A model selection framework to quantify microvascular liver function in gadoxetate-enhanced MRI: Application to healthy liver, diseased tissue, and hepatocellular carcinoma.

PURPOSE: We introduce a novel, generalized tracer kinetic model selection framework to quantify microvascular characteristics of liver and tumor tissue in gadoxetate-enhanced dynamic contrast-enhanced MRI (DCE-MRI). METHODS: Our framework includes a hierarchy of nested models, from which physiological parameters are derived in 2 regimes, corresponding to the active transport and free diffusion of gadoxetate. We use simulations to show the sensitivity of model selection and parameter estimation to temporal resolution, time-series duration, and noise. We apply the framework in 8 healthy volunteers (time-series duration up to 24 minutes) and 10 patients with hepatocellular carcinoma (6 minutes). RESULTS: The active transport regime is preferred in 98.6% of voxels in volunteers, 82.1% of patients' non-tumorous liver, and 32.2% of tumor voxels. Interpatient variations correspond to known co-morbidities. Simulations suggest both datasets have sufficient temporal resolution and signal-to-noise ratio, while patient data would be improved by using a time-series duration of at least 12 minutes. CONCLUSIONS: In patient data, gadoxetate exhibits different kinetics: (a) between liver and tumor regions and (b) within regions due to liver disease and/or tumor heterogeneity. Our generalized framework selects a physiological interpretation at each voxel, without preselecting a model for each region or duplicating time-consuming optimizations for models with identical functional forms.

Data-driven mapping of hypoxia-related tumor heterogeneity using DCE-MRI and OE-MRI.

PURPOSE: Previous work has shown that combining dynamic contrast-enhanced (DCE)-MRI and oxygen-enhanced (OE)-MRI binary enhancement maps can identify tumor hypoxia. The current work proposes a novel, data-driven method for mapping tissue oxygenation and perfusion heterogeneity, based on clustering DCE/OE-MRI data. METHODS: DCE-MRI and OE-MRI were performed on nine U87 (glioblastoma) and seven Calu6 (non-small cell lung cancer) murine xenograft tumors. Area under the curve and principal component analysis features were calculated and clustered separately using Gaussian mixture modelling. Evaluation metrics were calculated to determine the optimum feature set and cluster number. Outputs were quantitatively compared with a previous non data-driven approach. RESULTS: The optimum method located six robustly identifiable clusters in the data, yielding tumor region maps with spatially contiguous regions in a rim-core structure, suggesting a biological basis. Mean within-cluster enhancement curves showed physiologically distinct, intuitive kinetics of enhancement. Regions of DCE/OE-MRI enhancement mismatch were located, and voxel categorization agreed well with the previous non data-driven approach (Cohen's kappa = 0.61, proportional agreement = 0.75). CONCLUSION: The proposed method locates similar regions to the previous published method of binarization of DCE/OE-MRI enhancement, but renders a finer segmentation of intra-tumoral oxygenation and perfusion. This could aid in understanding the tumor microenvironment and its heterogeneity. Magn Reson Med 79:2236-2245, 2018. © 2017 The Authors Magnetic Resonance in Medicine published by Wiley Periodicals, Inc. on behalf of International Society for Magnetic Resonance in Medicine. This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

Quantifying antivascular effects of monoclonal antibodies to vascular endothelial growth factor: insights from imaging.

PURPOSE: Little is known concerning the onset, duration, and magnitude of direct therapeutic effects of anti-vascular endothelial growth factor (VEGF) therapies. Such knowledge would help guide the rational development of targeted therapeutics from bench to bedside and optimize use of imaging technologies that quantify tumor function in early-phase clinical trials. EXPERIMENTAL DESIGN: Preclinical studies were done using ex vivo microcomputed tomography and in vivo ultrasound imaging to characterize tumor vasculature in a human HM-7 colorectal xenograft model treated with the anti-VEGF antibody G6-31. Clinical evaluation was by quantitative magnetic resonance imaging in 10 patients with metastatic colorectal cancer treated with bevacizumab. RESULTS: Microcomputed tomography experiments showed reduction in perfused vessels within 24 to 48 h of G6-31 drug administration (P

Preliminary study of oxygen-enhanced longitudinal relaxation in MRI: a potential novel biomarker of oxygenation changes in solid tumors.

PURPOSE: There is considerable interest in developing non-invasive methods of mapping tumor hypoxia. Changes in tissue oxygen concentration produce proportional changes in the magnetic resonance imaging (MRI) longitudinal relaxation rate (R(1)). This technique has been used previously to evaluate oxygen delivery to healthy tissues and is distinct from blood oxygenation level-dependent (BOLD) imaging. Here we report application of this method to detect alteration in tumor oxygenation status. METHODS AND MATERIALS: Ten patients with advanced cancer of the abdomen and pelvis underwent serial measurement of tumor R(1) while breathing medical air (21% oxygen) followed by 100% oxygen (oxygen-enhanced MRI). Gadolinium-based dynamic contrast-enhanced MRI was then performed to compare the spatial distribution of perfusion with that of oxygen-induced DeltaR(1). RESULTS: DeltaR(1) showed significant increases of 0.021 to 0.058 s(-1) in eight patients with either locally recurrent tumor from cervical and hepatocellular carcinomas or metastases from ovarian and colorectal carcinomas. In general, there was congruency between perfusion and oxygen concentration. However, regional mismatch was observed in some tumor cores. Here, moderate gadolinium uptake (consistent with moderate perfusion) was associated with low area under the DeltaR(1) curve (consistent with minimal increase in oxygen concentration). CONCLUSIONS: These results provide evidence that oxygen-enhanced longitudinal relaxation can monitor changes in tumor oxygen concentration. The technique shows promise in identifying hypoxic regions within tumors and may enable spatial mapping of change in tumor oxygen concentration.

Comparison of normal tissue R1 and R*2 modulation by oxygen and carbogen.

Magnetic resonance imaging has shown promise for evaluating tissue oxygenation. In this study differences in the tissue longitudinal relaxation rate (R(1)) and effective transverse relaxation rate (R(*)(2)), induced by inhalation of pure oxygen and carbogen, were evaluated in 10 healthy subjects. Significant reductions in R(1) were demonstrated following both oxygen and carbogen inhalation in the spleen (both P < 0.001), liver (P = 0.002 air vs. oxygen; P = 0.001 air vs. carbogen), skeletal muscle (both P < 0.001), and renal cortex (P = 0.005 air vs. oxygen; P = 0.008 air vs. carbogen). No significant change in R(*)(2) occurred following pure oxygen in any organ. However, a significant increase in R(*)(2) was observed in the spleen (P < 0.001), liver (P = 0.001), skeletal muscle (P = 0.026), and renal cortex (P = 0.001) following carbogen inhalation, an opposite effect to that observed in many studies of tumor pathophysiology. Changes in R(1) and R(*)(2) were independent of the gas administration order in the spleen and skeletal muscle. These findings suggest that the R(1) and R(*)(2) responses to hyperoxic gases are independent biomarkers of oxygen physiology.

Tracer kinetic model-driven registration for dynamic contrast-enhanced MRI time-series data.

Dynamic contrast-enhanced MRI (DCE-MRI) time series data are subject to unavoidable physiological motion during acquisition (e.g., due to breathing) and this motion causes significant errors when fitting tracer kinetic models to the data, particularly with voxel-by-voxel fitting approaches. Motion correction is problematic, as contrast enhancement introduces new features into postcontrast images and conventional registration similarity measures cannot fully account for the increased image information content. A methodology is presented for tracer kinetic model-driven registration that addresses these problems by explicitly including a model of contrast enhancement in the registration process. The iterative registration procedure is focused on a tumor volume of interest (VOI), employing a three-dimensional (3D) translational transformation that follows only tumor motion. The implementation accurately removes motion corruption in a DCE-MRI software phantom and it is able to reduce model fitting errors and improve localization in 3D parameter maps in patient data sets that were selected for significant motion problems. Sufficient improvement was observed in the modeling results to salvage clinical trial DCE-MRI data sets that would otherwise have to be rejected due to motion corruption.

Organ-specific effects of oxygen and carbogen gas inhalation on tissue longitudinal relaxation times.

Molecular oxygen has been previously shown to shorten longitudinal relaxation time (T1) in the spleen and renal cortex, but not in the liver or fat. In this study, the magnitude and temporal evolution of this effect were investigated. Medical air, oxygen, and carbogen (95% oxygen/5% CO2) were administered sequentially in 16 healthy volunteers. T1 maps were acquired using spoiled gradient echo sequences (TR=3.5 ms, TE=0.9 ms, alpha=2 degrees/8 degrees/17 degrees) with six acquisitions on air, 12 on oxygen, 12 on carbogen, and six to 12 back on air. Mean T1 values and change in relaxation rate were compared between each phase of gas inhalation in the liver, spleen, skeletal muscle, renal cortex, and fat by one-way analysis of variance. Oxygen-induced T1-shortening occurred in the liver in fasted subjects (P<0.001) but not in non-fasted subjects (P=0.244). T1-shortening in spleen and renal cortex (both P<0.001) were greater than previously reported. Carbogen induced conflicting responses in different organs, suggesting a complex relationship with organ vasculature. Shortening of tissue T1 by oxygen is more pronounced and more complex than previously recognized. The effect may be useful as a biomarker of arterial flow and oxygen delivery to vascular beds.

Phase I evaluation of a fully human anti-alphav integrin monoclonal antibody (CNTO 95) in patients with advanced solid tumors.

PURPOSE: A fully human monoclonal antibody to anti-alpha(v) integrins (CNTO 95) has been shown to inhibit angiogenesis and tumor growth in preclinical studies. We assessed the safety and pharmacokinetics of CNTO 95 in patients with advanced refractory solid tumors. EXPERIMENTAL DESIGN: In this phase I trial, CNTO 95 (0.1, 0.3, 1.0, 3.0, and 10.0 mg/kg) was infused on days 0, 28, 35, and 42, and clinical assessments, dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI), and [(18)F]-2-fluorodeoxyglucose positron emission tomography (FDG-PET) were done. Patients achieving stable disease or better were eligible for extended dosing every 3 weeks for up to 12 months. RESULTS: Among the 24 enrolled patients, CNTO 95 was associated with one episode of grade III and four episodes of grade II infusion-related fever (all responded to acetaminophen). Of the six patients who received extended dosing, one patient (10.0 mg/kg), with cutaneous angiosarcoma, had a 9-month partial response. Pre- and post-treatment lesion biopsies confirmed tumor cell alpha(v) integrin expression, as well as CNTO 95 penetration of the tumor and localization to tumor cells in association with reduced bcl-2 expression. A lesion in one patient (10.0 mg/kg) with stable ovarian carcinosarcoma was no longer detectable by FDG-PET by day 49. Exposure to CNTO 95 seemed to increase in a greater-than-dose-proportional manner; dose-dependent mean half-life ranged from 0.26 to 6.7 days. CONCLUSIONS: CNTO 95 was generally well tolerated. Six patients received extended therapy, including one patient with a prolonged response. Biopsy data confirmed tumor localization and pharmacodynamic activity.

Experimentally-derived functional form for a population-averaged high-temporal-resolution arterial input function for dynamic contrast-enhanced MRI.

Rapid T(1)-weighted 3D spoiled gradient-echo (GRE) data sets were acquired in the abdomen of 23 cancer patients during a total of 113 separate visits to allow dynamic contrast-enhanced MRI (DCE-MRI) analysis of tumor microvasculature. The arterial input function (AIF) was measured in each patient at each visit using an automated AIF extraction method following a standardized bolus administration of gadodiamide. The AIFs for each patient were combined to obtain a mean AIF that is representative for any individual. The functional form of this general AIF may be useful for studies in which AIF measurements are not possible. Improvements in the reproducibility of DCE-MRI model parameters (K(trans), v(e), and v(p)) were observed when this new, high-temporal-resolution population AIF was used, indicating the potential for increased sensitivity to therapy-induced change.

Comparison of the performance of tracer kinetic model-driven registration for dynamic contrast enhanced MRI using different models of contrast enhancement.

RATIONALE AND OBJECTIVES: The quantitative analysis of dynamic contrast-enhanced (DCE) magnetic resonance imaging (MRI) data is subject to model fitting errors caused by motion during the time-series data acquisition. However, the time-varying features that occur as a result of contrast enhancement can confound motion correction techniques based on conventional registration similarity measures. We have therefore developed a heuristic, locally controlled tracer kinetic model-driven registration procedure, in which the model accounts for contrast enhancement, and applied it to the registration of abdominal DCE-MRI data at high temporal resolution. MATERIALS AND METHODS: Using severely motion-corrupted data sets that had been excluded from analysis in a clinical trial of an antiangiogenic agent, we compared the results obtained when using different models to drive the tracer kinetic model-driven registration with those obtained when using a conventional registration against the time series mean image volume. RESULTS: Using tracer kinetic model-driven registration, it was possible to improve model fitting by reducing the sum of squared errors but the improvement was only realized when using a model that adequately described the features of the time series data. The registration against the time series mean significantly distorted the time series data, as did tracer kinetic model-driven registration using a simpler model of contrast enhancement. CONCLUSION: When an appropriate model is used, tracer kinetic model-driven registration influences motion-corrupted model fit parameter estimates and provides significant improvements in localization in three-dimensional parameter maps. This has positive implications for the use of quantitative DCE-MRI for example in clinical trials of antiangiogenic or antivascular agents.

Tracer kinetic model-driven registration for dynamic contrast enhanced MRI time series.

Motion during time-series data acquisition causes model-fitting errors in quantitative dynamic contrast-enhanced (DCE) MRI studies. Motion correction techniques using conventional registration cost functions may produce biased results because they were not designed to deal with the time-varying information content due to contrast enhancement. We present a locally-controlled, 3D translational registration process driven by tracer kinetic modeling that successfully registers abdominal DCE-MRI data at high temporal resolution and compare this method to a similar approach based on registration to the time series mean image in data from 8 patients. When the registration is driven by an appropriate model, we find significant improvements in model-fitting. Also, model-driven registration influences parameter estimates and reduces repeat study variability in measurements of blood volume.