediction of vascular tumors.

Oncol Lett 2017 Jul 17;14(1):665-672. Epub 2017 May 17.

Department of Nuclear Medicine, Seoul National University Bundang Hospital, Seoul National University College of Medicine, Seongnam, Gyeonggi-do 13620, Republic of Korea.

The spectrum of vascular tumors ranges from hemangioma (HEM), to epithelioid hemangioendothelioma (EHE) and to angiosarcoma (AS). To the best of our knowledge, the usefulness of F-18 fluorodeoxyglucose positron emission tomography (FDG-PET) for vascular tumors has never been comprehensively studied. The present study investigated the usefulness of FDG-PET for pathologically diagnosed vascular tumors. The present study included 26 patients with vascular tumor (male:female, 17:9; age, 60.9±14.4 years; 7 HEM, 6 EHE and 13 AS) who underwent FDG-PET between January 2007 and May 2014 at the Seoul National University Bundang Hospital (Seongnam, Korea) and Konkuk University Medical Center, (Seoul, Korea). Representative FDG uptake was measured as the maximum standardized uptake value (SUVmax) over the lesion with the highest FDG uptake. Disease progression was clinically defined as the aggravation of known lesions or novel lesion development during follow-up on computed tomography, magnetic resonance imaging, or FDG-PET. FDG-PET revealed multi-organ involvement only in AS (6/13 [46.2%]), whereas HEM and EHE involved a single organ. Tumor SUVmax was significantly greater in AS (6.32±4.84) compared with EHE (3.10±2.68) and HEM (2.33±0.76) (P=0.0284). There was no difference in tumor SUVmax between HEM and EHE (P>0.05). Disease progression was primarily noticed in AS (9/13 [69.2%]). Only 1 patient with EHE (1/6=16.7%) and no patients with HEM (0/7=0%) experienced disease progression. Mortality was reported only in patients with AS (4/13 [30.8%]). Using the cutoff SUVmax of 3.0, the two-year progression-free survival rate of 14 patients with tumor SUVmax <3.0 (75.0%) was significantly higher compared with that of 12 patients with tumor SUVmax ≥3.0 (0%) (P=0.0053). In conclusion, FDG-PET is useful for the differential diagnosis and prognosis prediction of vascular tumors.
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http://dx.doi.org/10.3892/ol.2017.6192DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5494675PMC
July 2017

Nobiletin Inhibits Angiogenesis by Regulating Src/FAK/STAT3-Mediated Signaling through PXN in ER⁺ Breast Cancer Cells.

Int J Mol Sci 2017 Apr 30;18(5). Epub 2017 Apr 30.

Department of Pathology, School of Medicine, Institute of Biomedical Science and Technology, Konkuk University, Seoul 05029, Korea.

Tumor angiogenesis is one of the major hallmarks of tumor progression. Nobiletin is a natural flavonoid isolated from citrus peel that has anti-angiogenic activity. Steroid receptor coactivator (Src) is an intracellular tyrosine kinase so that focal adhesion kinase (FAK) binds to Src to play a role in tumor angiogenesis. Signal transducer and activator of transcription 3 (STAT3) is a marker for tumor angiogenesis which interacts with Src. Paxillin (PXN) acts as a downstream target for both FAK and STAT3. The main goal of this study was to assess inhibition of tumor angiogenesis by nobiletin in estrogen receptor positive (ER⁺) breast cancer cells via Src, FAK, and STAT3-mediated signaling through PXN. Treatment with nobiletin in MCF-7 and T47D breast cancer cells inhibited angiogenesis markers, based on western blotting and RT-PCR. Validation of in vitro angiogenesis in the human umbilical vein endothelial cells (HUVEC) endothelial cell line proved the anti-angiogenic activity of nobiletin. Electrophoretic mobility shift assay and the ChIP assay showed that nobiletin inhibits STAT3/DNA binding activity and STAT3 binding to a novel binding site of the gene promoter. We also investigated the migration and invasive ability of nobiletin in ER⁺ cells. Nobiletin inhibited tumor angiogenesis by regulating Src, FAK, and STAT3 signaling through PXN in ER⁺ breast cancer cells.
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http://dx.doi.org/10.3390/ijms18050935DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5454848PMC
April 2017

Molecular Testing of Lung Cancers.

J Pathol Transl Med 2017 May 21;51(3):242-254. Epub 2017 Apr 21.

Department of Pathology, National Cancer Center, Goyang, Korea.

Targeted therapies guided by molecular diagnostics have become a standard treatment of lung cancer. Epidermal growth factor receptor () mutations and anaplastic lymphoma kinase () rearrangements are currently used as the best predictive biomarkers for EGFR tyrosine kinase inhibitors and ALK inhibitors, respectively. Besides and , the list of druggable genetic alterations has been growing, including rearrangements, rearrangements, and alterations. In this situation, pathologists should carefully manage clinical samples for molecular testing and should do their best to quickly and accurately identify patients who will benefit from precision therapeutics. Here, we grouped molecular biomarkers of lung cancers into three categories-mutations, gene rearrangements, and amplifications-and propose expanded guidelines on molecular testing of lung cancers.
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http://dx.doi.org/10.4132/jptm.2017.04.10DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5445209PMC
May 2017

Diagnostic Limitation of Fine-Needle Aspiration (FNA) on Indeterminate Thyroid Nodules Can Be Partially Overcome by Preoperative Molecular Analysis: Assessment of RET/PTC1 Rearrangement in BRAF and RAS Wild-Type Routine Air-Dried FNA Specimens.

Int J Mol Sci 2017 Apr 12;18(4). Epub 2017 Apr 12.

Department of Surgery, Konkuk University School of Medicine, Seoul KS013, Korea.

Molecular markers are helpful diagnostic tools, particularly for cytologically indeterminate thyroid nodules. Preoperative rearrangement analysis in and wild-type indeterminate thyroid nodules would permit the formulation of an unambiguous surgical plan. Cycle threshold values according to the cell count for detection of the rearrangement by real-time reverse transcription-polymerase chain reaction (RT-PCR) using fresh and routine air-dried TPC1 cells were evaluated. The correlation of rearrangement between fine-needle aspiration (FNA) and paired formalin-fixed paraffin-embedded (FFPE) specimens was analyzed. rearrangements of 76 resected and wild-type classical PTCs were also analyzed. Results of RT-PCR and the Nanostring were compared. When 100 fresh and air-dried TPC1 cells were used, expression of rearrangement was detectable after 35 and 33 PCR cycles, respectively. The results of rearrangement in 10 FNA and paired FFPE papillary thyroid carcinoma (PTC) specimens showed complete correlation. Twenty-nine (38.2%) of 76 and wild-type classical PTCs had rearrangement. Comparison of rearrangement analysis between RT-PCR and the Nanostring showed moderate agreement with a κ value of 0.56 ( = 0.002). The rearrangement analysis by RT-PCR using routine air-dried FNA specimen was confirmed to be technically applicable. A significant proportion (38.2%) of the and wild-type PTCs harbored rearrangements.
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http://dx.doi.org/10.3390/ijms18040806DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5412390PMC
April 2017
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