Young Mog Shim

Prediction of Recurrence-Free Survival in Postoperative Non–Small Cell Lung Cancer Patients by Using an Integrated Model of Clinical Information and Gene Expression

Purpose: One of the main challenges of lung cancer research is identifying patients at high risk for recurrence after surgical resection. Simple, accurate, and reproducible methods of evaluating individual risks of recurrence are needed. Experimental Design: Based on a combined analysis of time-to-recurrence data, censoring information, and microarray data from a set of 138 patients, we selected statistically significant genes thought to be predictive of disease recurrence. The number of genes was further reduced by eliminating those whose expression levels were not reproducible by real-time quantitative PCR. Within these variables, a recurrence prediction model was constructed using Cox proportional hazard regression and validated via two independent cohorts (n = 56 and n = 59). Results: After performing a log-rank test of the microarray data and successively selecting genes based on real-time quantitative PCR analysis, the most significant 18 genes had P values of <0.05. After subsequent stepwise variable selection based on gene expression information and clinical variables, the recurrence prediction model consisted of six genes (CALB1, MMP7, SLC1A7, GSTA1, CCL19, and IFI44). Two pathologic variables, pStage and cellular differentiation, were developed. Validation by two independent cohorts confirmed that the proposed model is significantly accurate (P = 0.0314 and 0.0305, respectively). The predicted median recurrence-free survival times for each patient correlated well with the actual data. Conclusions: We have developed an accurate, technically simple, and reproducible method for predicting individual recurrence risks. This model would potentially be useful in developing customized strategies for managing lung cancer.

Tumor-Specific Methylation in Bronchial Lavage for the Early Detection of Non-Small-Cell Lung Cancer

PURPOSE The aim of this study was to identify tumor-specific methylation in bronchial lavage for the early detection of non-small-cell lung cancer (NSCLC) by differentiating the age-related methylation from the tumor-specific methylation in NSCLC. PATIENTS AND METHODS Eighty-five NSCLC patients and 127 cancer-free subjects participated in this study. Aberrant methylation at the promoters of the p16, Ras association domain family 1A (RASSF1A), fragile histidine triad (FHIT), H-cadherin, and retinoic acid receptor beta (RARbeta) genes were evaluated in the resected tumor tissues and bronchial lavage samples of NSCLC patients and in the bronchial lavage samples of cancer-free subjects by methylation-specific polymerase chain reaction. RESULTS Of the 127 cancer-free samples, methylation was detected in 6% for p16, 13% for RARbeta, 3% for H-cadherin, 4% for RASSF1A, and 28% for FHIT. Hypermethylation of the p16, RARbeta, H-cadherin, and RASSF1A genes was not associated with patient age and smoking, whereas hypermethylation of the FHIT promoter occurred more frequently in older patients (P =.02) and was associated with exposure to tobacco smoke (P =.001). A strong correlation between age and smoking was found in patients with hypermethylation of the FHIT gene (r = 0.36; P =.03). A total of 68% of the bronchial lavage samples from the 85 NSCLC patients showed methylation of at least one of p16, RARbeta, H-cadherin, and RASSF1A genes. CONCLUSION Our study suggests that tumor-specific methylation of the p16, RASSF1A, H-cadherin, and RARbeta genes may be a valuable biomarker for the early detection of NSCLC in bronchial lavage, and that the age-related methylation of FHIT gene in the normal bronchial epithelium is related to the exposure to tobacco smoke.

Evaluation of lymph node metastases in squamous cell carcinoma of the esophagus with positron emission tomography

BACKGROUND Previous studies suggest positron emission tomography (PET) may improve staging accuracy of esophageal cancer compared with conventional methods, especially in detecting occult distant metastases. We evaluated the accuracy of PET in the detection of lymph node metastasis prospectively with pathologic findings. METHODS Fifty-three patients with squamous cell carcinoma underwent whole-body PET scan and chest computed tomography (CT). The findings of PET and chest CT of 50 patients who underwent curative esophagectomy with radical lymph node dissection were compared with the pathologic findings. RESULTS Among 53 primary esophageal tumors, PET detected 51 (96.2%) and CT detected 49 (92.5%) tumors correctly. Nodal metastases were present in 108 of 436 dissected lymph node groups. PET detected 56 metastatic node groups (51.9% sensitivity, 94.2% specificity, 83.7% accuracy), compared with CT, which detected 16 (14.8% sensitivity, 96.7% specificity, 76.6% accuracy; sensitivity: p < 0.005). CONCLUSIONS PET was more sensitive than CT in the detection of nodal metastases and may improve staging of squamous cell carcinoma of the esophagus.

Discordance of Molecular Biomarkers Associated with Epidermal Growth Factor Receptor Pathway between Primary Tumors and Lymph Node Metastasis in Non-small Cell Lung Cancer

Introduction: For the identification of the patients who most likely benefit from epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors in non-small cell lung cancer (NSCLC), molecular assays are considered to be of paramount importance. Given the heterogeneity of NSCLC at the molecular level, this study was conducted to determine the discrepancy in EGFR mutations between primary tumors and the corresponding lymph node metastasis. Patients and Methods: Surgically resected 101 paired primary NSCLC and metastatic lymph nodes were evaluated for the EGFR mutations by direct DNA sequencing and heteroduplex analysis. Results: EGFR mutation was detected in 29.7% (30 of 101) of the primary tumors and in 27.7% of lymph node metastases (28 of 101) by either direct sequencing or heteroduplex analysis, respectively. By direct sequencing, 12 cases (11.9%) showed discordance in EGFR mutations between primary tumors and metastasis. In 11 cases, EGFR mutations were detected only in the primary tumor, whereas 1 case only in lymph node metastases. By heteroduplex analysis, 17 cases (16.8%) were discordant. Ten cases were primary tumor positive and lymph node negative, whereas seven cases were lymph node positive and primary tumor negative. Conclusions: A considerable proportion of NSCLC showed discrepancy in EGFR mutations between primary tumors and metastatic lymph nodes, suggesting tumor heterogeneity at the molecular level during the process of metastasis.

Treatment Outcomes for HIV-Uninfected Patients with Multidrug-Resistant and Extensively Drug-Resistant Tuberculosis

BACKGROUND Multidrug-resistant (MDR) tuberculosis (TB) is more difficult to treat than is drug-susceptible TB. To elucidate the optimal therapy for MDR TB, we assessed the treatment outcomes and prognostic factors for patients with MDR TB. METHODS This study included patients who received an individualized treatment regimen for MDR TB at Samsung Medical Center, a tertiary referral hospital in Seoul, Korea, from January 1995 through December 2004. To identify the prognostic factors related to favorable treatment outcomes, univariate comparison and multiple logistic regression were performed. RESULTS Of 155 patients, 18 (12%) had newly diagnosed MDR TB, 81 (52%) had previously received treatment with first-line drugs, and 56 (36%) had received treatment with second-line drugs. The isolated strains were resistant to a median of 5 drugs. Twenty-seven patients (17%) had extensively drug-resistant (XDR) TB at the start of treatment. Outcome assessment revealed that 102 patients (66%) were cured or completed therapy. The treatment success rates did not differ significantly between patients with non-XDR MDR TB and those with XDR TB (66% vs. 67%). Surgical resection was performed more frequently for patients with XDR TB than for those with non-XDR MDR TB (48% vs. 17%). Combined surgical resection, body mass index >/=18.5 (calculated as the weight in kilograms divided by the square of the height in meters), use of >4 effective drugs, and a negative sputum smear result were independent predictors of a favorable outcome. CONCLUSIONS Early aggressive treatment comprising at least 4 effective drugs and surgical resection, when indicated, may improve the outcome for patients with MDR TB or XDR TB.

Elevated mRNA levels of DNA methyltransferase‐1 as an independent prognostic factor in primary nonsmall cell lung cancer

Despite many reports about the involvement of DNA methyltransferases (DNMTs) in human cancers, including nonsmall cell lung cancer (NSCLC), the clinicopathologic significance of DNMTs in primary NSCLC remains to be elucidated.

Integrative and Comparative Genomic Analysis of Lung Squamous Cell Carcinomas in East Asian Patients

PURPOSE 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. RESULTS 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. CONCLUSION 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.

Improved Detection of Second Primary Cancer Using Integrated [18F] Fluorodeoxyglucose Positron Emission Tomography and Computed Tomography for Initial Tumor Staging

PURPOSE This study evaluated prospectively the value of integrated whole-body positron emission tomography and computed tomography (PET/CT) using [18F] fluorodeoxyglucose (FDG) in detecting a second primary cancer at the time of the initial staging in comparison with a conventional staging work-up (CSW). METHODS The participants were 547 patients diagnosed with cancer who underwent FDG PET/CT imaging for the initial staging. An additional diagnostic evaluation was performed when there were abnormal findings indicative of a second primary cancer on either PET/CT or CSW considering the site and the biologic behavior of the alleged primary tumor. RESULTS A total of 27 second primary malignant tumors were identified in 26 of the 547 patients (4.8%). FDG PET/CT found 45 lesions indicative of a second primary cancer, of which 24 lesions were proved to be a second primary cancer, seven were clinically unexpected metastases, and 14 lesions were benign. Therefore, sensitivity and positive predictive value of FDG PET/CT in detecting a second primary cancer or an unexpected metastasis were 91% (31 of 34) and 69% (31 of 45), respectively. In contrast, CSW could not identify 16 second primary cancers and one metastatic lesion. CONCLUSION FDG PET/CT at the time of the initial staging is useful for screening a second primary cancer with a high sensitivity. An additional diagnostic work-up is essential when abnormal findings, which are indicative of a second primary cancer, are obtained on PET/CT images to rule out the presence of either a second primary cancer or an unexpected metastasis.

Persistent pure ground-glass opacity lung nodules ≥ 10 mm in diameter at CT scan: histopathologic comparisons and prognostic implications.

BACKGROUND Little is known about the histopathology and prognosis of persistent pure ground-glass opacity nodules (GGNs) of ≥ 10 mm in diameter. We aimed to compare the morphologic features of persistent pure GGNs of ≥ 10 mm in diameter at thin-section CT (TSCT) scan with histopathology and patient prognosis. METHODS A total of 46 resected GGNs that were evaluated with TSCT scan and followed up for ≥ 3 years were included in this study. Correlations between histopathology (adenocarcinoma in situ [AIS], minimally invasive adenocarcinoma [MIA], and invasive adenocarcinoma) and CT scan characteristics were examined. CT scan and clinicodemographic data were investigated by univariate and multivariate analyses to identify features that helped distinguish invasive adenocarcinoma from AIS or MIA. Disease recurrence was also evaluated. RESULTS The nodules included 19 AISs (41%), nine MIAs (20%), and 18 invasive adenocarcinomas (39%). On univariate analysis, the presence of air bronchogram (P = .012), size of nodule (P = .032, cutoff = 16.4 mm in diameter), and mass of nodule (P = .040, cutoff = 0.472 g) were significant factors that differentiated invasive adenocarcinoma from AIS or MIA. On multivariate analysis, size (P = .010) and mass of nodule (P = .016) were significant determinants for invasive adenocarcinoma. There were no cases of recurrence during a follow-up period of ≥ 3 years after surgical resection. CONCLUSIONS In persistent pure GGNs of ≥ 10 mm in diameter, the size and mass of the nodule are determinants of invasive adenocarcinoma, for which surgical resection leads to excellent prognosis.

Natural History of Pure Ground-Glass Opacity Lung Nodules Detected by Low-Dose CT Scan

BACKGROUND Although focal ground-glass opacity (GGO) lung nodules are generally reported to grow slowly, their natural course is unclear. The purpose of this study was to elucidate the natural course of screening-detected pure GGO lung nodules in patients with no history of malignancy. METHODS We retrospectively reviewed the database of subjects who had undergone screenings involving low-dose CT scans. We included patients with pure GGO lung nodules who were followed for > 2 years after the initial screening. RESULTS Between June 1997 and September 2006, 122 pure GGO nodules were found in 89 patients. The median nodule size was 5.5 mm (range, 3-20 mm) in the largest diameter on initial low-dose CT scan. The median follow-up period per patient was 59 months. On a per-person basis, the frequency of growth was 13.5% (12 of 89 patients). On a per-nodule basis, the frequency of growth was 9.8% (12 of 122 nodules). Nodule growth was significantly associated with initial size and new development of an internal solid portion. The median volume doubling time was 769 days for growing pure GGO nodules. A total of 11 growing nodules were surgically validated, and all lesions were confirmed as primary lung cancer. CONCLUSIONS About 90% of the screening-detected pure GGO lung nodules did not grow during long-term follow-up in subjects with no history of malignancy and most growing nodules had an indolent clinical course. A strategy of long-term follow-up and selective surgery for growing nodules should be considered for pure GGO lung nodules.