Kristin L Granlund1,2, Hebert A Vargas1, Serge K Lyashchenko3, Phillip J DeNoble3, Vincent A Laudone4, James Eastham4, Ramon A Sosa1, Matthew A Kennedy1, Duane Nicholson1, YanWei W Guo1, Albert P Chen5, James Tropp6, Hedvig Hricak1,2, and Kayvan R Keshari1,2
1Radiology, Memorial Sloan Kettering Cancer Center, New York, NY, United States, 2Molecular Pharmacology, Memorial Sloan Kettering Cancer Center, New York, NY, United States, 3Radiochemistry & Imaging Probes (RMIP) Core, Memorial Sloan Kettering Cancer Center, New York, NY, United States, 4Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, United States, 5GE Healthcare, Toronto, ON, Canada, 6GE Healthcare, Fremont, CA, United States
Synopsis
Hyperpolarized
(HP) pyruvate has the potential to improve tumor grading and evaluate response
to treatment by probing the metabolism of lesions. Three patients with biopsy-proven
prostate cancers have been scanned with a 2D dynamic hyperpolarized pyruvate
protocol. Repeatability has been
evaluated in 2 patients to date. The data from these first 5 injections confirm
that HP prostate imaging is feasible and reproducible, and the 2D dynamics will inform 3D static acquisition timing.Purpose
Conventional
metabolic imaging techniques using nuclear methods have been limited in the
prostate due to the gland’s proximity to the extraction route (urinary tract).
Hyperpolarized (HP) MRI provides a means of dramatically enhancing the signals
of MR active nuclei, thus providing a means of utilizing MRI to visualize these
molecules and their metabolic products non-invasively, in vivo and in real time [1]. Since the lifetime of the HP molecule
is short (< 2min) imaging data acquired in less than 1 min has demonstrated
that this method is predominantly before urinary clearance, thus providing
contrast without background. In preclinical models, prostate cancer cells show
increased conversion of HP pyruvate to lactate due to upregulated glycolytic
metabolism [2], showcasing a potential application for HP MRSI in the clinic
for distinguishing tumor from normal as well as grading prostate cancer. The
feasibility and safety of HP [1-
13C] pyruvate has recently been
demonstrated utilizing a proof of concept hyperpolarizer [3]. In this work, we
demonstrate the feasibility of acquiring dynamic 2D HP
13C spectra
in humans using the SpinLab hyperpolarizer at 5T and accompanying sterile
fluid-paths.
Methods
Pre-surgical
prostate cancer patients were imaged using a clinical prostate screening
protocol followed by a dynamic 2D
13C spectroscopy sequence. To evaluate repeatability, patients are
scanned again following a second injection. GMP [1-
13C] pyruvic acid
(Isotec) was mixed with a stable organic free radical (15mM, GLP AH11501 sodium
salt, GE Healthcare) under sterile conditions and laser welded in a sterile
fluid-path (GE Healthcare). Patients were injected with 0.43 mL/kg followed by
a 20 mL saline flush.
All MR data were acquired
on a 3 T wide-bore scanner (GE
Healthcare) using a clamshell transmit coil (GE Healthcare) and a dual-tuned
1H/
13C
endorectal receiver coil (GE Healthcare). A 2D dynamic EPSI sequence was
initiated 5 s following the flush, with a 4.3 s temporal resolution. The EPSI
waveform was designed to acquire 16 spectra across a 16-cm FOV. Phase encoding was used to acquire 1x1x1.5 cm
voxels.
Results
Three pre-surgical prostate cancer patients (64±11 years,
PSA 9.6±2.6 ng/mL) have been imaged. The QC measurements for the patient doses
(n=5) are: 244±4 mM pyruvate, pH 7.1±0.5, 1.9±1.3 µM free radical, 35.0±1.6°C, and 19.0±0.5%
polarization; the injections occurred 44.4±10.0 s after the dissolution.
Figure 1 shows data from a 71-year-old man with
predominantly Gleason 3+4 in the left base of the prostate (PSA 6.05). 2D spectra from an early time point are shown
overlaid on a T2-weighted image. Spectra
from a single voxel (arrow) are shown at an early and late time point. In the
early time point, a large pyruvate peak is visible, as well as the pyruvate
hydrate peak. Later, the lactate peak is
visible. The dynamics of the pyruvate
deliver and its conversion to lactate are also shown. Figure 2 shows the
delivery of pyruvate to the prostate for the 5 injections. When corrected for
the arrival of the pyruvate in the neighboring vessels, the delivery dynamics
are consistent among patients.
Discussion
We
successfully imaged three prostate cancer patients using the SpinLab
hyperpolarizer and sterile fluid-paths. We observed HP pyruvate delivery and its
conversion to lactate, with higher lactate visible in the region of the tumor.
No adverse effects have been reported by any of the subjects.
This
study will test repeatability and robustness of studying prostate cancer
metabolism in patients. The dynamics
we’ve observed from 5 injections in 3 patients indicate the need for bolus
tracking for initiating a static acquisition.
Otherwise, the pyruvate-to-lactate ratio may be affected by differences
in perfusion.
Conclusion
With the high SNR higher achievable with hyperpolarization,
it will be possible to observe the delivery of pyruvate to the prostate,
conversion of pyruvate to lactate. The
acquisition of 2D data allows comparison of spectra with prostate cancer
histopathology.
Acknowledgements
NIH
R00 EB014328 and S10 OD016422
The
Center for Experimental Therapeutic
Mr. William H. and Mrs. Alice Goodwin and
the Commonwealth Foundation for Cancer Research
The Pelican Foundation
References
[1] Keshari KR, Wilson DM. Chemistry and
biochemistry of 13C hyperpolarized magnetic resonance using dynamic nuclear
polarization. Chem Soc Rev 2014; 43(5): 1627-1659.
[2] Albers MJ, Bok R, Chen AP, et al.
Hyperpolarized 13C lactate, pyruvate, and alanine: noninvasive biomarkers for
prostate cancer detection and grading. Cancer Res 2008; 68(20): 8607-8615.
[3]
Nelson SJ, Kurhanewicz, J,
Vigneron DB, et al. Metabolic imaging of patients with prostate cancer using hyperpolarized
[1-13C] pyruvate. Sci Trans Med
2013; 5(198): 198ra108.