Simultaneous estimation of the cellular water exchange rate, intracellular volume fraction, and longitudinal relaxation rate in cancer cells.

The purpose of the current study was to investigate the feasibility of simultaneously estimating the cellular water efflux rate ( k ie ), intracellular longitudinal relaxation rate ( R 10 i ), and intracellular volume fraction ( v i ) of a cell suspension using multiple samples with different gadolinium concentrations. Numerical simulation studies were conducted to assess the uncertainty in the estimation of k ie , R 10 i , and v i from saturation recovery data using single (SC) or multiple concentrations (MC) of gadolinium-based contrast agent (GBCA). In vitro experiments with 4 T1 murine breast cancer and SCCVII squamous cell cancer models were conducted at 11 T to compare parameter estimation using the SC protocol with that using the MC protocol. The cell lines were challenged with a Na+ /K+ -ATPase inhibitor, digoxin, to assess the treatment response in terms of k ie , R 10 i , and v i . Data analysis was conducted using the two-compartment exchange model for parameter estimation. The simulation study data demonstrate that the MC method, compared with the SC method, reduces the uncertainty of the estimated k ie by decreasing the interquartile ranges from 27.3% ± 3.7% to 18.8% ± 5.1% and the median differences from ground truth from 15.0% ± 6.3% to 7.2% ± 4.2%, while estimating R 10 i and v i simultaneously. In the cell studies, the MC method demonstrated reduced uncertainty in overall parameter estimation compared with the SC approach. MC method-measured parameter changes in cells treated with digoxin increased R 10 i by 11.7% (p = 0.218) and k ie by 5.9% (p = 0.234) for 4 T1 cells, respectively, and decreased R 10 i by 28.8% (p = 0.226) and k ie by 1.6% (p = 0.751) for SCCVII cells, respectively. v i did not change noticeably by the treatment. The results of this study substantiate the feasibility of using saturation recovery data of multiple samples with different GBCA concentrations for simultaneous measurement of the cellular water efflux rate, intracellular volume fraction, and intracellular longitudinal relaxation rate in cancer cells.

Textural Features of Mouse Glioma Models Measured by Dynamic Contrast-Enhanced MR Images with 3D Isotropic Resolution.

This paper investigates the effect of anisotropic resolution on the image textural features of pharmacokinetic (PK) parameters of a murine glioma model using dynamic contrast-enhanced (DCE) MR images acquired with an isotropic resolution at 7T with pre-contrast T1 mapping. The PK parameter maps of whole tumors at isotropic resolution were generated using the two-compartment exchange model combined with the three-site-two-exchange model. The textural features of these isotropic images were compared with those of simulated, thick-slice, anisotropic images to assess the influence of anisotropic voxel resolution on the textural features of tumors. The isotropic images and parameter maps captured distributions of high pixel intensity that were absent in the corresponding anisotropic images with thick slices. A significant difference was observed in 33% of the histogram and textural features extracted from anisotropic images and parameter maps, compared to those extracted from corresponding isotropic images. Anisotropic images in different orthogonal orientations demonstrated 42.1% of the histogram and textural features to be significantly different from those of isotropic images. This study demonstrates that the anisotropy of voxel resolution needs to be carefully considered when comparing the textual features of tumor PK parameters and contrast-enhanced images.

Evaluation of cellular water exchange in a mouse glioma model using dynamic contrast-enhanced MRI with two flip angles.

This manuscript aims to evaluate the robustness and significance of the water efflux rate constant (kio) parameter estimated using the two flip-angle Dynamic Contrast-Enhanced (DCE) MRI approach with a murine glioblastoma model at 7 T. The repeatability of contrast kinetic parameters and kio measurement was assessed by a test-retest experiment (n = 7). The association of kio with cellular metabolism was investigated through DCE-MRI and FDG-PET experiments (n = 7). Tumor response to a combination therapy of bevacizumab and fluorouracil (5FU) monitored by contrast kinetic parameters and kio (n = 10). Test-retest experiments demonstrated compartmental volume fractions (ve and vp) remained consistent between scans while the vascular functional measures (Fp and PS) and kio showed noticeable changes, most likely due to physiological changes of the tumor. The standardized uptake value (SUV) of tumors has a linear correlation with kio (R2 = 0.547), a positive correlation with Fp (R2 = 0.504), and weak correlations with ve (R2 = 0.150), vp (R2 = 0.077), PS (R2 = 0.117), Ktrans (R2 = 0.088) and whole tumor volume (R2 = 0.174). In the treatment study, the kio of the treated group was significantly lower than the control group one day after bevacizumab treatment and decreased significantly after 5FU treatment compared to the baseline. This study results support the feasibility of measuring kio using the two flip-angle DCE-MRI approach in cancer imaging.

Assessment of tumor treatment response using active contrast encoding (ACE)-MRI: Comparison with conventional DCE-MRI.

PURPOSE: To investigate the validity of contrast kinetic parameter estimates from Active Contrast Encoding (ACE)-MRI against those from conventional Dynamic Contrast-Enhanced (DCE)-MRI for evaluation of tumor treatment response in mouse tumor models. METHODS: The ACE-MRI method that incorporates measurement of T1 and B1 into the enhancement curve washout region, was implemented on a 7T MRI scanner to measure tracer kinetic model parameters of 4T1 and GL261 tumors with treatment using bevacizumab and 5FU. A portion of the same ACE-MRI data was used for conventional DCE-MRI data analysis with a separately measured pre-contrast T1 map. Tracer kinetic model parameters, such as Ktrans (permeability area surface product) and ve (extracellular space volume fraction), estimated from ACE-MRI were compared with those from DCE-MRI, in terms of correlation and Bland-Altman analyses. RESULTS: A three-fold increase of the median Ktrans by treatment was observed in the flank 4T1 tumors by both ACE-MRI and DCE-MRI. In contrast, the brain tumors did not show a significant change by the treatment in either ACE-MRI or DCE-MRI. Ktrans and ve values of the tumors from ACE-MRI were strongly correlated with those from DCE-MRI methods with correlation coefficients of 0.92 and 0.78, respectively, for the median values of 17 tumors. The Bland-Altman plot analysis showed a mean difference of -0.01 min-1 for Ktrans with the 95% limits of agreement of -0.12 min-1 to 0.09 min-1, and -0.05 with -0.37 to 0.26 for ve. CONCLUSION: The tracer kinetic model parameters estimated from ACE-MRI and their changes by treatment closely matched those of DCE-MRI, which suggests that ACE-MRI can be used in place of conventional DCE-MRI for tumor progression monitoring and treatment response evaluation with a reduced scan time.