Promoter hypermethylation of resected bronchial margins: a field defect of changes?

PURPOSE: Histologically positive bronchial margins after resection for non-small cell lung cancer are associated with shortened patient survival due to local recurrence. We hypothesized that DNA promoter hypermethylation changes at bronchial margins could be detected in patients with no histological evidence of malignancy and that they would reflect epigenetic events in the primary tumor. EXPERIMENTAL DESIGN: Bronchial margins, primary tumor, bronchoalveolar fluid, and paired nonmalignant lung were obtained from 20 non-small cell lung cancer patients who underwent a lobectomy or greater resection. Disease-specific recurrence was the primary end point. The methylation status of p16, MGMT, DAPK, SOCS1, RASSF1A, COX2, and RARbeta was examined using methylation-specific polymerase chain reaction. RESULTS: All malignancies had methylation in at least one locus. Concordance of one gene with an identical epigenetic change in the tumor or bronchial margin was observed in 85% of patients. Only one patient had methylation at the bronchial margin for a gene that was not methylated in the corresponding tumor. Median time to recurrence was 37 months (range, 5-71 months). There were two local recurrences and five metastases. There were no significant correlations between DNA methylation in tumor, margins, or bronchoalveolar fluid specimens and either regional recurrence or distant metastases. CONCLUSIONS: Histologically negative bronchial margins of resected non-small cell lung cancer exhibit frequent hypermethylation changes in multiple genes. These hyper-methylation abnormalities are also present in the primary tumor and thus may represent a field defect of preneoplastic changes that occurs early in carcinogenesis.     

Family history and recurrence of febrile seizures

To determine the value of a detailed family history for the assessment of the risk of recurrence of febrile seizures, 115 children who visited the emergency room of an academic children's hospital were studied prospectively. The recurrence risk of febrile seizures was analysed in relation to the child's family history and the proportion of relatives affected by febrile seizures using Kaplan-Meier estimates and Cox proportional hazard models. A first degree family history positive for febrile seizures (parents or siblings affected by febrile seizures) increased a child's two year recurrence risk from 27 to 52%. No significant increase of recurrence risk for febrile seizures was found in children with second degree relatives (grandparents and uncles/aunts) or cousins only affected by febrile seizures. Recurrence risk was significantly correlated with the proportion of first degree relatives affected by febrile seizures: risks were 27, 40, and 83% in children whose proportion was 0, 0-0.5, and > or = 0.5 respectively. Analysis of the recurrence risk in relation to a weighted proportion, adjusted for the attained age and sex of first degree relatives, showed similar results. It is concluded that the application of the proportion of first degree relatives affected by febrile seizures generates a more differentiated assessment of the recurrence risk of febrile seizures.     

Increased fatty acid synthase is a therapeutic target in mesothelioma.

Many common human cancer tissues express high levels of fatty acid synthase (FAS), the primary enzyme for the synthesis of fatty acids, and the differential expression of FAS between normal and neoplastic tissues has led to the consideration of FAS as a target for anticancer therapy. To investigate the potential of targeting FAS for the treatment of pleural mesothelioma, we first determined whether FAS is overexpressed in human mesothelioma. By immunohistochemistry, we found 22 of 30 human mesothelioma tissue samples tested to express significantly increased levels of FAS compared with normal tissues, including mesothelium. To further explore FAS as a therapeutic target in mesothelioma, we established a nude mouse xenograft model for human mesothelioma using the H-Meso cell line. The i.p. xenografts of this cell line have high levels of FAS expression and fatty acid synthesis pathway activity and grow along mesothelial surfaces in a manner similar to the growth pattern of human mesothelioma. Growth of these tumor xenografts was essentially abolished in mice treated with weekly i.p. injections of C75, a synthetic, small molecule inhibitor of FAS, at levels that resulted in no significant systemic toxicity except for reversible weight loss. These results suggest that FAS may be an effective target for pharmacological therapy in a high proportion of human mesotheliomas.