Lucas Carvajal

Metabolic imaging of patients with prostate cancer using hyperpolarized [1-¹³C]pyruvate.

Metabolic imaging with hyperpolarized pyruvate was used to safely and noninvasively visualize prostate tumors in patients. The Hyperpolarized Prostate Cancer cells have a different metabolism than healthy cells. Specifically, they consume more pyruvate—a key component in glycolysis—than their normal counterparts. Nelson and colleagues therefore used a hyperpolarized form of pyruvate ([1-13C]pyruvate) to sensitively image increased levels of its product, [1-13C]lactate, as well as the flux of pyruvate to lactate. The [1-13C]pyruvate agent was used here in a first-in-human study in men with prostate cancer. Patients received varying doses of [1-13C]pyruvate that were found to be safe. These patients were then rapidly imaged with hyperpolarized 13C magnetic resonance (MR), which was able to provide dynamic (time course) information as well as three-dimensional (3D) (spatial) data at a single time point. Tumors were detected in all patients with biopsy-proven cancer. And, importantly, with 13C MR imaging (MRI), Nelson et al. were able to see cancer in regions of the prostate that were previously considered to be tumor-free upon inspection with other conventional anatomic imaging methods. With the ability to safely image tumor location and also follow tumor metabolism over time, hyperpolarized 13C MRI may be useful both for initial diagnosis and for monitoring therapy. Although the patients in this study had early-stage disease, the authors believe that [1-13C]lactate/[1-13C]pyruvate flux will only increase with tumor grade, making this imaging technology amenable to more advanced and aggressive cancers. Future studies will focus on optimizing agent preparation and delivery to ensure that this imaging technology can benefit patients in all clinical settings. This first-in-man imaging study evaluated the safety and feasibility of hyperpolarized [1-13C]pyruvate as an agent for noninvasively characterizing alterations in tumor metabolism for patients with prostate cancer. Imaging living systems with hyperpolarized agents can result in more than 10,000-fold enhancement in signal relative to conventional magnetic resonance (MR) imaging. When combined with the rapid acquisition of in vivo 13C MR data, it is possible to evaluate the distribution of agents such as [1-13C]pyruvate and its metabolic products lactate, alanine, and bicarbonate in a matter of seconds. Preclinical studies in cancer models have detected elevated levels of hyperpolarized [1-13C]lactate in tumor, with the ratio of [1-13C]lactate/[1-13C]pyruvate being increased in high-grade tumors and decreased after successful treatment. Translation of this technology into humans was achieved by modifying the instrument that generates the hyperpolarized agent, constructing specialized radio frequency coils to detect 13C nuclei, and developing new pulse sequences to efficiently capture the signal. The study population comprised patients with biopsy-proven prostate cancer, with 31 subjects being injected with hyperpolarized [1-13C]pyruvate. The median time to deliver the agent was 66 s, and uptake was observed about 20 s after injection. No dose-limiting toxicities were observed, and the highest dose (0.43 ml/kg of 230 mM agent) gave the best signal-to-noise ratio for hyperpolarized [1-13C]pyruvate. The results were extremely promising in not only confirming the safety of the agent but also showing elevated [1-13C]lactate/[1-13C]pyruvate in regions of biopsy-proven cancer. These findings will be valuable for noninvasive cancer diagnosis and treatment monitoring in future clinical trials.

Quantitative In Vivo Magnetic Resonance Imaging of Multiple Sclerosis at 7 Tesla with Sensitivity to Iron

Magnetic resonance imaging at 7 Tesla produces high‐resolution gradient‐echo phase images of patients with multiple sclerosis (MS) that quantify the local field shifts from iron in the basal ganglia and lesions. Phase imaging is easily integrated into clinical examinations because it is a postprocessing technique and does not require additional scanning. The purpose of this study was to quantify local field shifts in MS and to investigate their relation to disease duration and disability status.

High-resolution phased-array MRI of the human brain at 7 tesla: initial experience in multiple sclerosis patients.

Recent advancement for magnetic resonance imaging (MRI) involves the incorporation of higher‐field strengths. Although imagers with higher magnetic field strengths were developed and tested in research labs, the direct application to patient MR studies have been extremely limited. Imaging at 7 Tesla (7T) affords advantages in signal‐to‐noise ratio and image contrast and resolution; however, these benefits can only be realized if the correct coils exist to capture the images. The objective of this study was to develop optimized high‐resolution 7T MRI techniques using high sensitivity, specialized phased‐array coils, for improved gray matter (GM) and white matter differentiation, in an effort to improve visualization of multiple sclerosis (MS) lesions in vivo. Twenty‐three subjects were enrolled in this preliminary study, 17 with clinically definite MS (11 females, 6 males; mean age 43.4 years; range 22‐64 years) and 6 healthy controls (2 females, 4 males; mean age 39.0 years; range 27‐67 years). MR imaging of MS patients at 7T was demonstrated to be safe, well tolerated, and provided high‐resolution anatomical images allowing visualization of structural abnormalities localized near or within the cortical layers. Clear involvement of the GM was observed with improved morphological detail in comparison to imaging at lower‐field strength.

In vivo bone and cartilage MRI using fully-balanced steady-state free-precession at 7 tesla

The purpose of this work was to investigated the feasibility of fully‐balanced steady‐state free‐precession (bSSFP) pulse sequence for trabecular bone and knee cartilage imaging in vivo using ultra‐high‐field (UHF) MRI at 7T in comparison with pulse sequences previously used at 3T. We showed that bSSFP and spin‐echo imaging is possible at higher field strengths within 3.2 W/kg specific absorption rate (SAR) constraints. All pulse sequences were numerically optimized based on measured tissue relaxation parameters from six healthy volunteers (T1 = 820 ± 128 ms, T2 = 43.5 ± 3 ms for bone marrow and T1 = 1745 ± 104 ms and T2 = 30 ± 4 ms for cartilage). From simulations of the Bloch equation, a signal‐to‐noise ratio (SNR) increase of more than 1.9 was predicted. Cartilage SNR of bSSFP was 2.4 times higher at 7T (51.3 ± 4.3) compared with 3T (21.3 ± 3.3). Bone SNR increased from 11.8 ± 2.0 to 13.2 ± 2.5 at the higher field strength. We concluded that there is SNR benefit and great potential for bone and cartilage imaging at higher field strength. Magn Reson Med, 2007.

Challenges in dynamic contrast‐enhanced MRI imaging of cervical lymph nodes to detect metastatic disease

To identify and overcome challenges in using dynamic contrast‐enhanced magnetic resonance imaging (MRI) to distinguish tumor from nontumor in the cervical lymph nodes of patients with squamous cell carcinoma of the head and neck.

In vivo hyperpolarized 13C MR spectroscopic imaging with 1H decoupling

Application of (13)C MRS in vivo on whole body MR system has been limited due to the low static field (and consequent low signal to noise ratio-SNR) of these scanners; thus there have been few reports of (1)H decoupled (13)C MRS in vivo using a clinical MR platform. The recent development of techniques to retain highly polarized spins in solution following DNP in a solid matrix has provided a mechanism to use endogenous pre-polarized (13)C labeled substrates to study real time cellular metabolism in vivo with high SNR. In a recent in vivo hyperpolarized metabolic imaging study using (13)C pyruvate, it has been demonstrated that the line shape (signal decay) of the resonances observed are greatly affected by J(CH) coupling in addition to inhomogeneous broadening. This study demonstrates the feasibility of improving hyperpolarized (13)C metabolic imaging in vivo by incorporating (1)H decoupling on a clinical whole body 3T MR scanner. No reduction of T1 of a pre-polarized (13)C substrate ([1-(13)C] lactate) in solution was observed when (1)H decoupling was applied with WALTZ16 sequence. Narrower linewidth for the [1-(13)C] lactate resonance was observed in hyperpolarized (13)C MRSI data in vivo with (1)H decoupling.

Dynamic Hyperpolarized Carbon-13 MR Metabolic Imaging of Nonhuman Primate Brain

To investigate hyperpolarized 13C metabolic imaging methods in the primate brain that can be translated into future clinical trials for patients with brain cancer.

Combined parallel and partial fourier MR reconstruction for accelerated 8-channel hyperpolarized carbon-13 in vivo magnetic resonance Spectroscopic imaging (MRSI).

To implement and evaluate combined parallel magnetic resonance imaging (MRI) and partial Fourier acquisition and reconstruction for rapid hyperpolarized carbon‐13 (13C) spectroscopic imaging. Short acquisition times mitigate hyperpolarized signal losses that occur due to T1 decay, metabolism, and radiofrequency (RF) saturation. Human applications additionally require rapid imaging to permit breath‐holding and to minimize the effects of physiologic motion.

Handheld electromagnet carrier for transfer of hyperpolarized carbon-13 samples.

Hyperpolarization of carbon‐13 (13C) nuclei by dissolution dynamic nuclear polarization increases signal‐to‐noise ratio (SNR) by >10,000‐fold for metabolic imaging, but care must be taken when transferring hyperpolarized (HP) samples from polarizer to MR scanner. Some 13C substrates relax rapidly in low ambient magnetic fields. A handheld electromagnet carrier was designed and constructed to preserve polarization by maintaining a sufficient field during sample transfer.

Development of methods and feasibility of using hyperpolarized carbon-13 imaging data for evaluating brain metabolism in patient studies.

Hyperpolarized carbon‐13 (13C) metabolic imaging is a noninvasive imaging modality for evaluating real‐time metabolism. The purpose of this study was to develop and implement experimental strategies for using [1‐13C]pyruvate to probe in vivo metabolism for patients with brain tumors and other neurological diseases.