Eva M. Serrao

Magnetic resonance imaging of tumor glycolysis using hyperpolarized 13C-labeled glucose

In this study, we monitored glycolysis in mouse lymphoma and lung tumors by measuring the conversion of hyperpolarized [U-2H, U-13C]glucose to lactate using 13C magnetic resonance spectroscopy and spectroscopic imaging. We observed labeled lactate only in tumors and not in surrounding normal tissue or other tissues in the body and found that it was markedly decreased at 24 h after treatment with a chemotherapeutic drug. We also detected an increase in a resonance assigned to 6-phosphogluconate in the pentose phosphate pathway. This technique could provide a new way of detecting early evidence of tumor treatment response in the clinic and of monitoring tumor pentose phosphate pathway activity.

Defining the learning curve for multiparametric magnetic resonance imaging (MRI) of the prostate using MRI-transrectal ultrasonography (TRUS) fusion-guided transperineal prostate biopsies as a validation tool

To determine the accuracy of multiparametric magnetic resonance imaging (mpMRI) during the learning curve of radiologists using MRI targeted, transrectal ultrasonography (TRUS) guided transperineal fusion biopsy (MTTP) for validation.

In vivo single-shot 13C spectroscopic imaging of hyperpolarized metabolites by spatiotemporal encoding.

Hyperpolarized metabolic imaging is a growing field that has provided a new tool for analyzing metabolism, particularly in cancer. Given the short life times of the hyperpolarized signal, fast and effective spectroscopic imaging methods compatible with dynamic metabolic characterizations are necessary. Several approaches have been customized for hyperpolarized (13)C MRI, including CSI with a center-out k-space encoding, EPSI, and spectrally selective pulses in combination with spiral EPI acquisitions. Recent studies have described the potential of single-shot alternatives based on spatiotemporal encoding (SPEN) principles, to derive chemical-shift images within a sub-second period. By contrast to EPSI, SPEN does not require oscillating acquisition gradients to deliver chemical-shift information: its signal encodes both spatial as well as chemical shift information, at no extra cost in experimental complexity. SPEN MRI sequences with slice-selection and arbitrary excitation pulses can also be devised, endowing SPEN with the potential to deliver single-shot multi-slice chemical shift images, with a temporal resolution required for hyperpolarized dynamic metabolic imaging. The present work demonstrates this with initial in vivo results obtained from SPEN-based imaging of pyruvate and its metabolic products, after injection of hyperpolarized [1-(13)C]pyruvate. Multi-slice chemical-shift images of healthy rats were obtained at 4.7T in the region of the kidney, and 4D (2D spatial, 1D spectral, 1D temporal) data sets were obtained at 7T from a murine lymphoma tumor model.

Hyperpolarized singlet lifetimes of pyruvate in human blood and in the mouse

Hyperpolarized NMR is a promising technique for non‐invasive imaging of tissue metabolism in vivo. However, the pathways that can be studied are limited by the fast T1 decay of the nuclear spin order. In metabolites containing pairs of coupled nuclear spins‐1/2, the spin order may be maintained by exploiting the non‐magnetic singlet (spin‐0) state of the pair. This may allow preservation of the hyperpolarization in vivo during transport to tissues of interest, such as tumors, or to detect slower metabolic reactions. We show here that in human blood and in a mouse in vivo at millitesla fields the 13C singlet lifetime of [1,2‐13C2]pyruvate was significantly longer than the 13C T1, although it was shorter than the T1 at field strengths of several tesla. We also examine the singlet‐derived NMR spectrum observed for hyperpolarized [1,2‐13C2]lactate, originating from the metabolism of [1,2‐13C2]pyruvate.

Detection of transgene expression using hyperpolarized 13C urea and diffusion-weighted magnetic resonance spectroscopy

To assess the potential of a gene reporter system, based on a urea transporter (UTB) and hyperpolarized [13C]urea.

Carbonic Anhydrase Activity Monitored In Vivo by Hyperpolarized 13C-Magnetic Resonance Spectroscopy Demonstrates Its Importance for pH Regulation in Tumors

Carbonic anhydrase buffers tissue pH by catalyzing the rapid interconversion of carbon dioxide (CO2) and bicarbonate (HCO3 (-)). We assessed the functional activity of CAIX in two colorectal tumor models, expressing different levels of the enzyme, by measuring the rate of exchange of hyperpolarized (13)C label between bicarbonate (H(13)CO3(-)) and carbon dioxide ((13)CO2), following injection of hyperpolarized H(13)CO3(-), using (13)C-magnetic resonance spectroscopy ((13)C-MRS) magnetization transfer measurements. (31)P-MRS measurements of the chemical shift of the pH probe, 3-aminopropylphosphonate, and (13)C-MRS measurements of the H(13)CO3(-)/(13)CO2 peak intensity ratio showed that CAIX overexpression lowered extracellular pH in these tumors. However, the (13)C measurements overestimated pH due to incomplete equilibration of the hyperpolarized (13)C label between the H(13)CO3(-) and (13)CO2 pools. Paradoxically, tumors overexpressing CAIX showed lower enzyme activity using magnetization transfer measurements, which can be explained by the more acidic extracellular pH in these tumors and the decreased activity of the enzyme at low pH. This explanation was confirmed by administration of bicarbonate in the drinking water, which elevated tumor extracellular pH and restored enzyme activity to control levels. These results suggest that CAIX expression is increased in hypoxia to compensate for the decrease in its activity produced by a low extracellular pH and supports the hypothesis that a major function of CAIX is to lower the extracellular pH.

Potential Clinical Roles for Metabolic Imaging with Hyperpolarized [1-13C]Pyruvate

Clinical oncology relies increasingly on biomedical imaging, with anatomical imaging, especially using CT and 1H-MRI, forming the mainstay of patient assessment, from diagnosis to treatment monitoring. However, the need for further improvements in specificity and sensitivity, coupled with imaging techniques that are reaching their limit of clinically attainable spatial resolution, has resulted in the emergence and growing use of imaging techniques with additional functional readouts, such as 18FDG-PET and multiparametric MRI. These techniques add a new dimension to our understanding of the biological behavior of tumors, allowing a more personalized approach to patient management. An important functional imaging target in cancer is metabolism. PET measurements of 18Fluorodeoxyglucose uptake (18FDG-PET), a 18F-labeled glucose analog, and 1H-MRS measurements, have both been used to investigate tumor metabolism for diagnostic purposes. However, clinical applications of MRS have been hampered by low sensitivity and consequently low spatial and temporal resolution (1). Nuclear spin hyperpolarization of 13C-labeled substrates, using dynamic nuclear polarization (DNP), which radically increases the sensitivity of these substrates to detection by 13C MRS (2), has created a renewed interest in MRS measurements of tissue metabolism. Successful translation of this technique to the clinic was achieved recently with measurements of [1-13C]pyruvate metabolism in prostate cancer (3) (see Figure ​Figure1).1). We explore here the potential clinical roles for metabolic imaging with hyperpolarized [1-13C]pyruvate. Figure 1 Imaging prostate cancer with hyperpolarized [1-13C]pyruvate. The T2-weighted image of a patient with biopsy-proven bilateral prostate cancer showed only a unilateral decrease in signal intensity. However, the metabolic image ([1-13C]lactate/[1-13C]pyruvate ...

(13) C magnetic resonance spectroscopic imaging of hyperpolarized [1-(13) C, U-(2) H5 ] ethanol oxidation can be used to assess aldehyde dehydrogenase activity in vivo.

Aldehyde dehydrogenase (ALDH2) is an emerging drug target for the treatment of heart disease, cocaine and alcohol dependence, and conditions caused by genetic polymorphisms in ALDH2. Noninvasive measurement of ALDH2 activity in vivo could inform the development of these drugs and accelerate their translation to the clinic.

Transperineal prostate biopsies for diagnosis of prostate cancer are well tolerated: a prospective study using patient-reported outcome measures.

We aimed to determine short-term patient-reported outcomes in men having general anesthetic transperineal (TP) prostate biopsies. A prospective cohort study was performed in men having a diagnostic TP biopsy. This was done using a validated and adapted questionnaire immediately post-biopsy and at follow-up of between 7 and 14 days across three tertiary referral hospitals with a response rate of 51.6%. Immediately after biopsy 43/201 (21.4%) of men felt light-headed, syncopal, or suffered syncope. Fifty-three percent of men felt discomfort after biopsy (with 95% scoring <5 in a 0-10 scale). Twelve out of 196 men (6.1%) felt pain immediately after the procedure. Despite a high incidence of symptoms (e.g., up to 75% had some hematuria, 47% suffered some pain), it was not a moderate or serious problem for most, apart from hemoejaculate which 31 men suffered. Eleven men needed catheterization (5.5%). There were no inpatient admissions due to complications (hematuria, sepsis). On repeat questioning at a later time point, only 25/199 (12.6%) of men said repeat biopsy would be a significant problem despite a significant and marked reduction in erectile function after the procedure. From this study, we conclude that TP biopsy is well tolerated with similar side effect profiles and attitudes of men to repeat biopsy to men having TRUS biopsies. These data allow informed counseling of men prior to TP biopsy and a benchmark for tolerability with local anesthetic TP biopsies being developed for clinical use.

(13) C magnetic resonance spectroscopy measurements with hyperpolarized [1-(13) C] pyruvate can be used to detect the expression of transgenic pyruvate decarboxylase activity in vivo.

Dissolution dynamic nuclear polarization can increase the sensitivity of the 13C magnetic resonance spectroscopy experiment by at least four orders of magnitude and offers a novel approach to the development of MRI gene reporters based on enzymes that metabolize 13C‐labeled tracers. We describe here a gene reporter based on the enzyme pyruvate decarboxylase (EC 4.1.1.1), which catalyzes the decarboxylation of pyruvate to produce acetaldehyde and carbon dioxide.