Publications by authors named "John Kurhanewicz"

223 Publications

Development of specialized magnetic resonance acquisition techniques for human hyperpolarized [ C, N ]urea + [1- C]pyruvate simultaneous perfusion and metabolic imaging.

Magn Reson Med 2022 09 8;88(3):1039-1054. Epub 2022 May 8.

Department of Radiology and Biomedical Imaging, University of California, San Francisco, San Francisco, California, USA.

Purpose: This study aimed to develop and demonstrate the in vivo feasibility of a 3D stack-of-spiral balanced steady-state free precession(3D-bSSFP) urea sequence, interleaved with a metabolite-specific gradient echo (GRE) sequence for pyruvate and metabolic products, for improving the SNR and spatial resolution of the first hyperpolarized C-MRI human study with injection of co-hyperpolarized [1- C]pyruvate and [ C, N ]urea.

Methods: A metabolite-specific bSSFP urea imaging sequence was designed using a urea-specific excitation pulse, optimized TR, and 3D stack-of-spiral readouts. Simulations and phantom studies were performed to validate the spectral response of the sequence. The image quality of urea data acquired by the 3D-bSSFP sequence and the 2D-GRE sequence was evaluated with 2 identical injections of co-hyperpolarized [1- C]pyruvate and [ C, N ]urea formula in a rat. Subsequently, the feasibility of the acquisition strategy was validated in a prostate cancer patient.

Results: Simulations and phantom studies demonstrated that 3D-bSSFP sequence achieved urea-only excitation, while minimally perturbing other metabolites (<1%). An animal study demonstrated that compared to GRE, bSSFP sequence provided an ∼2.5-fold improvement in SNR without perturbing urea or pyruvate kinetics, and bSSFP approach with a shorter spiral readout reduced blurring artifacts caused by J-coupling of [ C, N ]urea. The human study demonstrated the in vivo feasibility and data quality of the acquisition strategy.

Conclusion: The 3D-bSSFP urea sequence with a stack-of-spiral acquisition demonstrated significantly increased SNR and image quality for [ C, N ]urea in co-hyperpolarized [1- C]pyruvate and [ C, N ]urea imaging studies. This work lays the foundation for future human studies to achieve high-quality and high-SNR metabolism and perfusion images.
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http://dx.doi.org/10.1002/mrm.29266DOI Listing
September 2022

Identification of prostate cancer using multiparametric MR imaging characteristics of prostate tissues referenced to whole mount histopathology.

Magn Reson Imaging 2022 01 16;85:251-261. Epub 2021 Oct 16.

Deparment of Radiology and Biomedical Imaging, University of California, 185 Berry Street, San Francisco, CA, USA. Electronic address:

In this study, the objective was to characterize the MR signatures of the various benign prostate tissues and to differentiate them from cancer. Data was from seventy prostate cancer patients who underwent multiparametric MRI (mpMRI) and subsequent prostatectomy. The scans included T2-weighted imaging (T2W), diffusion weighted imaging, dynamic contrast-enhanced MRI (DCE MRI), and MR spectroscopic imaging. Histopathology tissue information was translated to MRI images. The mpMRI parameters were characterized separately per zone and by tissue type. The tissues were ordered according to trends in tissue parameter means. The peripheral zone tissue order was cystic atrophy, high grade prostatic intraepithelial neoplasia (HGPIN), normal, atrophy, inflammation, and cancer. Decreasing values for tissue order were exhibited by ADC (1.8 10 mm/s to 1.2 10 mm/s) and T2W intensity (3447 to 2576). Increasing values occurred for DCE MRI peak (143% to 157%), DCE MRI slope (101%/min to 169%/min), fractional anisotropy (FA) (0.16 to 0.19), choline (7.2 to 12.2), and choline / citrate (0.3 to 0.9). The transition zone tissue order was cystic atrophy, mixed benign prostatic hyperplasia (BPH), normal, atrophy, inflammation, stroma, anterior fibromuscular stroma, and cancer. Decreasing values occurred for ADC (1.6 10 mm/s to 1.1 10 mm/s) and T2W intensity (2863 to 2001). Increasing values occurred for DCE MRI peak (143% to 150%), DCE MRI slope (101%/min to 137%/min), FA (0.18 to 0.25), choline (7.9 to 11.7), and choline / citrate (0.3 to 0.7). Logistic regression was used to create parameter model fits to differentiate cancer from benign prostate tissues. The fits achieved AUCs ≥0.91. This study quantified the mpMRI characteristics of benign prostate tissues and demonstrated the capability of mpMRI to discriminate among benign as well as cancer tissues, potentially aiding future discrimination of cancer from benign confounders.
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http://dx.doi.org/10.1016/j.mri.2021.10.008DOI Listing
January 2022

Clinical translation of hyperpolarized C pyruvate and urea MRI for simultaneous metabolic and perfusion imaging.

Magn Reson Med 2022 01 10;87(1):138-149. Epub 2021 Aug 10.

Department of Radiology and Biomedical Imaging, University of California, San Francisco, San Francisco, California, USA.

Purpose: The combined hyperpolarized (HP) 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- C]pyruvic acid (PA) and [ C, N ]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- C]pyruvate and its downstream metabolites and a 3D balanced steady-state free precession (bSSFP) sequence for [ C, N ]urea.

Results: The combined PA/urea probe has a glass-formation ability similar to neat PA and can generate nearly 40% liquid-state 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- C]pyruvate, [1- C]lactate, [1- C]alanine, and [ C, N ]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 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 C MRI probe after pyruvate.
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http://dx.doi.org/10.1002/mrm.28965DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8616838PMC
January 2022

Specialized computational methods for denoising, B correction, and kinetic modeling in hyperpolarized C MR EPSI studies of liver tumors.

Magn Reson Med 2021 11 3;86(5):2402-2411. Epub 2021 Jul 3.

UC Berkeley-UCSF Graduate Program in Bioengineering, University of California, San Francisco and University of California, Berkeley, California, USA.

Purpose: To develop a novel post-processing pipeline for hyperpolarized (HP) C MRSI that integrates tensor denoising and correction to measure pyruvate-to-lactate conversion rates (k ) in patients with liver tumors.

Methods: Seven HP C MR scans of progressing liver tumors were acquired using a custom C surface transmit/receive coil and the echo-planar spectroscopic imaging (EPSI) data analysis included B 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 ( ) using a 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 .

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 and under-flipped regions overestimated k . correction addressed this issue.

Conclusion: The new HP C EPSI post-processing pipeline integrated tensor denoising and correction to measure k 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 estimations throughout the tumor and adjacent regions including normal-appearing tissue and additional lesions.
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http://dx.doi.org/10.1002/mrm.28901DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8565779PMC
November 2021

Magnetic resonance biomarkers in radiation oncology: The report of AAPM Task Group 294.

Med Phys 2021 Jul 20;48(7):e697-e732. Epub 2021 May 20.

Department of Radiation Oncology, MD Anderson Cancer Center, University of Texas, Houston, Texas, USA.

Purpose: A magnetic resonance (MR) biologic marker (biomarker) is a measurable quantitative characteristic that is an indicator of normal biological and pathogenetic processes or a response to therapeutic intervention derived from the MR imaging process. There is significant potential for MR biomarkers to facilitate personalized approaches to cancer care through more precise disease targeting by quantifying normal versus pathologic tissue function as well as toxicity to both radiation and chemotherapy. Both of which have the potential to increase the therapeutic ratio and provide earlier, more accurate monitoring of treatment response. The ongoing integration of MR into routine clinical radiation therapy (RT) planning and the development of MR guided radiation therapy systems is providing new opportunities for MR biomarkers to personalize and improve clinical outcomes. Their appropriate use, however, must be based on knowledge of the physical origin of the biomarker signal, the relationship to the underlying biological processes, and their strengths and limitations. The purpose of this report is to provide an educational resource describing MR biomarkers, the techniques used to quantify them, their strengths and weakness within the context of their application to radiation oncology so as to ensure their appropriate use and application within this field.
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http://dx.doi.org/10.1002/mp.14884DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8361924PMC
July 2021

Resistance to Androgen Deprivation Leads to Altered Metabolism in Human and Murine Prostate Cancer Cell and Tumor Models.

Metabolites 2021 Feb 26;11(3). Epub 2021 Feb 26.

Department of Radiology and Biomedical Imaging, University of California, San Francisco, CA 94143, USA.

Currently, no clinical methods reliably predict the development of castration-resistant prostate cancer (CRPC) that occurs almost universally in men undergoing androgen deprivation therapy. Hyperpolarized (HP) C magnetic resonance imaging (MRI) could potentially detect the incipient emergence of CRPC based on early metabolic changes. To characterize metabolic shifts occurring upon the transition from androgen-dependent to castration-resistant prostate cancer (PCa), the metabolism of [U-C]glucose and [U-C]glutamine was analyzed by nuclear magnetic resonance spectroscopy. Comparison of steady-state metabolite concentrations and fractional enrichment in androgen-dependent LNCaP cells and transgenic adenocarcinoma of the murine prostate (TRAMP) murine tumors versus castration-resistant PC-3 cells and treatment-driven CRPC TRAMP tumors demonstrated that CRPC was associated with upregulation of glycolysis, tricarboxylic acid metabolism of pyruvate; and glutamine, glutaminolysis, and glutathione synthesis. These findings were supported by C isotopomer modeling showing increased flux through pyruvate dehydrogenase (PDH) and anaplerosis; enzymatic assays showing increased lactate dehydrogenase, PDH and glutaminase activity; and oxygen consumption measurements demonstrating increased dependence on anaplerotic fuel sources for mitochondrial respiration in CRPC. Consistent with ex vivo metabolomic studies, HP [1-C]pyruvate distinguished androgen-dependent PCa from CRPC in cell and tumor models based on significantly increased HP [1-C]lactate.
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http://dx.doi.org/10.3390/metabo11030139DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7996870PMC
February 2021

Tumor metabolism and neurocognition in CNS lymphoma.

Neuro Oncol 2021 10;23(10):1668-1679

Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco (UCSF), San Francisco, California, USA.

Background: The mechanistic basis for neurocognitive deficits in central nervous system (CNS) lymphoma and other brain tumors is incompletely understood. We tested the hypothesis that tumor metabolism impairs neurotransmitter pathways and neurocognitive function.

Methods: We performed serial cerebrospinal fluid (CSF) metabolomic analyses using liquid chromatography-electrospray tandem mass spectrometry to evaluate changes in the tumor microenvironment in 14 patients with recurrent CNS lymphoma, focusing on 18 metabolites involved in neurotransmission and bioenergetics. These were paired with serial mini-mental state examination (MMSE) and MRI studies for tumor volumetric analyses. Patients were analyzed in the setting of the phase I trial of lenalidomide/rituximab. Associations were assessed by Pearson and Spearman correlation coefficient. Generalized estimating equation (GEE) models were also established, adjusting for within-subject repeated measures.

Results: Of 18 metabolites, elevated CSF lactate correlated most strongly with lower MMSE score (P < 8E-8, ρ = -0.67). High lactate was associated with lower gamma-aminobutyric acid (GABA), higher glutamate/GABA ratio, and dopamine. Conversely, high succinate correlated with higher MMSE scores. Serial analysis demonstrated a reproducible, time-dependent, reciprocal correlation between changes in lactate and GABA concentrations. While high lactate and low GABA correlated with tumor contrast-enhancing volume, they correlated more significantly with lower MMSE scores than tumor volumes.

Conclusions: We provide evidence that lactate production and Warburg metabolism may impact neurotransmitter dysregulation and neurocognition in CNS lymphomas. We identify novel metabolomic biomarkers that may be applied in future studies of neurocognition in CNS lymphomas. Elucidation of mechanistic interactions between lymphoma metabolism, neurotransmitter imbalance, and neurocognition may promote interventions that preserve cognitive function.
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http://dx.doi.org/10.1093/neuonc/noab045DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8485453PMC
October 2021

Modeling hyperpolarized lactate signal dynamics in cells, patient-derived tissue slice cultures and murine models.

NMR Biomed 2021 03 7;34(3):e4467. Epub 2021 Jan 7.

Radiology and Biomedical Imaging, University of California San Francisco, San Francisco, California, USA.

Determining the aggressiveness of renal cell carcinoma (RCC) noninvasively is a critical part of the diagnostic workup for treating this disease that kills more than 15,000 people annually in the USA. Recently, we have shown that not only the amount of lactate produced, as a consequence of the Warburg effect, but also its efflux out of the cell, is a critical marker of RCC aggressiveness and differentiating RCCs from benign renal tumors. Enzymatic conversions can now be measured in situ with hyperpolarized (HP) C magnetic resonance (MR) on a sub-minute time scale. Using RCC models, we have shown that this technology can interrogate in real time both lactate production and compartmentalization, which are associated with tumor aggressiveness. The dynamic HP MR data have enabled us to robustly characterize parameters that have been elusive to measure directly in intact living cells and murine tumors thus far. Specifically, we were able to measure the same intracellular lactate longitudinal relaxation time in three RCC cell lines of 16.42 s, and lactate efflux rate ranging from 0.14 to 0.8 s in the least to the most aggressive RCC cell lines and correlate it to monocarboxylate transporter isoform 4 expression. We also analyzed dynamic HP lactate and pyruvate data from orthotopic murine RCC tumors using a simplified one-compartment model, and showed comparable apparent pyruvate to lactate conversion rate (k ) values with those measured in vitro. This kinetic modeling was then extended to characterize the lactate dynamics in patient-derived living RCC tissue slices; and even without direct measurement of the extracellular lactate signal the efflux parameter was still assessed and was distinct between the benign renal tumors and RCCs. Across all these preclinical models, the rate parameters of k and lactate efflux correlated to cancer aggressiveness, demonstrating the validity of our modeling approach for noninvasive assessment of RCC aggressiveness.
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http://dx.doi.org/10.1002/nbm.4467DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8423093PMC
March 2021

False positive PSMA PET for tumor remnants in the irradiated prostate and other interpretation pitfalls in a prospective multi-center trial.

Eur J Nucl Med Mol Imaging 2021 02 17;48(2):501-508. Epub 2020 Aug 17.

Departments of Radiology and Biomedical Imaging and Pharmaceutical Chemistry, University of California San Francisco, San Francisco, CA, USA.

Purpose: Readers need to be informed about potential pitfalls of [Ga]Ga-PSMA-11 PET interpretation.

Methods: Here we report [Ga]Ga-PSMA-11 PET findings discordant with the histopathology/composite reference standard in a recently published prospective trial on 635 patients with biochemically recurrent prostate cancer.

Results: Consensus reads were false positive in 20 regions of 17/217 (8%) patients with lesion validation. Majority of the false positive interpretations (13 of 20, 65%) occurred in the context of suspected prostate (bed) relapse (T) after radiotherapy (n = 11); other false positive findings were noted for prostate bed post prostatectomy (T, n = 2), pelvic nodes (N, n = 2), or extra pelvic lesions (M, n = 5). Major sources of false positive findings were PSMA-expressing residual adenocarcinoma with marked post-radiotherapy treatment effect. False negative interpretation occurred in 8 regions of 6/79 (8%) patients with histopathology validation, including prostate (bed) (n = 5), pelvic nodes (n = 1), and extra pelvic lesions (n = 2). Lesions were missed mostly due to small metastases or adjacent bladder/urine uptake.

Conclusion: [Ga]Ga-PSMA-11 PET at biochemical recurrence resulted in less than 10% false positive interpretations. Post-radiotherapy prostate uptake was a major source of [Ga]Ga-PSMA-11 PET false positivity. In few cases, PET correctly detects residual PSMA expression post-radiotherapy, originating however from treated, benign tissue or potentially indolent tumor remnants.

Trial Registration Number: ClinicalTrials.gov Identifiers: NCT02940262 and NCT03353740.
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http://dx.doi.org/10.1007/s00259-020-04945-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7835157PMC
February 2021

Tensor image enhancement and optimal multichannel receiver combination analyses for human hyperpolarized C MRSI.

Magn Reson Med 2020 12 5;84(6):3351-3365. Epub 2020 Jun 5.

Department of Radiology and Biomedical Imaging, University of California, San Francisco, California, USA.

Purpose: With the initiation of human hyperpolarized C (HP- C) trials at multiple sites and the development of improved acquisition methods, there is an imminent need to maximally extract diagnostic information to facilitate clinical interpretation. This study aims to improve human HP- C MR spectroscopic imaging through means of Tensor Rank truncation-Image enhancement (TRI) and optimal receiver combination (ORC).

Methods: A data-driven processing framework for dynamic HP C MR spectroscopic imaging (MRSI) was developed. Using patient data sets acquired with both multichannel arrays and single-element receivers from the brain, abdomen, and pelvis, we examined the theory and application of TRI, as well as 2 ORC techniques: whitened singular value decomposition (WSVD) and first-point phasing. Optimal conditions for TRI were derived based on bias-variance trade-off.

Results: TRI and ORC techniques together provided a 63-fold mean apparent signal-to-noise ratio (aSNR) gain for receiver arrays and a 31-fold gain for single-element configurations, which particularly improved quantification of the lower-SNR-[ C]bicarbonate and [1- C]alanine signals that were otherwise not detectable in many cases. Substantial SNR enhancements were observed for data sets that were acquired even with suboptimal experimental conditions, including delayed (114 s) injection (8× aSNR gain solely by TRI), or from challenging anatomy or geometry, as in the case of a pediatric patient with brainstem tumor (597× using combined TRI and WSVD). Improved correlation between elevated pyruvate-to-lactate conversion, biopsy-confirmed cancer, and mp-MRI lesions demonstrated that TRI recovered quantitative diagnostic information.

Conclusion: Overall, this combined approach was effective across imaging targets and receiver configurations and could greatly benefit ongoing and future HP C MRI research through major aSNR improvements.
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http://dx.doi.org/10.1002/mrm.28328DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7718428PMC
December 2020

Simultaneous Metabolic and Perfusion Imaging Using Hyperpolarized C MRI Can Evaluate Early and Dose-Dependent Response to Radiation Therapy in a Prostate Cancer Mouse Model.

Int J Radiat Oncol Biol Phys 2020 08 25;107(5):887-896. Epub 2020 Apr 25.

Department of Radiology and Biomedical Imaging, University of California, San Francisco, California; Graduate Program in Bioengineering, University of California, Berkeley and University of California, San Francisco, California. Electronic address:

Purpose: To investigate use of a novel imaging approach, hyperpolarized (HP) C magnetic resonance imaging (MRI) for simultaneous metabolism and perfusion assessment, to evaluate early and dose-dependent response to radiation therapy (RT) in a prostate cancer mouse model.

Methods And Materials: Transgenic Adenocarcinoma of Mouse Prostate (TRAMP) mice (n = 18) underwent single-fraction RT (4-14 Gy steep dose across the tumor) and were imaged serially at pre-RT baseline and 1, 4, and 7 days after RT using HP C MRI with combined [1-C]pyruvate (metabolic active agent) and [C]urea (perfusion agent), coupled with conventional multiparametric H MRI including T2-weighted, dynamic contrast-enhanced, and diffusion-weighted imaging. Tumor tissues were collected 4 and 7 days after RT for biological correlative studies.

Results: We found a significant decrease in HP pyruvate-to-lactate conversion in tumors responding to RT, with concomitant significant increases in HP pyruvate-to-alanine conversion and HP urea signal; the opposite changes were observed in tumors resistant to RT. Moreover, HP lactate change was dependent on radiation dose; tumor regions treated with higher radiation doses (10-14 Gy) exhibited a greater decrease in HP lactate signal than low-dose regions (4-7 Gy) as early as 1 day post-RT, consistent with lactate dehydrogenase enzyme activity and expression data. We also found that HP [C]urea MRI provided assessments of tumor perfusion similar to those provided by H dynamic contrast-enhanced MRI in this animal model. However, apparent diffusion coefficien , a conventional H MRI functional biomarker, did not exhibit statistically significant changes within 7 days after RT.

Conclusion: These results demonstrate the ability of HP C MRI to monitor radiation-induced physiologic changes in a timely and dose-dependent manner, providing the basic science premise for further clinical investigation and translation.
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http://dx.doi.org/10.1016/j.ijrobp.2020.04.022DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7381368PMC
August 2020

Hyperpolarized C MRI data acquisition and analysis in prostate and brain at University of California, San Francisco.

NMR Biomed 2021 05 19;34(5):e4280. Epub 2020 Mar 19.

Department of Radiology and Biomedical Imaging, University of California, San Francisco, USA.

Based on the expanding set of applications for hyperpolarized carbon-13 (HP- C) MRI, this work aims to communicate standardized methodology implemented at the University of California, San Francisco, as a primer for conducting reproducible metabolic imaging studies of the prostate and brain. Current state-of-the-art HP- C acquisition, data processing/reconstruction and kinetic modeling approaches utilized in patient studies are presented together with the rationale underpinning their usage. Organized around spectroscopic and imaging-based methods, this guide provides an extensible framework for handling a variety of HP- C applications, which derives from two examples with dynamic acquisitions: 3D echo-planar spectroscopic imaging of the human prostate and frequency-specific 2D multislice echo-planar imaging of the human brain. Details of sequence-specific parameters and processing techniques contained in these examples should enable investigators to effectively tailor studies around individual-use cases. Given the importance of clinical integration in improving the utility of HP exams, practical aspects of standardizing data formats for reconstruction, analysis and visualization are also addressed alongside open-source software packages that enhance institutional interoperability and validation of methodology. To facilitate the adoption and further development of this methodology, example datasets and analysis pipelines have been made available in the supporting information.
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http://dx.doi.org/10.1002/nbm.4280DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7501204PMC
May 2021

Elevated Tumor Lactate and Efflux in High-grade Prostate Cancer demonstrated by Hyperpolarized C Magnetic Resonance Spectroscopy of Prostate Tissue Slice Cultures.

Cancers (Basel) 2020 Feb 26;12(3). Epub 2020 Feb 26.

Department of Radiology and Biomedical Imaging, University of California, San Francisco, CA 94158, USA.

Non-invasive assessment of the biological aggressiveness of prostate cancer (PCa) is needed for men with localized disease. Hyperpolarized (HP) C magnetic resonance (MR) spectroscopy is a powerful approach to image metabolism, specifically the conversion of HP [1-C]pyruvate to [1-C]lactate, catalyzed by lactate dehydrogenase (LDH). Significant increase in tumor lactate was measured in high-grade PCa relative to benign and low-grade cancer, suggesting that HP C MR could distinguish low-risk (Gleason score ≤3 + 4) from high-risk (Gleason score ≥4 + 3) PCa. To test this and the ability of HP C MR to detect these metabolic changes, we cultured prostate tissues in an MR-compatible bioreactor under continuous perfusion. P spectra demonstrated good viability and dynamic HP C-pyruvate MR demonstrated that high-grade PCa had significantly increased lactate efflux compared to low-grade PCa and benign prostate tissue. These metabolic differences are attributed to significantly increased expression and LDH activity, as well as significantly increased monocarboxylate transporter 4 (MCT4) expression in high- versus low- grade PCa. Moreover, lactate efflux, LDH activity, and MCT4 expression were not different between low-grade PCa and benign prostate tissues, indicating that these metabolic alterations are specific for high-grade disease. These distinctive metabolic alterations can be used to differentiate high-grade PCa from low-grade PCa and benign prostate tissues using clinically translatable HP [1-C]pyruvate MR.
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http://dx.doi.org/10.3390/cancers12030537DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7139946PMC
February 2020

Hyperpolarized pH imaging reveals grade-dependent acidification in prostate cancer.

Oncotarget 2019 Oct 22;10(58):6096-6110. Epub 2019 Oct 22.

Department of Radiology and Biomedical Imaging, University of California, San Francisco, CA, USA.

There is an unmet clinical need for new and robust imaging biomarkers to distinguish indolent from aggressive prostate cancer. Hallmarks of aggressive tumors such as a decrease in extracellular pH (pH) can potentially be used to identify aggressive phenotypes. In this study, we employ an optimized, high signal-to-noise ratio hyperpolarized (HP) C pH imaging method to discriminate between indolent and aggressive disease in a murine model of prostate cancer. Transgenic adenocarcinoma of the mouse prostate (TRAMP) mice underwent a multiparametric MR imaging exam, including HP [C] bicarbonate MRI for pH, with H apparent diffusion coefficient (ADC) mapping and HP [1-C] pyruvate MRI to study lactate metabolism. Tumor tissue was excised for histological staining and qRT-PCR to quantify mRNA expression for relevant glycolytic enzymes and transporters. We observed good separation in pH between low- and high-grade tumor regions, with high-grade tumors demonstrating a lower pH. The pH also correlated strongly with monocarboxylate transporter gene expression across all tumors, suggesting that lactate export via MCT4 is associated with acidification in this model. Our results implicate extracellular acidification as an indicator of indolent-to-aggressive transition in prostate cancer and suggest feasibility of HP pH imaging to detect high-grade, clinically significant disease in men as part of a multiparametric MRI examination.
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http://dx.doi.org/10.18632/oncotarget.27225DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6817439PMC
October 2019

Hyperpolarized C-pyruvate MRI detects real-time metabolic flux in prostate cancer metastases to bone and liver: a clinical feasibility study.

Prostate Cancer Prostatic Dis 2020 06 4;23(2):269-276. Epub 2019 Nov 4.

Department of Radiology and Biomedical Imaging, University of California, San Francisco, CA, USA.

Background: Hyperpolarized (HP) C-pyruvate MRI is a stable-isotope molecular imaging modality that provides real-time assessment of the rate of metabolism through glycolytic pathways in human prostate cancer. Heretofore this imaging modality has been successfully utilized in prostate cancer only in localized disease. This pilot clinical study investigated the feasibility and imaging performance of HP C-pyruvate MR metabolic imaging in prostate cancer patients with metastases to the bone and/or viscera.

Methods: Six patients who had metastatic castration-resistant prostate cancer were recruited. Carbon-13 MR examination were conducted on a clinical 3T MRI following injection of 250 mM hyperpolarized C-pyruvate, where pyruvate-to-lactate conversion rate (k) was calculated. Paired metastatic tumor biopsy was performed with histopathological and RNA-seq analyses.

Results: We observed a high rate of glycolytic metabolism in prostate cancer metastases, with a mean k value of 0.020 ± 0.006 (s) and 0.026 ± 0.000 (s) in bone (N = 4) and liver (N = 2) metastases, respectively. Overall, high k showed concordance with biopsy-confirmed high-grade prostate cancer including neuroendocrine differentiation in one case. Interval decrease of k from 0.026 at baseline to 0.015 (s) was observed in a liver metastasis 2 months after the initiation of taxane plus platinum chemotherapy. RNA-seq found higher levels of the lactate dehydrogenase isoform A (Ldha,15.7 ± 0.7) expression relative to the dominant isoform of pyruvate dehydrogenase (Pdha1, 12.8 ± 0.9).

Conclusions: HP C-pyruvate MRI can detect real-time glycolytic metabolism within prostate cancer metastases, and can measure changes in quantitative k values following treatment response at early time points. This first feasibility study supports future clinical studies of HP C-pyruvate MRI in the setting of advanced prostate cancer.
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http://dx.doi.org/10.1038/s41391-019-0180-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7196510PMC
June 2020

First hyperpolarized [2-C]pyruvate MR studies of human brain metabolism.

J Magn Reson 2019 12 8;309:106617. Epub 2019 Oct 8.

Department of Radiology and Biomedical Imaging, University of California, San Francisco, CA 94158, USA.

We developed methods for the preparation of hyperpolarized (HP) sterile [2-C]pyruvate to test its feasibility in first-ever human NMR studies following FDA-IND & IRB approval. Spectral results using this MR stable-isotope imaging approach demonstrated the feasibility of investigating human cerebral energy metabolism by measuring the dynamic conversion of HP [2-C]pyruvate to [2-C]lactate and [5-C]glutamate in the brain of four healthy volunteers. Metabolite kinetics, signal-to-noise (SNR) and area-under-curve (AUC) ratios, and calculated [2-C]pyruvate to [2-C]lactate conversion rates (k) were measured and showed similar but not identical inter-subject values. The k measurements were equivalent with prior human HP [1-C]pyruvate measurements.
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http://dx.doi.org/10.1016/j.jmr.2019.106617DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6880930PMC
December 2019

Amino Acid-Derived Sensors for Specific Zn Detection Using Hyperpolarized C Magnetic Resonance Spectroscopy.

Chemistry 2019 Sep 20;25(51):11842-11846. Epub 2019 Aug 20.

Department of Radiology and Biomedical Imaging, University of California San Francisco, San Francisco, CA (USA, 94107, USA.

Alterations in Zn concentration are seen in normal tissues and in disease states, and for this reason imaging of Zn is an area of active investigation. Herein, enriched [1- C]cysteine and [1- C ]iminodiacetic acid were developed as Zn -specific imaging probes using hyperpolarized C magnetic resonance spectroscopy. [1- C]cysteine was used to accurately quantify Zn in complex biological mixtures. These sensors can be employed to detect Zn via imaging mechanisms including changes in C chemical shift, resonance linewidth, or T .
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http://dx.doi.org/10.1002/chem.201902771DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6742520PMC
September 2019

Zero-field nuclear magnetic resonance of chemically exchanging systems.

Nat Commun 2019 07 5;10(1):3002. Epub 2019 Jul 5.

Department of Chemistry, University of California-Berkeley, Berkeley, CA, 94720-3220, USA.

Zero- to ultralow-field (ZULF) nuclear magnetic resonance (NMR) is an emerging tool for precision chemical analysis. In this work, we study dynamic processes and investigate the influence of chemical exchange on ZULF NMR J-spectra. We develop a computational approach that allows quantitative calculation of J-spectra in the presence of chemical exchange and apply it to study aqueous solutions of [N]ammonium (N[Formula: see text]) as a model system. We show that pH-dependent chemical exchange substantially affects the J-spectra and, in some cases, can lead to degradation and complete disappearance of the spectral features. To demonstrate potential applications of ZULF NMR for chemistry and biomedicine, we show a ZULF NMR spectrum of [2-C]pyruvic acid hyperpolarized via dissolution dynamic nuclear polarization (dDNP). We foresee applications of affordable and scalable ZULF NMR coupled with hyperpolarization to study chemical exchange phenomena in vivo and in situations where high-field NMR detection is not possible to implement.
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http://dx.doi.org/10.1038/s41467-019-10787-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6611813PMC
July 2019

Using bidirectional chemical exchange for improved hyperpolarized [ C]bicarbonate pH imaging.

Magn Reson Med 2019 09 3;82(3):959-972. Epub 2019 May 3.

Department of Radiology and Biomedical Imaging, University of California San Francisco, San Francisco, California.

Purpose: Rapid chemical exchange can affect SNR and pH measurement accuracy for hyperpolarized pH imaging with [ C]bicarbonate. The purpose of this work was to investigate chemical exchange effects on hyperpolarized imaging sequences to identify optimal sequence parameters for high SNR and pH accuracy.

Methods: Simulations were performed under varying rates of bicarbonate-CO chemical exchange to analyze exchange effects on pH quantification accuracy and SNR under different sampling schemes. Four pulse sequences, including 1 new technique, a multiple-excitation 2D EPI (multi-EPI) sequence, were compared in phantoms using hyperpolarized [ C]bicarbonate, varying parameters such as tip angles, repetition time, order of metabolite excitation, and refocusing pulse design. In vivo hyperpolarized bicarbonate-CO exchange measurements were made in transgenic murine prostate tumors to select in vivo imaging parameters.

Results: Modeling of bicarbonate-CO exchange identified a multiple-excitation scheme for increasing CO SNR by up to a factor of 2.7. When implemented in phantom imaging experiments, these sampling schemes were confirmed to yield high pH accuracy and SNR gains. Based on measured bicarbonate-CO exchange in vivo, a 47% CO SNR gain is predicted.

Conclusion: The novel multi-EPI pulse sequence can boost CO imaging signal in hyperpolarized C bicarbonate imaging while introducing minimal pH bias, helping to surmount a major hurdle in hyperpolarized pH imaging.
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http://dx.doi.org/10.1002/mrm.27780DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6559833PMC
September 2019

Measuring Dynamic Changes in the Labile Iron Pool in Vivo with a Reactivity-Based Probe for Positron Emission Tomography.

ACS Cent Sci 2019 Apr 3;5(4):727-736. Epub 2019 Apr 3.

Department of Pharmaceutical Chemistry, University of California, San Francisco, San Francisco, California 94158, United States.

Redox cycling of iron powers various enzyme functions crucial for life, making the study of iron acquisition, storage, and disposition in the whole organism a worthy topic of inquiry. However, despite its important role in biology and disease, imaging iron in animals with oxidation-state specificity remains an outstanding problem in biology and medicine. Here we report a first-generation reactivity-based probe of labile ferrous iron suitable for positron emission tomography studies in live animals. The responses of this reagent to systemic changes in labile iron disposition were revealed using iron supplementation and sequestration treatments in mice, while the potential of this approach for in vivo imaging of cancer was demonstrated using genetically and pathologically diverse mouse models, including spontaneous tumors arising in a genetically engineered model of prostate cancer driven by loss of PTEN.
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http://dx.doi.org/10.1021/acscentsci.9b00240DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6487455PMC
April 2019

NMR quantification of lactate production and efflux and glutamate fractional enrichment in living human prostate biopsies cultured with [1,6- C ]glucose.

Magn Reson Med 2019 08 28;82(2):566-576. Epub 2019 Mar 28.

Department of Radiology and Biomedical Imaging, University of California, San Francisco, California.

Purpose: Image-guided prostate biopsies are routinely acquired in the diagnosis and treatment monitoring of prostate cancer, yielding useful tissue for identifying metabolic biomarkers and therapeutic targets. We developed an optimized biopsy tissue culture protocol in combination with [1,6- C ]glucose labeling and quantitative high-resolution NMR to measure glycolysis and tricarboxcylic acid (TCA) cycle activity in freshly acquired living human prostate biopsies.

Methods: We acquired 34 MRI-ultrasound fusion-guided prostate biopsies in vials on ice from 22 previously untreated patients. Within 15 min, biopsies were transferred to rotary tissue culture in 37°C prostate medium containing [1,6- C ]glucose. Following 24 h of culture, tissue lactate and glutamate pool sizes and fractional enrichments were quantified using quantitative H high resolution magic angle spinning Carr-Purcell-Meiboom-Gill (CPMG) spectroscopy at 1°C with and without C decoupling. Lactate effluxed from the biopsy tissue was quantified in the culture medium using quantitative solution-state high-resolution NMR.

Results: Lactate concentration in low-grade cancer (1.15 ± 0.78 nmol/mg) and benign (0.74 ± 0.15 nmol/mg) biopsies agreed with prior published measurements of snap-frozen biopsies. There was substantial fractional enrichment of [3- C]lactate (≈70%) and [4- C]glutamate (≈24%) in both low-grade cancer and benign biopsies. Although a significant difference in tissue [3- C]lactate fractional enrichment was not observed, lactate efflux was significantly higher (P < 0.05) in low-grade cancer biopsies (0.55 ± 0.14 nmol/min/mg) versus benign biopsies (0.31 ± 0.04 nmol/min/mg).

Conclusion: A protocol was developed for quantification of lactate production-efflux and TCA cycle activity in single living human prostate biopsies, allowing metabolic labeling on a wide spectrum of human tissues (e.g., metastatic, post-non-surgical therapy) from patients not receiving surgery.
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http://dx.doi.org/10.1002/mrm.27739DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7150535PMC
August 2019

Coil combination methods for multi-channel hyperpolarized C imaging data from human studies.

J Magn Reson 2019 04 1;301:73-79. Epub 2019 Feb 1.

Department of Radiology and Biomedical Imaging, University of California, San Francisco, CA, United States.

Effective coil combination methods for human hyperpolarized C spectroscopy multi-channel data had been relatively unexplored. This study implemented and tested several coil combination methods, including (1) the sum-of-squares (SOS), (2) singular value decomposition (SVD), (3) Roemer method by using reference peak area as a sensitivity map (RefPeak), and (4) Roemer method by using ESPIRiT-derived sensitivity map (ESPIRiT). These methods were evaluated by numerical simulation, thermal phantom experiments, and human cancer patient studies. Overall, the SVD, RefPeak, and ESPIRiT methods demonstrated better accuracy and robustness than the SOS method. Extracting complex pyruvate signal provides an easy and excellent approximation of the coil sensitivity map while maintaining valuable phase information of the coil-combined data.
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http://dx.doi.org/10.1016/j.jmr.2019.01.015DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7170546PMC
April 2019

Hyperpolarized C MRI: State of the Art and Future Directions.

Radiology 2019 05 5;291(2):273-284. Epub 2019 Mar 5.

From the Department of Radiology and Biomedical Imaging, University of California San Francisco, San Francisco, CA 94143.

Hyperpolarized (HP) carbon 13 (C) MRI is an emerging molecular imaging method that allows rapid, noninvasive, and pathway-specific investigation of dynamic metabolic and physiologic processes that were previously inaccessible to imaging. This technique has enabled real-time in vivo investigations of metabolism that are central to a variety of diseases, including cancer, cardiovascular disease, and metabolic diseases of the liver and kidney. This review provides an overview of the methods of hyperpolarization and C probes investigated to date in preclinical models of disease. The article then discusses the progress that has been made in translating this technology for clinical investigation. In particular, the potential roles and emerging clinical applications of HP [1-C]pyruvate MRI will be highlighted. The future directions to enable the adoption of this technology to advance the basic understanding of metabolism, to improve disease diagnosis, and to accelerate treatment assessment are also detailed.
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http://dx.doi.org/10.1148/radiol.2019182391DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6490043PMC
May 2019

The Role of Lactate Metabolism in Prostate Cancer Progression and Metastases Revealed by Dual-Agent Hyperpolarized C MRSI.

Cancers (Basel) 2019 Feb 22;11(2). Epub 2019 Feb 22.

Department of Medicine, Division of Interdisciplinary Medicine, Beth Israel Deaconess Medical Center, Beth Israel Cancer Center, Harvard Medical School, Boston, MA 02215, USA.

This study applied a dual-agent, C-pyruvate and C-urea, hyperpolarized C magnetic resonance spectroscopic imaging (MRSI) and multi-parametric (mp) ¹H magnetic resonance imaging (MRI) approach in the transgenic adenocarcinoma of mouse prostate (TRAMP) model to investigate changes in tumor perfusion and lactate metabolism during prostate cancer development, progression and metastases, and after lactate dehydrogenase-A (LDHA) knock-out. An increased Warburg effect, as measured by an elevated hyperpolarized (HP) Lactate/Pyruvate (Lac/Pyr) ratio, and associated expression and LDH activity were significantly higher in high- versus low-grade TRAMP tumors and normal prostates. The hypoxic tumor microenvironment in high-grade tumors, as measured by significantly decreased HP C-urea perfusion and increased PIM staining, played a key role in increasing lactate production through increased and then expression. Increased lactate induced expression and an acidic tumor microenvironment that provided a potential mechanism for the observed high rate of lymph node (86%) and liver (33%) metastases. The knockdown in the triple-transgenic mouse model of prostate cancer resulted in a significant reduction in HP Lac/Pyr, which preceded a reduction in tumor volume or apparent water diffusion coefficient (ADC). The gene knockdown significantly reduced primary tumor growth and reduced lymph node and visceral metastases. These data suggested a metabolic transformation from low- to high-grade prostate cancer including an increased Warburg effect, decreased perfusion, and increased metastatic potential. Moreover, these data suggested that LDH activity and lactate are required for tumor progression. The lactate metabolism changes during prostate cancer provided the motivation for applying hyperpolarized C MRSI to detect aggressive disease at diagnosis and predict early therapeutic response.
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http://dx.doi.org/10.3390/cancers11020257DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6406929PMC
February 2019

Pulse sequence considerations for quantification of pyruvate-to-lactate conversion k in hyperpolarized C imaging.

NMR Biomed 2019 03 21;32(3):e4052. Epub 2019 Jan 21.

Department of Radiology and Biomedical Imaging, University of California, San Francisco, CA, USA.

Hyperpolarized C MRI takes advantage of the unprecedented 50 000-fold signal-to-noise ratio enhancement to interrogate cancer metabolism in patients and animals. It can measure the pyruvate-to-lactate conversion rate, k , a metabolic biomarker of cancer aggressiveness and progression. Therefore, it is crucial to evaluate k reliably. In this study, three sequence components and parameters that modulate k estimation were identified and investigated in model simulations and through in vivo animal studies using several specifically designed pulse sequences. These factors included a magnetization spoiling effect due to RF pulses, a crusher gradient-induced flow suppression, and intrinsic image weightings due to relaxation. Simulation showed that the RF-induced magnetization spoiling can be substantially improved using an inputless k fitting. In vivo studies found a significantly higher apparent k with an additional gradient that leads to flow suppression (k /k  = 1.37 ± 0.33, P < 0.01, N = 6), which agrees with simulation outcomes (12.5% k error with Δv = 40 cm/s), indicating that the gradients predominantly suppressed flowing pyruvate spins. Significantly lower k was found using a delayed free induction decay (FID) acquisition versus a minimum-T version (k /k  = 0.67 ± 0.09, P < 0.01, N = 5), and the lactate peak had broader linewidth than pyruvate (Δω /Δω  = 1.32 ± 0.07, P < 0.000 01, N = 13). This illustrated that lactate's T *, shorter than that of pyruvate, can affect calculated k values. We also found that an FID sequence yielded significantly lower k versus a double spin-echo sequence that includes spin-echo spoiling, flow suppression from crusher gradients, and more T weighting (k /k  = 2.40 ± 0.98, P < 0.0001, N = 7). In summary, the pulse sequence, as well as its interaction with pharmacokinetics and the tissue microenvironment, can impact and be optimized for the measurement of k . The data acquisition and analysis pipelines can work synergistically to provide more robust and reproducible k measures for future preclinical and clinical studies.
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http://dx.doi.org/10.1002/nbm.4052DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6380928PMC
March 2019

Hyperpolarized C MRI: Path to Clinical Translation in Oncology.

Neoplasia 2019 01 23;21(1):1-16. Epub 2018 Nov 23.

Department of Radiology, University of Pennsylvania, PA, USA.

This white paper discusses prospects for advancing hyperpolarization technology to better understand cancer metabolism, identify current obstacles to HP (hyperpolarized) C magnetic resonance imaging's (MRI's) widespread clinical use, and provide recommendations for overcoming them. Since the publication of the first NIH white paper on hyperpolarized C MRI in 2011, preclinical studies involving [1-C]pyruvate as well a number of other C labeled metabolic substrates have demonstrated this technology's capacity to provide unique metabolic information. A dose-ranging study of HP [1-C]pyruvate in patients with prostate cancer established safety and feasibility of this technique. Additional studies are ongoing in prostate, brain, breast, liver, cervical, and ovarian cancer. Technology for generating and delivering hyperpolarized agents has evolved, and new MR data acquisition sequences and improved MRI hardware have been developed. It will be important to continue investigation and development of existing and new probes in animal models. Improved polarization technology, efficient radiofrequency coils, and reliable pulse sequences are all important objectives to enable exploration of the technology in healthy control subjects and patient populations. It will be critical to determine how HP C MRI might fill existing needs in current clinical research and practice, and complement existing metabolic imaging modalities. Financial sponsorship and integration of academia, industry, and government efforts will be important factors in translating the technology for clinical research in oncology. This white paper is intended to provide recommendations with this goal in mind.
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http://dx.doi.org/10.1016/j.neo.2018.09.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6260457PMC
January 2019

Phase I Study of CTT1057, an F-Labeled Imaging Agent with Phosphoramidate Core Targeting Prostate-Specific Membrane Antigen in Prostate Cancer.

J Nucl Med 2019 07 21;60(7):910-916. Epub 2018 Nov 21.

Department of Radiology and Biomedical Imaging, University of California, San Francisco, San Francisco, California.

Agents targeting prostate-specific membrane antigen (PSMA) comprise a rapidly emerging class of radiopharmaceuticals for diagnostic imaging of prostate cancer. Unlike most other PSMA agents with a urea backbone, CTT1057 is based on a phosphoramidate scaffold that irreversibly binds to PSMA. We conducted a first-in-humans phase I study of CTT1057 in patients with localized and metastatic prostate cancer. Two patient cohorts were recruited. Cohort A patients had biopsy-proven localized prostate cancer preceding radical prostatectomy, and cohort B patients had metastatic castration-resistant prostate cancer. Cohort A patients were imaged at multiple time points after intravenous injection with 362 ± 8 MBq of CTT1057 to evaluate the kinetics of CTT1057 and estimate radiation dose profiles. Mean organ-absorbed doses and effective doses were calculated. CTT1057 uptake in the prostate gland and regional lymph nodes was correlated with pathology, PSMA staining, and the results of conventional imaging. In cohort B, patients were imaged 60-120 min after injection of CTT1057. PET images were assessed for overall image quality, and areas of abnormal uptake were contrasted with conventional imaging. In cohort A ( = 5), the average total effective dose was 0.023 mSv/MBq. The kidneys exhibited the highest absorbed dose, 0.067 mGy/MBq. The absorbed dose of the salivary glands was 0.015 mGy/MBq. For cohort B ( = 15), CTT1057 PET detected 97 metastatic lesions, and 44 of 56 bone metastases detected on CTT1057 PET (78.5%) were also detectable on bone scanning. Eight of 32 lymph nodes positive on CTT1057 PET (25%) were enlarged by size criteria on CT. CTT1057 is a promising novel phosphoramidate PSMA-targeting F-labeled PET radiopharmaceutical that demonstrates similar biodistribution to urea-based PSMA-targeted agents, with lower exposure to the kidneys and salivary glands. Metastatic lesions are detected with higher sensitivity on CTT1057 imaging than on conventional imaging. Further prospective studies with CTT1057 are warranted to elucidate its role in cancer imaging.
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http://dx.doi.org/10.2967/jnumed.118.220715DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6604687PMC
July 2019

Translation of Carbon-13 EPI for hyperpolarized MR molecular imaging of prostate and brain cancer patients.

Magn Reson Med 2019 04 30;81(4):2702-2709. Epub 2018 Oct 30.

Department of Radiology and Biomedical Imaging, University of California San Francisco, San Francisco, California.

Purpose: To develop and translate a metabolite-specific imaging sequence using a symmetric echo planar readout for clinical hyperpolarized (HP) Carbon-13 ( C) applications.

Methods: Initial data were acquired from patients with prostate cancer (N = 3) and high-grade brain tumors (N = 3) on a 3T scanner. Samples of [1- 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.

Results: High 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.

Conclusion: This study demonstrated the feasibility of symmetric EPI to acquire HP 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.
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http://dx.doi.org/10.1002/mrm.27549DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6372313PMC
April 2019

Dynamic diffusion-weighted hyperpolarized C imaging based on a slice-selective double spin echo sequence for measurements of cellular transport.

Magn Reson Med 2019 03 28;81(3):2001-2010. Epub 2018 Oct 28.

Department of Radiology and Biomedical Imaging, University of California, San Francisco, California.

Purpose: To develop a pulse sequence to dynamically measure the ADC of hyperpolarized substrates during their perfusion, metabolic conversion, and transport.

Methods: We proposed a slice-selective double spin echo sequence for dynamic hyperpolarized C diffusion-weighted imaging. The proposed pulse sequence was optimized for a high field preclinical scanner through theoretical analysis and simulation. The performance of the method was compared to non-slice-selective double spin echo via in vivo studies. We also validated the sequence for dynamic ADC measurement in both phantom studies and transgenic mouse model of prostate cancer studies.

Results: The optimized pulse sequence outperforms the traditional sequence with smaller saturation effects on the magnetization of hyperpolarized compounds that allowed more dynamic imaging frames covering a longer imaging time window. In pre-clinical studies (N = 8), the dynamic hyperpolarized lactate ADC maps of 6 studies in the prostate tumors showed an increase measured ADC over time, which might be related to lactate efflux from the tumor cells.

Conclusions: The proposed sequence was validated and shown to improve dynamic diffusion weighted imaging compared to the traditional double spin echo sequence, providing ADC maps of lactate through time.
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http://dx.doi.org/10.1002/mrm.27501DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6347546PMC
March 2019
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