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PurposeTo develop techniques and establish a workflow using hyperpolarized carbon-13 (13 C) MRI and the pyruvate-to-lactate conversion rate (kPL ) biomarker to guide MR-transrectal ultrasound fusion prostate biopsies.MethodsThe integrated multiparametric MRI (mpMRI) exam consisted of a 1-min hyperpolarized 13 C-pyruvate EPI acquisition added to a conventional prostate mpMRI exam. Maps of kPL values were calculated, uploaded to a picture archiving and communication system and targeting platform, and displayed as color overlays on T2 -weighted anatomic images. Abdominal radiologists identified 13 C research biopsy targets based on the general recommendation of focal lesions with kPL  >0.02(s-1 ), and created a targeting report for each study. Urologists conducted transrectal ultrasound-guided MR fusion biopsies, including the standard 1 H-mpMRI targets as well as 12-14 core systematic biopsies informed by the research 13 C-kPL targets. All biopsy results were included in the final pathology report and calculated toward clinical risk.ResultsThis study demonstrated the safety and technical feasibility of integrating hyperpolarized 13 C metabolic targeting into routine 1 H-mpMRI and transrectal ultrasound fusion biopsy workflows, evaluated via 5 men (median age 71 years, prostate-specific antigen 8.4 ng/mL, Cancer of the Prostate Risk Assessment score 2) on active surveillance undergoing integrated scan and subsequent biopsies. No adverse event was reported. Median turnaround time was less than 3 days from scan to 13 C-kPL targeting, and scan-to-biopsy time was 2 weeks. Median number of 13 C targets was 1 (range: 1-2) per patient, measuring 1.0 cm (range: 0.6-1.9) in diameter, with a median kPL of 0.0319 s-1 (range: 0.0198-0.0410).ConclusionsThis proof-of-concept work demonstrated the safety and feasibility of integrating hyperpolarized 13 C MR biomarkers to the standard mpMRI workflow to guide MR-transrectal ultrasound fusion biopsies.

PurposeThe combined hyperpolarized (HP) 13 C pyruvate and urea MRI has provided a simultaneous assessment of glycolytic metabolism and tissue perfusion for improved cancer diagnosis and therapeutic evaluation in preclinical studies. This work aims to translate this dual-probe HP imaging technique to clinical research.MethodsA co-polarization system was developed where [1-13 C]pyruvic acid (PA) and [13 C, 15 N2 ]urea in water solution were homogeneously mixed and polarized on a 5T SPINlab system. Physical and chemical characterizations and toxicology studies of the combined probe were performed. Simultaneous metabolic and perfusion imaging was performed on a 3T clinical MR scanner by alternatively applying a multi-slice 2D spiral sequence for [1-13 C]pyruvate and its downstream metabolites and a 3D balanced steady-state free precession (bSSFP) sequence for [13 C, 15 N2 ]urea.ResultsThe combined PA/urea probe has a glass-formation ability similar to neat PA and can generate nearly 40% liquid-state 13 C polarization for both pyruvate and urea in 3-4 h. A standard operating procedure for routine on-site production was developed and validated to produce 40 mL injection product of approximately 150 mM pyruvate and 35 mM urea. The toxicology study demonstrated the safety profile of the combined probe. Dynamic metabolite-specific imaging of [1-13 C]pyruvate, [1-13 C]lactate, [1-13 C]alanine, and [13 C, 15 N2 ]urea was achieved with adequate spatial (2.6 mm × 2.6 mm) and temporal resolution (4.2 s), and urea images showed reduced off-resonance artifacts due to the JCN coupling.ConclusionThe reported technical development and translational studies will lead to the first-in-human dual-agent HP MRI study and mark the clinical translation of the first HP 13 C MRI probe after pyruvate.

PurposeTo develop a novel post-processing pipeline for hyperpolarized (HP) 13 C MRSI that integrates tensor denoising and B1+ correction to measure pyruvate-to-lactate conversion rates (kPL ) in patients with liver tumors.MethodsSeven HP 13 C MR scans of progressing liver tumors were acquired using a custom 13 C surface transmit/receive coil and the echo-planar spectroscopic imaging (EPSI) data analysis included B0 correction, tensor rank truncation, and zero- and first-order phase corrections to recover metabolite signals that would otherwise be obscured by spectral noise as well as a correction for inhomogeneous transmit ( B1+ ) using a B1+ map aligned to the coil position for each patient scan. Processed HP data and corrected flip angles were analyzed with an inputless two-site exchange model to calculate kPL .ResultsDenoising averages SNR increases of pyruvate, lactate, and alanine were 37.4-, 34.0-, and 20.1-fold, respectively, with lactate and alanine dynamics most noticeably recovered and better defined. In agreement with Monte Carlo simulations, over-flipped regions underestimated kPL and under-flipped regions overestimated kPL . B1+ correction addressed this issue.ConclusionThe new HP 13 C EPSI post-processing pipeline integrated tensor denoising and B1+ correction to measure kPL in patients with liver tumors. These technical developments not only recovered metabolite signals in voxels that did not receive the prescribed flip angle, but also increased the extent and accuracy of kPL estimations throughout the tumor and adjacent regions including normal-appearing tissue and additional lesions.

PurposeTo develop and translate a metabolite-specific imaging sequence using a symmetric echo planar readout for clinical hyperpolarized (HP) Carbon-13 (13 C) applications.MethodsInitial data were acquired from patients with prostate cancer (N = 3) and high-grade brain tumors (N = 3) on a 3T scanner. Samples of [1-13 C]pyruvate were polarized for at least 2 h using a 5T SPINlab system operating at 0.8 K. Following injection of the HP substrate, pyruvate, lactate, and bicarbonate (for brain studies) were sequentially excited with a singleband spectral-spatial RF pulse and signal was rapidly encoded with a single-shot echo planar readout on a slice-by-slice basis. Data were acquired dynamically with a temporal resolution of 2 s for prostate studies and 3 s for brain studies.ResultsHigh pyruvate signal was seen throughout the prostate and brain, with conversion to lactate being shown across studies, whereas bicarbonate production was also detected in the brain. No Nyquist ghost artifacts or obvious geometric distortion from the echo planar readout were observed. The average error in center frequency was 1.2 ± 17.0 and 4.5 ± 1.4 Hz for prostate and brain studies, respectively, below the threshold for spatial shift because of bulk off-resonance.ConclusionThis study demonstrated the feasibility of symmetric EPI to acquire HP 13 C metabolite maps in a clinical setting. As an advance over prior single-slice dynamic or single time point volumetric spectroscopic imaging approaches, this metabolite-specific EPI acquisition provided robust whole-organ coverage for brain and prostate studies while retaining high SNR, spatial resolution, and dynamic temporal resolution.

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

Purpose: To develop techniques and establish a workflow using hyperpolarized carbon-13 ( 13 C) MRI and the pyruvate-to-lactate conversion rate (k PL ) biomarker to guide MR-transrectal ultrasound fusion prostate biopsies., Methods: The integrated multiparametric MRI (mpMRI) exam consisted of a 1-min hyperpolarized 13 C-pyruvate EPI acquisition added to a conventional prostate mpMRI exam. Maps of k PL values were calculated, uploaded to a picture archiving and communication system and targeting platform, and displayed as color overlays on T 2 -weighted anatomic images. Abdominal radiologists identified 13 C research biopsy targets based on the general recommendation of focal lesions with k PL  >0.02(s -1 ), and created a targeting report for each study. Urologists conducted transrectal ultrasound-guided MR fusion biopsies, including the standard 1 H-mpMRI targets as well as 12-14 core systematic biopsies informed by the research 13 C-k PL targets. All biopsy results were included in the final pathology report and calculated toward clinical risk., Results: This study demonstrated the safety and technical feasibility of integrating hyperpolarized 13 C metabolic targeting into routine 1 H-mpMRI and transrectal ultrasound fusion biopsy workflows, evaluated via 5 men (median age 71 years, prostate-specific antigen 8.4 ng/mL, Cancer of the Prostate Risk Assessment score 2) on active surveillance undergoing integrated scan and subsequent biopsies. No adverse event was reported. Median turnaround time was less than 3 days from scan to 13 C-k PL targeting, and scan-to-biopsy time was 2 weeks. Median number of 13 C targets was 1 (range: 1-2) per patient, measuring 1.0 cm (range: 0.6-1.9) in diameter, with a median k PL of 0.0319 s -1 (range: 0.0198-0.0410)., Conclusions: This proof-of-concept work demonstrated the safety and feasibility of integrating hyperpolarized 13 C MR biomarkers to the standard mpMRI workflow to guide MR-transrectal ultrasound fusion biopsies., (© 2022 International Society for Magnetic Resonance in Medicine.)

Purpose: The combined hyperpolarized (HP) 13 C pyruvate and urea MRI has provided a simultaneous assessment of glycolytic metabolism and tissue perfusion for improved cancer diagnosis and therapeutic evaluation in preclinical studies. This work aims to translate this dual-probe HP imaging technique to clinical research., Methods: A co-polarization system was developed where [1- 13 C]pyruvic acid (PA) and [ 13 C, 15 N 2 ]urea in water solution were homogeneously mixed and polarized on a 5T SPINlab system. Physical and chemical characterizations and toxicology studies of the combined probe were performed. Simultaneous metabolic and perfusion imaging was performed on a 3T clinical MR scanner by alternatively applying a multi-slice 2D spiral sequence for [1- 13 C]pyruvate and its downstream metabolites and a 3D balanced steady-state free precession (bSSFP) sequence for [ 13 C, 15 N 2 ]urea., Results: The combined PA/urea probe has a glass-formation ability similar to neat PA and can generate nearly 40% liquid-state 13 C polarization for both pyruvate and urea in 3-4 h. A standard operating procedure for routine on-site production was developed and validated to produce 40 mL injection product of approximately 150 mM pyruvate and 35 mM urea. The toxicology study demonstrated the safety profile of the combined probe. Dynamic metabolite-specific imaging of [1- 13 C]pyruvate, [1- 13 C]lactate, [1- 13 C]alanine, and [ 13 C, 15 N 2 ]urea was achieved with adequate spatial (2.6 mm × 2.6 mm) and temporal resolution (4.2 s), and urea images showed reduced off-resonance artifacts due to the J CN coupling., Conclusion: The reported technical development and translational studies will lead to the first-in-human dual-agent HP MRI study and mark the clinical translation of the first HP 13 C MRI probe after pyruvate., (© 2021 The Authors. Magnetic Resonance in Medicine published by Wiley Periodicals LLC on behalf of International Society for Magnetic Resonance in Medicine.)

Purpose: To develop a novel post-processing pipeline for hyperpolarized (HP) 13 C MRSI that integrates tensor denoising and B 1 + correction to measure pyruvate-to-lactate conversion rates (k PL ) in patients with liver tumors., Methods: Seven HP 13 C MR scans of progressing liver tumors were acquired using a custom 13 C surface transmit/receive coil and the echo-planar spectroscopic imaging (EPSI) data analysis included B 0 correction, tensor rank truncation, and zero- and first-order phase corrections to recover metabolite signals that would otherwise be obscured by spectral noise as well as a correction for inhomogeneous transmit ( B 1 + ) using a B 1 + map aligned to the coil position for each patient scan. Processed HP data and corrected flip angles were analyzed with an inputless two-site exchange model to calculate k PL ., Results: Denoising averages SNR increases of pyruvate, lactate, and alanine were 37.4-, 34.0-, and 20.1-fold, respectively, with lactate and alanine dynamics most noticeably recovered and better defined. In agreement with Monte Carlo simulations, over-flipped regions underestimated k PL and under-flipped regions overestimated k PL . B 1 + correction addressed this issue., Conclusion: The new HP 13 C EPSI post-processing pipeline integrated tensor denoising and B 1 + correction to measure k PL in patients with liver tumors. These technical developments not only recovered metabolite signals in voxels that did not receive the prescribed flip angle, but also increased the extent and accuracy of k PL estimations throughout the tumor and adjacent regions including normal-appearing tissue and additional lesions., (© 2021 International Society for Magnetic Resonance in Medicine.)

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 cm 3 , 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., (© 2018 International Society for Magnetic Resonance in Medicine.)