This is the first time that P-gp activity at the human BBB has been measured. The modest inhibition of human BBB P-gp by cyclosporine has implications for P-gp-based drug interactions at the human BBB. Our method for imaging P-gp activity can be used to identify multidrug-resistant tumors or to determine the contribution of P-gp polymorphism, inhibition, or induction to interindividual variability in drug response.

Purpose: The aim of this study is to compare glucose metabolism and hypoxia in four different tumor types using positron emission tomography (PET).18 F-labeled fluorodeoxyglucose (FDG) evaluates energy metabolism, whereas the uptake of 18 F-labeled fluoromisonidazole (FMISO) is proportional to tissue hypoxia. Although acute hypoxia results in accelerated glycolysis, cellular metabolism is slowed in chronic hypoxia, prompting us to look for discordance between FMISO and FDG uptake.Experimental Design: Forty-nine patients (26 with head and neck cancer, 11 with soft tissue sarcoma, 7 with breast cancer, and 5 with glioblastoma multiforme) who had both FMISO and FDG PET scans as part of research protocols through February 2003 were included in this study. The maximum standardized uptake value was used to depict FDG uptake, and hypoxic volume and maximum tissue: blood ratio were used to quantify hypoxia. Pixel-by-pixel correlation of radiotracer uptake was performed on coregistered images for each corresponding tumor plane.Results: Hypoxia was detected in all four patient groups. The mean correlation coefficients between FMISO and FDG uptake were 0.62 for head and neck cancer, 0.47 for breast cancer, 0.38 for glioblastoma multiforme, and 0.32 for soft tissue sarcoma. The correlation between the overall tumor maximum standardized uptake value for FDG and hypoxic volume was small (Spearman r ‫؍‬ 0.24), with highly significant differences among the different tumor types (P < 0.005).Conclusions: Hypoxia is a general factor affecting glucose metabolism; however, some hypoxic tumors can have modest glucose metabolism, whereas some highly metabolic tumors are not hypoxic, showing discordance in tracer uptake that can be tumor type specific.

Purpose: Hypoxia is associated with resistance to radiotherapy and chemotherapy and activates transcription factors that support cell survival and migration.We measured the volume of hypoxic tumor and the maximum level of hypoxia in glioblastoma multiforme before radiotherapy with [ Conclusions:The volume and intensity of hypoxia in glioblastoma multiforme before radiotherapy are strongly associated with poorer TTP and survival. This type of imaging could be integrated into new treatment strategies to target hypoxia more aggressively in glioblastoma multiforme and could be applied to assess the treatment outcomes.

The multiple-drug resistance (MDR) transporter P-glycoprotein (P-gp) is highly expressed at the human blood-brain barrier (BBB). P-gp actively effluxes a wide variety of drugs from the central nervous system, including anticancer drugs. We have previously demonstrated P-gp activity at the human BBB using PET of 11 C-verapamil distribution into the brain in the absence and presence of the P-gp inhibitor cyclosporine-A (CsA). Here we extend the initial noncompartmental analysis of these data and apply compartmental modeling to these human verapamil imaging studies. Methods: Healthy volunteers were injected with 15 O-water to assess blood flow, followed by 11 C-verapamil to assess BBB P-gp activity. Arterial blood samples and PET images were obtained at frequent intervals for 5 and 45 min, respectively, after injection. After a 60-min infusion of CsA (intravenously, 2.5 mg/kg/h) to inhibit P-gp, a second set of water and verapamil PET studies was conducted, followed by 11 C-CO imaging to measure regional blood volume. Blood flow was estimated using dynamic 15 O-water data and a flow-dispersion model. Dynamic 11 C-verapamil data were assessed by a 2-tissuecompartment (2C) model of delivery and retention and a 1-tissuecompartment model using the first 10 min of data (1C 10 ). Results: The 2C model was able to fit the full dataset both before and during P-pg inhibition. CsA modulation of P-gp increased blood-brain transfer (K 1 ) of verapamil into the brain by 73% (range, 30%2118%; n 5 12). This increase was significantly greater than changes in blood flow (13%; range, 12%249%; n 5 12, P , 0.001). Estimates of K 1 from the 1C 10 model correlated to estimates from the 2C model (r 5 0.99, n 5 12), indicating that a short study could effectively estimate P-gp activity. Conclusion: 11 C-verapamil and compartmental analysis can estimate P-gp activity at the BBB by imaging before and during P-gp inhibition by CsA, indicated by a change in verapamil transport (K 1 ). Inhibition of P-gp unmasks verapamil trapping in brain tissue that requires a 2C model for long imaging times; however, transport can be effectively measured using a short scan time with a 1C 10 model, avoiding complications with labeled metabolites and tracer retention. The blood-brain barrier (BBB) can significantly limit drug transport into the brain in, for example, chemotherapy of brain cancer (1,2). Drug efflux at the BBB is mediated by several transport proteins, of which P-glycoprotein (P-gp) is the most important (3-5). P-gp markedly restricts BBB transport of a broad range of drugs (6,7). Several strategies have been reported to improve delivery of therapeutics to the brain through circumvention of the BBB. One such strategy is the selective inhibition of P-gp, which has been shown in human studies to increase both drug delivery to the brain and therapeutic efficacy (8) of chemotherapeutic drugs. Methods to measure P-gp activity at the human BBB are required to assess this strategy.We have recently developed a method to measure P-gp activity at the hum...

Glioblastoma multiforme (GBM) are aggressive and uniformly fatal primary brain tumors characterized by their diffuse invasion of the normal appearing parenchyma peripheral to the clinical imaging abnormality. Hypoxia, a hallmark of aggressive tumor behavior often noted in GBMs, has been associated with resistance to therapy, poorer survival, and more malignant tumor phenotypes. Based on the existence of a set of novel imaging techniques and modeling tools, our objective was to assess a hypothesized quantitative link between tumor growth kinetics (assessed via mathematical model and routine MR imaging) and the hypoxic burden of the tumor (assessed via PET imaging). Our bio-mathematical model for glioma kinetics describes the spatial and temporal evolution of a glioma in terms of concentration of malignant tumor cells. This model has already been proved usefulas a novel tool to dynamically quantify the net rates of proliferation(ρ) and invasion (D) of the glioma cells in individual patients. Estimates of these kinetic rates can be calculated from routinely available pretreatment MR imaging invivo. Eleven adults withGBM were imaged pre-operatively with FMISO-PET and serial gadolinium-enhanced T1 (T1Gd) and T2-weighted MRIs to allow estimation of patient-specific net rates of proliferation (ρ) and invasion (D). Hypoxic volumes (HV) were quantified from each 18F-fluoromisonidazole (FMISO) PET scan following standard techniques. To control for tumor size variability, two measures of hypoxic burden were considered: relative hypoxia (RH), defined as the ratio of the HV to the T2-defined tumor volume, and the mean intensity on FMISO-PET scaled to the blood activity of the tracer (mean T/B). Pearson correlations between RH and the net rate of cell proliferation ρ reached significance (p < 0.04). Moreover, highly significant positive correlations were found between biological aggressiveness ratio ρ/D and both RH (p < 0.00003) and the mean T/B (p < 0.0007). Overall, biological aggressiveness assessed by serial MRI is linked with hypoxic burden assessed on FMISO-PET using a novel bio-mathematical model for glioma growth and invasion. This study suggests that patient-specific modeling of growth kinetics can provide novel and valuable insight into quantitative connections between disparate information provided by multimodality imaging.