Technique development of 3D dynamic CS-EPSI for hyperpolarized 13 C pyruvate MR molecular imaging of human prostate cancer

Abstract

Purpose: The purpose of this study was to develop a new 3D dynamic carbon-13 compressed sensing echoplanar spectroscopic imaging (EPSI) MR sequence and test it in phantoms, animal models, and then in prostate cancer patients to image the metabolic conversion of hyperpolarized [1-¹³ C]pyruvate to [1-¹³ C]lactate with whole gland coverage at high spatial and temporal resolution.

Methods: A 3D dynamic compressed sensing (CS)-EPSI sequence with spectral-spatial excitation was designed to meet the required spatial coverage, time and spatial resolution, and RF limitations of the 3T MR scanner for its clinical translation for prostate cancer patient imaging. After phantom testing, animal studies were performed in rats and transgenic mice with prostate cancers. For patient studies, a GE SPINlab polarizer (GE Healthcare, Waukesha, WI) was used to produce hyperpolarized sterile GMP [1-¹³ C]pyruvate. 3D dynamic ¹³ C CS-EPSI data were acquired starting 5 s after injection throughout the gland with a spatial resolution of 0.5 cm³ , 18 time frames, 2-s temporal resolution, and 36 s total acquisition time.

Results: Through preclinical testing, the 3D CS-EPSI sequence developed in this project was shown to provide the desired spectral, temporal, and spatial 5D HP ¹³ C MR data. In human studies, the 3D dynamic HP CS-EPSI approach provided first-ever simultaneously volumetric and dynamic images of the LDH-catalyzed conversion of [1-¹³ C]pyruvate to [1-¹³ C]lactate in a biopsy-proven prostate cancer patient with full gland coverage.

Conclusion: The results demonstrate the feasibility to characterize prostate cancer metabolism in animals, and now patients using this new 3D dynamic HP MR technique to measure k_PL , the kinetic rate constant of [1-¹³ C]pyruvate to [1-¹³ C]lactate conversion.

Keywords: 3D dynamic imaging; human prostate cancer; hyperpolarized C-13 pyruvate.

Figure 1

The HP-¹³C 3D CS-EPSI sequence diagram designed for in vivo studies. A) The double spin-echo enabled (DSE mode) was utilized in a previous report of mouse prostate cancer imaging [1]. B) The imaging mode (FID mode) in this study was chosen for larger imaging volumes and to account for peak B1 limitations with the human coil setup.

Figure 2

New spectral-spatial RF pulses were designed using the ss-RF toolbox by Larson et al. [17] A) The 6.3ms-long RF pulse excites ¹³C pyruvate and lactate with independent variable flip angles. (Red is magnitude, blue is real, and green is imaginary components.) The peak B1 of 0.597G is a 67% reduction from that used for preclinical studies B) Phantom data excited with progressive-increasing flip RF showed good agreement with simulated profile.

Figure 3

Phantom studies using the clinical setup, the 3D CS-EPSI sequence and the new RF pulses showed good spatial homogeneity in a urea syringe.

Figure 4

Similar to the “DSE” mode, the in-vivo dynamics of ¹³C biomarker acquired using the 3D dynamic CS-EPSI “FID” mode can be quantitatively analyzed by compartmental exchange models. Pyruvate and lactate dynamics were overlaid on T2-FSE scan in a low-grade TRAMP tumor. The calculated k_PL value was 0.0297(s⁻¹).

Figure 5

Pyruvate to lactate conversion in the kidneys of healthy rat is visualized in this ¹³C image overlaid on bSSFP reference. The calculated k_PL was 0.0058(s⁻¹).

Figure 6

Prostate cancer patient 3D dynamic CS-EPSI data with volumetric coverage from base to apex of HP pyruvate and its conversion to lactate (signal summed through time is shown in the overlays). Spatial resolution=0.5cm³, temporal=2s, 18 timepoints, starting 5s after injection of HP (37%) [1-¹³C]pyruvate. Region of high lactate conversion correlated with the bilateral biopsy-confirmed cancer.

Figure 7

A) 18 timepoints for HP ¹³C-pyruvate from a single slice with bilateral biopsy-confirmed prostate cancer. The acquisition began ~5s after injection. HP-¹³C pyruvate appears in the prostate at ~10s into the dynamic 3D CS-EPSI acquisition. This data demonstrates the feasibility of acquiring dynamically in three-dimensions that covered the entire prostate with 2s temporal resolution. B) Temporal dynamics of ¹³C-lactate from the same data and slice as in A. Conversion to lactate in the bilateral cancer regions was observed at ~20 seconds.

Figure 7

A) 18 timepoints for HP ¹³C-pyruvate from a single slice with bilateral biopsy-confirmed prostate cancer. The acquisition began ~5s after injection. HP-¹³C pyruvate appears in the prostate at ~10s into the dynamic 3D CS-EPSI acquisition. This data demonstrates the feasibility of acquiring dynamically in three-dimensions that covered the entire prostate with 2s temporal resolution. B) Temporal dynamics of ¹³C-lactate from the same data and slice as in A. Conversion to lactate in the bilateral cancer regions was observed at ~20 seconds.

Figure 8

The biopsy-proven Gleason 4+3 tumor in the patient’s right lateral midgland (red arrow) exhibited high lactate conversion following HP pyruvate injection. A) T2-FSE image showing the tumor voxel selected for the dynamic spectral plot in B). Also shown is the ADC map where the tumor region has substantially reduced ADC. C) Dynamic curves (corrected for variable flip angle) are shown with far higher conversion to lactate in cancer compared to normal appearing regions. D) Representative spectra for these regions at t=36 s. E) Pyruvate-to-lactate conversion rate k_PL parameter map overlays showed high k_PL on the opposite side (yellow arrows) as well, which was also confirmed as Gleason 4+3 prostate cancer by post-surgical histopathology.