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Chemokines play an important role in the pathogenesis of non-small cell lung cancer (NSCLC). However, aberrant methylation of CXCL12 has not been examined in NSCLC. CXCL12 mRNA expression and methylation were examined in 17 NSCLC cell lines by RT-PCR and methylation-specific PCR (MSP). MSP was performed on 236 tumor specimens from NSCLC patients who received curative intent surgery. CXCL12 and CXCR4 protein expression was examined in 90 of the 236 NSCLC specimens by immunohistochemistry. Down-regulation of CXCL12 expression was found in 10 of 17 (59%) NSCLC cell lines compared with normal bronchial cells. Treatment of 8 expression-negative cell lines with a demethylating agent restored expression in all cases. Twelve cell lines (71%) showed aberrant methylation, and good concordance between methylation and expression was present. Aberrant methylation occurred in 85 out of 236 (36%) primary NSCLCs in a tumor-specific manner. In multivariate analysis, CXCL12 methylation correlated strongly and independently with prognosis both in all patients with NSCLCs and in those with stage I NSCLCs (hazard ratio=1.68, P=0.015 and hazard ratio=3.58, P=0.017). Secreted protein CXCL12 and its receptor CXCR4 were abundant in NSCLC cells (72 out of 90, 80%; 57 out of 90, 63%) and correlated with the progression of NSCLCs. In conclusion, epigenetic silencing of CXCL12 is a frequent event in NSCLCs, and could be an independent and powerful prognostic marker in patients with NSCLCs and those with stage I disease. Analysis for CXCL12 may provide novel opportunities for prognosis and therapy of resected NSCLCs.

The PCR panels presented in Figs. 1 and 2 are incorrect. The authors provide the correct figures below. These changes do not affect the interpretation or conclusions of this work. The authors regret this error. [the original article was published in the International Journal of Oncology 33: 113-119, 2008 DOI: 10.3892/ijo.33.1.113]

Thymic carcinoma, which is a rare epithelial neoplasm of the thymus gland, is different from thymoma in its clinical and pathological features. To clarify the mechanism underlying the aggressive behavior of thymic carcinoma, we examined the clinicopathologic features, aberrant methylation patterns of the tumor suppressor genes, and epidermal growth factor receptor (EGFRs) mutation in both thymic carcinomas and thymomas. Clinical data of 11 thymic cancers and 13 thymomas were reviewed. Resected samples of 5 thymic cancers and 6 thymomas selected from 24 cases were used for methylation and mutation studies. Positive tumor markers were more frequent in thymic cancers than in thymomas (p=0.0233), and the methylation index, which reflects the overall methylation pattern, was significantly higher in thymic carcinomas (p=0.0053). No tumors showed a mutation of EGFR, KRAS, and HER2. Thymic carcinoma is distinct from thymoma not only with respect to clinicopathological features, but also aberrant methylation patterns of the tumor suppressor genes.

Cytochrome P450 2E1 (CYP2E1) catalyzes the metabolic activation of the procarcinogen, N-nitrosodimethylamine, and cytotoxic carbon tetrachloride compounds. A tandem repeat polymorphism in the 5'-flanking region of the CYP2E1 gene was investigated in non-small cell lung carcinoma (NSCLC) patients to clarify the relationship between CYP2E1 gene polymorphism and lung cancer susceptibility. Blood samples were taken from 236 healthy control subjects (192 males and 44 females) and 111 patients (78 males and 33 females) who underwent surgery for NSCLC in Japan. DNA was isolated from these samples and the 5'-flanking region of the CYP2E1 gene was amplified by polymerase chain reaction and examined for tandem repeat polymorphisms using DNA fragment analysis. Sequence analysis confirmed the presence of three alleles, A2, A3, and A4 (361, 367, and 457 bp, respectively), with four genotypes observed in the lung cancer group and five genotypes in the control group. There was a statistically significant difference in genotype distribution between the lung adenocarcinoma and control group (P=0.0088, A4/A4 vs. non-A4/A4). In the lung adenocarcinoma group, the univariate risk estimates for the A4/A4 subgroup compared to the most common subgroup (A2/A2) was 4.300 (95% confidence interval = 1.358-13.618, P=0.0131). We conclude that the A4/A4 genotype of the 5'-flanking region of CYP2E1 was significantly more frequent in lung adenocarcinoma cases than in healthy controls and, therefore, may be involved in the development of lung adenocarcinoma.

The radial endobronchial ultrasound (EBUS) probe is conventionally inserted through the working channel of the flexible bronchoscope and limits interventional diagnostics and therapeutics under direct ultrasound control. The aim of this study was to assess the new convex probe EBUS (CP-EBUS) in the visualization of the hilar lymph nodes in surgically resected specimens and explore its feasibility to perform transbronchial needle aspiration (TBNA) under direct EBUS guidance prior to its clinical use. Fourteen surgically resected specimens from lung cancer (n=12) and metastatic lung cancer (n=2) patients were included in the study. The resected specimens included eight right upper lobes, one right middle lobe, and five left lower lobes. The EBUS examination was performed with a flexible bronchoscope equipped with a 7.5 MHz convex probe (CP) that scans parallel to the insertion direction of the bronchoscope. The appearance of the hilar lymph nodes using this CP-EBUS was noted. The size of hilar lymph nodes was measured at CP-EBUS and compared with the actual size of the lymph nodes, which was measured with a Vernier's caliper. Hilar lymph nodes could be clearly visualized with CP-EBUS. There was a good correlation between the actual size of the lymph node and that measured using CP-EBUS (R(2)=0.950). A dedicated transbronchial aspiration needle could be inserted into the hilar lymph node under direct ultrasonic control. There is a possibility in the underestimation of the size of large lymph nodes due to the scanning nature of the convex probe. The CP-EBUS was successfully used to visualize the hilar lymph node and perform TBNA in surgical resected lung specimens. This technique has an excellent potential to perform direct ultrasound guided TBNA of mediastinal and hilar lymph nodes.

The World Health Organization (WHO) categorized large cell neuroendocrine carcinoma (LCNEC) as a variant of large cell carcinoma in 1999. However, cytologic features of these tumors have not yet been adequately characterized. The cytologic features of 24 cases of LCNEC were analyzed and compared to the features of 16 cases of classic large cell carcinoma (CLCC). Giant cells, neutrophils and cytophagocytosis were observed more frequently in CLCC than in LCNEC (p

We investigated the XBF-4B40 (4B40) thin bronchoscope, which has a 4.0-mm outer diameter and a 2.0-mm biopsy channel, and studied its impact on the diagnosis of lung carcinoma. We analyzed 30 peripheral lung carcinoma cases by performing bronchoscopic examination using the 4B40 and the type 200 videoscope and recorded the most distal bronchus level reached. In addition, transbronchial aspiration biopsy, forceps biopsy, or brushing was performed, and the diagnosis accuracy between the two instruments was determined. The mean of the most distal bronchus reached by the 4B40 and the type 200 videoscope was the 4.5th and the 3rd, respectively. The 4B40 reached significantly further into the distal bronchus than the type 200 videoscope (p

The cytologic findings of the tumor cells characteristic of the stages of thymomas were investigated to assess the invasiveness of the tumors. Forty-six patients with thymoma who underwent extensive thymectomy without pre-operative corticosteroid therapy were included in this study. The histologic subtypes included 18 round/oval, 20 mixed, and 8 spindle type. The stages of thymoma classified according to Masaoka's clinicopathological classification included 16 stage I, 20 stage II, 6 stage III, 2 stage IVa, and 2 stage IVb, and myasthenia gravis was recognized in 5 patients. Cytologic findings were retrospectively analyzed in the Papanicolaou-stained stamp smears obtained from the cut surfaces of thymoma specimens. Morphometry of the epithelial tumor cells using Cosmozone-1A was performed to evaluate the validity of our cytologic categories. Compared with the cytologic findings of stage I or II thymomas, those of epithelial tumor cells in stage III or IV more frequently showed necrotic background (50.0%-stage III or IV vs 11.1%-stage I or II, p=0.006), large clusters of epithelial tumor cells (70.0% vs 36.1%, p=0.055), marked nuclear enlargement (90.0% vs 52.7%, p=0.033), marked anisokaryosis (100% vs 52.7%, p=0.006), marked nuclear polymorphism (40.0% vs 5.5%, p=0.004), hyperchromasia (50.0% vs 11.4%, p=0.007) and prominent nucleoli (50.0% vs 16.6%, p=0.028) whereas no significant correlation was observed between cytologic findings and tumor volume. Morphometric studies of thymoma tumor cells revealed that the nuclear size (mean values, 78.8 microm(3)-stage III or IV vs 58.2 microm(3)-stage I or II), the coefficient of variation of the nuclear size (0.326 vs 0.282), and the nuclear rotundity (0.849 vs 0.858) differed significantly between the two categories (p

The prognosis of patients with multilevel mediastinal lymph node metastasis remains poor notwithstanding the progress in multimodal therapy in non-small cell lung cancer. We conducted a feasible study of intermittent adjuvant chemo-immunotherapy after surgery for patients with multilevel mediastinal lymph node metastasis of non-small cell lung cancer. Eleven patients with pathologically N2 or N3 lung cancer (10, adenocarcinomas; 1, squamous cell carcinoma) were enrolled. Five completely resected cases received systemic chemo-immunotherapy and six incompletely resected cases received local chemo-immunotherapy by an indwelling catheter in the thoracic cavity. Cisplatin-based and dose-dependent anti-cancer drugs were selected on the basis of sensitivity tests. Either adoptive immunotherapy with interleukin-2 and lymphokine-activated killer cell or combination of interferon gamma# and OK432 were administered after chemotherapy. This adjuvant therapy was performed every 2-3 months after surgery for 2 years. The 2-year survival rate for all cases were 72.7% and the 2-year disease-free survival were 36.4%. The 2-year survival rate for five completely resected cases and six incompletely resected cases was 80% and 66.7%, respectively. Combined intermittent chemo-immunotherapy after surgical resection of tumors may be a promising modality to improve the survival of patients with multilevel mediastinal lymph node metastasis in non-small cell lung cancer.