Dynamic Contrast-enhanced Magnetic Resonance Imaging Measurements Research Articles

Assessment of Background Parenchymal Enhancement at Dynamic Contrast-enhanced MRI in Predicting Breast Cancer Recurrence Risk.

Background Background parenchymal enhancement (BPE) at dynamic contrast-enhanced (DCE) MRI of cancer-free breasts increases the risk of developing breast cancer; implications of quantitative BPE in ipsilateral breasts with breast cancer are largely unexplored. Purpose To determine whether quantitative BPE measurements in one or both breasts could be used to predict recurrence risk in women with breast cancer, using the Oncotype DX recurrence score as the reference standard. Materials and Methods This HIPAA-compliant retrospective single-institution study included women diagnosed with breast cancer between January 2007 and January 2012 (development set) and between January 2012 and January 2017 (internal test set). Quantitative BPE was automatically computed using an in-house-developed computer algorithm in both breasts. Univariable logistic regression was used to examine the association of BPE with Oncotype DX recurrence score binarized into high-risk (recurrence score >25) and low- or intermediate-risk (recurrence score ≤25) categories. Models including BPE measures were assessed for their ability to distinguish patients with high risk versus those with low or intermediate risk and the actual recurrence outcome. Results The development set included 127 women (mean age, 58 years ± 10.2 [SD]; 33 with high risk and 94 with low or intermediate risk) with an actual local or distant recurrence rate of 15.7% (20 of 127) at a minimum 10 years of follow-up. The test set included 60 women (mean age, 57.8 years ± 11.6; 16 with high risk and 44 with low or intermediate risk). BPE measurements quantified in both breasts were associated with increased odds of a high-risk Oncotype DX recurrence score (odds ratio range, 1.27-1.66 [95% CI: 1.02, 2.56]; P < .001 to P = .04). Measures of BPE combined with tumor radiomics helped distinguish patients with a high-risk Oncotype DX recurrence score from those with a low- or intermediate-risk score, with an area under the receiver operating characteristic curve of 0.94 in the development set and 0.79 in the test set. For the combined models, the negative predictive values were 0.97 and 0.93 in predicting actual distant recurrence and local recurrence, respectively. Conclusion Ipsilateral and contralateral DCE MRI measures of BPE quantified in patients with breast cancer can help distinguish patients with high recurrence risk from those with low or intermediate recurrence risk, similar to Oncotype DX recurrence score. © RSNA, 2024 Supplemental material is available for this article. See also the editorial by Zhou and Rahbar in this issue.

Injection rate of contrast medium affects diagnostic ability of dynamic contrast-enhanced magnetic resonance imaging for endometrial carcinoma: a prospective cohort study

Dynamic contrast enhanced magnetic resonance imaging (DCE-MRI) can obtain semi-quantitative or quantitative parameters of tumors by capturing the images before and after injection of contrast medium. However, there has been no further research on the effect of flow rate of contrast medium on image quality and parameter sensitivity of DCE-MRI in endometrial carcinoma (EC). This was a prospective cohort study enrolling patients who were suspected of EC between January 2018 and June 2020. The baseline data of participants were collected. Post-surgical histological examination acted as the gold standard of EC diagnosis and some characteristics of tumors were recorded. We calculated 3 important parameters of DCE-MRI, including volume transfer constant (Ktrans), flux rate constant (Kep), and extravascular extracellular volume fraction (Ve), according to the MRI system. The image quality in DCE-MRI imaging was evaluated according to contrast, resolution, artifact, signal-to-noise ratio, and scanning time. To evaluate the diagnostic ability of DCE-MRI with different injection rate, receiver operating characteristic (ROC) curve was generated and the area under curve (AUC) was calculated. According to the different injection rate of contrast medium, participants were divided into three groups, including 2, 3, and 4 mL/s group. It was found that there were more grade 1 EC in the 3 mL/s group (52.4%) than other two groups (34.3% and 23.3%, respectively), and the difference was significant (P=0.021). No other significant differences were found among all other variables. It was found that Ktrans was much higher in the 4 mL/s group than in other two groups (P<0.001). Also, Ve was much higher in the 4 mL/s group than in other two groups (P<0.001). However, no significant difference was found in Kep between three groups (P=0.633). Besides, the 4 mL/s group had the highest quality of all three groups (P<0.001). The sensitivity, specificity, and accuracy were highest in 4 mL/s group. The AUC in three groups were 0.822, 0.832, and 0.888 in the 2, 3, and 4 mL/s group, respectively. The DCE-MRI measurement is useful for the diagnosis of EC, and faster injection rate may be beneficial to improve diagnostic accuracy and image quality.

Technical Note: Quantitative dynamic contrast-enhanced MRI of a 3-dimensional artificial capillary network.

Variability across devices, patients, and time still hinders widespread recognition of dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) as quantitative biomarker. The purpose of this work was to introduce and characterize a dedicated microchannel phantom as a model for quantitative DCE-MRI measurements. A perfusable, MR-compatible microchannel network was constructed on the basis of sacrificial melt-spun sugar fibers embedded in a block of epoxy resin. Structural analysis was performed on the basis of light microscopy images before DCE-MRI experiments. During dynamic acquisition the capillary network was perfused with a standard contrast agent injection system. Flow-dependency, as well as inter- and intrascanner reproducibility of the computed DCE parameters were evaluated using a 3.0T whole-body MRI. Semi-quantitative and quantitative flow-related parameters exhibited the expected proportionality to the set flow rate (mean Pearson correlation coefficient: 0.991, P<2.5e-5). The volume fraction was approximately independent from changes of the applied flow rate through the phantom. Repeatability and reproducibility experiments yielded maximum intrascanner coefficients of variation (CV) of 4.6% for quantitative parameters. All evaluated parameters were well in the range of known invivo results for the applied flow rates. The constructed phantom enables reproducible, flow-dependent, contrast-enhanced MR measurements with the potential to facilitate standardization and comparability of DCE-MRI examinations.

Comparison between perfusion computed tomography and dynamic contrast-enhanced magnetic resonance imaging in assessing glioblastoma microvasculature

PurposePerfusion computed tomography (PCT) and dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) provide independent measurements of biomarkers related to tumor perfusion. The aim of this study was to compare the two techniques in assessing glioblastoma microvasculature. Materials and methodsTwenty-five patients diagnosed with glioblastoma (14 males and 11 females; 51±11years old, ranging from 33 to 70 years) were includede in this prospective study. All patients underwent both PCT and DCE-MRI. Imaging was performed on a 256-slice CT scanner and a 3-T MRI system. PCT yielded permeability surface-area product (PS) using deconvolution physiological models; meanwhile, DCE-MRI determined volume transfer constant (Ktrans) using the Tofts-Kermode compartment model. All cases were submitted to surgical intervention, and CD105-microvascular density (CD105-MVD) was measured in each glioblastoma specimen. Then, Spearman’s correlation coefficients and Bland-Altman plots were obtained for PS, Ktrans and CD105-MVD. P<0.05 was considered statistically significant. ResultsTumor PS and Ktrans values were correlated with CD105-MVD (r=0.644, P<0.001; r=0.683, P<0.001). In addition, PS was correlated with Ktrans in glioblastoma (r=0.931, P<0.001). Finally, Bland-Altman plots showed no significant differences between PS and Ktrans (P=0.063). ConclusionPCT and DCE-MRI measurements of glioblastoma perfusion biomarkers have similar results, suggesting that both techniques may have comparable utility. Therefore, PCT may serve as an alternative modality to DCE-MRI for the in vivo evaluation of glioblastoma microvasculature.

Dynamic contrast-enhanced magnetic resonance imaging of the wrist in children with juvenile idiopathic arthritis

BackgroundDynamic contrast-enhanced MRI provides information on the heterogeneity of the synovium, the primary target of disease in children with juvenile idiopathic arthritis (JIA).ObjectiveTo evaluate the feasibility of dynamic contrast-enhanced MRI in the wrist of children with JIA using conventional descriptive measures and time-intensity-curve shape analysis. To explore the association between enhancement characteristics and clinical disease status.Materials and methodsThirty-two children with JIA and wrist involvement underwent dynamic contrast-enhanced MRI with movement-registration and were classified using validated criteria as clinically active (n = 27) or inactive (n = 5). Outcome measures included descriptive parameters and the classification into time-intensity-curve shapes, which represent the patterns of signal intensity change over time. Differences in dynamic contrast-enhanced MRI outcome measures between clinically active and clinically inactive disease were analyzed and correlation with the Juvenile Arthritis Disease Activity Score was determined.ResultsComprehensive evaluation of disease status was technically feasible and the quality of the dynamic dataset was improved by movement registration. The conventional descriptive measure maximum enhancement differed significantly between clinically active and inactive disease (P = 0.019), whereas time-intensity-curve shape analysis showed no differences. Juvenile Arthritis Disease Activity Score correlated moderately with enhancing volume (P = 0.484).ConclusionDynamic contrast-enhanced MRI is a promising biomarker for evaluating disease status in children with JIA and wrist involvement. Conventional descriptive dynamic contrast-enhanced MRI measures are better associated with clinically active disease than time-intensity-curve shape analysis.

Pulmonary transit time measurement by contrast-enhanced ultrasound in left ventricular dyssynchrony.

BackgroundPulmonary transit time (PTT) is an indirect measure of preload and left ventricular function, which can be estimated using the indicator dilution theory by contrast-enhanced ultrasound (CEUS). In this study, we first assessed the accuracy of PTT-CEUS by comparing it with dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI). Secondly, we tested the hypothesis that PTT-CEUS correlates with the severity of heart failure, assessed by MRI and N-terminal pro-B-type natriuretic peptide (NT-proBNP).Methods and resultsTwenty patients referred to our hospital for cardiac resynchronization therapy (CRT) were enrolled. DCE-MRI, CEUS, and NT-proBNP measurements were performed within an hour. Mean transit time (MTT) was obtained by estimating the time evolution of indicator concentration within regions of interest drawn in the right and left ventricles in video loops of DCE-MRI and CEUS. PTT was estimated as the difference of the left and right ventricular MTT. Normalized PTT (nPTT) was obtained by multiplication of PTT with the heart rate. Mean PTT-CEUS was 10.5±2.4s and PTT-DCE-MRI was 10.4±2.0s (P=0.88). The correlations of PTT and nPTT by CEUS and DCE-MRI were strong; r=0.75 (P=0.0001) and r=0.76 (P=0.0001), respectively. Bland–Altman analysis revealed a bias of 0.1s for PTT. nPTT-CEUS correlated moderately with left ventricle volumes. The correlations for PTT-CEUS and nPTT-CEUS were moderate to strong with NT-proBNP; r=0.54 (P=0.022) and r=0.68 (P=0.002), respectively.Conclusions(n)PTT-CEUS showed strong agreement with that by DCE-MRI. Given the good correlation with NT-proBNP level, (n)PTT-CEUS may provide a novel, clinically feasible measure to quantify the severity of heart failure.Clinical Trial Registry: NCT01735838

A pilot study using dynamic contrast enhanced-MRI as a response biomarker of the radioprotective effect of memantine in patients receiving whole brain radiotherapy.

PurposeThis pilot prospective study sought to determine whether dynamic contrast enhanced MRI (DCE-MRI) could be used as a clinical imaging biomarker of tissue toxicity from whole brain radiotherapy (WBRT).Method14 patients who received WBRT were imaged using dynamic contrast enhanced DCE-MRI prior to and at 8-weeks, 16-weeks and 24-weeks after the initiation of WBRT. Twelve of the patients were also enrolled in the RTOG 0614 trial, which randomized patients to the use of placebo or memantine. After the unblinding of the treatments received by RTOG 0614 patients, DCE-MRI measures of tumor tissue and normal appearing white matter (NAWM) vascular permeability (Initial Area Under the Curve (AUC) Blood Adjusted) was analyzed. Cognitive, quality-of-life (QOL) assessment and blood samples were collected according to the patient's ability to tolerate the exams. Circulating endothelial cells (CEC) were measured using flow cytometry.ResultsFollowing WBRT, there was an increasing trend in the vascular permeability of tumors (p=0.09) and NAWM (p=0.06) with time. Memantine significantly (p=0.01) reduced NAWM AUC changes following radiotherapy. Patients on memantine retained (COWA p= 0.03) better cognitive functions than those on placebo. No association was observed between the level of CEC and DCE-MRI changes, time from radiotherapy or memantine use.ConclusionsDCE-MRI can detect vascular damage secondary to WBRT. Our data suggests that memantine reduces WBRT-induced brain vasculature damages.

Relationship between diffusion parameters derived from intravoxel incoherent motion MRI and perfusion measured by dynamic contrast-enhanced MRI of soft tissue tumors.

Our aim was to evaluate the link between diffusion parameters measured by intravoxel incoherent motion (IVIM) diffusion-weighted imaging (DWI) and the perfusion metrics obtained with dynamic contrast-enhanced (DCE) MRI in soft tissue tumors (STTs). Twenty-eight patients affected by histopathologically confirmed STT were included in a prospective study. All patients underwent both DCE MRI and IVIM DWI. The perfusion fraction f, diffusion coefficient D and perfusion-related diffusion coefficient D* were estimated using a bi-exponential function to fit the DWI data. DCE MRI was acquired with a temporal resolution of 3-5 s. Maps of the initial area under the gadolinium concentration curve (IAUGC), time to peak (TTP) and maximum slope of increase (MSI) were derived using commercial software. The relationships between the DCE MRI and IVIM DWI measurements were assessed by Spearman's test. To exclude false positive results under multiple testing, the false discovery rate (FDR) procedure was applied. The Mann-Whitney test was used to evaluate the differences between all variables in patients with non-myxoid and myxoid STT. No significant relationship was found between IVIM parameters and any DCE MRI parameters. Higher f and D*f values were found in non-myxoid tumors compared with myxoid tumors (p = 0.004 and p = 0.003, respectively). MSI was significantly higher in non-myxoid tumors than in myxoid tumors (p = 0.029). From the visual assessments of single clinical cases, both f and D*f maps were in satisfactory agreement with DCE maps in the extreme cases of an avascular mass and a highly vascularized mass, whereas, for tumors with slight vascularity or with a highly heterogeneous perfusion pattern, this association was not straightforward. Although IVIM DWI was demonstrated to be feasible in STT, our data did not support evident relationships between perfusion-related IVIM parameters and perfusion measured by DCE MRI.

Physiologic characterization of inflammatory arthritis in a rabbit model with BOLD and DCE MRI at 1.5 Tesla.

Our aim was to test the feasibility of blood oxygen level dependent magnetic resonance imaging (BOLD MRI) and dynamic contrast-enhanced (DCE) MRI to monitor periarticular hypoxic/inflammatory changes over time in a juvenile rabbit model of arthritis. We examined arthritic and contralateral nonarthritic knees of 21 juvenile rabbits at baseline and days 1,14, and 28 after induction of arthritis by unilateral intra-articular injection of carrageenin with BOLD and DCE MRI at 1.5 Tesla (T). Nine noninjected rabbits served as controls. Associations between BOLD and DCE-MRI and corresponding intra-articular oxygen pressure (PO2) and blood flow [blood perfusion units (BPU)] (polarographic probes, reference standards) or clinical-histological data were measured by correlation coefficients. Percentage BOLD MRI change obtained in contralateral knees correlated moderately with BPU on day 0 (r = -0.51, p = 0.02) and excellently on day 28 (r = -0.84, p = 0.03). A moderate correlation was observed between peak enhancement DCE MRI (day 1) and BPU measurements in arthritic knees (r = 0.49, p = 0.04). In acute arthritis, BOLD and DCE MRI highly correlated (r = 0.89, p = 0.04; r = 1.0, p < 0.0001) with histological scores in arthritic knees. The proposed techniques are feasible to perform at 1.5 T, and they hold potential as surrogate measures to monitor hypoxic and inflammatory changes over time in arthritis at higher-strength MRI fields. • BOLD and DCE MRI detect interval perisynovial changes in a rabbit knee • BOLD and DCE MRI act as surrogate markers of physiologic changes in arthritis • BOLD MRI signal represents oxygen extraction compared with intra-articular PO 2 • DCE MRI measurements estimate physiologic periarticular vascular properties • In rabbit knees with acute arthritis, BOLD/DCE MRI highly correlated with histological scores.

Noninvasive tumor hypoxia measurement using magnetic resonance imaging in murine U87 glioma xenografts and in patients with glioblastoma.

There is a clinical need for noninvasive, nonionizing imaging biomarkers of tumor hypoxia and oxygenation. We evaluated the relationship of T1 -weighted oxygen-enhanced magnetic resonance imaging (OE-MRI) measurements to histopathology measurements of tumor hypoxia in a murine glioma xenograft and demonstrated technique translation in human glioblastoma multiforme. Preclinical evaluation was performed in a subcutaneous murine human glioma xenograft (U87MG). Animals underwent OE-MRI followed by dynamic contrast-enhanced MRI (DCE-MRI) and histological measurement including reduced pimonidazole adducts and CD31 staining. Area under the curve (AUC) was measured for the R1 curve for OE-MRI and the gadolinium concentration curve for DCE-MRI. Clinical evaluation in five patients used analogous imaging protocols and analyses. Changes in AUC of OE-MRI (AUCOE ) signal were regionally heterogeneous across all U87MG tumors. Tumor regions with negative AUCOE typically had low DCE-MRI perfusion, had positive correlation with hypoxic area (P = 0.029), and had negative correlation with vessel density (P = 0.004). DCE-MRI measurements did not relate to either hypoxia or vessel density in U87MG tumors. Clinical data confirmed comparable signal changes in patients with glioblastoma. These data support further investigation of T1 -weighted OE-MRI to identify regional tumor hypoxia. The quantification of AUCOE has translational potential as a clinical biomarker of hypoxia.

Assessment of the interstitial fluid pressure of tumors by dynamic contrast-enhanced magnetic resonance imaging with contrast agents of different molecular weights

Background. Cancer patients showing highly elevated interstitial fluid pressure (IFP) in the primary tumor may benefit from particularly aggressive treatment. There is some evidence that gadolinium diethylene-triamine penta-acetic acid (Gd-DTPA)-based dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) may be a useful non-invasive method for providing information on the IFP of tumors. The purpose of this preclinical study was to investigate whether any association between DCE-MRI-derived parametric images and tumor IFP can be strengthened by using MR contrast agents with higher molecular weights than that of Gd-DTPA. Material and methods. A-07 human melanoma xenografts were used as preclinical models of human cancer. Three contrast agents were compared: Gd-DTPA (0.55 kDa), P846 (3.5 kDa), and gadomelitol (6.5 kDa). A total of 46 tumors were subjected to DCE-MRI and subsequent measurement of IFP. Parametric images of Ktrans (the volume transfer constant of the contrast agent) and ve (the fractional distribution volume of the contrast agent) were produced by pharmacokinetic analysis of the DCE-MRI series. Results. Significant inverse correlations were found between median Ktrans and IFP for Gd-DTPA (p = 0.0076; R2 = 0.46; n = 14) and P846 (p = 0.0042; R2 = 0.45; n = 16), whereas there was no correlation between median Ktrans and IFP for gadomelitol (p > 0.05; n = 16). Significant correlation between median ve and IFP was not found for any of the contrast agents (p > 0.05 for Gd-DTPA, P846, and gadomelitol). Conclusion. Ktrans images, but not ve images, derived by pharmacokinetic analysis of DCE-MRI data for low-molecular-weight contrast agents may provide information on the IFP of tumors. Any association between Ktrans and IFP cannot be expected to be improved by using contrast agents with higher molecular weights than those of Gd-DTPA and P846.

155P - Effect of Bevacizumab on Tumour 5-Fluorouracil Concentration and Microcirculatory Parameters Obtained by Dynamic Contrast-Enhanced MRI in a Hepatocellular Carcinoma Xenograft Model

ABSTRACT Introduction Vascular endothelial growth factor (VEGF) is expressed by tumours to promote angiogenesis. Clinical trials of anti-VEGF therapy combined with chemotherapy demonstrate improvement in survival. We investigate the effect of bevacizumab (bev), a humanized monoclonal antibody that inhibits VEGF-A, on tumour 5-fluorouracil (5FU) concentration in a hepatocellular carcinoma (HCC) xenograft model, together with changes in tumour microcirculatory parameters obtained by dynamic contrast-enhanced (DCE) MRI. Methods 48 immunodeficient mice implanted with subcutaneous HCC xenografts were first injected with bev (1mg/kg or 10mg/kg) or omalizumab (control). 1 day later, they received 5FU and were sacrificed. Tumour and plasma 5FU concentration was measured by liquid chromatography-mass spectrometry. A subset of 17 mice underwent DCE MRI with gadolinium contrast at baseline and one day after bev/omalizumab injection. Scans employed a three-dimensional spoiled gradient recalled sequence with tracer concentration estimated using variable flip-angle technique. Data analysis employed a conventional two-compartment tracer kinetic model. Results Tumour 5FU concentration (µg/g) was significantly lower 1 day after bev (10mg/kg) compared to control (8.4 vs 21.6, p = 0.027). However, there was no significant difference in plasma 5FU concentration between the bev and control groups. Following bev (10mg/kg), DCE MRI measurements of tumour intravascular blood volume reduced by 38.3% (p = 0.01); there was no significant change in DCE-MRI parameters in the control group. Following bev (1mg/kg), tumour permeability-surface area product (ml/100ml/min) correlated with tumour 5FU concentration (r2 = 0.84, p = 0.01). Conclusion Bev causes vascular shutdown consistent with its anti-angiogenic mode of action. Reduced tumour 5FU concentration suggests that the reported synergism between anti-VEGF and chemotherapy may not be attributable to improved drug delivery at this early time point. DCE-MRI may play a role as a biomarker for tumour drug concentration following anti-VEGF therapy. Disclosure All authors have declared no conflicts of interest.

Assessment of tumor hypoxia and interstitial fluid pressure by gadomelitol-based dynamic contrast-enhanced magnetic resonance imaging

Background and purposeExtensive hypoxia and high interstitial fluid pressure (IFP) in the primary tumor may cause resistance to radiation treatment and promote metastatic spread. The potential of gadomelitol-based dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) in assessing the extent of hypoxia and the level of interstitial hypertension in tumors was investigated in this preclinical study. Materials and methodsTwenty-three A-07 tumors were subjected to DCE-MRI and subsequent measurement of IFP and fraction of pimonidazole-positive hypoxic tissue (HFPim). Parametric tumor images of Ktrans, ve, and VbTofts (Tofts model) and of Ki and VbPatlak (Patlak model) were produced by pharmacokinetic analyses of the DCE-MRI series. ResultsThere was no correlation between IFP and HFPim in the tumors. Ktrans and Ki decreased significantly with increasing HFPim, whereas VbTofts and VbPatlak increased significantly with increasing IFP. ConclusionInformation on both the extent of hypoxia and the level of interstitial hypertension in A-07 tumors can be derived from a single DCE-MRI series by using gadomelitol as contrast agent.

A phase Ib dose-escalation study of the safety, pharmacokinetics (PK), pharmacodynamics (PD), and antitumor activity of the humanized monoclonal antibody (huMAb) anti-EGFL7 (MEGF0444A) in combination with bevacizumab with or without paclitaxel in patients with advanced solid tumors.

2514 Background: Epidermal growth factor-like domain 7 (EGFL7), is a vascular-restricted, tumor selective, extracellular matrix protein that forms perivascular tracks and promotes endothelial cell adhesion and survival, especially under stress. Anti-EGFL7 (MEGF0444A) is a huMAb that inhibits these activities of EGFL7. In combination with an anti-VEGF antibody, anti-EGFL7 significantly enhances the anti-tumor activity of anti-VEGF in multiple murine tumor models. Methods: A standard 3+3 dose escalation design was used to study safety, PK, PD and anti-tumor activity in 40 patients (pts) with advanced solid tumors. In Arm A, MEGF0444A was given IV at doses of 2, 5 or 10 mg/kg followed by bevacizumab IV at 10 mg/kg on Days 1 and 15 of each 28-day cycle. Pts in Arm B also received paclitaxel (90 mg/m2) on Days 1, 8 and 15 of each 28 day cycle. PD biomarkers including circulating progenitor cells (CPC) and dynamic contrast enhanced magnetic resonance imaging (DCE-MRI) were assessed. Results: The combination of MEGF0444A and bevacizumab, with or without paclitaxel, was well tolerated without exacerbation of bevacizumab-related adverse events. MEGF0444A demonstrated linear PK typical of IgG1 monoclonal antibodies. Responses were observed in multiple tumor types in both arms of the on-going Phase Ib. Maximal changes in CPC and DCE-MRI measurements occurred at the 5 mg/kg dose level, consistent with anti-angiogenic effects. Conclusions: MEGF0444A has demonstrated favorable PK properties and is well tolerated in combination with bevacizumab and bevacizumab/paclitaxel. Activity of the combinations has been observed based upon clinical responses, changes in CPCs and DCE-MRI. Study data supports a Phase II dose of 5 mg/kg q2 wks (flat dose equivalent, 400mg q2 or 600mg q3 wks). Further studies of MEGF0444A in combination with chemotherapy and bevacizumab are planned.

Dynamic Contrast-enhanced MR Imaging Measurement of Vertebral Bone Marrow Perfusion May Be Indicator of Outcome of Acute Myeloid Leukemia Patients in Remission

To examine whether dynamic contrast material-enhanced (DCE) magnetic resonance (MR) imaging measurement of bone marrow perfusion in acute myeloid leukemia (AML) patients in complete remission (CR) is associated with outcome and survival. After institutional review board approval and informed consent were obtained, from September 2004 to October 2007, 51 patients (29 women, 22 men; mean age, 43.5 years; range, 17-66 years) agreed to undergo DCE MR imaging to assess bone marrow perfusion, among 96 patients with newly diagnosed de novo AML who had received induction chemotherapy and achieved CR. Two semiquantitative parameters (peak and slope) and another three quantitative parameters (amplitude, K(ep) [efflux rate constant], and K(el) [elimination rate constant]) were calculated. Overall survival (OS) and relapse-free survival (RFS) were assessed with the Kaplan-Meier model, while differences between patient groups with high and low DCE MR imaging parameter values were assessed by using the two-sided log-rank test. The median follow-up was 25.9 months. Univariate analysis results showed that high values of peak (≥0.42), slope (≥0.0235), amplitude (≥0.03), and K(ep) (≥0.0082) were associated with shorter OS (P = .004, 0.01, 0.034, and 0.026, respectively). Besides, a high value of K(ep) was also associated with shorter RFS (P = .008). When age, sex, and initial karyotype at diagnosis were included in multivariate Cox proportional hazards analysis, the results showed that only K(ep), but not other DCE MR imaging parameters, was an independent factor for OS (relative risk [RR], 30.305; P = .021) and RFS (RR, 6.477; P = .009). Bone marrow perfusion measured with DCE MR imaging in AML patients in CR can be an indicator of outcome and survival. K(ep) measured with kinetic modeling was useful and significantly associated with RFS, while heuristic parameters (peak and slope) were not.

Vascular effects of the vascular targeting agent NGR-hTNF in patients (pts) with advanced solid cancer: A dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) EORTC study.

e13525 Background: Vascular targeted TNF (NGR-hTNF) has antivascular properties. In a recent phase I study (EORTC 16041) it was not possible to select an optimal biological dose of NGR-hTNF from DCE-MRI measurements. We hypothesized this could be due to: (1) insufficient reproducibility of DCE-MRI; (2) non-specific vascular targeting of NGR-hTNF; (3) interference of vessel maturation with anti-vascular effects of NGR-hTNF (4) interference of pharmacodynamic (PD) effects with anti-vascular effects of NGR-hTNF. Methods: DCE-MRI analyses were performed at baseline and two hours after the first administration of NGR-hTNF in 31 cancer pts treated in the phase I study. Reproducibility was determined in 5 non-treated pts with liver metastases. Mean values of kep and Ktrans were calculated and histogram analyses were performed for metastases and healthy liver tissue. Specificity of vascular targeting was assessed by comparing results in metastases and healthy liver tissue. As a surrogate measure of vascular maturation, we assessed pretreatment tumor sizes and correlated these with DCE-MRI results. PD effects of NGR-hTNF were measured by the kinetics of soluble TNF receptors (sTNF-R). Results: Reproducibility of DCE-MRI was adequate, although superior in metastases compared to healthy liver tissue. Mean DCE-MRI parameters did not significantly change after NGR-hTNF administration, but histogram analyses showed significant changes in metastases and healthy liver tissue in some pts. The antivascular effect of NGR-hTNF was larger in smaller tumors, which have less mature vasculature. sTNF-R increased in a dose-dependent manner which could partly explain the failure of DCE-MRI to predict the optimal biological dose. Conclusions: The inability of DCE-MRI to determine the optimal biological dose of NGR-hTNF was not due to inadequate reproducibility, but most likely due to a combination of: (i) different profiles of vascular effects of NGR-hTNF in tumors and healthy liver tissue, (ii) dependency of the antivascular effect of NGR-hTNF on tumor vessel maturation and (iii) the shedding kinetics of soluble TNFα− R. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration MolMed

Abstract 4472: NVP-BKM120, a pan class I PI3K inhibitor impairs microvascular permeability and tumor growth as detected by DCE-MRI and IFP measurements via radio-telemetry: Comparison with NVP-BEZ235

Abstract Tumor blood vessels are distinctly abnormal in structure and function. When compared to normal vessels, they are enlarged and tortuous and leaky, poorly covered by pericytes and with a defective basement membrane. VEGF is a prominent cytokine responsible for the hyperpermeable state of tumor microvasculature to plasma macromolecules. The phosphatidylinositol 3-kinase (PI3K)-Akt signaling pathway functions downstream of VEGF and can activate the production of the free radical gas nitric oxide (NO) through the enzyme endothelial NO synthase (eNOS), a key player for the in vivo biological activity of VEGF. In the present study, we investigated the effect of NVP-BKM120, a novel, synthetic low molecular mass compound, which potently inhibits class I PI3K activity, on vascular leakage in tumors and its impact on tumor progression in an orthotopic breast cancer model (BN472) in syngeneic rats. Effects on the vasculature were investigated in normal and tumor tissues with a variety of technologies: dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI), tumor interstitial fluid pressure (IFP) measurements in conscious animals via radio-telemetry and a modified Miles assay, representing non invasive, minimally invasive and invasive methods, respectively. Tumor histology and western blots were used to confirm pathway inhibition. For comparison, the effect of NVP-BEZ235, a potent pan class I PI3K and mTOR activity inhibitor, was assessed head-to-head in the same experiments. BKM120 induced significant decreases in VEGF-induced vascular leakage in normal and tumor tissues. These effects were similar to those obtained following BEZ235 treatment. Western blot of total ear lysates from treated mice clearly demonstrated pathway inhibition. The inhibition of vessel permeability observed with BEZ235 and BKM120 correlated with their respective anti-tumor activities, IFP change and Ktrans (vascular permeability transfer constant measured by DCE-MRI) decrease. In conclusion, our data demonstrate that in BN472 tumors, BKM120 significantly decreases tumor microvascular leakage similar to BEZ235 at equipotent antitumor dose. Changes in Ktrans may be a useful independent clinical surrogate biomarker for NVP-BKM120 efficacy. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 4472.

An in vivo magnetic resonance imaging technique for measurement of rat lumbar vertebral body blood perfusion

The technical feasibility of dynamic contrast-enhanced magnetic resonance imaging (MRI) measurement of rat vertebral blood perfusion using a 1.5 T clinical scanner and a small surface coil was investigated in this study. Nine male 7-month-old Wistar-Kyoto rats were used. Computed tomographic assessment of lumbar vertebral bone mineral density (BMD) and MRI assessment of lumbar vertebral blood perfusion were performed twice with 8 weeks' interval. A 4.7 cm surface coil was used for receiving radiofrequency signal. Gadolinium-DOTA (0.3 mmol/kg) was injected through the tail vein of the rat as a quick bolus and dynamic MRI scan was carried out on the central sagittal plane of the lumbar spine for 8 min with a temporal resolution of 0.6 s. Blood perfusion parameters of wash-in rate, maximum enhancement and wash-out rate were derived from the dynamic MR images. No vertebral body size and vertebral BMD difference was detected between the two time points (P=0.222 and 0.123, respectively). Wash-in rate was 0.105 (+/-0.016)% and 0.111 (+/-0.018)%, maximum enhancement 126.5 (+/-10.6)% and 129.2 (+/-13.4)%, and wash-out rate 0.788 (+/-0.182)% and 0.792 (+/-0.182)% for the two time points. With these parameters, no difference was found between the two time points with a P value of 0.575, 0.889 and 0.754, respectively. We conclude that dynamic contrast-enhanced MRI measurement of rat vertebral blood perfusion using a 1.5 T clinical scanner and a small surface coil is feasible and reliable. This technique offers a non-invasive means to probe vertebral blood perfusion changes associated with rat disease models.

Semiquantitative and Quantitative Dynamic Contrast-Enhanced Magnetic Resonance Imaging Measurements Predict Radiation Response in Cervix Cancer

To evaluate semiquantitative and quantitative dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) measurements in predicting the response to radiotherapy in cervix cancer. Patients with cervix cancer treated radically with chemoradiotherapy had DCE-MRI at three time points: before starting treatment, after 2 weeks of radiotherapy, and in the 5th week of radiotherapy. Semiquantitative measurements obtained from the signal intensity vs. time plots included arrival time of contrast, the slope and maximum slope of contrast uptake, time for peak enhancement, and the contrast enhancement ratio (CER). Pharmacokinetic modeling with a modeled vascular input function was used for the quantitative measurements volume transfer constant (K(trans)), rate constant (k(ep)), fraction plasma volume (fPV), and the initial area under gadolinium-time curve. The correlation of these measurements at each of the three time points with radiologic tumor response was investigated. Thirteen patients had a total of 38 scans. There was no correlation between the DCE-MRI measurements and the corresponding tumor volumes. A statistically significant correlation with percentage tumor regression was shown with the pretreatment DCE-MRI semiquantitative parameters of peak time (p = 0.046), slope (p = 0.025), maximum slope (p = 0.046), and CER (p = 0.025) and the quantitative parameters K(trans) (p = 0.043) and k(ep) (p = 0.022). Second and third scan measurements did not show any correlation. This is the first study to show that pretreatment DCE-MRI quantitative parameters predict the radiation response in cervix cancer. These measurements may allow a more meaningful comparison of DCE-MRI studies from different centers.

Dynamic contrast-enhanced magnetic resonance imaging of tumor interstitial fluid pressure

Background and purpose High interstitial fluid pressure (IFP) in the primary tumor has been shown to promote metastasis in melanoma xenografts and to predict for poor survival in cervical cancer patients. The potential usefulness of gadolinium-diethylenetriaminepentaacetic acid (Gd-DTPA)-based dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) for assessing tumor IFP noninvasively was investigated in the present study. Materials and methods A-07 and R-18 melanoma xenografts with and without necrotic regions were subjected to DCE-MRI and subsequent measurement of IFP. Tumor images of E· F ( E is the initial extraction fraction of Gd-DTPA and F is blood perfusion) and λ ( λ is proportional to extracellular volume fraction) were produced by Kety analysis of DCE-MRI series. Results In tumors without necrosis, significant inverse correlations were found between E· F and IFP, both for A-07 and R-18 tumors, and between λ and IFP for A-07 tumors. Significant correlations beween E· F and IFP or between λ and IFP could not be detected for tumors with necrotic regions. Conclusions DCE-MRI may be developed to be a useful noninvasive method for assessing IFP in tumors without necrosis. This possibility warrants further studies involving several physiologically different experimental tumor lines, as well as human tumors.