3D Dynamic Hyperpolarized 13C-Pyruvate MR Metabolic Imaging of Human Prostate Cancer
Hsin-Yu Chen1, Peder E.Z. Larson1,2, Jeremy W. Gordon2, Robert A. Bok2, Marcus Ferrone3, Mark van Criekinge2, Lucas Carvajal2, Peng Cao2, Ilwoo Park2, Rahul Aggarwal4, Sarah J. Nelson1,2, John Kurhanewicz1,2, and Daniel B. Vigneron1,2

1Graduate Program in Bioengineering, UCSF and UC Berkeley, University of California, San Francisco, San Francisco, CA, United States, 2Department of Radiology and Biomedical Imaging, University of California, San Francisco, San Francisco, CA, United States, 3Department of Clinical Pharmacy, University of California, San Francisco, San Francisco, CA, United States, 4Department of Medicine, Division of Hematology/Oncology, University of California, San Francisco, San Francisco, CA, United States


To measure the 3D spatial and temporal dynamics of hyperpolarized [1-13C]pyruvate for patient studies, a new compressed-sensing EPSI sequence was developed for prostate cancer clinical research. Utilizing multiband, variable flip angle RF excitation, this sequence provided high temporal (2s) and spatial (0.5cm3) resolution data detecting pyruvate uptake and its rate of conversion to lactate. This approach provided a significant advance over initial human HP-13C studies in which just 1D or 2D dynamics were measured and 15s single-timepoint 3D spectra were acquired. Following phantom tests, patient data demonstrated high pyruvate to lactate conversion in regions corresponding to biopsy-confirmed prostate cancer.


Prior human HP 13C-pyruvate MR studies used older acquisition methods which provided either time-averaged 15s 3D MR spectroscopic imaging data or dynamic data that was limited to 1D spectroscopy or a single 2D slice, and did not cover the entire prostate1,2. In order to meet the clinical need of full gland coverage to detect all regions of cancer, a 3D dynamic compressed-sensing (CS) EPSI sequence was developed and tested first in phantoms and transgenic models of prostate cancer (TRAMP) before initiating human studies. Clinical studies require larger imaging volumes and reduced peak RF power for the large RF transmit coil. This study was designed to translate prior acquisition methods to enable human 3D dynamic HP acquisitions by addressing these challenges through the optimization of pulse design and sequence parameters.


Sequences: Reduced peak power spectral-spatial excitation pulses for a clinical transmit coil were designed using the SS-RF toolbox developed by Larson et al.3 These pulses incorporated multiband RF excitation and a variable flip angle schedule aimed to maximize total lactate signal. Our pre-clinical 3D CS-EPSI sequence used double spin-echo refocusing (“DSE” sequence)4, but these high-flip pulses can result in substantial magnetization losses with inhomogeneous B1 fields5. For clinical studies, we removed these refocusing pulses (“FID” sequence), and used a modified CS reconstruction including phasing and enforcing spectral sparsity to maintain narrow linewidths. Additional sequence parameters include TR = 150ms, TE = 6.3ms, spatial resolution: 3.3mm x 3.3mm x 5.4mm (mice), 6.7mm x 6.7mm x 10.8mm (rats), or 8mm x 8mm x 8mm with FOV=9.6x9.6x12.8cm (humans), temporal resolution = 2s, acquisition window = 36s.

MRI experiments: Figure 1 shows the sequence diagram and RF pulse design. To test the sequence in vivo prior to human studies, 11 sets of imaging studies were conducted on 6 transgenic mice of prostate tumor (TRAMP) and 3 healthy Sprague Dawley rats. [1-13C]pyruvate and 13C urea were co-polarized using a GE SpinLab polarizer for 2 hours, yielding 20-30% polarization. For the TRAMP studies, a 350ul bolus was injected over 15s, while rats received a 3ml bolus over 12s, both administered via a tail vein catheter. The sequence was initiated at t=15 seconds after injection began. In the clinical setup, a clamshell coil was used for 13C transmit, and a dual-tuned endorectal coil for reception1.

Image Reconstruction and Dynamic Modeling: Quantitative estimation of metabolism and perfusion were performed by calculating the area-under-curve (AUC) for lactate and pyruvate, then applying the compartmental exchange models to the HP-13C dynamic curves. Multiband excitation, variable flip angles and T1 relaxation were taken into account for signal-versus-concentration correction6.


In preclinical studies, we observed similar performance in the new “FID” sequence compared to the previous “DSE sequence”. The mean SNR was comparable between our “DSE” data (33.47±6.96 dB) and the 8 “FID” acquisitions (36.28±3.98dB) on TRAMP tumor (P>0.3). In the rat scans, both FOV and voxel size were doubled from mice, where high SNR was found in both rat kidney (43.84±4.68dB) and liver (37.75±4.75dB), showing robustness to scaling. While the “FID” sequence suffers from the inherent T2* loss, the 180° refocusing in the “DSE” sequence may spoil the HP magnetization at coil edge.

The spectral-spatial excitation pulse for clinical studies yielded a peak B1 of 0.597G, a 67% reduction compared to our previous preclinical designs (1.796G), and phantom data showed good agreement with the simulated performance (Fig.1). Figure 2 demonstrates full-gland coverage in a patient with bilateral biopsy-confirmed prostate cancer following the injection of sterile GMP [1-13C]pyruvate polarized to 37% in the 5T SpinLab. Figure 3 shows the dynamic pyruvate and lactate images acquired with a time resolution of 2s and a spatial resolution of 0.5cm3. This 5 dimensional (3 spatial, 1 spectral, 1 temporal) data (Fig.4) enable the detection of the dynamics of the conversion of pyruvate to lactate catalyzed by LDH that is known to be greatly up-regulated in prostate cancers.


This new clinical 3D dynamic acquisition method incorporating a new spectral-spatial RF, “FID” readout and modified CS reconstruction addressed the challenges of larger imaging volumes, reduced available peak RF power and increased B1 inhomogeneity required for human studies. The 3D dynamic CS-EPSI exhibited excellent performance and robustness in phantom, preclinical, and patient exams.


This work was supported by grants from the NIH (P41EB013598).


[1] Nelson SJ et al., Metabolic imaging of patients with prostate cancer using hyperpolarized [1-13C]pyruvate., Sci Transl Med.2013;5:198ra108

[2] Granlund KL et al., World Molecular Imaging Conference, Honolulu, HI, 2015, LBA 7.

[3] Larson PE et al., Investigation of tumor hyperpolarized [1-13C]-pyruvate dynamics using time-resolved multiband RF excitation echo-planar MRSI, Magn Reson Med. 2010; 63(3):582-591.

[4] Larson PE et al., Fast Dynamic 3D MR Spectroscopic Imaging With Compressed Sensing and Multiband Excitation Pulses for Hyperpolarized 13C Studies, Magn Reson Med. 2011; 65(3): 610-619.

[5] Josan S et al., Application of double spin echo spiral chemical shift imaging to rapid metabolic mapping of hyperpolarized [1-13C]-pyruvate, JMR 2011

[6] Bahrami N et al., Kinetic and perfusion modeling of hyperpolarized 13C pyruvate and urea in cancer with arbitrary RF flip angles, Quant Imaging Med Surg. 2014; 4(1): 24-32.


A) The HP-13C 3D CS-EPSI sequence diagram for human studies; designed to address both reduced peak B1 and increased B1 field inhomogeneity. B) The 6.3ms-long RF pulse excites 13C pyruvate and lactate with independent variable flip angles. The peak B1 of 0.597G is a 67% reduction from that used for preclinical studies C) Phantom data excited with progressive-increasing flip RF showed good agreement with simulated profile.

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

18 timepoints for HP 13C-pyruvate and 13C-lactate 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. Conversion to lactate in the cancer regions was observed later at ~20 seconds

The biopsy-proven Gleason 4+3 tumor in the peripheral zone (PZ) exhibited high lactate conversion following HP pyruvate injection. A) T2-FSE image showing the tumor voxel selected for the dynamic spectral plot in B). 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.

Proc. Intl. Soc. Mag. Reson. Med. 24 (2016)