Hyperpolarized Water for Coronary Artery Angiography and Whole-Heart Myocardial Perfusion Quantification.

Purpose: Water freely diffuses across cell membranes, making it suitable for measuring absolute tissue perfusion. In this study, we introduce an imaging method for conducting coronary artery angiography and quantifying myocardial perfusion across the entire heart using hyperpolarized water. Methods:1H was hyperpolarized using dissolution dynamic nuclear polarization (dDNP) with UV-generated radicals. Submillimeter resolution coronary artery images were acquired as 2D projections using a spoiled GRE (SPGRE) sequence gated on diastole. Dynamic perfusion images were obtained with a multi-slice SPGRE with diastole gating, covering the entire heart. Perfusion values were analyzed through histograms, and the most frequent estimated perfusion value (the mode of the distribution), was compared with the average values for 15O water PET from the literature. Results: A liquid state polarization of 10% at the time of the injection and a 30 s T1 in D2O TRIS buffer were measured. Both coronary artery and dynamic perfusion images exhibited good quality. The main and small coronary artery branches were well resolved. The most frequent estimated perfusion value is around 0.6 mL/g/min, which is lower than the average values obtained from the literature for 15O-water PET (around 1.1 and 1.5 mL/g/min). Conclusions: The study successfully demonstrated the feasibility of achieving high-resolution, motion-free coronary artery angiography and 3D whole-heart quantitative myocardial perfusion using hyperpolarized water.

Hyperpolarized 13C and 31P MRS detects differences in cardiac energetics, metabolism, and function in obesity, and responses following treatment.

Obesity is associated with important changes in cardiac energetics and function, and an increased risk of adverse cardiovascular outcomes. Multi-nuclear MRS and MRI techniques have the potential to provide a comprehensive non-invasive assessment of cardiac metabolic perturbation in obesity. A rat model of obesity was created by high-fat diet feeding. This model was characterized using in vivo hyperpolarized [1-13C]pyruvate and [2-13C]pyruvate MRS, echocardiography and perfused heart 31P MRS. Two groups of obese rats were subsequently treated with either caloric restriction or the glucagon-like peptide-1 analogue/agonist liraglutide, prior to reassessment. The model recapitulated cardiovascular consequences of human obesity, including mild left ventricular hypertrophy, and diastolic, but not systolic, dysfunction. Hyperpolarized 13C and 31P MRS demonstrated that obesity was associated with reduced myocardial pyruvate dehydrogenase flux, altered cardiac tricarboxylic acid (TCA) cycle metabolism, and impaired myocardial energetic status (lower phosphocreatine to adenosine triphosphate ratio and impaired cardiac ΔG~ATP). Both caloric restriction and liraglutide treatment were associated with normalization of metabolic changes, alongside improvement in cardiac diastolic function. In this model of obesity, hyperpolarized 13C and 31P MRS demonstrated abnormalities in cardiac metabolism at multiple levels, including myocardial substrate selection, TCA cycle, and high-energy phosphorus metabolism. Metabolic changes were linked with impairment of diastolic function and were reversed in concert following either caloric restriction or liraglutide treatment. With hyperpolarized 13C and 31P techniques now available for human use, the findings support a role for multi-nuclear MRS in the development of new therapies for obesity.

In vivo Metabolic Sensing of Hyperpolarized [1-13C]Pyruvate in Mice Using a Recyclable Perfluorinated Iridium Signal Amplification by Reversible Exchange Catalyst.

Real-time visualization of metabolic processes in vivo provides crucial insights into conditions like cancer and metabolic disorders. Metabolic magnetic resonance imaging (MRI), by amplifying the signal of pyruvate molecules through hyperpolarization, enables non-invasive monitoring of metabolic fluxes, aiding in understanding disease progression and treatment response. Signal Amplification By Reversible Exchange (SABRE) presents a simpler, cost-effective alternative to dissolution dynamic nuclear polarization, eliminating the need for expensive equipment and complex procedures. We present the first in vivo demonstration of metabolic sensing in a human pancreatic cancer xenograft model compared to healthy mice. A novel perfluorinated Iridium SABRE catalyst in a fluorinated solvent and methanol blend facilitated this breakthrough with a 1.2-fold increase in [1-13C]pyruvate SABRE hyperpolarization. The perfluorinated moiety allowed easy separation of the heavy-metal-containing catalyst from the hyperpolarized [1-13C]pyruvate target. The perfluorinated catalyst exhibited recyclability, maintaining SABRE-SHEATH activity through subsequent hyperpolarization cycles with minimal activity loss after the initial two cycles. Remarkably, the catalyst retained activity for at least 10 cycles, with a 3.3-fold decrease in hyperpolarization potency. This proof-of-concept study encourages wider adoption of SABRE hyperpolarized [1-13C]pyruvate MR for studying in vivo metabolism, aiding in diagnosing stages and monitoring treatment responses in cancer and other diseases.

Moving from conventional to adaptive risk stratification for oropharyngeal cancer.

Oropharyngeal cancer (OPC) poses a complex therapeutic dilemma for patients and oncologists alike, made worse by the epidemic increase in new cases associated with the oncogenic human papillomavirus (HPV). In a counterintuitive manner, the very thing which gives patients hope, the high response rate of HPV-associated OPC to conventional chemo-radiation strategies, has become one of the biggest challenges for the field as a whole. It has now become clear that for ~30-40% of patients, treatment intensity could be reduced without losing therapeutic efficacy, yet substantially diminishing the acute and lifelong morbidity resulting from conventional chemotherapy and radiation. At the same time, conventional approaches to de-escalation at a population (selected or unselected) level are hampered by a simple fact: we lack patient-specific information from individual tumors that can predict responsiveness. This results in a problematic tradeoff between the deleterious impact of de-escalation on patients with aggressive, treatment-refractory disease and the beneficial reduction in treatment-related morbidity for patients with treatment-responsive disease. True precision oncology approaches require a constant, iterative interrogation of solid tumors prior to and especially during cancer treatment in order to tailor treatment intensity to tumor biology. Whereas this approach can be deployed in hematologic diseases with some success, our ability to extend it to solid cancers with regional metastasis has been extremely limited in the curative intent setting. New developments in metabolic imaging and quantitative interrogation of circulating DNA, tumor exosomes and whole circulating tumor cells, however, provide renewed opportunities to adapt and individualize even conventional chemo-radiation strategies to diseases with highly variable biology such as OPC. In this review, we discuss opportunities to deploy developing technologies in the context of institutional and cooperative group clinical trials over the coming decade.

Current methods for hyperpolarized [1-13C]pyruvate MRI human studies.

MRI with hyperpolarized (HP) 13C agents, also known as HP 13C MRI, can measure processes such as localized metabolism that is altered in numerous cancers, liver, heart, kidney diseases, and more. It has been translated into human studies during the past 10 years, with recent rapid growth in studies largely based on increasing availability of HP agent preparation methods suitable for use in humans. This paper aims to capture the current successful practices for HP MRI human studies with [1-13C]pyruvate-by far the most commonly used agent, which sits at a key metabolic junction in glycolysis. The paper is divided into four major topic areas: (1) HP 13C-pyruvate preparation; (2) MRI system setup and calibrations; (3) data acquisition and image reconstruction; and (4) data analysis and quantification. In each area, we identified the key components for a successful study, summarized both published studies and current practices, and discuss evidence gaps, strengths, and limitations. This paper is the output of the "HP 13C MRI Consensus Group" as well as the ISMRM Hyperpolarized Media MR and Hyperpolarized Methods and Equipment study groups. It further aims to provide a comprehensive reference for future consensus, building as the field continues to advance human studies with this metabolic imaging modality.

Hyperpolarized Xenon-129 Chemical Exchange Saturation Transfer (HyperCEST) Molecular Imaging: Achievements and Future Challenges.

Molecular magnetic resonance imaging (MRI) is an emerging field that is set to revolutionize our perspective of disease diagnosis, treatment efficacy monitoring, and precision medicine in full concordance with personalized medicine. A wide range of hyperpolarized (HP) 129Xe biosensors have been recently developed, demonstrating their potential applications in molecular settings, and achieving notable success within in vitro studies. The favorable nuclear magnetic resonance properties of 129Xe, coupled with its non-toxic nature, high solubility in biological tissues, and capacity to dissolve in blood and diffuse across membranes, highlight its superior role for applications in molecular MRI settings. The incorporation of reporters that combine signal enhancement from both hyperpolarized 129Xe and chemical exchange saturation transfer holds the potential to address the primary limitation of low sensitivity observed in conventional MRI. This review provides a summary of the various applications of HP 129Xe biosensors developed over the last decade, specifically highlighting their use in MRI. Moreover, this paper addresses the evolution of in vivo applications of HP 129Xe, discussing its potential transition into clinical settings.

Hyperpolarized 13C magnetic resonance imaging in neonatal hypoxic-ischemic encephalopathy: First investigations in a large animal model.

Early biomarkers of cerebral damage are essential for accurate prognosis, timely intervention, and evaluation of new treatment modalities in newborn infants with hypoxia and ischemia at birth. Hyperpolarized 13C magnetic resonance imaging (MRI) is a novel method with which to quantify metabolism in vivo with unprecedented sensitivity. We aimed to investigate the applicability of hyperpolarized 13C MRI in a newborn piglet model and whether this method may identify early changes in cerebral metabolism after a standardized hypoxic-ischemic (HI) insult. Six piglets were anesthetized and subjected to a standardized HI insult. Imaging was performed prior to and 2 h after the insult on a 3-T MR scanner. For 13C studies, [1-13C]pyruvate was hyperpolarized in a commercial polarizer. Following intravenous injection, images were acquired using metabolic-specific imaging. HI resulted in a metabolic shift with a decrease in pyruvate to bicarbonate metabolism and an increase in pyruvate to lactate metabolism (lactate/bicarbonate ratio, mean [SD]; 2.28 [0.36] vs. 3.96 [0.91]). This is the first study to show that hyperpolarized 13C MRI can be used in newborn piglets and applied to evaluate early changes in cerebral metabolism after an HI insult.

Distinguishing metabolic signals of liver tumors from surrounding liver cells using hyperpolarized 13 C MRI and gadoxetate.

PURPOSE: To use the hepatocyte-specific gadolinium-based contrast agent gadoxetate combined with hyperpolarized (HP) [1-13 C]pyruvate MRI to selectively suppress metabolic signals from normal hepatocytes while preserving the signals arising from tumors. METHODS: Simulations were performed to determine the expected changes in HP 13 C MR signal in liver and tumor under the influence of gadoxetate. CC531 colon cancer cells were implanted into the livers of five Wag/Rij rats. Liver and tumor metabolism were imaged at 3 T using HP [1-13 C] pyruvate chemical shift imaging before and 15 min after injection of gadoxetate. Area under the curve for pyruvate and lactate were measured from voxels containing at least 75% of normal-appearing liver or tumor. RESULTS: Numerical simulations predicted a 36% decrease in lactate-to-pyruvate (L/P) ratio in liver and 16% decrease in tumor. In vivo, baseline L/P ratio was 0.44 ± 0.25 in tumors versus 0.21 ± 0.08 in liver (p = 0.09). Following administration of gadoxetate, mean L/P ratio decreased by an average of 0.11 ± 0.06 (p < 0.01) in normal-appearing liver. In tumors, mean L/P ratio post-gadoxetate did not show a statistically significant change from baseline. Compared to baseline levels, the relative decrease in L/P ratio was significantly greater in liver than in tumors (-0.52 ± 0.16 vs. -0.19 ± 0.25, p < 0.05). CONCLUSIONS: The intracellular hepatobiliary contrast agent showed a greater effect suppressing HP 13 C MRI metabolic signals (through T1 shortening) in normal-appearing liver when compared to tumors. The combined use of HP MRI with selective gadolinium contrast agents may allow more selective imaging in HP 13 C MRI.

Inductively coupled, transmit-receive coils for proton MRI and X-nucleus MRI/MRS in small animals.

We report several inductively coupled RF coil designs that are very easy to construct, produce high signal-to-noise ratio (SNR) and high spatial resolution while accommodating life support, anesthesia and monitoring in small animals. Inductively coupled surface coils were designed for hyperpolarized 13 C MR spectroscopic imaging (MRSI) of mouse brain, with emphases on the simplicity of the circuit design, ease of use, whole-brain coverage, and high SNR. The simplest form was a resonant loop designed to crown the mouse head for a snug fit to achieve full coverage of the brain with high sensitivity when inductively coupled to a broadband pick-up coil. Here, we demonstrated the coil's performance in hyperpolarized 13 C MRSI of a normal mouse and a glioblastoma mouse model at 4.7 T. High SNR exceeding 70:1 was obtained in the brain with good spatial resolution (1.53 mm × 1.53 mm). Similar inductively coupled loop for other X-nuclei can be made very easily in a few minutes and achieve high performance, as demonstrated in 31 P spectroscopy. Similar design concept was expanded to splitable, inductively coupled volume coils for high-resolution proton MRI of marmoset at 3T and 9.4T, to easily accommodate head restraint, vital-sign monitoring, and anesthesia delivery.

Current Methods for Hyperpolarized [1-13C]pyruvate MRI Human Studies.

MRI with hyperpolarized (HP) 13C agents, also known as HP 13C MRI, can measure processes such as localized metabolism that is altered in numerous cancers, liver, heart, kidney diseases, and more. It has been translated into human studies during the past 10 years, with recent rapid growth in studies largely based on increasing availability of hyperpolarized agent preparation methods suitable for use in humans. This paper aims to capture the current successful practices for HP MRI human studies with [1-13C]pyruvate - by far the most commonly used agent, which sits at a key metabolic junction in glycolysis. The paper is divided into four major topic areas: (1) HP 13C-pyruvate preparation, (2) MRI system setup and calibrations, (3) data acquisition and image reconstruction, and (4) data analysis and quantification. In each area, we identified the key components for a successful study, summarized both published studies and current practices, and discuss evidence gaps, strengths, and limitations. This paper is the output of the "HP 13C MRI Consensus Group" as well as the ISMRM Hyperpolarized Media MR and Hyperpolarized Methods & Equipment study groups. It further aims to provide a comprehensive reference for future consensus building as the field continues to advance human studies with this metabolic imaging modality.

Pulmonary functional MRI: Detecting the structure-function pathologies that drive asthma symptoms and quality of life.

Pulmonary functional MRI (PfMRI) using inhaled hyperpolarized, radiation-free gases (such as 3 He and 129 Xe) provides a way to directly visualize inhaled gas distribution and ventilation defects (or ventilation heterogeneity) in real time with high spatial (~mm3 ) resolution. Both gases enable quantitative measurement of terminal airway morphology, while 129 Xe uniquely enables imaging the transfer of inhaled gas across the alveolar-capillary tissue barrier to the red blood cells. In patients with asthma, PfMRI abnormalities have been shown to reflect airway smooth muscle dysfunction, airway inflammation and remodelling, luminal occlusions and airway pruning. The method is rapid (8-15 s), cost-effective (~$300/scan) and very well tolerated in patients, even in those who are very young or very ill, because unlike computed tomography (CT), positron emission tomography and single-photon emission CT, there is no ionizing radiation and the examination takes only a few seconds. However, PfMRI is not without limitations, which include the requirement of complex image analysis, specialized equipment and additional training and quality control. We provide an overview of the three main applications of hyperpolarized noble gas MRI in asthma research including: (1) inhaled gas distribution or ventilation imaging, (2) alveolar microstructure and finally (3) gas transfer into the alveolar-capillary tissue space and from the tissue barrier into red blood cells in the pulmonary microvasculature. We highlight the evidence that supports a deeper understanding of the mechanisms of asthma worsening over time and the pathologies responsible for symptoms and disease control. We conclude with a summary of approaches that have the potential for integration into clinical workflows and that may be used to guide personalized treatment planning.

Comparison of Hyperpolarized 3He and 129Xe MR Imaging in Cystic Fibrosis Patients.

PURPOSE: In this study, we compared hyperpolarized 3He and 129Xe images from patients with cystic fibrosis using two commonly applied magnetic resonance sequences, standard gradient echo (GRE) and balanced steady-state free precession (TrueFISP) to quantify regional similarities and differences in signal distribution and defect analysis. MATERIALS AND METHODS: Ten patients (7M/3F) with cystic fibrosis underwent hyperpolarized gas MR imaging with both 3He and 129Xe. Six had MRI with both GRE, and TrueFISP sequences and four patients had only GRE sequence but not TrueFISP. Ventilation defect percentages (VDPs) were calculated as lung voxels with <60% of the whole-lung hyperpolarized gas signal mean and was measured in all datasets. The voxel signal distributions of both 129Xe and 3He gases were visualized and compared using violin plots. VDPs of hyperpolarized 3 He and 129 Xe were compared in Bland-Altman plots; Pearson correlation coefficients were used to evaluate the relationships between inter-gas and inter-scan to assess the reproducibility. RESULTS: A significant correlation was demonstrated between 129Xe VDP and 3He VDP for both GRE and TrueFISP sequences (ρ = 0.78, p<0.0004). The correlation between the GRE and TrueFISP VDP for 3He was ρ = 0.98 and was ρ = 0.91 for 129Xe. Overall, 129Xe (27.2±9.4) VDP was higher than 3He (24.3±6.9) VDP on average on cystic fibrosis patients. CONCLUSION: In patients with cystic fibrosis, the selection of hyperpolarized 129Xe or 3He gas is most likely inconsequential when it comes to measure the overall lung function by VDP although 129Xe may be more sensitive to starker lung defects, particularly when using a TrueFISP sequence.

Detection of metabolic change in glioblastoma cells after radiotherapy using hyperpolarized 13 C-MRI.

Dynamic nuclear polarization (DNP) of 13 C-labeled substrates enables the use of magnetic resonance imaging (MRI) to monitor specific enzymatic reactions in tumors and offers an opportunity to investigate these differences. In this study, DNP-MRI chemical shift imaging with hyperpolarized [1-13 C] pyruvate was conducted to evaluate the metabolic change in glycolytic profiles after radiation of two glioma stem-like cell-derived gliomas (GBMJ1 and NSC11) and an adherent human glioblastoma cell line (U251) in an orthotopic xenograft mouse model. The DNP-MRI showed an increase in Lac/Pyr at 6 and 16 h after irradiation (18% ± 4% and 14% ± 3%, respectively; mean ± SEM) compared with unirradiated controls in GBMJ1 tumors, whereas no significant change was observed in U251 and NSC11 tumors. Metabolomic analysis likewise showed a significant increase in lactate in GBMJ1 tumors at 16 h. An immunoblot assay showed upregulation of lactate dehydrogenase-A expression in GBMJ1 following radiation exposure, consistent with DNP-MRI and metabolomic analysis. In conclusion, our preclinical study demonstrates that the DNP-MRI technique has the potential to be a powerful diagnostic method with which to evaluate GBM tumor metabolism before and after radiation in the clinical setting.

pH Dependence of T2 for Hyperpolarizable 13C-Labelled Small Molecules Enables Spatially Resolved pH Measurement by Magnetic Resonance Imaging.

Hyperpolarized 13C magnetic resonance imaging often uses spin-echo-based pulse sequences that are sensitive to the transverse relaxation time T2. In this context, local T2-changes might introduce a quantification bias to imaging biomarkers. Here, we investigated the pH dependence of the apparent transverse relaxation time constant (denoted here as T2) of six 13C-labelled molecules. We obtained minimum and maximum T2 values within pH 1-13 at 14.1 T: [1-13C]acetate (T2,min = 2.1 s; T2,max = 27.7 s), [1-13C]alanine (T2,min = 0.6 s; T2,max = 10.6 s), [1,4-13C2]fumarate (T2,min = 3.0 s; T2,max = 18.9 s), [1-13C]lactate (T2,min = 0.7 s; T2,max = 12.6 s), [1-13C]pyruvate (T2,min = 0.1 s; T2,max = 18.7 s) and 13C-urea (T2,min = 0.1 s; T2,max = 0.1 s). At 7 T, T2-variation in the physiological pH range (pH 6.8-7.8) was highest for [1-13C]pyruvate (ΔT2 = 0.95 s/0.1pH) and [1-13C]acetate (ΔT2 = 0.44 s/0.1pH). Concentration, salt concentration, and temperature alterations caused T2 variations of up to 45.4% for [1-13C]acetate and 23.6% for [1-13C]pyruvate. For [1-13C]acetate, spatially resolved pH measurements using T2-mapping were demonstrated with 1.6 pH units accuracy in vitro. A strong proton exchange-based pH dependence of T2 suggests that pH alterations potentially influence signal strength for hyperpolarized 13C-acquisitions.

Hyperpolarized magnetic resonance shows that the anti-ischemic drug meldonium leads to increased flux through pyruvate dehydrogenase in vivo resulting in improved post-ischemic function in the diabetic heart.

The diabetic heart has a decreased ability to metabolize glucose. The anti-ischemic drug meldonium may provide a route to counteract this by reducing l-carnitine levels, resulting in improved cardiac glucose utilization. Therefore, the aim of this study was to use the novel technique of hyperpolarized magnetic resonance to investigate the in vivo effects of treatment with meldonium on cardiac metabolism and function in control and diabetic rats. Thirty-six male Wistar rats were injected either with vehicle, or with streptozotocin (55 mg/kg) to induce a model of type 1 diabetes. Daily treatment with either saline or meldonium (100 mg/kg/day) was undertaken for three weeks. in vivo cardiac function and metabolism were assessed with CINE MRI and hyperpolarized magnetic resonance respectively. Isolated perfused hearts were challenged with low-flow ischemia/reperfusion to assess the impact of meldonium on post-ischemic recovery. Meldonium had no significant effect on blood glucose concentrations or on baseline cardiac function. However, hyperpolarized magnetic resonance revealed that meldonium treatment elevated pyruvate dehydrogenase flux by 3.1-fold and 1.2-fold in diabetic and control animals, respectively, suggesting an increase in cardiac glucose oxidation. Hyperpolarized magnetic resonance further demonstrated that meldonium reduced the normalized acetylcarnitine signal by 2.1-fold in both diabetic and control animals. The increase in pyruvate dehydrogenase flux in vivo was accompanied by an improvement in post-ischemic function ex vivo, as meldonium elevated the rate pressure product by 1.3-fold and 1.5-fold in the control and diabetic animals, respectively. In conclusion, meldonium improves in vivo pyruvate dehydrogenase flux in the diabetic heart, contributing to improved cardiac recovery after ischemia.

Hyperpolarized 13 C MRI data acquisition and analysis in prostate and brain at University of California, San Francisco.

Based on the expanding set of applications for hyperpolarized carbon-13 (HP-13 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-13 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-13 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.

Optimizing SNR for multi-metabolite hyperpolarized carbon-13 MRI using a hybrid flip-angle scheme.

PURPOSE: To improve the SNR of hyperpolarized carbon-13 MRI of [1-13 C]pyruvate using a multispectral variable flip angle (msVFA) scheme in which the spectral profile and flip angle vary dynamically with time. METHODS: Each image acquisition in a time-resolved imaging experiment used a unique spectrally varying RF pulse shape for msVFA. Therefore, the flip angle for every acquisition was optimized for pyruvate and each of its metabolites to yield the highest SNR across the acquisition. Multispectral VFA was compared with a spectrally varying constant flip-angle excitation model through simulations and in vivo. A modified broadband chemical shift-encoded gradient-echo sequence was used for in vivo experiments on six pregnant guinea pigs. Regions of interest placed in the placentae, maternal liver, and maternal kidneys were used as areas for SNR measurement. RESULTS: In vivo experiments showed significant increases in SNR for msVFA relative to constant flip angle of up to 250% for multiple metabolites. CONCLUSION: Hyperpolarized carbon-13 imaging with msVFA excitation produces improved SNR for all metabolites in organs of interest.

Using Hyperpolarized Xenon-129 MRI to Quantify Early-Stage Lung Disease in Smokers.

RATIONALE AND OBJECTIVES: Hyperpolarized xenon-129 magnetic resonance (MR) provides sensitive tools that may detect early stages of lung disease in smokers before it has progressed to chronic obstructive pulmonary disease (COPD) apparent to conventional spirometric measures. We hypothesized that the functional alveolar wall thickness as assessed by hyperpolarized xenon-129 MR spectroscopy would be elevated in clinically healthy smokers before xenon MR diffusion measurements would indicate emphysematous tissue destruction. MATERIALS AND METHODS: Using hyperpolarized xenon-129 MR we measured the functional septal wall thickness and apparent diffusion coefficient of the gas phase in 16 subjects with smoking-related COPD, 9 clinically healthy current or former smokers, and 10 healthy never smokers. All subjects were age-matched and characterized by conventional pulmonary function tests. A total of 11 data sets from younger healthy never smokers were added to determine the age dependence of the septal wall thickness measurements. RESULTS: In healthy never smokers the septal wall thickness increased by 0.04 µm per year of age. The healthy smoker cohort exhibited normal pulmonary function test measures that did not significantly differ from the never-smoker cohort. The age-corrected septal wall thickness correlated well with diffusion capacity for carbon monoxide (R2 = 0.56) and showed a highly significant difference between healthy subjects and COPD patients (8.8 µm vs 12.3 µm; p < 0.001), but was the only measure that actually discriminated healthy subjects from healthy smokers (8.8 µm vs 10.6 µm; p < 0.006). CONCLUSION: Functional alveolar wall thickness assessed by hyperpolarized xenon-129 MR allows discrimination between healthy subjects and healthy smokers and could become a powerful new measure of early-stage lung disease.

Hyperpolarized 13C magnetic resonance imaging, using metabolic imaging to improve the detection and management of prostate, bladder, and kidney urologic malignancies.

Approximately 25% of the 2 million new cancer diagnoses in the United States in 2018 were comprised of malignancies of the urogenital system. Of these cancers, 75% occurred in the kidney/renal pelvis, prostate, and urinary bladder. Early diagnosis is beneficial to long-term survival. Currently, urologists rely heavily on computed tomography (CT), magnetic resonance imaging (MRI), ultrasound (US), and positron emission tomography (PET) to both diagnose and offer prognoses, but these techniques are limited in their resolution and are more effective when cancers have reached macroscopic size in later stages. Recent developments in cancer metabolomics have revealed that cancerous cells preferentially upregulate specific metabolic pathways as a means of conserving their resources and maximizing their growth potential. This has opened a new avenue for early diagnosis with much higher resolution, reliability, and accuracy through 13C hyperpolarized MRI. Preferential cancer pathways can be elucidated through this technique using 13C-labeled molecules utilized for energy generation and tumor growth. As these pathways are identified, targeted therapies are being designed to inhibit these pathways to allow for treatment that is cytotoxic to malignant cells but preserves native cells. In this paper, we review the current understanding of urologic cancer metabolomics, specifically in the kidney, prostate, and bladder. We will review the basic physics of MRI and demonstrate how hyperpolarized 13C MRI offers an innovative solution to early diagnosis as well as creates novel avenues for more targeted therapy.

New Imaging Techniques in Prostate Cancer.

Rapid advances in diagnostic imaging have been developed in parallel with the changes in the contemporary management of prostate cancer. Increasingly, clinical management and decision making in prostate cancer are influenced by technologies such as magnetic resonance imaging-targeted prostate biopsies for men with elevated PSA, imaging for active surveillance, and nuclear medicine studies for men with advanced or recurrent prostate cancer. Furthermore, novel imaging techniques have been developed such as hyperpolarized MRI, choline and prostate-specific membrane antigen positron emission tomography that exploit features like the unique metabolism in prostate cancer tissues, as well as altered glycoprotein conformation. These technologies have allowed for the identification of tiny foci of prostate cancer in men with early biochemical recurrence, greatly surpassing the limitations of traditional morphological imaging. With promising findings, studies are ongoing to uncover the clinical application of these imaging modalities. Ultimately, several factors such as cost-effectiveness and the overall reduction in disease mortality will dictate the implementation of these imaging technologies in the future. This chapter provides an overview on new and emerging prostate imaging techniques that can be used in the diagnosis of primary cancer as well as the staging and detection of metastatic disease.