Clinical evaluation of metabolic MRI using hyperpolarized (HP) C-13 agents has begun in earnest at multiple sites with the availability of the SpinLab commercial polarizer. For this technology to succeed, robust imaging and analysis methods for quantification of metabolic activity are required. The goal of this project was to develop and apply specialized calibration schemes, efficient dynamic imaging methods, and robust kinetic models for quantitative clinical HP MR exams.

Dynamic Imaging: Single time-point imaging with HP C-13 agents, as applied in the first clinical trial [1], can provide ratiometric quantification (e.g. lactate:pyruvate), but this approach is highly susceptible to variations in HP agent delivery times (Fig. 1).

In our clinical HP ¹³C-pyruvate studies of brain and prostate tumors, we are using dynamic imaging methods with kinetic modeling to provide more robust measurements of metabolic conversion.

In a Phase I trial of prostate cancer [1], we imaged 4 patients with a 2D dynamic MRSI acquisition with the following key parameters: multiband RF excitation (10º pyruvate, 20º lactate), symmetric EPSI, 10mm in-plane resolution, 1.2-3.5 cm slice thickness, temporal resolution = 5 s, imaging started 5 sec after end of saline flush.

Currently we are performing patient exams with a 3D dynamic MRSI acquisition using compressed sensing, based on [2] with variable flip angle RF pulse schemes aimed to maximize total lactate signal [3]. Other key parameters include: 8mm isotropic resolution, 12x12x16 matrix size, temporal resolution = 2 s, imaging started 5 sec after end of saline flush.

We have also developed a multi-slice metabolite-specific acquisition for clinical applications based on spectral-spatial excitation of a single metabolite (lactate and pyruvate) followed by an EPI readout similar to [4] with optimizations to reduce TE, improve SNR efficiency, and eliminate EPI artifacts [5].

Studies were performed with ≈250 mM HP [1-¹³C]-pyruvate at a dose of 0.43 mL/kg polarized using a 5T GE SpinLab instrument (additional details can be found in [1]).

Metabolism Quantification: We quantified our data using a 2-site kinetic model, in which pyruvate was taken to be the input and k_PL values were fit [6], and accounting for variable flip angles [7]. We also used an area under curve ratio (AUC_ratio), AUC_lac:AUC_pyr, which has been shown to correlate with k_PL for both constant [8] and variable flips [7].

C-13 Calibration Methods: Achieving high SNR efficiency and robust quantification requires accurate hardware calibration. Custom 13C calibration procedures were used: First, the frequency of a ¹³C-urea reference embedded in the endo-rectal coil was measured. ¹³C RF calibration was performed using the urea reference, and adjusted based on phantom B1+ maps (shown below). B1+ was measured using double angle measurements. To improve the B0 homogeneity, we used the same shimming procedure as for our ¹H MRSI clinical prostate studies.

Bolus dynamics: In the Phase I trial, peak pyruvate in the prostate was observed at 13 ± 6 s following injection due to individual physiologic and experimental variations (Fig. 1, Table 1), which is much larger than what we observe in preclinical experiments. Furthermore, this was in a relatively healthy population of patients with localized prostate cancer, no significant history of cardiac disease and adequate baseline organ function. The bolus delivery variability will increase in a broader range of patients with more significant disease burdens and larger variations in cardiac function.

Quantification of metabolic conversion: Both k_PL and AUC_ratio corresponded well with regions of biopsy-proven prostate cancer with 2D and 3D dynamic MRSI acquisitions (Figs. 2 & 3). These two metrics of pyruvate to lactate conversion were similar, as we observed previously in a prostate tumor mouse model [7].

C-13 Calibration: Figure 4 shows ¹³C transmit RF (B1+) phantom results, which are used for RF calibration. These maps could also be used to improve the accuracy of kinetic modeling. We also measured B1+ in 5 prostate cancer patients following the imaging study, and found the flip angle to be 9.3 ± 4.2% less than expected, although some underestimation will result from slice profile effects [9] and biases towards the residual magnetization. In patient studies, we measured the peak B1+ at the ¹³C-urea reference to be 0.84 ± 0.30 G. We chose to limit the peak RF amplitude to 0.60 G, which has been achieved in all human prostate cancer studies.

Evaluation and widespread adoption of clinical HP MR requires robust imaging and analysis methods for quantification of metabolic activity. We have developed and are applying efficient dynamic imaging methods, robust kinetic models, and specialized calibration schemes to enable accurate and reproducible quantifications in clinical hyperpolarized MR studies.