C. Chad Quarles

Improving the reliability of obtaining tumor hemodynamic parameters in the presence of contrast agent extravasation

A new approach to improve the reliability of dynamic susceptibility contrast MRI for the evaluation of brain tumor hemodynamics in the presence of contrast agent extravasation is described. This model‐based technique simultaneously estimates the voxel‐wise tumor residue function and the temporal extravascular T1 changes following contrast agent leakage. With these estimates the model corrects the measured MRI signal, which is then used to calculate tumor hemodynamic parameters. The feasibility of this technique is demonstrated with computer simulations that cover a wide range of hemodynamic conditions and by application to eight tumor‐bearing rats. The simulations demonstrate that the corrected hemodynamic parameters precisely matched the actual values with a maximum percentage error of 4.2% compared to 68.6% for the uncorrected parameters. The corrected parameters are also essentially independent of the tumor hemodynamic state and degree of contrast extravasation. Consistent with these improvements, significant differences between corrected and uncorrected parameters, calculated from a gradient‐echo sequence, are shown in a rat 9L gliosarcoma model. This method combined with the hemodynamic parameters derived from GE and SE sequences shows promise as a new tool to evaluate tumor angiogenesis and its therapy. Magn Reson Med 53:1307–1316, 2005.

Assessment of the morphological and functional effects of the anti‐angiogenic agent SU11657 on 9L gliosarcoma vasculature using dynamic susceptibility contrast MRI

To investigate the influence of anti‐angiogenic agents on tumor perfusion, we employed a dynamic susceptibility contrast (DSC)‐MRI method that utilizes a simultaneous gradient‐echo (GE) and spin‐echo (SE) imaging sequence to derive perfusion parameters (blood flow, blood volume, and mean transit time (MTT)). These parameters are sensitive to both the total vasculature (from the GE data) and the microvasculature (from the SE data), and can also provide a measure of the mean vessel diameter (mVD). This approach was used to evaluate the response of a 9L rat brain tumor model to 20 mg/kg and 40 mg/kg of the anti‐angiogenic agent SU11657. The 20‐mg/kg dose significantly decreased mVD by 29.9% (P = 0.02). The 40‐mg/kg dose significantly decreased mVD by 30.4% (P = 0.0007), SE blood volume by 31.8% (P = 0.03), GE and SE MTT by 46.9% (P = 0.03) and 62.0% (P = 0.0005), and increased GE and SE blood flow by 36.6% (P = 0.04) and 52.6% (P = 0.02). These findings demonstrate that DSC‐MRI perfusion methods can play a key role in the noninvasive evaluation of morphological and functional changes in tumor vasculature in response to therapy. Magn Reson Med 57:680–687, 2007.

Radiogenomics to characterize regional genetic heterogeneity in glioblastoma

Background Glioblastoma (GBM) exhibits profound intratumoral genetic heterogeneity. Each tumor comprises multiple genetically distinct clonal populations with different therapeutic sensitivities. This has implications for targeted therapy and genetically informed paradigms. Contrast-enhanced (CE)-MRI and conventional sampling techniques have failed to resolve this heterogeneity, particularly for nonenhancing tumor populations. This study explores the feasibility of using multiparametric MRI and texture analysis to characterize regional genetic heterogeneity throughout MRI-enhancing and nonenhancing tumor segments. Methods We collected multiple image-guided biopsies from primary GBM patients throughout regions of enhancement (ENH) and nonenhancing parenchyma (so called brain-around-tumor, [BAT]). For each biopsy, we analyzed DNA copy number variants for core GBM driver genes reported by The Cancer Genome Atlas. We co-registered biopsy locations with MRI and texture maps to correlate regional genetic status with spatially matched imaging measurements. We also built multivariate predictive decision-tree models for each GBM driver gene and validated accuracies using leave-one-out-cross-validation (LOOCV). Results We collected 48 biopsies (13 tumors) and identified significant imaging correlations (univariate analysis) for 6 driver genes: EGFR, PDGFRA, PTEN, CDKN2A, RB1, and TP53. Predictive model accuracies (on LOOCV) varied by driver gene of interest. Highest accuracies were observed for PDGFRA (77.1%), EGFR (75%), CDKN2A (87.5%), and RB1 (87.5%), while lowest accuracy was observed in TP53 (37.5%). Models for 4 driver genes (EGFR, RB1, CDKN2A, and PTEN) showed higher accuracy in BAT samples (n = 16) compared with those from ENH segments (n = 32). Conclusion MRI and texture analysis can help characterize regional genetic heterogeneity, which offers potential diagnostic value under the paradigm of individualized oncology.

Dexamethasone Normalizes Brain Tumor Hemodynamics as Indicated by Dynamic Susceptibility Contrast MRI Perfusion Parameters

The purpose of this study is to demonstrate the utility of dynamic susceptibility contrast (DSC) MRI-derived perfusion parameters to characterize the hemodynamic effects of dexamethasone in a 9L gliosarcoma tumor model. Twenty-four rats underwent intracerebral inoculation with 9L tumor cells. Fifteen were treated with a total of 3mg/kg of dexamethasone on days 10–14 post-inoculation, while the remaining 9 rats served as controls. Fourteen days post-inoculation, MRI images, sensitive to total and micro-vascular cerebral blood flow (CBF), mean transit time (MTT), and intravoxel transit time distributions (TTD)s were obtained using a simultaneous gradient-echo(GE)/spin-echo(SE) DSC-MRI method. Dexamethasone-treated animals had a microvascular (SE) tumor CBF that was 45.9% higher (p = 0.0008) and a MTT that was 47.8% lower (p = 0.0005) than untreated animals. With treatment, there was a non-significant 91.3% increase in total (GE) vascular CBF (p = 0.35), and a significant decrease in MTT (49.1%, p = 0.02). The total vascular and microvascular TTDs from the treated tumors were similar to normal brain, unlike the TTDs in the untreated tumors. These findings demonstrate that DSC-MRI perfusion methods can be used to non-invasively detect the morphological and functional changes in tumor vasculature that occur in response to dexamethasone treatment.

Quantitative [18F]FMISO PET Imaging Shows Reduction of Hypoxia Following Trastuzumab in a Murine Model of HER2+ Breast Cancer

PurposeEvaluation of [18F]fluoromisonidazole ([18F]FMISO)-positron emission tomography (PET) imaging as a metric for evaluating early response to trastuzumab therapy with histological validation in a murine model of HER2+ breast cancer.ProceduresMice with BT474, HER2+ tumors, were imaged with [18F]FMISO-PET during trastuzumab therapy. Pimonidazole staining was used to confirm hypoxia from imaging.Results[18F]FMISO-PET indicated significant decreases in hypoxia beginning on day 3 (Pu2009<u20090.01) prior to changes in tumor size. These results were confirmed with pimonidazole staining on day 7 (Pu2009<u20090.01); additionally, there was a significant positive linear correlation between histology and PET imaging (r2u2009=u20090.85).Conclusions[18F]FMISO-PET is a clinically relevant modality which provides the opportunity to (1) predict response to HER2+ therapy before changes in tumor size and (2) identify decreases in hypoxia which has the potential to guide subsequent therapy.

Trastuzumab improves tumor perfusion and vascular delivery of cytotoxic therapy in a murine model of HER2+ breast cancer: preliminary results

To employ in vivo imaging and histological techniques to identify and quantify vascular changes early in the course of treatment with trastuzumab in a murine model of HER2+ breast cancer. Dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) was used to quantitatively characterize vessel perfusion/permeability (via the parameter Ktrans) and the extravascular extracellular volume fraction (ve) in the BT474 mouse model of HER2+ breast cancer (Nxa0=xa020) at baseline, day one, and day four following trastuzumab treatment (10xa0mg/kg). Additional cohorts of mice were used to quantify proliferation (Ki67), microvessel density (CD31), pericyte coverage (α-SMA) by immunohistochemistry (Nxa0=xa044), and to quantify human VEGF-A expression (Nxa0=xa029) throughout the course of therapy. Longitudinal assessment of combination doxorubicinxa0±xa0trastuzumab (Nxa0=xa042) tested the hypothesis that prior treatment with trastuzumab will increase the efficacy of subsequent doxorubicin therapy. Compared to control tumors, trastuzumab-treated tumors exhibited a significant increase in Ktrans (Pxa0=xa00.035) on day four, indicating increased perfusion and/or vessel permeability and a simultaneous significant increase in ve (Pxa0=xa00.01), indicating increased cell death. Immunohistochemical and ELISA analyses revealed that by day four the trastuzumab-treated tumors had a significant increase in vessel maturation index (i.e., the ratio of α-SMA to CD31 staining) compared to controls (Pxa0<xa00.001) and a significant decrease in VEGF-A (Pxa0=xa00.03). Additionally, trastuzumab dosing prior to doxorubicin improved the overall effectiveness of the therapies (Pxa0<xa00.001). This study identifies and validates improved perfusion characteristics following trastuzumab therapy, resulting in an improvement in trastuzumab-doxorubicin combination therapy in a murine model of HER2+ breast cancer. This data suggests properties of vessel maturation. In particular, the use of DCE-MRI, a clinically available imaging method, following treatment with trastuzumab may provide an opportunity to optimize the scheduling and improve delivery of subsequent cytotoxic therapy.

Hypoxia Imaging with PET Correlates with Anti-Tumor Activity of the Hypoxia-Activated Prodrug Evofosfamide (TH-302) in Rodent Glioma Models

High-grade gliomas are often characterized by hypoxia, which is associated with both poor long-term prognosis and therapy resistance. The adverse role hypoxia plays in treatment resistance and disease progression has led to the development of hypoxia imaging methods and hypoxia-targeted treatments. Here, we determined the tumor hypoxia and vascular perfusion characteristics of 2 rat orthotopic glioma models using 18-fluoromisonidozole positron emission tomography. In addition, we determined tumor response to the hypoxia-activated prodrug evofosfamide (TH-302) in these rat glioma models. C6 tumors exhibited more hypoxia and were less perfused than 9L tumors. On the basis of these differences in their tumor hypoxic burden, treatment with evofosfamide resulted in 4- and 2-fold decreases in tumor growth rates of C6 and 9L tumors, respectively. This work shows that imaging methods sensitive to tumor hypoxia and perfusion are able to predict response to hypoxia-targeted agents. This has implications for improved patient selection, particularly in clinical trials, for treatment with hypoxia-activated cytotoxic prodrugs, such as evofosfamide.

Translocator Protein PET Imaging in a Preclinical Prostate Cancer Model

PurposeThe identification and targeting of biomarkers specific to prostate cancer (PCa) could improve its detection. Given the high expression of translocator protein (TSPO) in PCa, we investigated the use of [18F]VUIIS1008 (a novel TSPO-targeting radioligand) coupled with positron emission tomography (PET) to identify PCa in mice and to characterize their TSPO uptake.ProceduresPtenpc−/−, Trp53pc−/− prostate cancer-bearing mice (nxa0=xa09, 4–6xa0months old) were imaged in a 7T MRI scanner for lesion localization. Within 24xa0h, the mice were imaged using a microPET scanner for 60xa0min in dynamic mode following a retro-orbital injection of ~xa018xa0MBq [18F]VUIIS1008. Following imaging, tumors were harvested and stained with a TSPO antibody. Regions of interest (ROIs) were drawn around the tumor and muscle (hind limb) in the PET images. Time-activity curves (TACs) were recorded over the duration of the scan for each ROI. The mean activity concentrations between 40 and 60xa0min post radiotracer administration between tumor and muscle were compared.ResultsTumor presence was confirmed by visual inspection of the MR images. The uptake of [18F]VUIIS1008 in the tumors was significantly higher (pxa0<xa00.05) than that in the muscle, where the percent injected dose per unit volume for tumor was 7.1xa0±xa01.6xa0%xa0ID/ml and that of muscle was <xa01xa0%xa0ID/ml. In addition, positive TSPO expression was observed in tumor tissue analysis.ConclusionsThe foregoing preliminary data suggest that TSPO may be a useful biomarker of PCa. Therefore, using TSPO-targeting PET ligands, such as [18F]VUIIS1008, may improve PCa detectability and characterization.

Optimization of DSC MRI Echo Times for CBV Measurements Using Error Analysis in a Pilot Study of High-Grade Gliomas.

BACKGROUND AND PURPOSE: The optimal TE must be calculated to minimize the variance in CBV measurements made with DSC MR imaging. Simulations can be used to determine the influence of the TE on CBV, but they may not adequately recapitulate the in vivo heterogeneity of precontrast T2*, contrast agent kinetics, and the biophysical basis of contrast agent–induced T2* changes. The purpose of this study was to combine quantitative multiecho DSC MRI T2* time curves with error analysis in order to compute the optimal TE for a traditional single-echo acquisition. MATERIALS AND METHODS: Eleven subjects with high-grade gliomas were scanned at 3T with a dual-echo DSC MR imaging sequence to quantify contrast agent–induced T2* changes in this retrospective study. Optimized TEs were calculated with propagation of error analysis for high-grade glial tumors, normal-appearing white matter, and arterial input function estimation. RESULTS: The optimal TE is a weighted average of the T2* values that occur as a contrast agent bolus transverses a voxel. The mean optimal TEs were 30.0 ± 7.4 ms for high-grade glial tumors, 36.3 ± 4.6 ms for normal-appearing white matter, and 11.8 ± 1.4 ms for arterial input function estimation (repeated-measures ANOVA, P < .001). CONCLUSIONS: Greater heterogeneity was observed in the optimal TE values for high-grade gliomas, and mean values of all 3 ROIs were statistically significant. The optimal TE for the arterial input function estimation is much shorter; this finding implies that quantitative DSC MR imaging acquisitions would benefit from multiecho acquisitions. In the case of a single-echo acquisition, the optimal TE prescribed should be 30–35 ms (without a preload) and 20–30 ms (with a standard full-dose preload).

Multisite Concordance of DSC-MRI Analysis for Brain Tumors: Results of a National Cancer Institute Quantitative Imaging Network Collaborative Project

DSC-MR imaging data were collected after a preload and during a bolus injection of gadolinium contrast agent using a gradient recalled-echo-EPI sequence. Forty-nine low-grade and high-grade glioma datasets were uploaded to The Cancer Imaging Archive. Datasets included a predetermined arterial input function, enhancing tumor ROIs, and ROIs necessary to create normalized relative CBV and CBF maps. Seven sites computed 20 different perfusion metrics. For normalized relative CBV and normalized CBF, 93% and 94% of entries showed good or excellent cross-site agreement. All metrics could distinguish low- from high-grade tumors. BACKGROUND AND PURPOSE: Standard assessment criteria for brain tumors that only include anatomic imaging continue to be insufficient. While numerous studies have demonstrated the value of DSC-MR imaging perfusion metrics for this purpose, they have not been incorporated due to a lack of confidence in the consistency of DSC-MR imaging metrics across sites and platforms. This study addresses this limitation with a comparison of multisite/multiplatform analyses of shared DSC-MR imaging datasets of patients with brain tumors. MATERIALS AND METHODS: DSC-MR imaging data were collected after a preload and during a bolus injection of gadolinium contrast agent using a gradient recalled-echo–EPI sequence (TE/TR = 30/1200 ms; flip angle = 72°). Forty-nine low-grade (n = 13) and high-grade (n = 36) glioma datasets were uploaded to The Cancer Imaging Archive. Datasets included a predetermined arterial input function, enhancing tumor ROIs, and ROIs necessary to create normalized relative CBV and CBF maps. Seven sites computed 20 different perfusion metrics. Pair-wise agreement among sites was assessed with the Lin concordance correlation coefficient. Distinction of low- from high-grade tumors was evaluated with the Wilcoxon rank sum test followed by receiver operating characteristic analysis to identify the optimal thresholds based on sensitivity and specificity. RESULTS: For normalized relative CBV and normalized CBF, 93% and 94% of entries showed good or excellent cross-site agreement (0.8 ≤ Lin concordance correlation coefficient ≤ 1.0). All metrics could distinguish low- from high-grade tumors. Optimum thresholds were determined for pooled data (normalized relative CBV = 1.4, sensitivity/specificity = 90%:77%; normalized CBF = 1.58, sensitivity/specificity = 86%:77%). CONCLUSIONS: By means of DSC-MR imaging data obtained after a preload of contrast agent, substantial consistency resulted across sites for brain tumor perfusion metrics with a common threshold discoverable for distinguishing low- from high-grade tumors.