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.

Quantification of kinetic parameters based on plasma-input models leads to comparable results when spatial resolution between HRRT and HR+ data is matched. When using reference-tissue models, differences remain that are likely caused by differences in attenuation and scatter corrections and/or image reconstruction.

Central neurotoxicity of chemotherapy is likely to be multifactorial. There are two hypotheses regarding endogenous mechanisms that may be involved, namely the target and the blood-brain barrier transporter hypotheses. Here, we will review candidate genetic determinants for the risk of chemotherapy-induced neurotoxicity, such as polymorphisms involved in the target mechanism. These include polymorphisms in folate metabolizing enzymes and apolipoprotein E, as well as those in blood-brain barrier transporter genes. Currently, the exact role of pharmacogenetics in mechanisms that lead to central neurotoxicity of chemotherapy has not been fully unraveled. Larger, prospective, longitudinal and more uniform studies are needed, with prechemotherapy and follow-up measurements of neuropsychological performance, MRI, PET, genetic profiles and biomarkers relevant for the proposed target and transporter mechanisms.

Following tumor resection, the majority of high-grade glioma (HGG) patients are treated with a combined modality regimen of radiotherapy and temozolomide. As a result of the tumor itself or as treatment-related neurotoxic side-effects, these patients may experience cognitive deficits. Additionally, radiological abnormalities expressed as white matter hyperintensities (WMH) and cerebral atrophy (CA) can develop. In this study, these functional and morphological parameters are evaluated, and their relation is investigated. After surgery, HGG patients underwent chemo-irradiation for six weeks, followed by six cycles of temozolomide. Assessments were performed before chemo-irradiation, post-concomitantly, after the third and sixth adjuvant cycle, and 3 and 7 months after treatment. Degree of WMH and CA was scored on MRI. Patients' neuropsychological performance was compared to healthy matched controls, yielding six cognitive domain z-scores. Development or progression of pre-existing WMH and CA during follow-up was observed in 36 and 45 % of the patients (n = 39) respectively. Cognitive functioning remained stable or improved in 70 % of the patients and deteriorated in 30 % of the patients (n = 33). Of the cognitive decliners, 80 % had tumor progression within 4 months thereafter. No clear association between cognitive functioning and WMH or CA was found. Central neurotoxic effects of combined modality treatment in HGG patients expressed by radiological abnormalities are encountered in approximately 40 % of patients. However, functional impact as indexed by cognitive functioning was found to be limited. Furthermore, development or progression of pre-existing WMH and CA does not consistently result in functional impairment as measured by cognitive tests.

Background[11C]Flumazenil and positron emission tomography (PET) are used clinically to assess gamma-aminobutyric acid (GABA)-ergic function and to localize epileptic foci prior to resective surgery. Enhanced P-glycoprotein (P-gp) activity has been reported in epilepsy and this may confound interpretation of clinical scans if [11C]flumazenil is a P-gp substrate. The purpose of this study was to investigate whether [11C]flumazenil is a P-gp substrate.Methods[11C]Flumazenil PET scans were performed in wild type (WT) (n = 9) and Mdr1a/1b, (the genes that encode for P-gp) double knockout (dKO) (n = 10) mice, and in naive rats (n = 10). In parallel to PET scanning, [11C]flumazenil plasma concentrations were measured in rats. For 6 of the WT and 6 of the dKO mice a second, [11C]flumazenil scan was acquired after administration of the P-gp inhibitor tariquidar. Cerebral [11C]flumazenil concentrations in WT and Mdr1a/1b dKO mice were compared (genetic disruption model). Furthermore, pre and post P-gp-blocking cerebral [11C]flumazenil concentrations were compared in all animals (pharmacological inhibition model).ResultsMdr1a/1b dKO mice had approximately 70% higher [11C]flumazenil uptake in the brain than WT mice. After administration of tariquidar, cerebral [11C]flumazenil uptake in WT mice increased by about 80% in WT mice, while it remained the same in Mdr1a/1b dKO mice. In rats, cerebral [11C]flumazenil uptake increased by about 60% after tariquidar administration. Tariquidar had only a small effect on plasma clearance of flumazenil.ConclusionsThe present study showed that [11C]flumazenil is a P-gp substrate in rodents. Consequently, altered cerebral [11C]flumazenil uptake, as observed in epilepsy, may not reflect solely GABAA receptor density changes but also changes in P-gp activity.

Resistance to current drug therapy is an important issue in the treatment of epilepsy. Inadequate access of central nervous system drugs to their targets in the brain may be caused by overexpression or overactivity of multidrug transporters, such as P-glycoprotein (P-gp), at the blood-brain barrier. Laniquidar, an inhibitor of P-gp, has been labeled with 11 C for use in PET studies of P-gp expression in humans. Given potential interspecies differences in biodistribution, the purpose of this study was to ensure safe use of 11 C-laniquidar by determining the dosimetry of 11 C-laniquidar using whole-body PET studies. Methods: Six healthy volunteers were subjected to a series of 10 whole-body PET scans within approximately 70 min. Five blood samples were taken during the series. Results: High uptake of 11 Claniquidar was seen in liver, spleen, kidneys, and lung, whereas brain uptake was low. The effective dose for 11 C-laniquidar was 4.76 6 0.13 and 3.69 6 0.01 mSvÁMBq 21 for women and men, respectively. Conclusion: Biodistribution and measured effective dose indicate that 11 C-laniquidar is a safe tracer for PET imaging, with a total dose of about 2 mSv for a brain PET/CT protocol.Key Words: P-glycoprotein; PET; 11 C-laniquidar; dosimetry; multidrug transporter Nucl Med 2013; 54:2101 54: -2103 54: DOI: 10.2967 Resi stance to drug therapy affects approximately 30% of all patients with epilepsy (1) and may be due, at least in part, to decreased passage of antiepileptic drugs across the blood-brain barrier. Uptake and efflux drug transporters play a major functional role in regulating drug entry into the brain. Two large and important drug transporter families are the organic anion-transporting polypeptide (OATP) family and the adenosine triphosphate-binding cassette transporter superfamily (2,3). Several members of both families are expressed at the human blood-brain barrier, including OATP1A2, OATP1C1, and OATP3A1 (members of the OATP family) and P-glycoprotein (P-gp), breast cancer resistance protein, and multidrug resistance protein 4 (members of the adenosine triphosphate-binding transporter superfamily) (2,3). In this paper, the focus is on the most widely studied efflux transporter, P-gp. It has been proposed that changes in P-gp expression or function at the blood-brain barrier play an important role in pharmacoresistance in epilepsy (4). The multidrug transporter P-gp and other efflux transporters actively transport substrates, including many central nervous system drugs, against a concentration gradient from brain to blood and cerebrospinal fluid. Hence, overexpression or increased activity of the transporter system may result in reduced tissue concentrations of central nervous system drugs in the brain, thereby greatly limiting their therapeutic efficacy. There are two case reports suggesting that inhibiting P-gp in medically refractory epilepsy patients decreases seizure frequency, at least temporarily (5,6). P-gp functionality can be assessed in vivo by means of (R)-11 C-verapamil and 11 C-N-desmethyllo...