Background: Breast cancer cells deficient for BRCA1 are hypersensitive to agents inducing DNA double-strand breaks (DSB), such as bifunctional alkylators and platinum agents. Earlier, we had developed a comparative genomic hybridisation (CGH) classifier based on BRCA1 -mutated breast cancers. We hypothesised that this BRCA1-like CGH classifier could also detect loss of function of BRCA1 due to other causes besides mutations and, consequently, might predict sensitivity to DSB-inducing agents. Patients and methods: We evaluated this classifier in stage III breast cancer patients, who had been randomly assigned between adjuvant high-dose platinum-based (HD-PB) chemotherapy, a DSB-inducing regimen, and conventional anthracycline-based chemotherapy. Additionally, we assessed BRCA1 loss through mutation or promoter methylation and immunohistochemical basal-like status in the triple-negative subgroup (TN subgroup). Results: We observed greater benefit from HD-PB chemotherapy versus conventional chemotherapy among patients with BRCA1-like CGH tumours [41/230 = 18%, multivariate hazard ratio (HR) = 0.12, 95% confidence interval (CI) 0.04–0.43] compared with patients with non-BRCA1-like CGH tumours (189/230 = 82%, HR = 0.78, 95% CI 0.50–1.20), with a significant difference (test for interaction P = 0.006). Similar results were obtained for overall survival ( P interaction = 0.04) and when analyses were restricted to the TN subgroup. Sixty-three percent (20/32) of assessable BRCA1-like CGH tumours harboured either a BRCA1 mutation ( n = 8) or BRCA1 methylation ( n = 12). Conclusion: BRCA1 loss as assessed by CGH analysis can identify patients with substantially improved outcome after adjuvant DSB-inducing chemotherapy when compared with standard anthracycline-based chemotherapy in our series.
Neither levetiracetam nor valproic acid was associated with additional cognitive deficits in HGG patients. Both AEDs even appeared to have a beneficial effect on verbal memory in these patients.
The overexpression of P-glycoprotein (Pgp) is thought to be an important mechanism of pharmacoresistance in epilepsy. Recently, 11 C-phenytoin has been evaluated preclinically as a tracer for Pgp. The aim of the present study was to assess the optimal plasma kinetic model for quantification of 11 C-phenytoin studies in humans. Methods: Dynamic 11 C-phenytoin PET scans of 6 healthy volunteers with arterial sampling were acquired twice on the same day and analyzed using single-and 2-tissue-compartment models with and without a blood volume parameter. Global and regional testretest (TRT) variability was determined for both plasma to tissue rate constant (K 1 ) and volume of distribution (V T ). Results: According to the Akaike information criterion, the reversible single-tissue-compartment model with blood volume parameter was the preferred plasma input model. Mean TRT variability ranged from 1.5% to 16.9% for K 1 and from 0.5% to 5.8% for V T . Larger volumes of interest showed better repeatabilities than smaller regions. A 45-min scan provided essentially the same K 1 and V T values as a 60-min scan. Conclusion: A reversible single-tissue-compartment model with blood volume seems to be a good candidate model for quantification of dynamic 11 C-phenytoin studies. Scan duration may be reduced to 45 min without notable loss of accuracy and precision of both K 1 and V T , although this still needs to be confirmed under pathologic conditions.
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