Identification of variable stages in murine pancreatic tumors by a multiparametric approach employing hyperpolarized ¹³C MRSI, ¹H diffusivity and ¹H T₁ MRI

Abstract

This study explored the usefulness of multiple quantitative MRI approaches to detect pancreatic ductal adenocarcinomas in two murine models, PAN-02 and KPC. Methods assayed included 1 H T 1 and T 2 measurements, quantitative diffusivity mapping, magnetization transfer (MT) 1 H MRI throughout the abdomen and hyperpolarized 13 C spectroscopic imaging. The progress of the disease was followed as a function of its development; studies were also conducted for wildtype control mice and for mice with induced mild acute pancreatitis. Customized methods developed for scanning the motion-and artifact-prone mice abdomens allowed us to obtain quality 1 H images for these targeted regions. Contrasts between tumors and surrounding tissues, however, were significantly different. Anatomical images, T 2 maps and MT did not yield significant contrast unless tumors were large. By contrast, tumors showed statistically lower diffusivities than their surroundings (≈8.3 ± 0.4 x 10 −4 for PAN-02 and ≈10.2 ± 0.6 x 10 −4 for KPC vs 13 ± 1 x 10 −3 mm 2 s −1 for surroundings), longer T 1 relaxation times (≈1.44 ± 0.05 for PAN-02 and ≈1.45 ± 0.05 for KPC vs 0.95 ± 0.10 seconds for surroundings) and significantly higher lactate/ pyruvate ratios by hyperpolarized 13 C MR (0.53 ± 0.2 for PAN-02 and 0.78 ± 0.2 for KPC vs 0.11 ± 0.04 for control and 0.31 ± 0.04 for pancreatitis-bearing mice). Although the latter could also distinguish early-stage tumors from healthy animal controls, their response was similar to that in our pancreatitis model. Still, this ambiguity could be lifted using the 1 H-based reporters. If confirmed for other kinds of pancreatic tumors this means that these approaches, combined, can provide a route to an early detection of pancreatic cancer.

Deuterium MRSI characterizations of glucose metabolism in orthotopic pancreatic cancer mouse models

“…Another size‐related consideration worth mentioning relates to the fact that in only two instances did DMI successfully detect substantial lactate, when tumors were smaller than ~ 5 mm in diameter. This is in contrast to what was observed in previous hyperpolarized 13 C MRSI research, 22 which although limited by the timescales that it could probe to ~ 1 min, appeared to have a higher ability to reveal PDAC masses at earlier stages. It remains to be seen if improvements in DMI methodology can deal with this early detection question.…”

“…The DMI experiments presented here succeeded equally well in highlighting the presence of the tumors in both models, by the generation of deuterated lactate. This is reminiscent of results observed using hyperpolarized 13 C MRSI, 22 where once again only minor differences between these two tumor models could be detected.…”

“…1 H‐based MRI methods should excel in characterizing soft glands such as the pancreas, yet tumors show little contrast in it when weighted by their natural T 1 , T 2 relaxation times, or even when relying on Gd‐based contrast agents, which show limited extravasation 6–8 . The main MR‐based procedure for the diagnosis of PDAC remains magnetic resonance cholangiopancreatography 7 ; also, diffusivity has led to promising data that can be used to highlight tumors in vivo 8–12 . Overall, imaging contrast for this kind of tumor is hard to achieve, and when available it is hard to discern from cysts and inflammations.…”

“…The introduction of dissolution dynamic nuclear polarization (dDNP) MRI has opened a window to do so, primarily by detecting pyruvate's enhanced metabolic conversion into lactate in tumors 13–17 . A range of animal and human dDNP studies showed evidence that indeed lactate can be used as a reporter for PDAC 18–22 . One of the main drawbacks of metabolic imaging by 13 C dDNP stems from the method's stringent imaging time demands, limited by the metabolite's T 1 , and the ensuing loss of 13 C hyperpolarization.…”

Deuterium imaging of the Warburg effect at sub‐millimolar concentrations by joint processing of the kinetic and spectral dimensions

“…Both approaches improved substantially DMI's sensitivity, remained truthful to both the spectral and kinetic information, and endowed the IDEAL processing with extra robustness. The second of the routes explored focused on denoising the 2 H spatial images arising from the IDEAL‐based processing of ME‐bSSFP data, with a number of methods described in the literature 5,28–32 . Finally, the combination of image denoising and spectral/kinetic‐constrained methodologies into a single processing pipeline was tested, leading to a ≥8x overall SNR improvement over the original IDEAL‐based processing of ME‐bSSFP data, at no evident cost.…”