Temozolomide single-agent chemotherapy for newly diagnosed anaplastic oligodendroglioma.

The treatment of patients with anaplastic oligodendroglioma (AO) has been significantly impacted by the molecular detection of loss of sequences on chromosomes 1p and 19q. We performed a clinical trial to prospectively evaluate the safety of treating patients with AO with temozolomide (TMZ) alone in patients with chromosome 1p/19q loss and with chemo-radiation in patients not harboring this loss. Forty-eight patients were enrolled, 36/48 (75%) with evidence of chromosome 1p/19q loss treated with TMZ alone and 12/18 (25%) without such losses, treated with pre-radiation TMZ followed by chemo-radiation. Despite more aggressive treatment, patients without 1p/19q loss had a shorter progression-free survival (PFS) of 13.5 months. With a median follow-up time of 32 months, patients with 1p/19q LOH had a median TTP of 28.7 months. Patients with AO with 1p/19q LOH can be safely treated with single-agent TMZ and do not appear to experience earlier or more frequent tumor progression. This treatment regimen should be studied as part of a formal randomized clinical trial.

Spatial patterns of cadmium and lead deposition on and adjacent to National Park Service lands in the vicinity of Red Dog Mine, Alaska.

Heavy metal escapement associated with ore trucks is known to occur along the DeLong Mountain Regional Transportation System (DMTS) haul road corridor in Cape Krusenstern National Monument, northwest Alaska. Heavy metal concentrations in Hylocomium splendens moss (n = 226) were used in geostatistical models to predict the extent and pattern of atmospheric deposition of Cd and Pb on Monument lands. A stratified grid-based sample design was used with more intensive sampling near mine-related activity areas. Spatial predictions were used to produce maps of concentration patterns, and to estimate the total area in 10 moss concentration categories. Heavy metal levels in moss were highest immediately adjacent to the DMTS haul road (Cd > 24 mg/kg dw; Pb > 900 mg/kg dw). Spatial regression analyses indicated that heavy metal deposition decreased with the log of distance from the DMTS haul road and the DMTS port site. Analysis of subsurface soil suggested that observed patterns of heavy metal deposition reflected in moss were not attributable to subsurface lithology at the sample points. Further, moss Pb concentrations throughout the northern half of the study area were high relative to concentrations previously reported from other Arctic Alaska sites. Collectively, these findings indicate the presence of mine-related heavy metal deposition throughout the northern portion of Cape Krusenstern National Monument. Geospatial analyses suggest that the Pb depositional area extends 25 km north of the haul road to the Kisimilot/Iyikrok hills, and possibly beyond. More study is needed to determine whether higher moss heavy metal concentrations in the northernmost portion of the study area reflect deposition from mining-related activities, weathering from mineralized Pb/Zn outcrops in the broader region, or a combination of the two. South of the DMTS haul road, airborne deposition appears to be constrained by the Tahinichok Mountains. Heavy metal levels continue to diminish south of the mountains, reaching a minimum in the southernmost portion of the study area near the Igichuk Hills (45 km from the haul road). The influence of the mine site was not studied.

Characterisation of the promoter region of the human DNA-repair gene Rad51.

PURPOSE OF INVESTIGATION: Regulatory elements of the 5'-flanking region of the DNA-repair gene Rad51 were analysed to characterise pathological alterations of Rad51 mRNA expression during tumour development. METHODS: Various fragments of the Rad51 promoter were cloned into the pGL3 reporter vector and the respective promoter activity was determined by luciferase assays in transfected U2-OS cells. Transcription factor binding was identified using Protein/DNA arrays. RESULTS: The region encompassing base pairs -204 to -58 was identified as crucial for Rad51 gene transcription. Down regulator sequences are present upstream (-305 to -204) and downstream (-48 and +204) of this core promoter element. Promoter activity is significantly enhanced by substituting G at the polymorphic positions +135 and +172 for C and T, respectively. Transcription factors Ets1/PEA3, E2F1, p53, EGR1, and Stat5 were identified as relevant for regulating expression of Rad51. CONCLUSION: We identified three separate cis-sequence elements within the Rad51 transcriptional promoter, one ensuring basal levels of expression and two elements limiting expression to relatively low levels. The characterisation of transcription factor binding might help to explain high-level expression of Rad51 in a variety of solid tumours. The polymorphic sites appear important for the increased risk of breast and/or ovarian cancer for BRCA2 mutation carriers.

Inter-individual differences in cytokine release in patients undergoing cardiac surgery with cardiopulmonary bypass.

Cardiac surgery with cardiopulmonary bypass (CPB) leads to a systemic inflammatory response with secretion of cytokines (e.g. IL-6, TNF-alpha, IL-1 beta and sIL-2R). The objective of the following study was to investigate in vitro and in vivo cytokine responses and white blood cell counts (WBC) of patients with high versus low cytokine secretion after a coronary artery bypass grafting (CABG) procedure. Twenty male patients undergoing elective CABG surgery with CPB under general anaesthesia were enrolled in the study. On the day of surgery (postoperatively), serum levels of TNF-alpha and IL-1 beta were significantly higher in patients of the high IL-6 level group compared to the respective values in the patient group with low IL-6 levels. The inter-individual differences in IL-6 release in patients undergoing CABG surgery with CPB were accompanied by differences in the release of other cytokines, such as TNF-alpha, IL-1 beta and sIL-2R. To understand whether genetic background plays a role in influencing cytokine plasma levels under surgical stress, we examined the distribution of polymorphic elements within the promoter regions of the TNF-alpha and IL-6 genes, and determined their genotype regarding the BAT2 gene and TNF-beta intron polymorphisms. Our preliminary data suggests that regulatory polymorphisms in or near the TNF locus, more precisely the allele set 140/150 of the BAT2 microsatellite marker combined with the G allele at -308 of the TNF-alpha gene, could be one of the genetic constructions providing for a less sensitive response to various stimuli. Our results suggest: (1) close relationships between cytokine release in the postoperative period, and (2) inter-individually varying patterns of cytokine release in patients undergoing CABG surgery with CPB.

DNA repair and recombination factor Rad51 is over-expressed in human pancreatic adenocarcinoma.

Molecular processes that could contribute to differences in chemo- and radioresistance include variations in DNA repair mechanisms. In mammalian cells, the product of the rad51 gene mediates DNA repair via homologous recombination. We describe that in contrast to conventional monolayer cell systems Rad51 protein accumulates to high-levels in three-dimensional cell culture models as well as in orthotopic xeno-transplants of human pancreatic cancer cells. Strikingly, over-expression of wild-type Rad51 was also found in 66% of human pancreatic adenocarcinoma tissue specimens. Functional analysis revealed that Rad51 over-expression enhances survival of cells after induction of DNA double strand breaks. These data suggest that perturbations of Rad51 expression contribute to the malignant phenotype of pancreatic cancer. Oncogene (2000).