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Aims: Impaired energy metabolism has been implicated in the pathogenesis of heart failure. Hyperpolarized (13)C magnetic resonance (MR), in which (13)C-labelled metabolites are followed using MR imaging (MRI) or spectroscopy (MRS), has enabled non-invasive assessment of pyruvate metabolism. We investigated the hypothesis that if we serially examined a model of heart failure using non-invasive hyperpolarized [(13)C]pyruvate with MR, the profile of in vivo pyruvate oxidation would change throughout the course of the disease.Methods and Results: Dilated cardiomyopathy (DCM) was induced in pigs (n = 5) by rapid pacing. Pigs were examined using MR at weekly time points: cine-MRI assessed cardiac structure and function; hyperpolarized [2-(13)C]pyruvate was administered intravenously, and (13)C MRS monitored [(13)C]glutamate production; (31)P MRS assessed cardiac energetics [phosphocreatine (PCr)/ATP]; and hyperpolarized [1-(13)C]pyruvate was administered for MRI of pyruvate dehydrogenase complex (PDC)-mediated pyruvate oxidation via [(13)C]bicarbonate production. Early in pacing, the cardiac index decreased by 25%, PCr/ATP decreased by 26%, and [(13)C]glutamate production decreased by 51%. After clinical features of DCM appeared, end-diastolic volume increased by 40% and [(13)C]bicarbonate production decreased by 67%. Pyruvate dehydrogenase kinase 4 protein increased by two-fold, and phosphorylated Akt decreased by half. Peroxisome proliferator-activated receptor-α and carnitine palmitoyltransferase-1 gene expression decreased by a half and a third, respectively.Conclusion: Despite early changes associated with cardiac energetics and (13)C incorporation into the Krebs cycle, pyruvate oxidation was maintained until DCM developed, when the heart's capacity to oxidize both pyruvate and fats was reduced. Hyperpolarized (13)C MR may be important to characterize metabolic changes that occur during heart failure progression. [ABSTRACT FROM AUTHOR]

Purpose: Treatment response assessment for gliomas currently uses changes in tumour size as measured with T 1 - and T 2 -weighted MRI. However, changes in tumour size may occur many weeks after therapy completion and are confounded by radiation treatment effects. Advanced MRI techniques sensitive to tumour physiology may provide complementary information to evaluate tumour response at early timepoints during therapy. The objective of this review is to provide a summary of the history and current knowledge regarding advanced MRI techniques for early treatment response evaluation in glioma., Methods: The literature survey included perfusion MRI, diffusion-weighted imaging, quantitative magnetization transfer imaging, and chemical exchange transfer MRI. Select articles spanning the history of each technique as applied to treatment response evaluation in glioma were chosen. This report is a narrative review, not formally systematic., Results: Chemical exchange saturation transfer imaging potentially offers the earliest method to detect tumour response due to changes in metabolism. Diffusion-weighted imaging is sensitive to changes in tumour cellularity later during radiotherapy and is prognostic for progression-free and overall survival. Substantial evidence suggests that perfusion MRI can differentiate between tumour recurrence and treatment effect, but consensus regarding acquisition, processing, and interpretation is still lacking. Magnetization transfer imaging shows promise for detecting subtle white matter damage which could indicate tumour invasion, but more research in this area is needed., Conclusion: Advanced MRI techniques show potential for early treatment response assessment, but each technique alone lacks specificity. Multiparametric imaging may be necessary to aid biological interpretation and enable treatment guidance., Competing Interests: Declarations Ethical approval The studies used to generate the figures in this article were granted ethics approval by our institution’s Research Ethics Board. Consent to participate Written informed consent was obtain from all individual participants in the studies used for the figures in this article, including consent to publish anonymized data. Consent to publish See above. Competing interests LSPL has accepted travel expenses from Elekta. AS has research grants with Elekta, BrainLab, and Seagen Inc. He has been a consultant for Elekta and BrainLab. He has received honoraria for educational seminars from Elekta, Varian, BrainLab, AstraZeneca, Seagen Inc, Cerapedics, CarboFIX, and Servier. He has also accepted travel expenses from Elekta, BrainLab, and Cerapedics. He is the President of the International Stereotactic Radiosurgery Society (ISRS). SD serves as the Provincial Lead for CNS Cancers at Ontario Health (Cancer Care Ontario). He receives royalties from Oxford University Press and research funding from Synaptive, VPiX and Cure51. He is a speaker for the American Association of Neurological Surgeons and Congress of Neurological Surgeons and is on the advisory board of the Subcortical Surgery Group. PJM, GJS, and AZL have no relevant financial or non-financial interests to disclose., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Pyroglutamic acidosis (PGA) or 5-Oxoprolinuria is an uncommon and often overlooked cause of high anion gap metabolic acidosis (HAGMA). This case highlights the importance of systematically approaching HAGMA, and to consider PGA as a differential diagnosis when medications that disrupt the γ-glutamyl cycle such as flucloxacillin and paracetamol are present., Competing Interests: Aaron Yee Shuen See, Asthon Zheng‐Boon Lau, Srivathsan Thiruvengadam have none to declare., (© 2024 The Author(s). Clinical Case Reports published by John Wiley & Sons Ltd.)

Chemoradiotherapy is the standard treatment after maximal safe resection for glioblastoma (GBM). Despite advances in molecular profiling, surgical techniques, and neuro-imaging, there have been no major breakthroughs in radiotherapy (RT) volumes in decades. Although the majority of recurrences occur within the original gross tumor volume (GTV), treatment of a clinical target volume (CTV) ranging from 1.5 to 3.0 cm beyond the GTV remains the standard of care. Over the past 15 years, the incorporation of standard and functional MRI sequences into the treatment workflow has become a routine practice with increasing adoption of MR simulators, and new integrated MR-Linac technologies allowing for daily pre-, intra- and post-treatment MR imaging. There is now unprecedented ability to understand the tumor dynamics and biology of GBM during RT, and safe CTV margin reduction is being investigated with the goal of improving the therapeutic ratio. The purpose of this review is to discuss margin strategies and the potential for adaptive RT for GBM, with a focus on the challenges and opportunities associated with both online and offline adaptive workflows. Lastly, opportunities to biologically guide adaptive RT using non-invasive imaging biomarkers and the potential to define appropriate volumes for dose modification will be discussed., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background and Purpose: Survival in glioblastoma might be extended by escalating the radiotherapy dose to treatment-resistant tumour and adapting to tumour changes. Diffusion-weighted imaging (DWI) on MRI-linear accelerators (MR-Linacs) could be used to identify a dose escalation target, but its prognostic value must be demonstrated. The purpose of this study was to determine whether MR-Linac DWI can assess treatment response in glioblastoma and whether changes in DWI show greater prognostic value than changes in the contrast-enhancing gross tumour volume (GTV)., Materials and Methods: Seventy-five patients with glioblastoma were treated with chemoradiotherapy, of which 32 were treated on a 1.5 T MRI-linear accelerator (MR-Linac). Patients were imaged with simulation MRI scanners (MR-sim) at treatment planning and weeks 2, 4, and 10 after treatment start. Twenty-eight patients had additional MR-Linac DWI sequences. Cox modelling was used to evaluate the correlation of overall and progression-free survival (OS and PFS) with clinical variables and volumetric changes in the GTV and low-ADC regions (ADC < 1.25 µm 2 /ms within GTV)., Results: In total, 479 MR-Linac DWI and 289 MR-sim DWI datasets were analyzed. MR-Linac low-ADC changes between weeks 2 and 5 inclusive were prognostic for OS (hazard ratio lower limits ≥ 1.2, p-values ≤ 0.02). MR-sim low-ADC changes showed greater correlation with OS and PFS than GTV changes (e.g., OS hazard ratio at week 2 was 3.4 (p <0.001) for low-ADC versus 2.0 (p = 0.022) for GTV)., Conclusion: MR-Linac DWI can measure low-ADC tumour volumes that correlate with OS and PFS better than contrast-enhancing GTV. Low-ADC regions could serve as dose escalation targets., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Author(s). Published by Elsevier B.V. All rights reserved.)

Background and Purpose: The apparent diffusion coefficient (ADC), a potential imaging biomarker for radiotherapy response, needs to be reproducible before translation into clinical use. The aim of this study was to evaluate the multi-centre delineation- and calculation-related ADC variation and give recommendations to minimize it., Materials and Methods: Nine centres received identical diffusion-weighted and anatomical magnetic resonance images of different cancerous tumours (adrenal gland, pelvic oligo metastasis, pancreas, and prostate). All centres delineated the gross tumour volume (GTV), clinical target volume (CTV), and viable tumour volume (VTV), and calculated ADCs using both their local calculation methods and each of the following calculation conditions: b-values 0-500 vs. 150-500 s/mm 2 , region-of-interest (ROI)-based vs. voxel-based calculation, and mean vs. median. ADC variation was assessed using the mean coefficient of variation across delineations (CV D ) and calculation methods (CV C ). Absolute ADC differences between calculation conditions were evaluated using Friedman's test. Recommendations for ADC calculation were formulated based on observations and discussions within the Elekta MRI-linac consortium image analysis working group., Results: The median (range) CV D and CV C were 0.06 (0.02-0.32) and 0.17 (0.08-0.26), respectively. The ADC estimates differed 18% between b-value sets and 4% between ROI/voxel-based calculation (p-values < 0.01). No significant difference was observed between mean and median (p = 0.64). Aligning calculation conditions between centres reduced CV C to 0.04 (0.01-0.16). CV D was comparable between ROI types., Conclusion: Overall, calculation methods had a larger impact on ADC reproducibility compared to delineation. Based on the results, significant sources of variation were identified, which should be considered when initiating new studies, in particular multi-centre investigations., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Author(s). Published by Elsevier B.V. All rights reserved.)

Background: Cysteine-dense peptides (CDPs) are an attractive pharmaceutical scaffold that display extreme biochemical properties, low immunogenicity, and the ability to bind targets with high affinity and selectivity. While many CDPs have potential and confirmed therapeutic uses, synthesis of CDPs is a challenge. Recent advances have made the recombinant expression of CDPs a viable alternative to chemical synthesis. Moreover, identifying CDPs that can be expressed in mammalian cells is crucial in predicting their compatibility with gene therapy and mRNA therapy. Currently, we lack the ability to identify CDPs that will express recombinantly in mammalian cells without labour intensive experimentation. To address this, we developed CysPresso, a novel machine learning model that predicts recombinant expression of CDPs based on primary sequence., Results: We tested various protein representations generated by deep learning algorithms (SeqVec, proteInfer, AlphaFold2) for their suitability in predicting CDP expression and found that AlphaFold2 representations possessed the best predictive features. We then optimized the model by concatenation of AlphaFold2 representations, time series transformation with random convolutional kernels, and dataset partitioning., Conclusion: Our novel model, CysPresso, is the first to successfully predict recombinant CDP expression in mammalian cells and is particularly well suited for predicting recombinant expression of knottin peptides. When preprocessing the deep learning protein representation for supervised machine learning, we found that random convolutional kernel transformation preserves more pertinent information relevant for predicting expressibility than embedding averaging. Our study showcases the applicability of deep learning-based protein representations, such as those provided by AlphaFold2, in tasks beyond structure prediction., (© 2023. The Author(s).)

Purpose: This study reports the workflow and initial clinical experience of high grade glioma (HGG) radiotherapy on the 1.5 T MR-Linac (MRL), with a focus on the temporal variations of the tumor and feasibility of multi-parametric image (mpMRI) acquisition during routine treatment workflow., Materials and Methods: Ten HGG patients treated with radiation within the first year of the MRL's clinical operation, between October 2019 and August 2020, were identified from a prospective database. Workflow timings were recorded and online adaptive plans were generated using the Adapt-To-Position (ATP) workflow. Temporal variation within the FLAIR hyperintense region (FHR) was assessed by the relative FHR volumes (n = 281 contours) and migration distances (maximum linear displacement of the volume). Research mpMRIs were acquired on the MRL during radiation and changes in selected functional parameters were investigated within the FHR., Results: All patients completed radiotherapy to a median dose of 60 Gy (range, 54-60 Gy) in 30 fractions (range, 30-33), receiving a total of 287 fractions on the MRL. The mean in-room time per fraction with or without post-beam research imaging was 42.9 minutes (range, 25.0-69.0 minutes) and 37.3 minutes (range, 24.0-51.0 minutes), respectively. Three patients (30%) required re-planning between fractions 9 to 12 due to progression of tumor and/or edema identified on daily MRL imaging. At the 10, 20, and 30-day post-first fraction time points 3, 3, and 4 patients, respectively, had a FHR volume that changed by at least 20% relative to the first fraction. Research mpMRIs were successfully acquired on the MRL. The median apparent diffusion coefficient (ADC) within the FHR and the volumes of FLAIR were significantly correlated when data from all patients and time points were pooled ( R =0.68, p <.001)., Conclusion: We report the first clinical series of HGG patients treated with radiotherapy on the MRL. The ATP workflow and treatment times were clinically acceptable, and daily online MRL imaging triggered adaptive re-planning for selected patients. Acquisition of mpMRIs was feasible on the MRL during routine treatment workflow. Prospective clinical outcomes data is anticipated from the ongoing UNITED phase 2 trial to further refine the role of MR-guided adaptive radiotherapy., Competing Interests: C-LT has received travel accommodations/expenses & honoraria for past educational seminars by Elekta and belongs to the Elekta MR-Linac Research Consortium. JS is employed at Sunnybrook Health Sciences Centre, Toronto, Ontario, Canada. SM has received research support from Novartis AG, honoraria from Novartis AG and Ipsen and travel support from Elekta, none related to this work. SD serves as the Provincial Lead for CNS Oncology at Ontario Health, Cancer Care Ontario; he receives laboratory research support from Alkermes; he serves on the advisory board of the Subcortical Surgery Group and Xpan Medical; he is a speaker for the Congress of Neurological Surgeons. MR is a co‐inventor of and owns associated intellectual property specific to the image‐guidance system on the Gamma Knife Icon, none related to this work. AS has been a consultant for Varian, Elekta Gamma Knife Icon, BrainLAB, Merck, Abbvie, Roche; Vice President of the International Stereotactic Radiosurgery Society ISRS; Co-Chair of the AO Spine Knowledge Forum Tumor; received honorarium for past educational seminars for AstraZeneca, Elekta AB, Varian, BrainLAB, Accuray, Seagen Inc.; research grant with Elekta AB, Varian, Seagen Inc., BrainLAB; and travel accommodations/expenses with Elekta, Varian and BrainLAB. AS also belongs to the Elekta MR Linac Research Consortium and is a Clinical Steering Committee Member, and chairs the Elekta Oligometastases Group and the Elekta Gamma Knife Icon Group. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Tseng, Chen, Stewart, Lau, Chan, Lawrence, Myrehaug, Soliman, Detsky, Lim-Fat, Lipsman, Das, Heyn, Maralani, Binda, Perry, Keller, Stanisz, Ruschin and Sahgal.)

Purpose: Target localization, for stereotactic radiosurgery (SRS) treatment with Gamma Knife, has become increasingly reliant on the co-registration between the planning MRI and the stereotactic cone-beam computed tomography (CBCT). Validating image registration between modalities would be particularly beneficial when considering the emergence of novel functional and metabolic MRI pulse sequences for target delineation. This study aimed to develop a phantom-based methodology to quantitatively compare the co-registration accuracy of the standard clinical imaging protocol to a representative MRI sequence that was likely to fail co-registration. The comparative methodology presented in this study may serve as a useful tool to evaluate the clinical translatability of novel MRI sequences., Methods: A realistic human skull phantom with fiducial marker columns was designed and manufactured to fit into a typical MRI head coil and the Gamma Knife patient positioning system. A series of "optimized" 3D MRI sequences-T 1 -weighted Dixon, T 1 -weighted fast field echo (FFE), and T 2 -weighted fluid-attenuated inversion recovery (FLAIR)-were acquired and co-registered to the CBCT. The same sequences were "compromised" by reconstructing without geometric distortion correction and re-collecting with lower signal-to-noise-ratio (SNR) to simulate a novel MRI sequence with poor co-registration accuracy. Image similarity metrics-structural similarity (SSIM) index, mean squared error (MSE), and peak SNR (PSNR)-were used to quantitatively compare the co-registration of the optimized and compromised MR images., Results: The ground truth fiducial positions were compared to positions measured from each optimized image volume revealing a maximum median geometric uncertainty of 0.39 mm (LR), 0.92 mm (AP), and 0.13 mm (SI) between the CT and CBCT, 0.60 mm (LR), 0.36 mm (AP), and 0.07 mm (SI) between the CT and T 1 -weighted Dixon, 0.42 mm (LR), 0.23 mm (AP), and 0.08 mm (SI) between the CT and T 1 -weighted FFE, and 0.45 mm (LR), 0.19 mm (AP), and 1.04 mm (SI) between the CT and T 2 -weighted FLAIR. Qualitatively, pairs of optimized and compromised image slices were compared using a fusion image where separable colors were used to differentiate between images. Quantitatively, MSE was the most predictive and SSIM the second most predictive metric for evaluating co-registration similarity. A clinically relevant threshold of MSE, SSIM, and/or PSNR may be defined beyond which point an MRI sequence should be rejected for target delineation based on its dissimilarity to an optimized sequence co-registration. All dissimilarity thresholds calculated using correlation coefficients with in-plane geometric uncertainty would need to be defined on a sequence-by-sequence basis and validated with patient data., Conclusion: This study utilized a realistic skull phantom and image similarity metrics to develop a methodology capable of quantitatively assessing whether a modern research-based MRI sequence can be co-registered to the Gamma Knife CBCT with equal or less than equal accuracy when compared to a clinically accepted protocol., (© 2022 American Association of Physicists in Medicine.)

Background: GBA1 mutation is the most common genetic risk factor for Parkinson's disease (PD). Replacement of the lysosomal enzyme glucocerebrosidase (GCase) slows neurodegeneration in PD models and may be a promising disease-modifying therapy in patients with PD. However, recombinant GCase has limited penetration through the blood-brain barrier (BBB). Microbubble-mediated magnetic resonance-guided focused ultrasound (MRgFUS) can reversibly disrupt the BBB for drug delivery., Methods: This open-label phase I study investigated the safety and feasibility of MRgFUS putaminal delivery of intravenous GCase at escalating doses (15 to 30 to 60 IU/kg) every 2 weeks in four patients with PD with GBA1 mutations., Results: BBB permeability was achieved and restored in all patients as quantified by dynamic contrast-enhanced magnetic resonance imaging after treatment. There were no serious adverse events. Two patients developed transient dyskinesia after treatment. Blinded Movement Disorder Society-Unified Parkinson's Disease Rating Scale motor scores off medication decreased by 12% at 6 months from baseline (from 26 ± 9 to 22 ± 6). Standardized uptake value ratio on fluorodeoxyglucose positron emission tomography imaging in the treated putamen reduced from 1.66 ± 0.14 to 1.27 ± 0.08., Conclusions: Results from this study demonstrate the safety and feasibility of MRgFUS GCase delivery in PD and support further investigation of this approach. © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society., (© 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.)

Purpose: To review and evaluate the efficacy and complication rates of external and internal blepharoptosis repair techniques in pediatric patients., Methods: The systematic review protocol was published on PROSPERO (CRD42020197343). Embase, MEDLINE, CENTRAL, and ClinicalTrials.gov were searched without date limitations. Two independent reviewers evaluated the articles for inclusion. Study quality and risk of bias were assessed using GRADE and Cochrane's ROBINS-I tool, respectively., Results: Of 2,228 articles screened, 23 studies involving 730 patients were included. There were 20 case series and 3 retrospective cohort studies, but no randomized controlled studies. Overall study quality was low with serious risk of bias according to the GRADE and ROBINS-I criteria, respectively. External levator resection was the most studied procedure, evaluated in 18 studies. Seven studies investigated internal approaches including the Fasanella-Servat procedure. There was no standardized evaluation of surgical efficacy. Reoperation rates were 16.6% (range 3.6-50.9%) for external levator resection compared with 22.2% (range 0.0-25.8%) for internal approaches. The commonest postoperative complications were not sight-threatening. The most consistently reported complication was undercorrection, occurring at rates of 8.4% (range 2.4-16.7%) and 15.3% (range 2.7-75.0%) for external levator resection and internal approaches, respectively. There were no consistently applied, validated patient-reported outcomes or cosmetic outcomes., Conclusions: External and internal approaches have been successfully employed in pediatric blepharoptosis repair. However, noncomparative designs and risk-of-bias limit existing studies. Thus, prospectively designed studies with standardized outcome measures are required to minimize reporting bias, facilitate evidence synthesis, and support clinical decision making., Competing Interests: The authors have no financial or conflicts of interest to disclose., (Copyright © 2021 The American Society of Ophthalmic Plastic and Reconstructive Surgery, Inc.)

Elevated production of lactate is a key characteristic of aberrant tumour cell metabolism and can be non-invasively measured as an early marker of tumour response using deuterium ( 2 H) MRS. Following treatment, changes in the 2 H-labelled lactate signal could identify tumour cell death or impaired metabolic function, which precede morphological changes conventionally used to assess tumour response. In this work, the association between apoptotic cell death, extracellular lactate concentration, and early treatment-induced changes in the 2 H-labelled lactate signal was established in an in vitro tumour model. Experiments were conducted at 7 T on acute myeloid leukaemia (AML) cells, which had been treated with 10 μg/mL of the chemotherapeutic agent cisplatin. At 24 and 48 h after cisplatin treatment the cells were supplied with 20 mM of [6,6'- 2 H 2 ]glucose and scanned over 2 h using a two-dimensional 2 H MR spectroscopic imaging sequence. The resulting signals from 2 H-labelled glucose, lactate, and water were quantified using a spectral fitting algorithm implemented on the Oxford Spectroscopy Analysis MATLAB toolbox. After scanning, the cells were processed for histological stains (terminal deoxynucleotidyl transferase UTP nick end labelling and haematoxylin and eosin) to assess apoptotic area fraction and cell morphology respectively, while a colorimetric assay was used to measure extracellular lactate concentrations in the supernatant. Significantly lower levels of 2 H-labelled lactate were observed in the 48 h treated cells compared with the untreated and 24 h treated cells, and these changes were significantly correlated with an increase in apoptotic fraction and a decrease in extracellular lactate. By establishing the biological processes associated with treatment-induced changes in the 2 H-labelled lactate signal, these findings suggest that 2 H MRS of lactate may be valuable in evaluating early tumour response., (© 2021 John Wiley & Sons, Ltd.)

Background and Purpose: MRI linear accelerators (MR-Linacs) may allow treatment adaptation to be guided by quantitative MRI including diffusion-weighted imaging (DWI). The aim of this study was to evaluate the accuracy and precision of apparent diffusion coefficient (ADC) measurements from DWI on a 1.5 T MR-Linac in patients with central nervous system (CNS) tumours through comparison with a diagnostic scanner., Materials and Methods: CNS patients were treated using a 1.5 T Elekta Unity MR-Linac. DWI was acquired during MR-Linac treatment and on a Philips Ingenia 1.5 T. The agreement between the two scanners on median ADC over the gross tumour/clinical target volumes (GTV/CTV) and in brain regions (white/grey matter, cerebrospinal fluid (CSF)) was computed. Repeated scans were used to estimate ADC repeatability. Daily changes in ADC over the GTV of high-grade gliomas were characterized from MR-Linac scans., Results: DWI from 59 patients was analyzed. MR-Linac ADC measurements showed a small bias relative to Ingenia measurements in white matter, grey matter, GTV, and CTV (bias: -0.05 ± 0.03, -0.08 ± 0.05, -0.1 ± 0.1, -0.08 ± 0.07 μm 2 /ms). ADC differed substantially in CSF (bias: -0.5 ± 0.3 μm 2 /ms). The repeatability of MR-Linac ADC over white/grey matter was similar to previous reports (coefficients of variation for median ADC: 1.4%/1.8%). MR-Linac ADC changes in the GTV were detectable., Conclusions: It is possible to obtain ADC measurements in the brain on a 1.5 T MR-Linac that are comparable to those of diagnostic-quality scanners. This technical validation study adds to the foundation for future studies that will correlate brain tumour ADC with clinical outcomes., Competing Interests: Conflicts of Interest Dr. Arjun Sahgal: Advisor/consultant with Abbvie, Merck, Roche, Varian (Medical Advisory Group), Elekta (Gamma Knife Icon), BrainLAB, and VieCure (Medical Advisory Board); Past educational seminars with Elekta AB, Accuray Inc., Varian (CNS Teaching Faculty), BrainLAB, Medtronic Kyphon; Research grant with Elekta AB; Travel accommodations/expenses by Elekta, Varian, BrainLAB. Dr. Chia-Lin Tseng: Travel accommodations/expenses & honoraria for past educational seminars by Elekta; belongs to the Elekta MR-Linac Research Consortium; advisor/consultant with Sanofi. Dr. Sten Myrehaug: Received research support from Novartis AG, honoraria from Novartis AG and Ipsen and travel support from Elekta. None related to this work. Dr. Mark Ruschin: Co‐inventor of and owns associated intellectual property specific to the image‐guidance system on the Gamma Knife Icon. None related to this work. Mrs. Mikki Campbell: Received honorarium for past educational seminars with Elekta AB; received research grants with Elekta AB; and travel accommodations/expenses by Elekta; belongs to the Elekta MR Linac Research Consortium. Dr. Brige Chugh: Previously held an industry partnership grant with Modus QA., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Purpose: To describe the implementation and initial results of using Chemical Exchange Saturation Transfer (CEST) for monitoring patients with central nervous system (CNS) tumours treated using a 1.5 tesla MR-guided radiotherapy system., Methods: CNS patients were treated with up to 30 fractions (total dose up to 60 Gy) using a 1.5 T Elekta Unity MR-Linac. CEST scans were obtained in 54 subjects at one or more time points during treatment. CEST metrics, including the amide magnetization transfer ratio (MTR Amide ), nuclear Overhauser effect (NOE) MTR (MTR NOE ) and asymmetry, were quantified in phantoms and CNS patients. The signal was investigated between tumour and white matter, across time, and across disease categories including high- and low-grade tumours., Results: The gross tumour volume (GTV) exhibited lower MTR Amide and MTR NOE and higher asymmetry compared to contralateral normal appearing white matter. Signal changes in the GTV during fractionated radiotherapy were observed. There were differences between high- and low-grade tumours, with higher CEST asymmetry associated with higher grade disease., Conclusion: CEST MRI using a 1.5 T MR-Linac was demonstrated to be feasible for in vivo imaging of CNS tumours. CEST images showed tumour/white-matter contrast, temporal CEST signal changes, and associations with tumour grade. These results show promise for the eventual goal of using metabolic imaging to inform the design of adaptive radiotherapy protocols., (Copyright © 2021 The Author(s). Published by Elsevier B.V. All rights reserved.)

Hyperpolarized (HP) [1- 13 C]lactate is an attractive alternative to [1- 13 C]pyruvate as a substrate to investigate cardiac metabolism in vivo: it can be administered safely at a higher dose and can be polarized to a degree similar to pyruvate via dynamic nuclear polarization. While 13 C cardiac experiments using HP lactate have been performed in small animal models, they have not been demonstrated in large animal models or humans. Utilizing the same hardware and data acquisition methods as the first human HP 13 C cardiac study, 13 C metabolic images were acquired following injections of HP [1- 13 C]lactate in porcine hearts. Data were also acquired using HP [1- 13 C]pyruvate for comparison. The 13 C bicarbonate signal was localized to the myocardium and had a similar appearance with both substrates for all animals. No 13 C pyruvate signal was detected in the experiments following injection of HP 13 C lactate. The signal-to-noise ratio (SNR) of injected lactate was 88 ± 4% of the SNR of injected pyruvate, and the SNR of bicarbonate in the experiments using lactate as the substrate was 52 ± 19% of the SNR in the experiments using pyruvate as the substrate. The lower SNR was likely due to the shorter T 1 of [1- 13 C]lactate as compared with [1- 13 C]pyruvate and the additional enzyme-catalyzed metabolic conversion step before the 13 C nuclei from [1- 13 C]lactate were detected as 13 C bicarbonate. While challenges remain, the potential of HP lactate as a substrate for clinical metabolic imaging of human heart has been demonstrated., (© 2021 John Wiley & Sons, Ltd.)

Background: Clinical target volume (CTV) contouring guidelines are frequently developed through studies in which experts contour the CTV for a representative set of cases for a given treatment site and the consensus CTVs are analyzed to generate margin recommendations. Measures of interobserver variability are used to quantify agreement between experts. In cases where an isotropic margin is not appropriate, however, there is no standard method to compute margins in specified directions that represent possible routes of tumor spread. Moreover, interobserver variability metrics are often measures of volume overlap that do not account for the dependence of disagreement on direction. To aid in the development of consensus contouring guidelines, this study demonstrates a novel method of quantifying CTV margins and interobserver variability in clinician-specified directions., Methods: The proposed algorithm was applied to 11 cases of non-spine bone metastases to compute the consensus CTV margin in each direction of intraosseous and extraosseous disease. The median over all cases for each route of spread yielded the recommended margins. The disagreement between experts on the CTV margin was quantified by computing the median of the coefficients of variation for intraosseous and extraosseous margins., Results: The recommended intraosseous and extraosseous margins were 7.0 mm and 8.0 mm, respectively. The median coefficient of variation quantifying the margin disagreement between experts was 0.59 and 0.48 for intraosseous and extraosseous disease., Conclusions: The proposed algorithm permits the generation of margin recommendations in relation to adjacent anatomy and quantifies interobserver variability in specified directions. This method can be applied to future consensus CTV contouring studies.

Patients undergoing standard chemoradiation post-resection had MRIs at radiation planning and fractions 10 and 20 of chemoradiation. MRIs were 1.5T and 3D T2-FLAIR, pre- and post-contrast 3D T1-weighted (T1) and echo planar DWI with three b-values (0, 500, and 1000s/mm 2 ) were acquired. T2-FLAIR was coregistered to T1C images. Non-overlapping T1 contrast-enhancing (T1C) and nonenhancing T2-FLAIR hyperintense regions were segmented, with necrotic/cystic regions, the surgical cavity, and large vessels excluded. The simplified IVIM model was used to calculate voxelwise diffusion coefficient ( D ) and perfusion fraction ( f ) maps; ADC was calculated using the natural logarithm of b  = 1000 over b  = 0 images. T1C and T2-FLAIR segmentations were brought into this space, and medians calculated. MGMT promoter methylation status (MGMT PMS ), age at diagnosis, and Eastern Cooperative Oncology Group (ECOG) performance status were extracted from electronic medical records. The data were presented, analyzed, and described in the article, "Intravoxel incoherent motion (IVIM) modeling of diffusion MRI during chemoradiation predicts therapeutic response in IDH wildtype Glioblastoma", published in Radiotherapy and Oncology [1]., Competing Interests: Arjun Sahgal: Advisor/consultant: AbbVie, Merck, Roche, Varian, Elekta, BrainLAB, VieCure Board Member: International Stereotactic Radiosurgery Society Co-Chair: AO Spine Knowledge Forum Tumor Past educational seminars: Elekta AB, Accuray Inc., Varian, BrainLAB, Medtronic Kyphon Research support: Elekta AB Travel support: Elekta, Varian, BrainLAB Consortia: Elekta MR Linac Research Consortium, Elekta Spine, Oligometastases and Linac Based SRS Consortia. Sten Myrehaug: Research support: Novartis AG Honoraria: Novartis AG, Ipsen Travel support: Elekta Chia-Lin Tseng: Honoraria: Elekta Travel support: Elekta Consortia: Elekta MR Linac Research Consortium Hany Soliman: Horaria: Elekta AB Travel support: Elekta AB Sunit Das: Advisor/consultant: AbbVie, Xpan Medical, Synaptive Board member: Subcortical Surgery Group Past educational seminars: AbbVie, Congress of Neurological Surgeons, American Association of Neurological Surgeons, Society for NeuroOncology Research supports: Alkerme, Medicenna Travel support: Subcortical Surgery Group, Congress of Neurological Surgeons, American Association of Neurological Surgeons, Society for NeuroOncology, Integra All other authors declare that they have no known competing financial interests or personal relationships which have, or could be perceived to have, influenced the work reported in this article., (© 2021 The Author(s). Published by Elsevier Inc.)

Background: Prediction of early progression in glioblastoma may provide an opportunity to personalize treatment. Simplified intravoxel incoherent motion (IVIM) MRI offers quantitative estimates of diffusion and perfusion metrics. We investigated whether these metrics, during chemoradiation, could predict treatment outcome., Methods: 38 patients with newly diagnosed IDH-wildtype glioblastoma undergoing 6-week/30-fraction chemoradiation had standardized post-operative MRIs at baseline (radiation planning), and at the 10th and 20th fractions. Non-overlapping T1-enhancing (T1C) and non-enhancing T2-FLAIR hyperintense regions were independently segmented. Apparent diffusion coefficient (ADC T1C , ADC T2-FLAIR ) and perfusion fraction (f T1C , f T2-FLAIR ) maps were generated with simplified IVIM modelling. Parameters associated with progression before or after 6.9 months (early vs late progression, respectively), overall survival (OS) and progression-free survival (PFS) were investigated., Results: Higher ADC T2-FLAIR at baseline [Odds Ratio (OR) = 1.06, 95% CI 1.01-1.15, p = 0.025], lower f T2-FLAIR at fraction 10 (OR = 2.11, 95% CI 1.04-4.27, p = 0.018), and lack of increase in ADC T2-FLAIR at fraction 20 compared to baseline (OR = 1.12, 95% CI 1.02-1.22, p = 0.02) were associated with early progression. Combining ADC T2-FLAIR at baseline, f T2-FLAIR at fraction 10, ECOG and MGMT promoter methylation status significantly improved AUC to 90.3% compared to a model with only ECOG and MGMT promoter methylation status (p = 0.001). Using multivariable analysis, neither IVIM metrics were associated with OS but higher f T2-FLAIR at fraction 10 (HR = 0.72, 95% CI 0.56-0.95, p = 0.018) was associated with longer PFS., Conclusion: ADC T2-FLAIR at baseline, its lack of increase from baseline to fraction 20, or f T2-FLAIR at fraction 10 significantly predicted early progression. f T2-FLAIR at fraction 10 was associated with PFS., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2021 The Authors. Published by Elsevier B.V. All rights reserved.)

Purpose: Magnetic resonance image (MRI) guided radiation therapy has the potential to improve outcomes for glioblastoma by adapting to tumor changes during radiation therapy. This study quantifies interfraction dynamics (tumor size, position, and geometry) based on sequential magnetic resonance imaging scans obtained during standard 6-week chemoradiation., Methods and Materials: Sixty-one patients were prospectively imaged with gadolinium-enhanced T1 (T1c) and T2/FLAIR axial sequences at planning (Fx0), fraction 10 (Fx10), fraction 20 (Fx20), and 1 month after the final fraction of chemoradiation therapy (P1M). Gross tumor volumes (GTVs) and clinical target volumes (CTVs) were contoured at all time points. Target dynamics were quantified by absolute volume (V), volume relative to Fx0 (V rel ), and the migration distance (d migrate ; the linear displacement of the GTV or CTV relative to Fx0). Temporal changes were assessed using a linear mixed-effects model., Results: Median volumes at Fx0, Fx10, Fx20, and P1M for the GTV were 18.4 cm 3 (range, 1.1-110.5 cm 3 ), 14.7 cm 3 (range, 0.9-115.1 cm 3 ), 13.7 cm 3 (range, 0.6-174.2 cm 3 ), and 13.0 cm 3 (range, 0.9-76.3 cm 3 ), respectively, with corresponding median V rel of 0.88 at Fx10, 0.77 at Fx20, and 0.71 at P1M relative to Fx0 (P < .001 for all). The GTV (CTV) migration distances were greater than 5 mm in 46% (54%) of patients at Fx10, 50% (58%) of patients at Fx20, and 52% (57%) of patients at P1M. Dynamic tumor morphologic changes were observed, with 40% of patients exhibiting a decreased GTV (V rel ≤1) with a d migrate >5 mm during chemoradiation therapy., Conclusions: Clinically meaningful tumor dynamics were observed during chemoradiation therapy for glioblastoma, supporting evaluation of daily MRI guided radiation therapy and treatment plan adaptation., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Purpose: Quantitative MRI (qMRI) was performed using a 1.5T protocol that includes a novel chemical exchange saturation transfer/magnetization transfer (CEST/MT) approach. The purpose of this prospective study was to determine if qMRI metrics at baseline, at the 10th and 20th fraction during a 30 fraction/6 week standard chemoradiation (CRT) schedule, and at 1 month following treatment could be an early indicator of response for glioblastoma (GBM)., Methods: The study included 51 newly diagnosed GBM patients. Four regions-of-interest (ROI) were analyzed: (i) the radiation defined clinical target volume (CTV), (ii) radiation defined gross tumor volume (GTV), (iii) enhancing-tumor regions, and (iv) FLAIR-hyperintense regions. Quantitative CEST, MT, T 1 and T 2 parameters were compared between those patients progressing within 6.9 months (early), and those progressing after CRT (late), using mixed modelling. Exploratory predictive modelling was performed to identify significant predictors of early progression using a multivariable LASSO model., Results: Results were dependent on the specific tumor ROI analyzed and the imaging time point. The baseline CEST asymmetry within the CTV was significantly higher in the early progression cohort. Other significant predictors included the T 2 of the MT pools (for semi-solid at fraction 20 and water at 1 month after CRT), the exchange rate (at fraction 20) and the MGMT methylation status., Conclusions: We observe the potential for multiparametric qMRI, including a novel pulsed CEST/MT approach, to show potential in distinguishing early from late progression GBM cohorts. Ultimately, the goal is to personalize therapeutic decisions and treatment adaptation based on non-invasive imaging-based biomarkers.

Rationale: The recent development of hyperpolarized 13 C magnetic resonance spectroscopy has made it possible to measure cellular metabolism in vivo, in real time., Objective: By comparing participants with and without type 2 diabetes mellitus (T2DM), we report the first case-control study to use this technique to record changes in cardiac metabolism in the healthy and diseased human heart., Methods and Results: Thirteen people with T2DM (glycated hemoglobin, 6.9±1.0%) and 12 age-matched healthy controls underwent assessment of cardiac systolic and diastolic function, myocardial energetics ( 31 P-magnetic resonance spectroscopy), and lipid content ( 1 H-magnetic resonance spectroscopy) in the fasted state. In a subset (5 T2DM, 5 control), hyperpolarized [1- 13 C]pyruvate magnetic resonance spectra were also acquired and in 5 of these participants (3 T2DM, 2 controls), this was successfully repeated 45 minutes after a 75 g oral glucose challenge. Downstream metabolism of [1- 13 C]pyruvate via PDH (pyruvate dehydrogenase, [ 13 C]bicarbonate), lactate dehydrogenase ([1- 13 C]lactate), and alanine transaminase ([1- 13 C]alanine) was assessed. Metabolic flux through cardiac PDH was significantly reduced in the people with T2DM (Fasted: 0.0084±0.0067 [Control] versus 0.0016±0.0014 [T2DM], Fed: 0.0184±0.0109 versus 0.0053±0.0041; P =0.013). In addition, a significant increase in metabolic flux through PDH was observed after the oral glucose challenge ( P <0.001). As is characteristic of diabetes mellitus, impaired myocardial energetics, myocardial lipid content, and diastolic function were also demonstrated in the wider study cohort., Conclusions: This work represents the first demonstration of the ability of hyperpolarized 13 C magnetic resonance spectroscopy to noninvasively assess physiological and pathological changes in cardiac metabolism in the human heart. In doing so, we highlight the potential of the technique to detect and quantify metabolic alterations in the setting of cardiovascular disease.

Purpose: To compare magnetization transfer (MT) and CEST effects between 1.5T and 3T in phantom and in vivo experiments., Methods: A pulsed saturation scheme using block-shaped pulses separated by gaps was used to overcome the single RF amplifier duty cycle limitations of a clinical 1.5T scanner. Modeling was performed by incorporating the extended phase graph formalism into a Bloch-McConnell simulation. Two saturation pulse types (with long and short pulses) were used. Estimated parameters for MT (the semi-solid pool fraction, M 0 B ; the semi-solid transverse relaxation time, T 2 B ) and CEST (asymmetry; areas) were compared between 1.5T and 3T in phantoms and in the healthy brain., Results: Improved fits were shown after inclusion of extended phase graphs. Semi-solid pool fractions in phantom (for agar with ammonium chloride) were higher for short compared to long pulses at 3T (by 19% over all concentrations) and higher at 1.5T compared to 3T (by 5%) using short pulses. In the in vivo experiments, differentiation of white and gray matter was seen in the brain at both field strengths with improved white-gray matter contrast at 3T. In white matter, the mean semi-solid fractions were 18 ± 2% at 3T and 15 ± 2% at 1.5T. The CEST asymmetry in white matter was negative (-4.9 ± 0.4%) at 3T and zero (0.0 ± 0.3%) at 1.5T., Conclusions: The pulsed saturation method with short pulses, using the extended phase graph formalism in the Bloch McConnell simulations, led to improved model fits to the data, when compared to those without extended phase graphs., (© 2019 International Society for Magnetic Resonance in Medicine.)

Purpose: Prostate cancer can be detected using a multicomponent T 2 mapping technique termed luminal water imaging. The purpose of this study is twofold: 1) To accelerate the luminal water imaging acquisition by using inner volume selection as part of a gradient and spin echo sequence, and 2) to evaluate the accuracy of luminal water fractions and multicomponent T 2 relaxation times., Methods: The accuracy of parameter estimates was assessed using Monte Carlo simulations, in phantom experiments and in the prostate (in 5 healthy subjects). Two fitting methods, nonnegative least squares and biexponential fitting with stimulated echo correction, were compared., Results: Results demonstrate that inner volume selection in a gradient and spin echo sequence is effective for accelerating prostate luminal water imaging by at least threefold. Evaluation of the accuracy shows that the estimated luminal water fractions are relatively accurate, but the short- and long-T 2 relaxation times should be interpreted with caution in noisy scenarios (SNR < 100) and when the corresponding fractions are small ( < 0.5). The mean luminal water fractions obtained at SNR above 100 are 0.27 ± 0.07 for the peripheral zone for both fitting methods, 0.16 ± 0.04 for the transition zone with nonnegative least squares, and 0.16 ± 0.03 for the transition zone with biexponential fitting including stimulated echo correction., Conclusion: The shortened scan duration allows the luminal water imaging sequence to be easily integrated into a standard multiparametric prostate MRI protocol., (© 2018 International Society for Magnetic Resonance in Medicine.)

Objectives: The aim of this study was to determine if hyperpolarized [1,4- 13 C 2 ]malate imaging could measure cardiomyocyte necrosis after myocardial infarction (MI)., Background: MI is defined by an acute burst of cellular necrosis and the subsequent cascade of structural and functional adaptations. Quantifying necrosis in the clinic after MI remains challenging. Magnetic resonance-based detection of the conversion of hyperpolarized [1,4- 13 C 2 ]fumarate to [1,4- 13 C 2 ]malate, enabled by disrupted cell membrane integrity, has measured cellular necrosis in vivo in other tissue types. Our aim was to determine whether hyperpolarized [1,4- 13 C 2 ]malate imaging could measure necrosis after MI., Methods: Isolated perfused hearts were given hyperpolarized [1,4- 13 C 2 ]fumarate at baseline, immediately after 20 min of ischemia, and after 45 min of reperfusion. Magnetic resonance spectroscopy measured conversion into [1,4- 13 C 2 ]malate. Left ventricular function and energetics were monitored throughout the protocol, buffer samples were collected and hearts were preserved for further analyses. For in vivo studies, magnetic resonance spectroscopy and a novel spatial-spectral magnetic resonance imaging sequence were implemented to assess cardiomyocyte necrosis in rats, 1 day and 1 week after cryo-induced MI., Results: In isolated hearts, [1,4- 13 C 2 ]malate production became apparent after 45 min of reperfusion, and increased 2.7-fold compared with baseline. Expression of dicarboxylic acid transporter genes were negligible in healthy and reperfused hearts, and lactate dehydrogenase release and infarct size were significantly increased in reperfused hearts. Nonlinear regression revealed that [1,4- 13 C 2 ]malate production was induced when adenosine triphosphate was depleted by >50%, below 5.3 mmol/l (R 2  = 0.904). In vivo, the quantity of [1,4- 13 C 2 ]malate visible increased 82-fold over controls 1 day after infarction, maintaining a 31-fold increase 7 days post-infarct. [1,4- 13 C 2 ]Malate could be resolved using hyperpolarized magnetic resonance imaging in the infarct region one day after MI; [1,4- 13 C 2 ]malate was not visible in control hearts., Conclusions: Malate production in the infarcted heart appears to provide a specific probe of necrosis acutely after MI, and for at least 1 week afterward. This technique could offer an alternative noninvasive method to measure cellular necrosis in heart disease, and warrants further investigation in patients., (Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.)

Hyperpolarised MRI with Dynamic Nuclear Polarisation overcomes the fundamental thermodynamic limitations of conventional magnetic resonance, and is translating to human studies with several early-phase clinical trials in progress including early reports that demonstrate the utility of the technique to observe lactate production in human brain cancer patients. Owing to the fundamental coupling of metabolism and tissue function, metabolic neuroimaging with hyperpolarised [1- 13 C]pyruvate has the potential to be revolutionary in numerous neurological disorders (e.g. brain tumour, ischemic stroke, and multiple sclerosis). Through the use of [1- 13 C]pyruvate and ethyl-[1- 13 C]pyruvate in naïve brain, a rodent model of metastasis to the brain, or porcine brain subjected to mannitol osmotic shock, we show that pyruvate transport across the blood-brain barrier of anaesthetised animals is rate-limiting. We show through use of a well-characterised rat model of brain metastasis that the appearance of hyperpolarized [1- 13 C]lactate production corresponds to the point of blood-brain barrier breakdown in the disease. With the more lipophilic ethyl-[1- 13 C]pyruvate, we observe pyruvate production endogenously throughout the entire brain and lactate production only in the region of disease. In the in vivo porcine brain we show that mannitol shock permeabilises the blood-brain barrier sufficiently for a dramatic 90-fold increase in pyruvate transport and conversion to lactate in the brain, which is otherwise not resolvable. This suggests that earlier reports of whole-brain metabolism in anaesthetised animals may be confounded by partial volume effects and not informative enough for translational studies. Issues relating to pyruvate transport and partial volume effects must therefore be considered in pre-clinical studies investigating neuro-metabolism in anaesthetised animals, and we additionally note that these same techniques may provide a distinct biomarker of blood-brain barrier permeability in future studies.

Purpose: To investigate the feasibility of performing large FOV hyperpolarized 13 C metabolic imaging using simultaneous multislice excitation., Methods: A spectral-spatial multislice excitation pulse was constructed by cosine modulation and incorporated into a 13 C spiral imaging sequence. Phantom and in vivo pig experiments were performed to test the feasibility of simultaneous multislice data acquisition and image reconstruction. In vivo cardiac-gated images of hyperpolarized pyruvate, bicarbonate, and lactate were obtained at 1 × 1 × 1 cm 3 resolution over a 48 × 48 × 24 cm 3 FOV with 2-fold acceleration in the slice direction. Sensitivity encoding was used for image reconstruction with both autocalibrated and numerically calculated coil sensitivities., Results: Simultaneous multislice images obtained with 2-fold acceleration were comparable to reference unaccelerated images. Retained SNR figures greater than 80% were achieved over the part of the image containing the heart., Conclusion: This method is anticipated to enable large FOV imaging studies using hyperpolarized 13 C substrates, with an aim toward whole-body exams that have to date been out of reach., (© 2018 The Authors Magnetic Resonance in Medicine published by Wiley Periodicals, Inc. on behalf of International Society for Magnetic Resonance in Medicine.)

The aim of this work was to investigate the use of 13 C-labelled acetoacetate and β-hydroxybutyrate as novel hyperpolarized substrates in the study of cardiac metabolism. [1- 13 C]Acetoacetate was synthesized by catalysed hydrolysis, and both it and [1- 13 C]β-hydroxybutyrate were hyperpolarized by dissolution dynamic nuclear polarization (DNP). Their metabolism was studied in isolated, perfused rat hearts. Hyperpolarized [1- 13 C]acetoacetate metabolism was also studied in the in vivo rat heart in the fed and fasted states. Hyperpolarization of [1- 13 C]acetoacetate and [1- 13 C]β-hydroxybutyrate provided liquid state polarizations of 8 ± 2% and 3 ± 1%, respectively. The hyperpolarized T 1 values for the two substrates were 28 ± 3 s (acetoacetate) and 20 ± 1 s (β-hydroxybutyrate). Multiple downstream metabolites were observed within the perfused heart, including acetylcarnitine, citrate and glutamate. In the in vivo heart, an increase in acetylcarnitine production from acetoacetate was observed in the fed state, as well as a potential reduction in glutamate. In this work, methods for the generation of hyperpolarized [1- 13 C]acetoacetate and [1- 13 C]β-hydroxybutyrate were investigated, and their metabolism was assessed in both isolated, perfused rat hearts and in the in vivo rat heart. These preliminary investigations show that DNP can be used as an effective in vivo probe of ketone body metabolism in the heart., (© 2018 The Authors. NMR in Biomedicine published by John Wiley & Sons Ltd.)

Rationale: Current cardiovascular clinical imaging techniques offer only limited assessment of innate immune cell-driven inflammation, which is a potential therapeutic target in myocardial infarction (MI) and other diseases. Hyperpolarized magnetic resonance (MR) is an emerging imaging technology that generates contrast agents with 10- to 20 000-fold improvements in MR signal, enabling cardiac metabolite mapping., Objective: To determine whether hyperpolarized MR using [1- 13 C]pyruvate can assess the local cardiac inflammatory response after MI., Methods and Results: We performed hyperpolarized [1- 13 C]pyruvate MR studies in small and large animal models of MI and in macrophage-like cell lines and measured the resulting [1- 13 C]lactate signals. MI caused intense [1- 13 C]lactate signal in healing myocardial segments at both day 3 and 7 after rodent MI, which was normalized at both time points after monocyte/macrophage depletion. A near-identical [1- 13 C]lactate signature was also seen at day 7 after experimental MI in pigs. Hyperpolarized [1- 13 C]pyruvate MR spectroscopy in macrophage-like cell suspensions demonstrated that macrophage activation and polarization with lipopolysaccharide almost doubled hyperpolarized lactate label flux rates in vitro; blockade of glycolysis with 2-deoxyglucose in activated cells normalized lactate label flux rates and markedly inhibited the production of key proinflammatory cytokines. Systemic administration of 2-deoxyglucose after rodent MI normalized the hyperpolarized [1- 13 C]lactate signal in healing myocardial segments at day 3 and also caused dose-dependent improvement in IL (interleukin)-1β expression in infarct tissue without impairing the production of key reparative cytokines. Cine MRI demonstrated improvements in systolic function in 2-DG (2-deoxyglucose)-treated rats at 3 months., Conclusions: Hyperpolarized MR using [1- 13 C]pyruvate provides a novel method for the assessment of innate immune cell-driven inflammation in the heart after MI, with broad potential applicability across other cardiovascular disease states and suitability for early clinical translation., (© 2018 The Authors.)

Purpose: Echo planar imaging is an attractive rapid imaging readout that can image hyperpolarized compounds in vivo. By alternating the sign of the phase encoding gradient waveform, spatial offsets arising from uncertain frequency shifts can be determined. We show here that blip-reversed echo planar imaging can also be used to correct for susceptibility and B 0 inhomogeneity effects that would otherwise produce image-domain distortion in the heart., Methods: Previously acquired blip-reversed cardiac 3D-Spectral-Spatial echo planar imaging volumetric timecourses of hyperpolarized [1- 13 C]pyruvate were distortion corrected by a deformation field estimated by reconstructing signal-to-noise ratio (SNR)-weighted progressively subsampled temporally summed images of each metabolite., Results: Reconstructing blip-reversed data as proposed produced volumetric timecourses that overlaid with proton reference images more consistently than without such corrections., Conclusion: The method proposed may form an attractive method to correct for image-domain distortions in hyperpolarized echo planar imaging experiments. Magn Reson Med 79:2135-2141, 2018. © 2017 The Authors Magnetic Resonance in Medicine published by Wiley Periodicals, Inc. on behalf of International Society for Magnetic Resonance in Medicine. This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited., (© 2017 The Authors Magnetic Resonance in Medicine.)

Previous studies have demonstrated that using hyperpolarized [2- 13 C]pyruvate as a contrast agent can reveal 13 C signals from metabolites associated with the tricarboxylic acid (TCA) cycle. However, the metabolites detectable from TCA cycle-mediated oxidation of [2- 13 C]pyruvate are the result of several metabolic steps. In the instance of the [5- 13 C]glutamate signal, the amplitude can be modulated by changes to the rates of pyruvate dehydrogenase (PDH) flux, TCA cycle flux and metabolite pool size. Also key is the malate-aspartate shuttle, which facilitates the transport of cytosolic reducing equivalents into the mitochondria for oxidation via the malate-α-ketoglutarate transporter, a process coupled to the exchange of cytosolic malate for mitochondrial α-ketoglutarate. In this study, we investigated the mechanism driving the observed changes to hyperpolarized [2- 13 C]pyruvate metabolism. Using hyperpolarized [1,2- 13 C]pyruvate with magnetic resonance spectroscopy (MRS) in the porcine heart with different workloads, it was possible to probe 13 C-glutamate labeling relative to rates of cytosolic metabolism, PDH flux and TCA cycle turnover in a single experiment non-invasively. Via the [1- 13 C]pyruvate label, we observed more than a five-fold increase in the cytosolic conversion of pyruvate to [1- 13 C]lactate and [1- 13 C]alanine with higher workload. 13 C-Bicarbonate production by PDH was increased by a factor of 2.2. Cardiac cine imaging measured a two-fold increase in cardiac output, which is known to couple to TCA cycle turnover. Via the [2- 13 C]pyruvate label, we observed that 13 C-acetylcarnitine production increased 2.5-fold in proportion to the 13 C-bicarbonate signal, whereas the 13 C-glutamate metabolic flux remained constant on adrenergic activation. Thus, the 13 C-glutamate signal relative to the amount of 13 C-labeled acetyl-coenzyme A (acetyl-CoA) entering the TCA cycle was decreased by 40%. The data strongly suggest that NADH (reduced form of nicotinamide adenine dinucleotide) shuttling from the cytosol to the mitochondria via the malate-aspartate shuttle is limited on adrenergic activation. Changes in [5- 13 C]glutamate production from [2- 13 C]pyruvate may play an important future role in non-invasive myocardial assessment in patients with cardiovascular diseases, but careful interpretation of the results is required., (Copyright © 2017 John Wiley & Sons, Ltd.)

Purpose: To demonstrate the feasibility of mapping intracellular pH within the in vivo rodent heart. Alterations in cardiac acid-base balance can lead to acute contractile depression and alterations in Ca 2+ signaling. The transient reduction in adenosine triphosphate (ATP) consumption and cardiac contractility may be initially beneficial; however, sustained pH changes can be maladaptive, leading to myocardial damage and electrical arrhythmias., Methods: Spectrally selective radiofrequency (RF) pulses were used to excite the HCO3- and CO 2 resonances individually while preserving signal from the injected hyperpolarized [1- 13 C]pyruvate. The large flip angle pulses were placed within a three-dimensional (3D) imaging acquisition, which exploited CA-mediated label exchange between HCO3- and CO 2 . Images at 4.5 × 4.5 × 5 mm 3 resolution were obtained in the in vivo rodent heart. The technique was evaluated in healthy rodents scanned at baseline and during high cardiac workload induced by dobutamine infusion., Results: The intracellular pH was measured to be 7.15 ± 0.04 at baseline, and decreased to 6.90 ± 0.06 following 15 min of continuous β-adrenergic stimulation., Conclusions: Volumetric maps of intracellular pH can be obtained following an injection of hyperpolarized [1- 13 C]pyruvate. The new method is anticipated to enable assessment of stress-inducible ischemia and potential ventricular arrythmogenic substrates within the ischemic heart. Magn Reson Med 77:1810-1817, 2017. © 2016 The Authors Magnetic Resonance in Medicine published by Wiley Periodicals, Inc. on behalf of International Society for Magnetic Resonance in Medicine. This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited., (© 2016 The Authors Magnetic Resonance in Medicine published by Wiley Periodicals, Inc. on behalf of International Society for Magnetic Resonance in Medicine.)

Purpose: To demonstrate the feasibility of imaging a bolus of co-polarized [1- 13 C]pyruvate and 13 C-urea to simultaneously assess both metabolism and perfusion in the rodent heart., Methods: Copolarized [1- 13 C]pyruvate and 13 C-urea was imaged using a multi-echo, flow-sensitized spiral pulse sequence. Healthy rats were scanned in a two-factor factorial design (n = 12 total; metabolism: overnight fasting versus fed with dichloroacetate injection; perfusion: rest versus adenosine stress-induced hyperemia)., Results: Alterations in metabolism were detected by changes in pyruvate metabolism into 13 C-bicarbonate. Statistically independent alterations in perfusion were detected by changes in myocardial pyruvate and urea signals., Conclusion: The new pulse sequence was used to obtain maps of metabolism and perfusion in the rodent heart in a single acquisition. This hyperpolarized 13 C imaging test is expected to enable new studies in which the cardiac metabolism/perfusion mismatch can be studied in the acute environment. Magn Reson Med 77:151-158, 2017. © 2016 The Authors Magnetic Resonance in Medicine published by Wiley Periodicals, Inc. on behalf of International Society for Magnetic Resonance in Medicine., (© 2016 The Authors Magnetic Resonance in Medicine published by Wiley Periodicals, Inc. on behalf of International Society for Magnetic Resonance in Medicine.)

Purpose: To demonstrate the feasibility of accelerating measurements of cardiac fiber structure using simultaneous multislice (SMS) imaging., Methods: SMS excitation with a blipped controlled aliasing (CAIPI) readout was incorporated into a diffusion-encoded stimulated echo pulse sequence to obtain diffusion measurements in three separate slices of the heart (8-mm thickness, 12-mm gap). A novel image entropy-based method for removing image ghosts in blipped CAIPI acquisitions is also introduced that enables SMS imaging of closely spaced slices in the heart., Results: The average retained signal-to-noise ratio (SNR) using this acquisition scheme is 70% ± 5%, higher than the standard 1/3 = 57% SNR penalty with three-fold acceleration. No significant difference was observed in the apparent diffusion coefficient and helix angle diffusion parameters between a time-equivalent conventional single-slice scan and the three-fold accelerated SMS acquisition. A 10% mean bias was observed in fractional anisotropy between single-slice and SMS acquisitions., Conclusion: The new sequence was used to obtain high-quality diffusion measurements in three closely spaced cardiac slices in a clinically feasible nine breath-hold examination. The accelerated multiband sequence is anticipated to improve quantitative measurements of cardiac microstructure by reducing the number of breath-holds required for the scan, making it practical to incorporate diffusion tensor measurements within a comprehensive clinical examination., (© 2014 Wiley Periodicals, Inc.)

Objective: The recent identification of functional depots of brown adipose tissue (BAT) in adult humans has potential implications for the treatment of obesity. In order to evaluate new therapies aimed at inducing the production of more BAT or activating BAT in humans, it will be important to develop noninvasive methods to assess the functional state of the tissue in vivo. In this study, we investigate the feasibility of using hyperpolarized (13)C imaging to noninvasively identify functional, activated BAT in an in vivo rodent model, in less than 1 min, following an infusion of pre-polarized [1-(13)C] pyruvate., Design: Hyperpolarized (13)C imaging was used to monitor BAT metabolic conversion of pre-polarized [1-(13)C] pyruvate in rats during baseline and norepinephrine (NE)-stimulated conditions., Results: Activated BAT, stimulated by NE injection, can be detected in rats by increased conversion of pre-polarized [1-(13)C] pyruvate into its downstream products (13)C bicarbonate and [1-(13)C] lactate. The colocalization of the (13)C signal to interscapular BAT was validated using hematoxylin-eosin histological staining., Conclusion: The radiation-free nature and recent translation into the clinic of the hyperpolarized (13)C-imaging test may potentially facilitate trials of therapeutics targeting BAT activation in humans.

MR imaging using hyperpolarized (13)C substrates has become a promising tool to study real-time cardiac-metabolism in vivo. For such fast imaging of nonrecoverable prepolarized magnetization it is important to optimize the RF-coils to obtain the best signal-to-noise ratio possible, given the required coverage. In this work, three different receiver-coil configurations were computed in pig and human models. The sensitivity maps were demonstrated in phantoms and in vivo experiments performed in pigs. Signal-to-noise ratio in the posterior heart was increased up to 80% with the best multichannel coil as expected. These new coil configurations will allow imaging of the different metabolite signals even in the posterior regions of the myocardium, which is not possible with a single-channel surface-coil., (Copyright © 2012 Wiley Periodicals, Inc.)

Spatially resolved images of hyperpolarized (13) C substrates and their downstream products provide insight into real-time metabolic processes occurring in vivo. Recently, hyperpolarized (13) C pyruvate has been used to characterize in vivo cardiac metabolism in the rat and pig, but accurate and reproducible measurements remain challenging due to the limited period available for imaging as well as physiological motion. In this article, time-resolved cardiac- and respiratory-gated images of [1-(13) C] pyruvate, [1-(13) C] lactate, and (13) C bicarbonate in the heart are acquired without the need for a breathhold. The robustness of these free-breathing measurements is demonstrated using the time-resolved data to produce a normalized metric of pyruvate dehydrogenase and lactate dehydrogenase activity in the heart. The values obtained are reproducible in a controlled metabolic state. In a 60-min ischemia/reperfusion model, significant differences in hyperpolarized bicarbonate and lactate, normalized using the left ventricular pyruvate signal, were detected between scans performed at baseline and 45 min after reperfusion. The sequence is anticipated to improve quantitative measurements of cardiac metabolism, leading to feasible validation studies using fewer subjects, and potentially improved diagnosis, serial monitoring, and treatment of cardiac disease in patients., (Copyright © 2012 Wiley Periodicals, Inc.)

(13)C MR spectroscopy studies performed on hearts ex vivo and in vivo following perfusion of prepolarized [1-(13)C]pyruvate have shown that changes in pyruvate dehydrogenase (PDH) flux may be monitored non-invasively. However, to allow investigation of Krebs cycle metabolism, the (13)C label must be placed on the C2 position of pyruvate. Thus, the utilization of either C1 or C2 labeled prepolarized pyruvate as a tracer can only afford a partial view of cardiac pyruvate metabolism in health and disease. If the prepolarized pyruvate molecules were labeled at both C1 and C2 positions, then it would be possible to observe the downstream metabolites that were the results of both PDH flux ((13)CO(2) and H(13)CO(3)(-)) and Krebs cycle flux ([5-(13)C]glutamate) with a single dose of the agent. Cardiac pH could also be monitored in the same experiment, but adequate SNR of the (13)CO(2) resonance may be difficult to obtain in vivo. Using an interleaved selective RF pulse acquisition scheme to improve (13)CO(2) detection, the feasibility of using dual-labeled hyperpolarized [1,2-(13)C(2)]pyruvate as a substrate for dynamic cardiac metabolic MRS studies to allow simultaneous investigation of PDH flux, Krebs cycle flux and pH, was demonstrated in vivo., (Copyright © 2011 John Wiley & Sons, Ltd.)

Hyperpolarization of (13) C labeled substrates via dynamic nuclear polarization has been used as a method to noninvasively study real-time metabolic processes occurring in vivo. In these studies, proper calibration of radiofrequency transmit power is required to efficiently observe rapidly decaying magnetization. Conventional transmit radiofrequency field (B₁⁺) mapping methods rely on placing magnetization in a fixed, known state prior to imaging, making them unsuitable for imaging of hyperpolarized magnetization. Recently, a phase-based B(1) mapping method based on the Bloch-Siegert shift has been reported. This method uses a B(1) -dependent shift in the resonance frequency of nuclei in the presence of an off-resonance radiofrequency pulse. In this article, we investigate the feasibility of Bloch-Siegert B(1) mapping and observation of metabolism of hyperpolarized [1-¹³C] pyruvate in vivo, in a single injection. The technique is demonstrated with phantom experiments, and in normal rat and pigs in vivo. This method is anticipated to improve quantitative measurements of hyperpolarized (13) C metabolism in vivo by enabling accurate flip-angle corrections. This work demonstrates the use of Bloch-Siegert B(1) mapping under challenging out-of-equilibrium imaging conditions., (Copyright © 2011 Wiley-Liss, Inc.)

Dynamic nuclear polarization and dissolution offer the exciting possibility of imaging biochemical reactions in vivo, including some of the key enzymatic reactions involved in cellular metabolism. The development of new pulse sequence strategies has been motivated by demanding applications, such as the imaging of hyperpolarized metabolite distributions in the heart. In this article, the key considerations surrounding the application of spectral-spatial imaging pulse sequences for hyperpolarized (13)C metabolic imaging in cardiac and cancer applications are explored. Spiral pulse sequences for multislice imaging of [1-(13)C]pyruvate in the heart were developed, as well as time-resolved, three-dimensional, echo-planar imaging sequences for the imaging of [1-(13)C]pyruvate-lactate exchange in cancer. The advantages and challenges associated with these sequences were determined by testing in pig and rat models., (Copyright © 2011 John Wiley & Sons, Ltd.)

Hyperpolarization of spins via dynamic nuclear polarization (DNP) has been explored as a method to non-invasively study real-time metabolic processes occurring in vivo using (13)C-labeled substrates. Recently, hyperpolarized (13)C pyruvate has been used to characterize in vivo cardiac metabolism in the rat and pig. Conventional 3D spectroscopic imaging methods require in excess of 100 excitations, making it challenging to acquire a full cardiac-gated, breath-held, whole-heart volume. In this article, the development of a rapid multislice cardiac-gated spiral (13)C imaging pulse sequence consisting of a large flip-angle spectral-spatial excitation RF pulse combined with a single-shot spiral k-space trajectory for rapid imaging of cardiac metabolism is described. This sequence permits whole-heart coverage (6 slices, 8.8-mm in-plane resolution) in any plane, allowing imaging of the metabolites of interest, [1-(13)C] pyruvate, [1-(13)C] lactate, and (13)C bicarbonate, within a single breathhold. Pyruvate and bicarbonate cardiac volumes were acquired, while lactate images were not acquired due to low lactate levels in the animal model studied. The sequence was demonstrated with phantom experiments and in vivo testing in a pig model., (Copyright © 2010 Wiley-Liss, Inc.)