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author:("Kim, chinook")
1.  Mitochondrial Variations in Non-Small Cell Lung Cancer (NSCLC) Survival 
Cancer Informatics  2015;14(Suppl 1):1-9.
Mutations in the mtDNA genome have long been suspected to play an important role in cancer. Although most cancer cells harbor mtDNA mutations, the question of whether such mutations are associated with clinical prognosis of lung cancer remains unclear. We resequenced the entire mitochondrial genomes of tumor tissue from a population of 250 Korean patients with non-small cell lung cancer (NSCLC). Our analysis revealed that the haplogroup (D/D4) was associated with worse overall survival (OS) of early-stage NSCLC [adjusted hazard ratio (AHR), 1.95; 95% CI, 1.14–3.33; Ptrend = 0.03]. By comparing the mtDNA variations between NSCLC tissues and matched blood samples, we found that haplogroups M/N and/or D/D4 were hotspots for somatic mutations, suggesting a more complicated mechanism of mtDNA somatic mutations other than the commonly accepted mechanism of sequential accumulation of mtDNA mutations.
PMCID: PMC4310616  PMID: 25657573
mitochondria genome; mitochondria mutations; lung cancer survival; haplogroup; mitochondrial genome resequencing
2.  Integrative and Comparative Genomic Analysis of Lung Squamous Cell Carcinomas in East Asian Patients 
Journal of Clinical Oncology  2013;32(2):121-128.
Lung squamous cell carcinoma (SCC) is the second most prevalent type of lung cancer. Currently, no targeted therapeutics are approved for treatment of this cancer, largely because of a lack of systematic understanding of the molecular pathogenesis of the disease. To identify therapeutic targets and perform comparative analyses of lung SCC, we probed somatic genome alterations of lung SCC by using samples from Korean patients.
Patients and Methods
We performed whole-exome sequencing of DNA from 104 lung SCC samples from Korean patients and matched normal DNA. In addition, copy-number analysis and transcriptome analysis were conducted for a subset of these samples. Clinical association with cancer-specific somatic alterations was investigated.
This cancer cohort is characterized by a high mutational burden with an average of 261 somatic exonic mutations per tumor and a mutational spectrum showing a signature of exposure to cigarette smoke. Seven genes demonstrated statistical enrichment for mutation: TP53, RB1, PTEN, NFE2L2, KEAP1, MLL2, and PIK3CA). Comparative analysis between Korean and North American lung SCC samples demonstrated a similar spectrum of alterations in these two populations in contrast to the differences seen in lung adenocarcinoma. We also uncovered recurrent occurrence of therapeutically actionable FGFR3-TACC3 fusion in lung SCC.
These findings provide new steps toward the identification of genomic target candidates for precision medicine in lung SCC, a disease with significant unmet medical needs.
PMCID: PMC4062710  PMID: 24323028
3.  Is video-assisted thoracic surgery lobectomy in benign disease practical and effective? 
Journal of Thoracic Disease  2014;6(9):1225-1229.
The aim of this study was to analyze the surgical outcomes of video-assisted thoracic surgery (VATS) lobectomy for benign pulmonary disease and to propose surgical guidelines based on the retrospective cohort study.
From January 2004 to December 2009, all lobectomies performed in a university-based tertiary care hospital were analyzed. The inclusion criteria were as follows: (I) VATS lobectomy for benign disease; (II) thoracotomy conversion cases initially approached by VATS lobectomy. All malignant cases were excluded. Electronic medical records were retrospectively analyzed and patients were divided into two groups: with infection and without infection. The primary outcomes were the thoracotomy conversion rate, length of hospital stay, period of thoracic drainage and complications.
VATS was performed in 163 (42%) of 385 patients who underwent lobectomy for benign disease. There were 68 in the infection group and 95 in the group without infection. VATS lobectomy was successful in 157 (96%) patients while 6 were converted into thoracotomy. The mean operation time and blood loss were 160 minutes and 326 mL. Comparing two groups, operation time and blood loss were not statistically different (P value =0.92, 0.63). Moreover conversion rate, length of hospital stay, period of thoracic drainage and complications (P value =0.67, 0.18, 0.25, and 0.50) were not different.
VATS lobectomy for benign disease is practical and effective in selected cases regardless of the presence of infection. However, because various technical obstacles may be encountered during the procedure, therefore, careful patient selection is needed.
PMCID: PMC4178091  PMID: 25276364
Minimally invasive surgery; lobectomy (lung); lung benign or congenital lesions
4.  Mycobacterium abscessus Lung Disease in a Patient with Kartagener Syndrome 
Primary ciliary dyskinesia (PCD) is characterized by the congenital impairment of mucociliary clearance. When accompanied by situs inversus, chronic sinusitis and bronchiectasis, PCD is known as Kartagener syndrome. The main consequence of impaired ciliary function is a reduced mucus clearance from the lungs, and susceptibility to chronic respiratory infections due to opportunistic pathogens, including nontuberculous mycobacteria (NTM). There has been no report of NTM lung disease combined with Kartagener syndrome in Korea. Here, we report an adult patient with Kartagener syndrome complicated with Mycobacterium abscessus lung disease. A 37-year-old female presented to our hospital with chronic cough and sputum. She was ultimately diagnosed with M. abscessus lung disease and Kartagener syndrome. M. abscessus was repeatedly isolated from sputum specimens collected from the patient, despite prolonged antibiotic treatment. The patient's condition improved and negative sputum culture conversion was achieved after sequential bilateral pulmonary resection.
PMCID: PMC4192312  PMID: 25309609
Kartagener Syndrome; Primary Ciliary Dyskinesia; Bronchiectasis; Nontuberculous Mycobacteria; Mycobacterium Infections, Nontuberculous
5.  Thoracoscopic Removal of Ectopic Mediastinal Parathyroid Adenoma 
Ectopic mediastinal parathyroid adenomas or hyperplasias account for up to 25% of primary hyperparathyroidism cases. Most abnormal parathyroid glands are found in the superior mediastinum within the thymus and can be removed through a cervical incision; however, a few of these glands are not accessible using standard cervical surgical approaches. Surgical resection has traditionally been performed via median sternotomy or thoracotomy. However, recent advancement in video-assisted thoracic surgery techniques has decreased the need for sternotomy or thoracotomy to remove these ectopic parathyroid glands. Here, we report a successful case of video-assisted thoracoscopic removal of a mediastinal parathyroid adenoma.
PMCID: PMC4157490  PMID: 25207237
1. Parathyroid neoplasms; 2. Thoracic surgery, video-assisted; 3. Mediastinum
6.  Pulmonary metastasectomy for colorectal cancer: How many nodules, how many times? 
Colorectal cancer (CRC) is one of the most common cancers worldwide, with 5%-15% of CRC patients eventually developing lung metastasis (LM). Despite doubts about the role of locoregional therapy in the management of systemic disease, many surgeons have performed pulmonary metastasectomy (PM) for CRC in properly selected patients. However, the use of pulmonary metastasectomy remains controversial due to the lack of randomized controlled studies. This article reviews the results of surgical treatment of pulmonary metastases for CRC, focusing on (1) current treatment guidelines and surgical techniques of PM in patients with LM from CRC; (2) outcomes of PM and its prognostic factors; and (3) controversial issues in PM, focusing on repeated metastasectomy, bilateral multiple metastases, and combined liver and lung metastasectomy.
PMCID: PMC4033452  PMID: 24876735
Colorectal cancer; Pulmonary metastasectomy; Surgery; Metastases
7.  Pleural Mesothelioma: An Institutional Experience of 66 Cases 
Korean Journal of Pathology  2014;48(2):91-99.
Malignant mesothelioma of the pleura is an aggressive tumor known to be associated with asbestos. Histological diagnosis of mesothelioma is challenging and is usually aided by immunohistochemical markers.
During an 18-year period (1995-2012), 66 patients with pleural mesothelioma were diagnosed at the Samsung Medical Center in Seoul. We reviewed hematoxylin and eosin and immunohistochemical slides of pleural mesothelioma and evaluated their pathological and clinical features.
The male-to-female ratio was 1.75:1, and age of patients ranged from 28 to 80 years with an average age of 56.84 years. Twenty-two out of 66 patients underwent curative pneumonectomy. Follow-up data was available in 60 patients (90.9%), and 50 of them (83.3%) died from the disease. The average overall survival was 15.39 months. Histologically, the epithelioid type was the most common, followed by the sarcomatoid and the biphasic types. Epidemiologic information was not available in most cases, and only one patient was confirmed to have a history of asbestos exposure.
Malignant mesothelioma of the pleura is a fatal tumor, and the therapeutic benefit of pneumonectomy remains unproven. The combination of calretinin, Wilms tumor 1, HMBE-1, and thyroid transcription factor-1 may provide high diagnostic accuracy in diagnosing mesothelioma.
PMCID: PMC4026814  PMID: 24868221
Pleura; Mesothelioma; Immunohistochemistry
8.  Quantitative CT Variables Enabling Response Prediction in Neoadjuvant Therapy with EGFR-TKIs: Are They Different from Those in Neoadjuvant Concurrent Chemoradiotherapy? 
PLoS ONE  2014;9(2):e88598.
Background and Purpose
To correlate changes of various CT parameters after the neoadjuvant treatment in patients with lung adenocarcinoma with pathologic responses, focused on their relationship with different therapeutic options, particularly of EGFR-TKI and concurrent chemoradiation therapy (CCRT) settings.
Materials and Methods
We reviewed pre-operative CT images of primary tumors and surgical specimens obtained after neoadjuvant therapy (TKI, n = 23; CCRT, n = 28) from 51 patients with lung adenocarcinoma. Serial changes in tumor volume, density, mass, skewness/kurtosis, and size-zone variability/intensity variability) were assessed from CT datasets. The changes in CT parameters were correlated with histopathologic responses, and the relationship between CT variables and histopathologic responses was compared between TKI and CCRT groups.
Tumor volume, mass, kurtosis, and skewness were significant predictors of pathologic response in CCRT group in univariate analysis. Using multivariate analysis, kurtosis was found to be independent predictor. In TKI group, intensity variability and size-zone variability were significantly decreased in pathologic responder group. Intensity variability was found to be an independent predictor for pathologic response on multivariate analysis.
Quantitative CT variables including histogram or texture analysis have potential as a predictive tool for response evaluation, and it may better reflect treatment response than standard response criteria based on size changes.
PMCID: PMC3935840  PMID: 24586348
9.  Identification of new ALK and RET gene fusions from colorectal and lung cancer biopsies 
Nature medicine  2012;18(3):382-384.
Applying a next-generation sequencing assay targeting 145 cancer-relevant genes in 40 colorectal cancer and 24 non–small cell lung cancer formalin-fixed paraffin-embedded tissue specimens identified at least one clinically relevant genomic alteration in 59% of the samples and revealed two gene fusions, C2orf44-ALK in a colorectal cancer sample and KIF5B-RET in a lung adenocarcinoma. Further screening of 561 lung adenocarcinomas identified 11 additional tumors with KIF5B-RET gene fusions (2.0%; 95% CI 0.8–3.1%). Cells expressing oncogenic KIF5B-RET are sensitive to multi-kinase inhibitors that inhibit RET.
PMCID: PMC3916180  PMID: 22327622
10.  Usual Interstitial Pneumonia with Lung Cancer: Clinicopathological Analysis of 43 Cases 
Korean Journal of Pathology  2014;48(1):10-16.
Previous studies have suggested an association between usual interstitial pneumonia (UIP) and lung cancer (Ca). However, clinical and histological information is not enough to determine such an association, due to the low incidence and short survival time of patients with both conditions.
We retrospectively reviewed the clinical and histological records of Ca patients with UIP between January 1999 and August 2013 at the Samsung Medical Center, Seoul, Korea. We found 43 patients who had Ca with UIP (UIP-Ca). Previously reported data of eighty-four patients with UIP-only were included as a comparison group.
Smoking is related to poor prognosis in patients with UIP-Ca, and the number of patients with a high smoking index of more than 30 pack-years significantly increased in UIP-Ca patients compared with UIP-only patients. There is no significant prognostic differentiation between UIP-Ca patients and UIP-only patients. Microscopically, UIP-Ca patients showed characteristically heterogeneous histological patterns and degrees of differentiation. There were many foci of squamous metaplasia or dysplasia at the peripheral area of squamous cell carcinomas.
We report 43 cases of UIP-Ca. Our results suggest that smoking is related to cancer occurrence in UIP patients and poor prognosis in UIP-Ca patients.
PMCID: PMC3950229  PMID: 24627689
Idiopathic pulmonary fibrosis; Lung neoplasms; Metaplasia; Smoking; Etiology; Survival
11.  Aberrant CDK4 Amplification in Refractory Rhabdomyosarcoma as Identified by Genomic Profiling 
Scientific Reports  2014;4:3623.
Rhabdomyosarcoma (RMS) is the most commonly occurring type of soft tissue tumor in children. However, it is rare in adults, and therefore, very little is known about the most appropriate treatment strategy for adult RMS patients. We performed genomic analysis of RMS cells derived from a 27-year-old male patient whose disease was refractory to treatment. A peritoneal seeding nodule from the primary tumor, pleural metastases, malignant pleural effusion, and ascites obtained during disease progression, were analyzed. Whole exome sequencing revealed 23 candidate variants, and 10 of 23 mutations were validated by Sanger sequencing. Three of 10 mutations were present in both primary and metastatic tumors, and 3 mutations were detected only in metastatic specimens. Comparative genomic hybridization array analysis revealed prominent amplification in the 12q13–14 region, and more specifically, the CDK4 proto-oncogene was highly amplified. ALK overexpression was observed at both protein and RNA levels. However, an ALK fusion assay using NanoString technology failed to show any ALK rearrangements. Little genetic heterogeneity was observed between primary and metastatic RMS cells. We propose that CDK4, located at 12q14, is a potential target for drug development for RMS treatment.
PMCID: PMC3887377  PMID: 24406431
12.  Whole-genome sequencing of matched primary and metastatic hepatocellular carcinomas 
To gain biological insights into lung metastases from hepatocellular carcinoma (HCC), we compared the whole-genome sequencing profiles of primary HCC and paired lung metastases.
We used whole-genome sequencing at 33X-43X coverage to profile somatic mutations in primary HCC (HBV+) and metachronous lung metastases (> 2 years interval).
In total, 5,027-13,961 and 5,275-12,624 somatic single-nucleotide variants (SNVs) were detected in primary HCC and lung metastases, respectively. Generally, 38.88-78.49% of SNVs detected in metastases were present in primary tumors. We identified 65–221 structural variations (SVs) in primary tumors and 60–232 SVs in metastases. Comparison of these SVs shows very similar and largely overlapped mutated segments between primary and metastatic tumors. Copy number alterations between primary and metastatic pairs were also found to be closely related. Together, these preservations in genomic profiles from liver primary tumors to metachronous lung metastases indicate that the genomic features during tumorigenesis may be retained during metastasis.
We found very similar genomic alterations between primary and metastatic tumors, with a few mutations found specifically in lung metastases, which may explain the clinical observation that both primary and metastatic tumors are usually sensitive or resistant to the same systemic treatments.
PMCID: PMC3896667  PMID: 24405831
Cancer; Hepatocellular carcinomas (HCC); Lung metastasis; Somatic; Next-generation sequencing (NGS)
13.  Two Cases of Glomus Tumor Arising in Large Airway: Well Organized Radiologic, Macroscopic and Microscopic Findings 
Glomus tumors of the lung are rare benign neoplasm, originating from modified smooth muscle cells. The patients are usually presented with no or non-specific symptoms such as cough, dyspnea or hemoptysis. Although surgical treatment is considered as the treatment of choice, the endobronchial therapy can be applied to the patients who are unfit for surgical excision. Herein, we describe two rare cases of glomus tumor originated at large airway (trachea and main bronchus) without respiratory symptoms and review their characteristic radiologic, macroscopic and pathological features.
PMCID: PMC3919963  PMID: 24523816
Glomus Tumor; Lung; Trachea
14.  Loss of E-cadherin activates EGFR-MEK/ERK signaling, which promotes invasion via the ZEB1/MMP2 axis in non-small cell lung cancer 
Oncotarget  2013;4(12):2512-2522.
Loss of E-cadherin, a hallmark of epithelial-mesenchymal transition (EMT), can significantly affect metastatic dissemination. However, the molecular mechanism of EMT-associated metastatic dissemination by loss of E-cadherin still remains unclear in non-small cell lung cancers (NSCLCs). In the present study, we show that the knockdown of E-cadherin was sufficient to convert A549 NSCLC cells into mesenchymal type with the concurrent up-regulation of typical EMT inducers such as ZEB1 and TWIST1. Interestingly, the EMT-induced cells by E-cadherin depletion facilitate invasion in a matrix metalloproteinase-2 (MMP2)-dependent manner with aberrant activation of EGFR signaling. We demonstrated that the elevated invasiveness was a result of the activated EGFR-MEK/ERK signaling, which in turn leads to ZEB1 dependent MMP2 induction. These results suggest that the EGFR-MEK/ERK/ZEB1/MMP2 axis is responsible for promoted invasion in EMT-induced NSCLCs. Consistently, ERK activation and loss of E-cadherin were both observed in the disseminating cancer cells at the invasive tumor fronts in NSCLC cancer tissues. Thereby, these data suggest that the EGFR-MEK/ERK signaling would be a promising molecular target to control aberrant MMP2 expression and consequent invasion in the EMT-induced NSCLCs
PMCID: PMC3926845  PMID: 24318272
E-Cadherin; EGFR-MEK/ERK signaling; ZEB1; MMP2; Invasion
15.  Bronchial Schwannomas: Clinicopathologic Analysis of 7 Cases 
Korean Journal of Pathology  2013;47(4):326-331.
It has long been recognized that bronchial schwannomas are extremely rare. As such, diagnosing tumors in this extraordinary location can sometimes be problematic.
We reviewed seven cases of bronchoscopically or surgically resected endobronchial schwannomas and evaluated their clinical and pathologic features.
The present study included five female and two male patients, with ages ranging from 16 to 81 years (mean age, 44.9 years). The clinical presentation varied according to tumor size and location. Patients with more centrally (trachea or main bronchus) located tumors experienced respiratory symptoms (80%) more often than patients with more peripherally (lobar or segmental bronchus) located tumors (0%). Histologically, the tumors were composed of spindle cells that stained with S100 protein. Some of the tumors showed typical Antoni A areas with Verocay body formation. Five of six patients (83.3%) underwent complete tumor removal by rigid bronchoscopy.
Pathologists should consider endobronchial schwannoma in the differential diagnosis of a spindle cell tumor involving the bronchus. Additionally, our results showed that rigid bronchoscopy is an effective tool for tumor removal in endobronchial schwannoma patients.
PMCID: PMC3759631  PMID: 24009627
Schwannoma; Neurilemmoma; Bronchi; Brnchoscopy
16.  Pulmonary Mucinous Cystadenocarcinoma: Report a Case and Review of CT Findings 
Korean Journal of Radiology  2013;14(2):384-388.
A pulmonary mucinous cystadenocarcinoma is an extremely rare tumor that is considered to be a cystic variant of mucin-producing lung adenocarcinoma. We present a case of pulmonary mucinous cystadenocarcinoma in a 54-year-old woman. Chest CT scans showed a 4.3-cm-sized, lobulated, well-defined, and homogeneous mass in the right middle lobe with peripheral stippled calcifications that demonstrated low-attenuation with no enhancement after contrast administration; 18F-fluorodeoxyglucose (FDG) PET/CT demonstrated mild heterogeneous FDG uptake. The mass was diagnosed as adenocarcinoma with mucin production by transbronchial lung biopsy. Right middle lobectomy was performed, and the pathologic examination disclosed a pulmonary mucinous cystadenocarcinoma.
PMCID: PMC3590356  PMID: 23483761
Pulmonary mucinous cystadenocarcinoma; Lung cancer; CT; PET/CT
17.  A High-Dimensional, Deep-Sequencing Study of Lung Adenocarcinoma in Female Never-Smokers 
PLoS ONE  2013;8(2):e55596.
Deep sequencing techniques provide a remarkable opportunity for comprehensive understanding of tumorigenesis at the molecular level. As omics studies become popular, integrative approaches need to be developed to move from a simple cataloguing of mutations and changes in gene expression to dissecting the molecular nature of carcinogenesis at the systemic level and understanding the complex networks that lead to cancer development.
Here, we describe a high-throughput, multi-dimensional sequencing study of primary lung adenocarcinoma tumors and adjacent normal tissues of six Korean female never-smoker patients. Our data encompass results from exome-seq, RNA-seq, small RNA-seq, and MeDIP-seq. We identified and validated novel genetic aberrations, including 47 somatic mutations and 19 fusion transcripts. One of the fusions involves the c-RET gene, which was recently reported to form fusion genes that may function as drivers of carcinogenesis in lung cancer patients. We also characterized gene expression profiles, which we integrated with genomic aberrations and gene regulations into functional networks. The most prominent gene network module that emerged indicates that disturbances in G2/M transition and mitotic progression are causally linked to tumorigenesis in these patients. Also, results from the analysis strongly suggest that several novel microRNA-target interactions represent key regulatory elements of the gene network.
Our study not only provides an overview of the alterations occurring in lung adenocarcinoma at multiple levels from genome to transcriptome and epigenome, but also offers a model for integrative genomics analysis and proposes potential target pathways for the control of lung adenocarcinoma.
PMCID: PMC3566005  PMID: 23405175
18.  Primary leiomyoma of the trachea, bronchus, and pulmonary parenchyma — a single-institutional experience 
Primary leiomyoma of the respiratory tract is a rare disease. Based on our experience, we investigated its clinical characteristics and outcomes of treatment.
Between 1997 and 2008, 16 patients in our institution (nine male, seven female) were found to have primary leiomyoma of the respiratory tract. The median patient age was 46.5 years (range 17–66 years). The tumor was located in the trachea in four patients, in the carina and main bronchus in four, in the bronchus intermedius in four, in the lobar or segmental bronchus in two, and in the lung parenchyma in two.
Tumor removal through bronchoscopic intervention using Nd–YAG (neodymium–yttrium–aluminum–garnet) laser cauterization was attempted in 11 patients; it failed in two with wide-based tumors. Surgical resection was performed in seven patients. Operative procedures included tracheal resection and end-to-end anastomosis (n = 3), lobectomy (n = 3), and bilobectomy (n = 1). There were no in-hospital mortalities. During a median follow-up duration of 43.2 months, one patient who underwent bronchoscopic removal had recurrence, for which segmental resection of the trachea and main bronchus with carinal reconstruction was performed.
Bronchoscopic intervention can offer successful control of primary leiomyoma of the main airway stem; however, in cases of a wide-based tumor, bronchoscopic intervention can result in incomplete resection or recurrence. Surgical complete resection can yield satisfactory outcomes in patients with primary leiomyoma occurring in the respiratory tract.
PMCID: PMC3241106  PMID: 21767960
Primary leiomyoma of the respiratory tract; Rigid bronchoscopy; Surgery
19.  High Dose Involved Field Radiation Therapy as Salvage for Loco-Regional Recurrence of Non-Small Cell Lung Cancer 
Yonsei Medical Journal  2012;53(6):1120-1127.
To determine the effectiveness of salvage radiation therapy (RT) in patients with loco-regional recurrences (LRR) following initial complete resection of non-small cell lung cancer (NSCLC) and assess prognostic factors affecting survivals.
Materials and Methods
Between 1994 and 2007, 64 patients with LRR after surgery of NSCLC were treated with high dose RT alone (78.1%) or concurrent chemo-radiation therapy (CCRT, 21.9%) at Samsung Medical Center. Twenty-nine patients (45.3%) had local recurrence, 26 patients (40.6%) had regional recurrence and 9 patients (14.1%) had recurrence of both components. The median RT dose was 54 Gy (range, 44-66 Gy). The radiation target volume included the recurrent lesions only.
The median follow-up time from the start of RT in survivors was 32.0 months. The rates of in-field failure free survival, intra-thoracic failure free survival and extra-thoracic failure free survival at 2 years were 52.3%, 33.9% and 59.4%, respectively. The median survival after RT was 18.5 months, and 2-year overall survival (OS) rate was 47.9%. On both univariate and multivariate analysis, the interval from surgery till recurrence and CCRT were significant prognostic factors for OS.
The current study demonstrates that involved field salvage RT is effective for LRR of NSCLC following surgery.
PMCID: PMC3481375  PMID: 23074111
Concurrent chemo-radiation therapy; locoregional recurrence; non-small cell lung cancer; radiation therapy; salvage treatment
20.  Is There a Role of Postoperative Radiation Therapy in Completely Resected Stage I/II Thymic Epithelial Tumor? 
Retrospective analyses of patients with stage I-II thymic epithelial tumors (TET) who were treated with either surgery alone (S) or surgery plus postoperative radiation therapy (SRT) were conducted to evaluate the role of adjuvant radiation therapy (RT).
Materials and Methods
A total of 110 stage I-II TET patients following complete resection were included in this study. Postoperative radiation therapy was recommended for those with aggressive histologic type and/or invasive features according to the surgeons' judgment during the operation. A median dose of 54.0 Gy (range, 44 to 60 Gy) focused on the primary tumor bed was administered to 57 patients (51.8%).
In all patients, the rates of overall survival, disease-specific survival, and disease-free survival at 10 years were 91.7%, 97.1%, and 95.8%, respectively. No significant differences in disease-specific survival (100% in the S group and 93.5% in the SRT group at 10 years, p=0.12) and disease-free survival (98.1% in the S group and 94.5% in the SRT group at 10 years, p=0.41) were observed between the treatment groups, although a significantly larger number of World Health Organization (WHO)-type B2-C (p<0.001) and Masaoka stage II (p=0.03) tumors were observed in the SRT group than in the S group. No local recurrence was observed in the SRT group. No grade 2 or greater RT-related toxicities were observed in the SRT group.
Excellent outcomes were achieved in patients with stage I-II TET who underwent complete resection. Considering excellent local control and low morbidity, adjuvant RT may be considered in high risk patients with WHO-type B2-C histology and Masaoka stage II.
PMCID: PMC3467419  PMID: 23091442
Thymic neoplasms; Surgery; Adjuvant radiotherapy
21.  Thymoma of the Middle Mediastinum 
Thymoma is a common anterior mediastinal mass, although thymomas have occasionally been found in the neck, pulmonary hillus, or posterior mediastinum. But a thymoma within the middle mediastinum has rarely been reported. We report a thymoma arising in the middle mediastinum with a review of the literature.
PMCID: PMC3413836  PMID: 22880176
Thymoma; Mediastinal neoplasms
22.  Clinicopathological Analysis of 21 Thymic Neuroendocrine Tumors 
Korean Journal of Pathology  2012;46(3):221-225.
Thymic neuroendocrine carcinomas (NECs) are uncommon, for which there is no established information available because of a limited number of epidemiological study in Asia.
We reviewed 21 cases of surgically resected thymic NECs, and evaluated their pathological and clinical features.
It showed male predominance (male/female ratio, 15/6) with wide age range from 20 to 72 years (mean age, 49 years). All 21 cases were divided into two types according to the World Health Organization criteria: atypical carcinoid (n=18) and large cell NEC (n=3). Three cases of atypical carcinoid (AC) were associated with ectopic Cushing's syndrome. All the patients (3/3) with large cell NEC (3/3) and 16.7% (3/18) of those with AC died of tumor progression. Common sites of metastasis included lung, lymph node, brain, lumbar spine, mediastinum, bone, and liver.
In conclusion, thymic neuroendocrine tumors carry a poor prognosis. Regarding the tumor classification, our results showed that a vast majority of carcinoids in the thymus correspond to ACs. In addition, our results also indicate that typical carcinoid is a very rare entity. Some cases of AC exhibited a large size, solid pattern and they showed aggressive clinical behavior, which highlights the spectrum of histologic appearances of thymic NECs.
PMCID: PMC3479770  PMID: 23110006
Thymus gland; Carcinoid tumor; Carcinoma, neuroendocrine
23.  Prediction of Postoperative Recurrence-Free Survival in Non-small Cell Lung Cancer by Using an Internationally Validated Gene Expression Model 
This study was performed to discover prognostic genomic markers associated with post-operative outcome of stage I-III non-small cell lung cancer (NSCLC) that are reproducible between geographically distant and demographically distinct patient populations.
Experimental design
American patients (n=27) were stratified on the basis of recurrence and microarray profiling of their tumors was performed to derive a training set of 44 genes. A larger Korean patient validation cohort (n=138) was also stratified by recurrence and screened for these genes. Four reproducible genes were identified and used to construct genomic and clinicogenomic Cox models for both cohorts.
Four genomic markers, DBN1 (drebrin 1), CACNB3 (calcium channel beta 3), FLAD1 (PP591; flavin adenine dinucleotide synthetase), and CCND2 (cyclin D2), exhibited highly significant differential expression in recurrent tumors in the training set (P<0.001). In the validation set, DBN1, FLAD1 (PP591) and CACNB3 were significant by Cox univariate analysis (P≤0.035), whereas only DBN1 was significant by multivariate analysis. Genomic and clinicogenomic models for recurrence free survival (RFS) were equally effective for risk stratification of stage I-II or I-III patients (all models P<0.0001). For stage I-II or I-III patients, 5-y RFS of the low- and high-risk patients was ∼ 70 vs. 30% for both models. The genomic model for overall survival (OS) of stage I-III patients was improved by addition of pT and pN stage (P<0.0013 vs. 0.010).
A 4-gene prognostic model incorporating the multivariate marker DBN1 exhibits potential clinical utility for risk stratification of stage I-III NSCLC patients.
PMCID: PMC3086939  PMID: 21242119
NSCLC recurrence; DBN1; CACNB3; FLAD1; CCND2
24.  Analysis of 1,067 Cases of Video-Assisted Thoracic Surgery Lobectomy 
Video-assisted thoracic surgery (VATS) lobectomy has been performed with increasing frequency over the last decade. However, there is still controversy as to its indications, safety, and feasibility. Especially regarding lung cancer surgery, it is not certain whether it can reduce local recurrences and improve overall survival.
Materials and Methods
We retrospectively reviewed 1,067 cases of VATS lobectomy performed between 2003 and 2009, including the indications, postoperative morbidity, mortality, recurrence, and survival rate.
One thousand and sixty seven patients underwent VATS lobectomy for the following indications: non-small cell lung cancer (NSCLC) (n=832), carcinoid tumors (n=12), metastatic lung cancer (n=48), and benign or other diseases (n=175). There were 63 cases (5.9%) of conversion to open thoracotomy during VATS lobectomy. One hundred thirty one (15.7%) of the 832 NSCLC patients experienced pathologic upstaging postoperatively. The hospital mortality rate was 0.84% (9 patients), and all of them died of acute respiratory distress syndrome. One hundred forty-nine patients (14.0%) experienced postoperative complications. The median follow-up was 22.9 months for patients with NSCLC. During follow-up, 120 patients had a recurrence and 55 patients died. For patients with pathologic stage I, the overall survival rate and disease-free survival rate at 3 years was 92.2±1.5% and 86.2±1.9%, respectively. For patients with pathologic stage II disease, the overall survival rate and disease-free survival rate at 3 years was 79.2±6.5% and 61.9±6.6%, respectively.
Our results suggest that VATS lobectomy is a technically feasible and safe operation, which can be applied to various lung diseases. In patients with early-stage lung cancer, excellent survival can be also achieved.
PMCID: PMC3249295  PMID: 22263146
Video-assisted thoracic surgery; Lobectomy; Lung neoplasm
25.  Cancer-Associated Splicing Variant of Tumor Suppressor AIMP2/p38: Pathological Implication in Tumorigenesis 
PLoS Genetics  2011;7(3):e1001351.
Although ARS-interacting multifunctional protein 2 (AIMP2, also named as MSC p38) was first found as a component for a macromolecular tRNA synthetase complex, it was recently discovered to dissociate from the complex and work as a potent tumor suppressor. Upon DNA damage, AIMP2 promotes apoptosis through the protective interaction with p53. However, it was not demonstrated whether AIMP2 was indeed pathologically linked to human cancer. In this work, we found that a splicing variant of AIMP2 lacking exon 2 (AIMP2-DX2) is highly expressed by alternative splicing in human lung cancer cells and patient's tissues. AIMP2-DX2 compromised pro-apoptotic activity of normal AIMP2 through the competitive binding to p53. The cells with higher level of AIMP2-DX2 showed higher propensity to form anchorage-independent colonies and increased resistance to cell death. Mice constitutively expressing this variant showed increased susceptibility to carcinogen-induced lung tumorigenesis. The expression ratio of AIMP2-DX2 to normal AIMP2 was increased according to lung cancer stage and showed a positive correlation with the survival of patients. Thus, this work identified an oncogenic splicing variant of a tumor suppressor, AIMP2/p38, and suggests its potential for anti-cancer target.
Author Summary
Lung cancer is one of the most common cancers and a leading cause of death resulting from cancer. Despite intensive investigation, effective therapeutic targets and reliable biomarkers are still limited. Here we found that a tumor suppressor, AIMP2 (MSC p38), produces a variant lacking a part of its structure in cancer tissues. We designated it AIMP2-DX2. This smaller version of AIMP2 compromises the normal tumor suppressive activity of AIMP2 and induces tumor formation. We also found that the expression of AIMP2-DX2 was increased according to cancer progression. In addition, the patients with higher expression of AIMP2-DX2 showed lower survival than those with lower levels of this variant. Suppression of AIMP2-DX2 slowed tumor growth, suggesting it as a new therapeutic target. In summary, this work newly identified a tumor-inducing factor, AIMP2-DX2, that can be used as a therapeutic target and biomarker associated with lung cancer.
PMCID: PMC3069106  PMID: 21483803

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