13C MRI Research Articles

Imaging breast cancer using hyperpolarized carbon-13 MRI

Our purpose is to investigate the feasibility of imaging tumor metabolism in breast cancer patients using 13C magnetic resonance spectroscopic imaging (MRSI) of hyperpolarized 13C label exchange between injected [1-13C]pyruvate and the endogenous tumor lactate pool. Treatment-naïve breast cancer patients were recruited: four triple-negative grade 3 cancers; two invasive ductal carcinomas that were estrogen and progesterone receptor-positive (ER/PR+) and HER2/neu-negative (HER2-), one grade 2 and one grade 3; and one grade 2 ER/PR+ HER2- invasive lobular carcinoma (ILC). Dynamic 13C MRSI was performed following injection of hyperpolarized [1-13C]pyruvate. Expression of lactate dehydrogenase A (LDHA), which catalyzes 13C label exchange between pyruvate and lactate, hypoxia-inducible factor-1 (HIF1α), and the monocarboxylate transporters MCT1 and MCT4 were quantified using immunohistochemistry and RNA sequencing. We have demonstrated the feasibility and safety of hyperpolarized 13C MRI in early breast cancer. Both intertumoral and intratumoral heterogeneity of the hyperpolarized pyruvate and lactate signals were observed. The lactate-to-pyruvate signal ratio (LAC/PYR) ranged from 0.021 to 0.473 across the tumor subtypes (mean ± SD: 0.145 ± 0.164), and a lactate signal was observed in all of the grade 3 tumors. The LAC/PYR was significantly correlated with tumor volume (R = 0.903, P = 0.005) and MCT 1 (R = 0.85, P = 0.032) and HIF1α expression (R = 0.83, P = 0.043). Imaging of hyperpolarized [1-13C]pyruvate metabolism in breast cancer is feasible and demonstrated significant intertumoral and intratumoral metabolic heterogeneity, where lactate labeling correlated with MCT1 expression and hypoxia.

NIMG-57. SERIAL HYPERPOLARIZED 13C PYRUVATE AND 1H METABOLIC IMAGING IN RECURRENT HIGH-GRADE GLIOMA

Abstract INTRODUCTION Hyperpolarized (HP) 13C MRI is a novel metabolic imaging that allows for real time in vivo probing of pathway-specific metabolic processes relevant to gliomas. The first human brain application reports were published recently. In this study, we characterized longitudinal dynamic and static brain metabolism changes from serial HP 13C and 1H metabolic imaging in a patient with multiply recurrent glioma. METHODS Eight dynamic HP 13C imaging, 1H MRI and MRSI examinations were acquired over a period of 15 months in a patient with multiply recurrent glioma that underwent malignant transformation. The patient was imaged after initial tumor debulking, after chemoradiotherapy, at first recurrence, after re-irradiation and anti-angiogentic therapy, and at second recurrence. Ratios of pyruvate-to-lactate and pyruvate-to-bicarbonate were calculated from HP 13C imaging and choline-to-NAA index (CNI) was derived from 1H MRSI. RESULTS/ DISCUSSION Successful therapies are usually associated with a drop in pyruvate-to-lactate conversion, mediated by different mechanisms from various treatments. We identified three key findings over repeat HP 13C MRIs: 1) a marked response to therapy with a reduction in pyruvate-to-lactate conversion corresponding to associated imaging response to therapy at the primary site of disease. Following chemoradiotherapy, the volume of T2 hyperintensity decreased from 28.21cc to 15.29 cc, and the volume of metabolic abnormality (CNI >3) decreased from 27.84 cc to 10.36 cc. 2) increasing pyruvate-to-lactate conversion in a region of recurrence before morphologic signal abnormality, and 3) a reduction in pyruvate-to-lactate conversion in a recurrent lesion following anti-angiogenic therapy. CONCLUSION Here we show that one can reliably image glioma patients using HP 13C MRI alongside standard of care morphologic and physiologic MRI including diffusion, perfusion, and 1H MRSI. Serial HP 13C MRI can be performed in the neuro-oncologic clinical setting and pyruvate-to-lactate metabolism may be useful to monitor treatment response.

Lactate topography of the human brain using hyperpolarized 13C-MRI

Lactate is now recognized as an important intermediate in brain metabolism, but its role is still under investigation. In this work we mapped the distribution of lactate and bicarbonate produced from intravenously injected 13C-pyruvate over the whole brain using a new imaging method, hyperpolarized 13C MRI (N = 14, ages 23 to 77). Segmenting the 13C-lactate images into brain atlas regions revealed a pattern of lactate that was preserved across individuals. Higher lactate signal was observed in cortical grey matter compared to white matter and was highest in the precuneus, cuneus and lingual gyrus. Bicarbonate signal, indicating flux of [1–13C]pyruvate into the TCA cycle, also displayed consistent spatial distribution. One-way ANOVA to test for significant differences in lactate among atlas regions gave F = 87.6 and p < 10−6. This report of a “lactate topography” in the human brain and its consistent pattern is evidence of region-specific lactate biology that is preserved across individuals.

Abstract 1962: Visualizing the efficacy of PI3K inhibitor combination treatment on tumor metabolism

Abstract Purpose: Many types of cancer exhibit an upregulation in glycolysis. Cancer therapies that target tumor metabolism include PI3K inhibitor combinations, which are currently in clinical trials. Real-time metabolic imaging can be possible using hyperpolarization, which is a signal enhancement technique for MRI that increases the signal by a factor of 10,000 or more. The purpose of this work was to determine whether the anti-metabolic effect of such therapies on preclinical breast cancer models could be visualized non-invasively by MRI of hyperpolarized 13C-pyruvate to lactate conversion. Methods: Experiments were carried out on a 9.4 T animal MRI scanner (Biospec 94/20, Bruker, Billerica MA), and all animal studies were done with IACUC approval. Two models of triple negative BRCA1 mutant breast cancer, either resistant (T1R1, n=4) or sensitive (T2S, n=4) to PARP inhibition, were implanted in the inguinal fat pad of mice. Animals with tumor sizes of approximately 10x10x10 mm3 were then imaged prior to and after four consecutive days of combination treatment with a PI3K inhibitor and PARP inhibitor. In order to visualize the interconversion of pyruvate to lactate in vivo, a bolus of hyperpolarized 13C pyruvate (Hypersense, Oxford Instruments, Oxfordshire UK) with concentration=100 mM and volume=200uL was administered to the mouse via tail vein. 13C MR images were acquired using echo-planar spectroscopic imaging (Flip angle=4 degrees; matrix size=16x16; resolution = 2.5mm; slice thickness=5mm; spectral points=512; spectral width=4kHz; repetitions=32) with a 13C radiofrequency transmit/receive surface coil (Bruker, MA) and overlaid on proton anatomical images obtained using a proton volume coil (78 mm diameter, Bruker, MA). Data were reconstructed (Mathematica, Wolfram) to obtain pixel by pixel time integrated pyruvate and lactate spectra for an axial slice. The area under the curve for both metabolites was calculated for all pixels and summed within the tumor to obtain a lactate to pyruvate ratio for each case. Statistical analysis was carried out using a paired t-test. Results: For the animals with T2S tumors, the lactate to pyruvate ratio reduced from 1.65 ± 0.44 to 0.84 ± 0.32 (mean ± std. dev.) after treatment with significance p = 0.0378. For animals with T1R1 tumors, the ratio before and after treatment was 0.91 ± 0.44 and 0.93 ± 0.20 (p = 0.9553). Conclusions: Noninvasive visualization of pyruvate to lactate interconversion can be achieved using 13C MRI, allowing for imaging the efficacy of treatments on cancer metabolism. Citation Format: Manushka Vaidya, Olmo Sonzogni, Cody Callahan, Jocelin Pinto, Gerburg M. Wulf, Aaron Grant. Visualizing the efficacy of PI3K inhibitor combination treatment on tumor metabolism [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1962.

Hyperpolarised 13C MRI: a new horizon for non-invasive diagnosis of aggressive breast cancer

Hyperpolarised 13C MRI (HP-MRI) is a novel imaging technique that allows real-time analysis of metabolic pathways in vivo.1 The technology to conduct HP-MRI in humans has recently become available and is starting to be clinically applied. As knowledge of molecular biology advances, it is increasingly apparent that cancer cell metabolism is related to disease outcomes, with lactate attracting specific attention. 2 Recent reviews of breast cancer screening programs have raised concerns and increased public awareness of over treatment. The scientific community needs to shift focus from improving cancer detection alone to pursuing novel methods of distinguishing aggressive breast cancers from those which will remain indolent. HP-MRI offers the opportunity to identify aggressive tumour phenotypes and help monitor/predict therapeutic response. Here we report one of the first cases of breast cancer imaged using HP-MRI alongside correlative conventional imaging, including breast MRI.

Molecular Imaging of Renal Malignancy: A Review

Renal cell carcinoma (RCC) is a common malignancy that is often detected incidentally in patients undergoing cross-sectional imaging of the abdomen for workup of pain or other symptoms. Due to overlap in imaging findings of RCC and benign tumors, biopsy may be necessary to confirm the diagnosis. Biopsies are occasionally non-diagnostic, however, and in small lesions or patients with comorbidities may not be technically feasible. Molecular imaging techniques can characterize tumors as being more likely malignant or benign and obviate the need for invasive testing, as well as providing accurate whole-body staging in patients with known RCC. PET/CT with 18F-FDG and other radionuclides can identify primary renal masses with higher malignant potential and also allows for sensitive detection of metastatic RCC. SPECT/CT imaging with 99mTc-sestamibi can provide useful information to support the diagnosis of benign oncocytic neoplasms over more aggressive RCC subtypes. Investigational molecular imaging techniques such as immunoPET and hyperpolarized 13C MRI have also shown promise in renal mass characterization. This review article aims to outline the various molecular imaging modalities available in the evaluation of primary renal tumors and in whole-body staging of metastatic RCC.

Hyperpolarized 13C MRI: State of the Art and Future Directions.

Hyperpolarized (HP) carbon 13 (13C) MRI is an emerging molecular imaging method that allows rapid, noninvasive, and pathway-specific investigation of dynamic metabolic and physiologic processes that were previously inaccessible to imaging. This technique has enabled real-time in vivo investigations of metabolism that are central to a variety of diseases, including cancer, cardiovascular disease, and metabolic diseases of the liver and kidney. This review provides an overview of the methods of hyperpolarization and 13C probes investigated to date in preclinical models of disease. The article then discusses the progress that has been made in translating this technology for clinical investigation. In particular, the potential roles and emerging clinical applications of HP [1-13C]pyruvate MRI will be highlighted. The future directions to enable the adoption of this technology to advance the basic understanding of metabolism, to improve disease diagnosis, and to accelerate treatment assessment are also detailed.

First-in-human in vivo non-invasive assessment of intra-tumoral metabolic heterogeneity in renal cell carcinoma.

Intratumoral genetic heterogeneity and the role of metabolic reprogramming in renal cell carcinoma have been extensively documented. However, the distribution of these metabolic changes within the tissue has not been explored. We report on the first-in-human in vivo non-invasive metabolic interrogation of renal cell carcinoma using hyperpolarized carbon-13 (13C) MRI and describe the validation of in vivo lactate metabolic heterogeneity against multi regional ex vivo mass spectrometry. hyperpolarized carbon-13 (13C)-MRI provides an in vivo assessment of metabolism and provides a novel opportunity to safely and non-invasively assess cancer heterogeneity.

Synthesis and evaluation of 13C-labeled 5-5-dimethyl-1-pyrroline-N-oxide aimed at in vivo detection of reactive oxygen species using hyperpolarized 13C-MRI

Effective means to identify the role of reactive oxygen species (ROS) mediating several diseases including cancer, ischemic heart disease, stroke, Alzheimer's and other inflammatory conditions in in vivo models would be useful. The cyclic nitrone 5,5-Dimethyl-1-pyrroline-N-oxide (DMPO) is a spin trap frequently used to detect free radicals in vitro using Electron Paramagnetic Resonance (EPR) spectroscopy. In this study, we synthesized 13C-labeled DMPO for hyperpolarization by dynamic nuclear polarization, in which 13C NMR signal increases more than 10,000-fold. This allows in vivo 13C MRI to investigate the feasibility of in vivo ROS detection by the 13C-MRI. DMPO was 13C-labeled at C5 position, and deuterated to prolong the T1 relaxation time. The overall yield achieved for 5–13C-DMPO-d9 was 15%. Hyperpolarized 5–13C-DMPO-d9 provided a single peak at 76 ppm in the 13C-spectrum, and the T1 was 60 s in phosphate buffer making it optimal for in vivo 13C MRI. The buffered solution of hyperpolarized 5–13C-DMPO-d9 was injected into a mouse placed in a 3 T scanner, and 13C-spectra were acquired every 1 s. In vivo studies showed the signal of 5–13C-DMPO-d9 was detected in the mouse, and the T1 decay of 13C signal of hyperpolarized 5–13C-DMPO-d9 was 29 s. 13C-chemical shift imaging revealed that 5–13C-DMPO-d9 was distributed throughout the body in a minute after the intravenous injection. A strong signal of 5–13C-DMPO-d9 was detected in heart/lung and kidney, whereas the signal in liver was small compared to other organs. The results indicate hyperpolarized 5–13C-DMPO-d9 provided sufficient 13C signal to be detected in the mouse in several organs, and can be used to detect ROS in vivo.

Improved Decoupling for Low Frequency MRI Arrays using Non-conventional Preamplifier Impedance.

In this study, we describe a method to improve preamplifier decoupling in low frequency MRI receive coil arrays, where sample loading is low and coils exhibit a high Q-factor. The method relies on the higher decoupling obtained when coils are matched to an impedance higher than 50 Ω. Preamplifiers with inductive (and low resistive) input impedance, increase even further the effectiveness of the method. We show that for poorly sample loaded coils, coupling to other elements in an array is a major source of SNR degradation due to a reduction of the coil Q-factor. An 8-channel 13C array at 32 MHz for imaging of the human head has been designed following this strategy. The improved decoupling even allowed constructing the array without overlapping of neighboring coils. Parallel imaging performance is also evaluated demonstrating a better spatial encoding of the array due to its non-overlapped geometry. The proposed design strategy for coil arrays is beneficial for low frequency coils where the coil thermal noise is dominant. The method has been demonstrated on an 8-channel array for the human head for 13C MRI at 3 T (32 MHz), with almost 2-fold SNR enhancement when compared to a traditional array of similar size and number of elements. The proposed method is of relevance for low frequency arrays, where sample loading is low, and noise correlation is high due to insufficient coil decoupling.

Effects of Deuteration of 13C-Enriched Phospholactate on Efficiency of Parahydrogen-Induced Polarization by Magnetic Field Cycling.

We report herein a large-scale (>10 g) synthesis of isotopically enriched 1-13C-phosphoenolpyruvate and 1-13C-phosphoenolpyruvate-d2 for application in hyperpolarized imaging technology. The 1-13C-phosphoenolpyruvate-d2 was synthesized with 57% overall yield (over two steps), and >98% 2H isotopic purity, representing an improvement over the previous report. The same outcome was achieved for 1-13C-phosphoenolpyruvate. These two unsaturated compounds with C=C bonds were employed for parahydrogen-induced polarization via pairwise parahydrogen addition in aqueous medium. We find that deuteration of 1-13C-phosphoenolpyruvate resulted in overall increase of 1H T1 of nascent hyperpolarized protons (4.30 ± 0.04 s versus 2.06 ± 0.01 s) and 1H polarization (~2.5% versus ~0.7%) of the resulting hyperpolarized 1-13C-phospholactate. The nuclear spin polarization of nascent parahydrogen-derived protons was transferred to 1-13C nucleus via magnetic field cycling procedure. The proton T1 increase in hyperpolarized deuterated 1-13C-phospholactate yielded approximately 30% better 13C polarization compared to non-deuterated hyperpolarized 1-13C-phospholactate. Analysis of T1 relaxation revealed that deuteration of 1-13C-phospholactate may have resulted in approximately 3-fold worse H→13C polarization transfer efficiency via magnetic field cycling. Since magnetic field cycling is a key polarization transfer step in the Side-Arm Hydrogenation approach, the presented findings may guide more rationale design of contrast agents using parahydrogen polarization of a broad range of 13C hyperpolarized contrast agents for molecular imaging employing 13C MRI. The hyperpolarized 1-13C-phospholactate-d2 is of biomedical imaging relevance because it undergoes in vivo dephosphorylation and becomes 13C hyperpolarized lactate, which as we show can be detected in the brain using 13C hyperpolarized MRI; an implication for future imaging of neurodegenerative diseases and dementia.

Direct and indirect assessment of cancer metabolism explored by MRI.

Magnetic resonance-based approaches to obtain metabolic information on cancer have been explored for decades. Electron paramagnetic resonance (EPR) has been developed to pursue metabolic profiling and successfully used to monitor several physiologic parameters such as pO2 , pH, and redox status. All these parameters are associated with pathophysiology of various diseases. Especially in oncology, cancer hypoxia has been intensively studied because of its relationship with metabolic alterations, acquiring treatment resistance, or a malignant phenotype. Thus, pO2 imaging leads to an indirect metabolic assessment in this regard. Proton electron double-resonance imaging (PEDRI) is an imaging technique to visualize EPR by using the Overhauser effect. Most biological parameters assessed in EPR can be visualized using PEDRI. However, EPR and PEDRI have not been evaluated sufficiently for clinical application due to limitations such as toxicity of the probes or high specific absorption rate. Hyperpolarized (HP) 13 C MRI is a novel imaging technique that can directly visualize the metabolic profile. Production of metabolites of the HP 13 C probe delivered to target tissue are evaluated in this modality. Unlike EPR or PEDRI, which require the injection of radical probes, 13 C MRI requires a probe that can be physiologically metabolized and efficiently hyperpolarized. Among several methods for hyperpolarizing probes, dissolution dynamic nuclear hyperpolarization is a widely used technique for in vivo imaging. Pyruvate is the most suitable probe for HP 13 C MRI because it is part of the glycolytic pathway and the high efficiency of pyruvate-to-lactate conversion is a distinguishing feature of cancer. Its clinical applicability also makes it a promising metabolic imaging modality. Here, we summarize the applications of these indirect and direct MR-based metabolic assessments focusing on pO2 and pyruvate-to-lactate conversion. The two parameters are strongly associated with each other, hence the acquired information is potentially interchangeable when evaluating treatment response to oxygen-dependent cancer therapies.

Metabolic and Physiologic Imaging Biomarkers of the Tumor Microenvironment Predict Treatment Outcome with Radiation or a Hypoxia-Activated Prodrug in Mice.

Pancreatic ductal adenocarcinoma (PDAC) is characterized by hypoxic niches that lead to treatment resistance. Therefore, studies of tumor oxygenation and metabolic profiling should contribute to improved treatment strategies. Here, we define two imaging biomarkers that predict differences in tumor response to therapy: (i) partial oxygen pressure (pO2), measured by EPR imaging; and (ii) [1-13C] pyruvate metabolism rate, measured by hyperpolarized 13C MRI. Three human PDAC xenografts with varying treatment sensitivity (Hs766t, MiaPaCa2, and Su.86.86) were grown in mice. The median pO2 of the mature Hs766t, MiaPaCa2, and Su.86.86 tumors was 9.1 ± 1.7, 11.1 ± 2.2, and 17.6 ± 2.6 mm Hg, and the rate of pyruvate-to-lactate conversion was 2.72 ± 0.48, 2.28 ± 0.26, and 1.98 ± 0.51 per minute, respectively (n = 6, each). These results are in agreement with steady-state data of matabolites quantified by mass spectroscopy and histologic analysis, indicating glycolytic and hypoxia profile in Hs766t, MiaPaca2, and Su.86.86 tumors. Fractionated radiotherapy (5 Gy × 5) resulted in a tumor growth delay of 16.7 ± 1.6 and 18.0 ± 2.7 days in MiaPaca2 and Su.86.86 tumors, respectively, compared with 6.3 ± 2.7 days in hypoxic Hs766t tumors. Treatment with gemcitabine, a first-line chemotherapeutic agent, or the hypoxia-activated prodrug TH-302 was more effective against Hs766t tumors (20.0 ± 3.5 and 25.0 ± 7.7 days increase in survival time, respectively) than MiaPaCa2 (2.7 ± 0.4 and 6.7 ± 0.7 days) and Su.86.86 (4.7 ± 0.6 and 0.7 ± 0.6 days) tumors. Collectively, these results demonstrate the ability of molecular imaging biomarkers to predict the response of PDAC to treatment with radiotherapy and TH-302.Significance: pO2 imaging data and clinically available metabolic imaging data provide useful insight into predicting the treatment efficacy of chemotherapy, radiation, and a hypoxia-activated prodrug as monotherapies and combination therapies in PDAC tumor xenograft models. Cancer Res; 78(14); 3783-92. ©2018 AACR.

Using a local low rank plus sparse reconstruction to accelerate dynamic hyperpolarized 13C imaging using the bSSFP sequence

Acceleration of dynamic 2D (T2 Mapping) and 3D hyperpolarized 13C MRI acquisitions using the balanced steady-state free precession sequence was achieved with a specialized reconstruction method, based on the combination of low rank plus sparse and local low rank reconstructions. Methods were validated using both retrospectively and prospectively undersampled in vivo data from normal rats and tumor-bearing mice. Four-fold acceleration of 1–2 mm isotropic 3D dynamic acquisitions with 2–5 s temporal resolution and two-fold acceleration of 0.25–1 mm2 2D dynamic acquisitions was achieved. This enabled visualization of the biodistribution of [2-13C]pyruvate, [1-13C]lactate, [13C, 15N2]urea, and HP001 within heart, kidneys, vasculature, and tumor, as well as calculation of high resolution T2 maps.

High spatiotemporal resolution bSSFP imaging of hyperpolarized [1-13 C]pyruvate and [1-13 C]lactate with spectral suppression of alanine and pyruvate-hydrate.

PurposeThe balanced steady‐state free precession (bSSFP) acquisition enables high spatiotemporal resolution for hyperpolarized 13C MRI at 3T but is limited by spectral contamination from adjacent resonances. The purpose of this study was to develop a framework for in vivo dynamic high resolution imaging of hyperpolarized [1‐13C]pyruvate and [1‐13C]lactate generated in vivo at 3T by simplifying the spectrum through the use of selective suppression pulses.MethodsSpectral suppression pulses were incorporated into the bSSFP sequence for suppression of [1‐13C]alanine and [1‐13C]pyruvate‐hydrate signals, leaving only the pyruvate and lactate resonances. Subsequently, the bSSFP pulse width, time‐bandwidth, and repetition time were optimized for imaging these dual resonances.ResultsThe spectral suppression reduced both the alanine and pyruvate‐hydrate signals by 85.5 ± 4.9% and had no significant effect on quantitation of pyruvate to lactate conversion (liver: P = 0.400, kidney: P = 0.499). High resolution (2 × 2 mm2 and 3 × 3 mm2) subsecond 2D coronal projections and 3D 2.5 mm isotropic images were obtained in rats and tumor‐bearing mice with 1.8–5 s temporal resolution, allowing for calculation of lactate‐to‐pyruvate ratios and kPL.ConclusionThe developed framework presented here shows the capability for dynamic high resolution volumetric hyperpolarized bSSFP imaging of pyruvate‐to‐lactate conversion on a clinical 3T MR scanner.

Molecular imaging of tumor photoimmunotherapy: Evidence of photosensitized tumor necrosis and hemodynamic changes.

Near-infrared photoimmunotherapy (NIR PIT) employs the photoabsorbing dye IR700 conjugated to antibodies specific for cell surface epidermal growth factor receptor (EGFR). NIR PIT has shown highly selective cytotoxicity in vitro and in vivo. Cell necrosis is thought to be the main mode of cytotoxicity based mainly on in vitro studies. To better understand the acute effects of NIR PIT, molecular imaging studies were performed to assess its cellular and vascular effects. In addition to in vitro studies for cytotoxicity of NIR PIT, the in vivo tumoricidal effects and hemodynamic changes induced by NIR PIT were evaluated by 13C MRI using hyperpolarized [1,4-13C2] fumarate, R2* mapping from T2*-weighted MRI, and photoacoustic imaging. In vitro studies confirmed that NIR PIT resulted in rapid cell death via membrane damage, with evidence for rapid cell expansion followed by membrane rupture. Following NIR PIT, metabolic MRI using hyperpolarized fumarate showed the production of malate in EGFR-expressing A431 tumor xenografts, providing direct evidence for photosensitized tumor necrosis induced by NIR PIT. R2* mapping studies showed temporal changes in oxygenation, with an accompanying increase of deoxyhemoglobin at the start of light exposure followed by a sustained decrease after cessation of light exposure. This result suggests a rapid decrease of blood flow in EGFR-expressing A431 tumor xenografts, which is supported by the results of the photoacoustic imaging experiments. Our findings suggest NIR PIT mediates necrosis and hemodynamic changes in tumors by photosensitized oxidation pathways and that these imaging modalities, once translated, may be useful in monitoring clinical treatment response.

Renal Urea Transport Alterations with Prolonged Renal Urea Transport Alterations with Prolonged Hyperglycaemia

PurposeTo explore whether hyperpolarized urea could serve as a possible imaging bio‐marker of the renal function via the intra‐renal osmolality gradient in diabetes.MethodsThirteen 250 g female wistar rats were randomly grouped in a diabetic group (four weeks of untreated type‐1 diabetes) of six animals and a healthy control group of seven animals. Diabetes was induced by an i.v. injection of freshly prepared streptozotocin (STZ; 55 mg/kg body weight). Rats were considered diabetic when the blood glucose levels exceeded 15 mmol/L at 48 h after injection of STZ. For the MR examinations, the rats were anesthetized and a tail vein catheterisation was performed. The MR examination was performed with a 9.4 T pre‐clinical MR system (Agilent, UK) equipped with a dual tuned 13C/1H volume rat coil (Doety scientic, US). Urea was polarized in a 5T SPINLab (GE Healthcare, Brøndby, DK) to a reproducible polarization of more than 40% [1]. The hyperpolarized sample was rapidly dissolved and a final solution of 1.5 ml hyperpolarized urea was injected intravenously to the animal over a period of 15 sec. A 1H gradient echo coronal and axial scan was acquired (TR/TE 100 ms/2.6 ms, flip 20°, FOV 60 mm2, matrix 128 × 128). The scan was performed as an anatomical 1H scout (Figure 1A). 3D 13C balanced steady state free precession (BSSFP) imaging sequences were performed (flip 15°, TR/TE 5.4 ms/2.7 ms, sw 20kHz, FOV 60 mm3, matrix 48×48×48 covering both kidneys) and initiated 35 s after the start of hyperpolarized [13C,15N]urea injection (Figure 1B).At the time of euthanasia, both kidneys were rapidly dissected. Cortex and inner medulla (IM) were collected separately and analyses for different urea transporters were done with qPCR.ResultsThe rats administered with STZ, all developed sustained hyperglycaemia within 48 hours. 3D balanced steady state 13C MRI images of hyperpolarized urea showed a cortico‐medullary urea gradient (Figure 1) with an accumulation of urea in the medullary and pelvic segments. A significant higher urea‐to‐total‐signal in the cortical region (p=0.008) concomitant with a significant decreased urea‐to‐total‐signal in the pelvic region (p=0.03) were found in the diabetic animals (Figure 2A). This resulted in a reduced intra‐renal urea‐to‐cortical distribution in the medulla (p=0.04) and pelvic (p=0.002) regions in the diabetics when compared to controls (Figure 2B). A significant intra‐renal increased urea accumulation from the cortex to the pelvis was found in both the diabetic and the control kidney, (p&lt;0.0001) (Figure 2B). The transcription levels of the urea transporters were all significantly altered in the diabetic rat kidney compared to the control animals (Figure 3).ConclusionThis study illustrated the potential of using hyperpolarized urea in estimating renal function, by showing a decreased intra‐renal distribution after prolonged hyperglycemia. This was consistent with the findings of a gradually decreasing function found in the diabetic kidney. The transcription of the urea transporters was generally up‐regulated, supporting the increased oxygen consumption. In contrast, the lower urea gradient in the diabetic kidney, compared to the healthy controls, verified the reduced renal function after four weeks of diabetes.Support or Funding InformationThe Danish Research Council supported the study.

Multiband RF pulses with improved performance via convex optimization

Selective RF pulses are commonly designed with the desired profile as a low pass filter frequency response. However, for many MRI and NMR applications, the spectrum is sparse with signals existing at a few discrete resonant frequencies. By specifying a multiband profile and releasing the constraint on “don’t-care” regions, the RF pulse performance can be improved to enable a shorter duration, sharper transition, or lower peak B1 amplitude. In this project, a framework for designing multiband RF pulses with improved performance was developed based on the Shinnar–Le Roux (SLR) algorithm and convex optimization. It can create several types of RF pulses with multiband magnitude profiles, arbitrary phase profiles and generalized flip angles. The advantage of this framework with a convex optimization approach is the flexible trade-off of different pulse characteristics. Designs for specialized selective RF pulses for balanced SSFP hyperpolarized (HP) 13C MRI, a dualband saturation RF pulse for 1H MR spectroscopy, and a pre-saturation pulse for HP 13C study were developed and tested.

Development and testing of hyperpolarized 13C MR calibrationless parallel imaging

A calibrationless parallel imaging technique developed previously for 1H MRI was modified and tested for hyperpolarized 13C MRI for applications requiring large FOV and high spatial resolution. The technique was demonstrated with both retrospective and prospective under-sampled data acquired in phantom and in vivo rat studies. A 2-fold acceleration was achieved using a 2D symmetric EPI readout equipped with random blips on the phase encode dimension. Reconstructed images showed excellent qualitative agreement with fully sampled data. Further acceleration can be achieved using acquisition schemes that incorporate multi-dimensional under-sampling.

The Need and Initial Practice of Parallel Imaging and Compressed Sensing in Hyperpolarized 13C MRI in vivo.

The Need and Initial Practice of Parallel Imaging and Compressed Sensing in Hyperpolarized 13C MRI in vivo.