Joungho Han

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.

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.

Prognostic Determinants among Clinical, Thin-Section CT, and Histopathologic Findings for Fibrotic Idiopathic Interstitial Pneumonias: Tertiary Hospital Study

PURPOSE To evaluate the utility of clinical, thin-section computed tomography (CT), and histopathologic findings in predicting the prognosis of patients with usual interstitial pneumonia (UIP) or fibrotic nonspecific interstitial pneumonia (NSIP). MATERIALS AND METHODS The institutional review board approved this retrospective study, with waiver of informed consent. Included were 108 patients (71 men, 37 women; mean age, 61 years +/- 8 [standard deviation]) with UIP (n = 79; 60 men, 19 women; mean age, 63 years +/- 7.4) and fibrotic NSIP (n = 29; 11 men, 18 women; mean age, 57 years +/- 12.9). Patients underwent pulmonary function tests (PFTs), bronchoalveolar lavage (BAL) fluid analysis, and thin-section CT. Two chest radiologists independently assigned scores for the extent of lung abnormalities detected at CT twice at 3-month intervals. The effect of histopathologic diagnoses and clinical and thin-section CT features on survival was evaluated by using Cox regression analyses. RESULTS The 5-year survival rate (mean follow-up, 45 months) of patients with fibrotic NSIP was 76% in contrast to 46% for patients with UIP (P = .006). With multivariate analysis, a high fibrotic score (the extent of reticulation plus honeycombing) (hazard ratio = 1.200, P = .043) and an initial low diffusing capacity of lung for carbon monoxide (Dlco) level (hazard ratio = 0.973, P = .025) were identified as associated with increased death risk. CONCLUSION Patients with UIP or fibrotic NSIP who have a high fibrotic score determined at thin-section CT and a low Dlco level appear to have a high death risk.

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.

Halo sign on high resolution CT: findings in spectrum of pulmonary diseases with pathologic correlation.

The halo sign in a pulmonary nodule refers to the condition in which soft tissue attenuation of a pulmonary nodule is surrounded by peripheral ground glass attenuation on high resolution CT. The halo sign can be caused by several pathologic processes: hemorrhagic pulmonary nodules, tumor cell infiltration, and nonhemorrhagic inflammatory lesions. Hemorrhagic pulmonary nodules may occur in infectious diseases including invasive pulmonary aspergillosis, mucormycosis, and candidiasis and noninfectious diseases including Wegener granulomatosis and primary and metastatic hemorrhagic tumors. Tumor cell infiltration in bronchioloalveolar carcinoma, pulmonary lymphoma, and pulmonary metastatic neoplasm may appear with the halo sign. Eosinophilic lung disease and organizing pneumonia are representative of inflammatory lesions showing the sign.

Cohypermethylation of p16 and FHIT Promoters as a Prognostic Factor of Recurrence in Surgically Resected Stage I Non–Small Cell Lung Cancer

Despite advances in the detection and treatment of lung cancer, the prognosis for patients with lung cancer is poor, partly as a result of recurrences. We retrospectively analyzed the relationship between recurrence and survival in patients with non-small cell lung cancers (NSCLC), and the promoter methylation of p16, GSTP1, FHIT, H-cadherin, and RARbeta2 genes to identify a prognostic molecular marker associated with the recurrence of NSCLC. Methylation status from 335 paraffin blocks was determined by methylation-specific PCR. Of the 335 NSCLC samples, promoter methylation was detected in 35% for p16, 39% for RARbeta2, 42% for H-cadherin, 7% for GSTP1, and 21% for FHIT. Recurrence was observed in 39% (132 of 335) of the patients. Recurrence was significantly associated with histology (P = 0.001) and pathologic stage (P = 0.009). Hypermethylation of any single gene was not associated with recurrence in patients. However, cohypermethylation of p16 and FHIT genes in stage I NSCLCs was associated with an increased risk of recurrence [odds ratio, 6.43; 95% confidence interval (CI), 1.04-20.19; P = 0.02] and poor recurrence-free survival after surgery (hazard ratio, 2.03; 95% CI, 1.09-6.23; P = 0.02). In addition, their survival after recurrence was also 4.62 times poorer (95% CI, 1.27-16.48; P = 0.005) than for those without cohypermethylation of both genes. In conclusion, the present study suggests that cohypermethylation of p16 and FHIT genes in patients with stage I NSCLC may be a valuable biomarker for predicting the recurrence-associated prognosis of the disease.

Thoracic involvement of systemic lupus erythematosus: clinical, pathologic, and radiologic findings.

Thoracic involvement occurs more frequently in systemic lupus erythematosus than in any other connective tissue diseases, and more than half of patients with the disease suffer from the involvement. Primary intrathoracic manifestations include pleural disease (effusions and/or thickening), acute lupus pneumonitis, subacute interstitial lung disease including bronchiolitis obliterans organizing pneumonia and non-specific interstitial pneumonia with fibrosis, chronic interstitial lung disease of usual interstitial pneumonia, pulmonary hemorrhage, pulmonary vascular disease, small airway disease of bronchiolitis obliterans, and pulmonary arterial hypertension. Secondary intrathoracic manifestations include atelectasis due to diaphragmatic dysfunction, opportunistic pneumonia, drug and oxygen toxicity, aspiration, and pleuropulmonary consequences of cardiac and renal failure.

Significance of thymidylate synthase and thyroid transcription factor 1 expression in patients with nonsquamous non-small cell lung cancer treated with pemetrexed-based chemotherapy.

Introduction: This study is to evaluate whether thymidylate synthase (TS) or thyroid transcription factor 1 (TTF1) protein expression can predict clinical outcomes for pemetrexed-based chemotherapy in patients with nonsquamous non-small cell lung cancer (NSCLC). Methods: Two hundred eighty-five consecutive patients with nonsquamous NSCLC treated with pemetrexed-based chemotherapy were immunohistochemically analyzed for the expressions of TS and TTF1. Results: TS and TTF1 expression were successfully analyzed in 193 and 284 cases, respectively. Tumors with TS-negativity or TTF1-positivity were more frequent in patients who were female, younger, had adenocarcinoma, or had never smoked. Higher response rates for pemetrexed-based chemotherapy were associated with TS-negativity (33.7% versus 14.1%, p = 0.002) and TTF1-positivity (28.1% versus 9.8%, p < 0.001). In univariate analysis, progression-free survival for pemetrexed-based chemotherapy was significantly longer in groups with adenocarcinoma (2.9 versus 1.4 months, p = 0.001), TS-negativity (4.1 versus 2.0 months, p = 0.001), and TTF1-positivity (3.8 versus 1.3 months, p < 0.001). In multivariate analysis, TS-negativity (hazard ratio [HR] = 0.70; 95% confidence interval [CI], 0.51–0.97) and TTF1-positivity (HR = 0.51; 95% CI, 0.35–0.73) were associated with longer progression-free survival. Patients with TTF1-positive tumors also had significantly longer overall survival times than patients with TTF1-negative tumors (25.4 versus 14.2 months, HR = 0.55; 95% CI, 0.39–0.77). Conclusions: Low TS or high TTF1 protein expression was significantly associated with better clinical outcomes in nonsquamous NSCLC patients who were treated with pemetrexed-based chemotherapy. The predictive role of TS or TTF1 expression should be further validated in a prospective randomized study.

Pulmonary inflammatory pseudotumor (inflammatory myofibroblastic tumor): CT features with pathologic correlation.

The objective of this study was to assess the CT features of pulmonary inflammatory myofibroblastic tumors with pathologic correlation. The authors retrospectively reviewed CT and pathologic findings of 10 patients with surgically resected inflammatory myofibroblastic tumor of the lung. On CT, five patients showed a polypoid endotracheal (n = 3) or endobronchial nodule in the left main bronchus (n = 2). Two patients showed a central parenchymal mass, and the remaining three patients showed a peripheral pulmonary nodule. All tumors had well defined margins and were round to ovoid; they ranged in diameter from 13 to 52 mm and showed varying degrees of contrast enhancement (range 13-89 H). On histopathologic examination, the two central parenchymal masses involving segmental bronchi were also mainly endobronchial in location. The three peripheral pulmonary nodules also showed a peribronchiolar location, with a bronchial mucosal lining spared in part. The authors conclude that pulmonary inflammatory myofibroblastic tumors are closely related to the airway.

ERCC1 expression as a prognostic marker in N2(+) nonsmall-cell lung cancer patients treated with platinum-based neoadjuvant concurrent chemoradiotherapy.

Excision repair cross‐complementation Group 1 (ERCC1) overexpression is associated with resistance to cisplatin‐based chemotherapy in patients with nonsmall‐cell lung cancer (NSCLC). A preliminary study also suggested that ERCC1 expression is associated with radioresistance in lung cancer cells. The aim of this study was to evaluate the clinical implications of ERCC1 expression in stage IIIA N2‐positive NSCLC patients treated with platinum‐based neoadjuvant concurrent chemoradiotherapy (CCRT) followed by surgery.