A Simulation of the Effects of Diffusion on Hyperpolarized [1-13C]-Pyruvate Signal Evolution.

OBJECTIVE: Hyperpolarized [1-13C]-pyruvate magnetic resonance imaging is an emerging metabolic imaging method that offers unprecedented spatiotemporal resolution for monitoring tumor metabolism in vivo. To establish robust imaging biomarkers of metabolism, we must characterize phenomena that may modulate the apparent pyruvate-to-lactate conversion rate (kPL). Here, we investigate the potential effect of diffusion on pyruvate-to-lactate conversion, as failure to account for diffusion in pharmacokinetic analysis may obscure true intracellular chemical conversion rates. METHODS: Changes in hyperpolarized pyruvate and lactate signal were calculated using a finite-difference time domain simulation of a two-dimensional tissue model. Signal evolution curves with intracellular kPL values from 0.02 to 1.00 s-1 were analyzed using spatially invariant one-compartment and two-compartment pharmacokinetic models. A second spatially variant simulation incorporating compartmental instantaneous mixing was fit with the same one-compartment model. RESULTS: When fitting with the one-compartment model, apparent kPL underestimated intracellular kPL by approximately 50% at an intracellular kPL of 0.02 s-1. This underestimation increased for larger kPL values. However, fitting the instantaneous mixing curves showed that diffusion accounted for only a small part of this underestimation. Fitting with the two-compartment model yielded more accurate intracellular kPL values. SIGNIFICANCE: This work suggests diffusion is not a significant rate-limiting factor in pyruvate-to-lactate conversion given that our model assumptions hold true. In higher order models, diffusion effects may be accounted for by a term characterizing metabolite transport. Pharmacokinetic models used to analyze hyperpolarized pyruvate signal evolution should focus on carefully selecting the analytical model for fitting rather than accounting for diffusion effects.

Model-constrained reconstruction accelerated with Fourier-based undersampling for hyperpolarized [1-13 C] pyruvate imaging.

PURPOSE: Model-constrained reconstruction with Fourier-based undersampling (MoReFUn) is introduced to accelerate the acquisition of dynamic MRI using hyperpolarized [1-13 C]-pyruvate. METHODS: The MoReFUn method resolves spatial aliasing using constraints introduced by a pharmacokinetic model that describes the signal evolution of both pyruvate and lactate. Acceleration was evaluated on three single-channel data sets: a numerical digital phantom that is used to validate the accuracy of reconstruction and model parameter restoration under various SNR and undersampling ratios, prospectively and retrospectively sampled data of an in vitro dynamic multispectral phantom, and retrospectively undersampled imaging data from a prostate cancer patient to test the fidelity of reconstructed metabolite time series. RESULTS: All three data sets showed successful reconstruction using MoReFUn. In simulation and retrospective phantom data, the restored time series of pyruvate and lactate maintained the image details, and the mean square residual error of the accelerated reconstruction increased only slightly (< 10%) at a reduction factor up to 8. In prostate data, the quantitative estimation of the conversion-rate constant of pyruvate to lactate was achieved with high accuracy of less than 10% error at a reduction factor of 2 compared with the conversion rate derived from unaccelerated data. CONCLUSION: The MoReFUn technique can be used as an effective and reliable imaging acceleration method for metabolic imaging using hyperpolarized [1-13 C]-pyruvate.

Projection-based stereolithography for direct 3D printing of heterogeneous ultrasound phantoms.

Modern ultrasound (US) imaging is increasing its clinical impact, particularly with the introduction of US-based quantitative imaging biomarkers. Continued development and validation of such novel imaging approaches requires imaging phantoms that recapitulate the underlying anatomy and pathology of interest. However, current US phantom designs are generally too simplistic to emulate the structure and variability of the human body. Therefore, there is a need to create a platform that is capable of generating well-characterized phantoms that can mimic the basic anatomical, functional, and mechanical properties of native tissues and pathologies. Using a 3D-printing technique based on stereolithography, we fabricated US phantoms using soft materials in a single fabrication session, without the need for material casting or back-filling. With this technique, we induced variable levels of stable US backscatter in our printed materials in anatomically relevant 3D patterns. Additionally, we controlled phantom stiffness from 7 to >120 kPa at the voxel level to generate isotropic and anisotropic phantoms for elasticity imaging. Lastly, we demonstrated the fabrication of channels with diameters as small as 60 micrometers and with complex geometry (e.g., tortuosity) capable of supporting blood-mimicking fluid flow. Collectively, these results show that projection-based stereolithography allows for customizable fabrication of complex US phantoms.

The effect of transmit B1 inhomogeneity on hyperpolarized [1-13 C]-pyruvate metabolic MR imaging biomarkers.

PURPOSE: A specialized Helmholtz-style 13 C volume transmit "clamshell" coil is currently being utilized for 13 C excitation in pre-clinical and clinical hyperpolarized 13 C MRI studies aimed at probing the metabolic activity of tumors in various target anatomy. Due to the widespread use of this 13 C clamshell coil design, it is important that the effects of the 13 C clamshell coil B1 + profile on HP signal evolution and quantification are well understood. The goal of this study was to characterize the B1 + field of the 13 C clamshell coil and assess the impact of inhomogeneities on semi-quantitative and quantitative hyperpolarized MR imaging biomarkers of metabolism. METHODS: The B1 + field of the 13 C clamshell coil was mapped by hand using a network analyzer equipped with an S-parameter test set. Pharmacokinetic models were used to simulate signal evolution as a function of position-dependent local excitation angles, for various nominal excitation angles, which were assumed to be accurately calibrated at the isocenter. These signals were then quantified according to the normalized lactate ratio (nLac) and the apparent rate constant for the conversion of pyruvate to lactate (kPL ). The percent difference between these metabolic imaging biomarker maps and the reference value observed at the isocenter of the clamshell coil was calculated to estimate the potential for error due to position within the clamshell coil. Finally, regions were identified within the clamshell coil where deviations in B1 + field inhomogeneity or imaging biomarker errors imparted by the B1 + field were within ±10% of the value at the isocenter. RESULTS: The B1 + field maps show that a limited volume encompassed by a region measuring approximately 12.9 × 11.5 × 13.4 cm (X-direction, Y-direction, Z-direction) centered in the 13 C clamshell coil will produce deviations in the B1 + field within ±10% of that at the isocenter. For the metabolic imaging biomarkers that we evaluated, the case when the pyruvate excitation angle (θP ) and lactate excitation angle (θL ) were equal to 10° produced the largest volumetric region with deviations within ±10% of the value at the isocenter. Higher excitation angles yielded higher signal and SNR, but the size of the region in which uniform measurements could be collected near the isocenter of the coil was reduced at higher excitation angles. The tradeoff between the size of the homogenous region at the isocenter and signal intensity must be weighed carefully depending on the particular imaging application. CONCLUSION: This work identifies regions and optimal excitation angles (θP and θL ) within the 13 C clamshell coil where deviations in B1 + field inhomogeneity or imaging biomarker errors imparted by the B1 + field were within ±10% of the respective value at the isocenter, and thus where excitation angles are reproducible and well-calibrated. Semi-quantitative and quantitative metabolic imaging biomarkers can vary with position in the clamshell coil as a result of B1 + field inhomogeneity, necessitating care in patient positioning and the selection of an excitation angle set that balances reproducibility and SNR performance over the target imaging volume.

Development of a rational strategy for integration of lactate dehydrogenase A suppression into therapeutic algorithms for head and neck cancer.

BACKGROUND: Lactate dehydrogenase (LDH) is a critical metabolic enzyme. LDH A (LDHA) overexpression is a hallmark of aggressive malignancies and has been linked to tumour initiation, reprogramming and progression in multiple tumour types. However, successful LDHA inhibition strategies have not materialised in the translational and clinical space. We sought to develop a rational strategy for LDHA suppression in the context of solid tumour treatment. METHODS: We utilised a doxycycline-inducible short hairpin RNA (shRNA) system to generate LDHA suppression. Lactate and LDH activity levels were measured biochemically and kinetically using hyperpolarised 13C-pyruvate nuclear magnetic resonance spectroscopy. We evaluated effects of LDHA suppression on cellular proliferation and clonogenic survival, as well as on tumour growth, in orthotopic models of anaplastic thyroid carcinoma (ATC) and head and neck squamous cell carcinoma (HNSCC), alone or in combination with radiation. RESULTS: shRNA suppression of LDHA generated a time-dependent decrease in LDH activity with transient shifts in intracellular lactate levels, a decrease in carbon flux from pyruvate into lactate and compensatory shifts in metabolic flux in glycolysis and the Krebs cycle. LDHA suppression decreased cellular proliferation and temporarily stunted tumour growth in ATC and HNSCC xenografts but did not by itself result in tumour cure, owing to the maintenance of residual viable cells. Only when chronic LDHA suppression was combined with radiation was a functional cure achieved. CONCLUSIONS: Successful targeting of LDHA requires exquisite dose and temporal control without significant concomitant off-target toxicity. Combinatorial strategies with conventional radiation are feasible as long as the suppression is targeted, prolonged and non-toxic.

Technical Note: A deuterated 13 C-urea reference for clinical multiparametric MRI prostate cancer studies including hyperpolarized pyruvate.

PURPOSE: Metabolic magnetic resonance imaging (MRI) using hyperpolarized [1-13 C]-pyruvate offers unprecedented new insight into disease and response to therapy. 13 C-enriched reference standards are required to enable fast and accurate calibration for 13 C studies, but care must be taken to ensure that the reference is compatible with both 13 C and 1 H acquisitions. The goal of this study was to optimize the composition of a 13 C-urea reference for a dual-tuned 13 C/1 H endorectal coil and minimize imaging artifacts in metabolic and multiparametric MRI studies involving hyperpolarized [1-13 C]-pyruvate. METHODS: Due to a high amount of Gd doping for the purpose of reducing the spin-lattice relaxation time (T1 ) of urea, the 1 H signal produced by a reference of 13 C-urea in normal water was rapidly relaxed, resulting in severe artifacts in heavily T1 -weighted images. Hyperintense ringing artifacts in 1 H images were mitigated by reducing the 1 H concentration in a 13 C-urea reference via deuteration and lyophilization. Several references were fabricated and their SNR was compared using 1 H and 13 C imaging sequences on a 3T MRI scanner. Finally, 1 H prostate phantom imaging was conducted to compare image quality and 1 H signal intensity of normal and deuterated urea references. RESULTS: The deuterated 13 C-urea reference provides strong 13 C signal for calibration and an attenuated 1 H signal that does not interfere with heavily T1 -weighted scans. Deuteration and lyophilization were fundamental to the reduction in 1 H signal and hyperintense ringing artifacts. There was a 25-fold reduction in signal intensity when comparing the nondeuterated reference to the deuterated reference, while the 13 C signal was unaffected. CONCLUSION: A deuterated reference reduced hyperintense ringing artifacts in 1 H images by reducing the 1 H signal produced from the 13 C-urea in the reference. The deuterated reference can be used to improve anatomical image quality in future clinical 1 H and hyperpolarized [1-13 C]-pyruvate MRI prostate imaging studies.