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The concentration of sodium ions (Na+) is raised in solid tumours and can be measured at the cellular, tissue and patient levels. At the cellular level, the Na+ gradient across the membrane powers the transport of H+ ions and essential nutrients for normal activity. The maintenance of the Na+ gradient requires a large proportion of the cell's ATP. Na+ is a major contributor to the osmolarity of the tumour microenvironment, which affects cell volume and metabolism as well as immune function. Here, we review evidence indicating that Na+ handling is altered in tumours, explore our current understanding of the mechanisms that may underlie these alterations and consider the potential consequences for cancer progression. Dysregulated Na+ balance in tumours may open opportunities for new imaging biomarkers and re-purposing of drugs for treatment. [ABSTRACT FROM AUTHOR]

Hyperpolarized carbon-13 ( 13 C) magnetic resonance imaging (MRI) has shown promise for non-invasive assessment of the cerebral metabolism of [1- 13 C]pyruvate in both healthy volunteers and patients. The exchange of pyruvate to lactate catalysed by lactate dehydrogenase (LDH) and that of pyruvate flux to bicarbonate through pyruvate dehydrogenase (PDH) are the most widely studied reactions in vivo. Here we show the potential of the technique to probe additional enzymatic activity within the brain. Approximately 50 s after intravenous injection of hyperpolarized pyruvate, high-flip-angle pulses were used to detect cerebral 13 C-labelled carbon dioxide ( 13 CO 2 ), in addition to the 13 C-bicarbonate (H 13 CO 3 - ) subsequently formed by carbonic anhydrase (CA). Brain pH measurements, which were weighted towards the extracellular compartment, were calculated from the ratio of H 13 CO 3 - to 13 C]aspartate was also detected, demonstrating irreversible pyruvate carboxylation to oxaloacetate by pyruvate carboxylase (PC) and subsequent transamination by aspartate aminotransferase (AST), with the average flux being on average 11% ± 3% of that through PDH. A hyperpolarized [1- 2 in seven volunteers using the Henderson-Hasselbalch equation, demonstrating an average pH ± SD of 7.40 ± 0.02, with inter-observer reproducibility of 0.04. In addition, hyperpolarized [1- 13 C]aspartate was also detected, demonstrating irreversible pyruvate carboxylation to oxaloacetate by pyruvate carboxylase (PC) and subsequent transamination by aspartate aminotransferase (AST), with the average flux being on average 11% ± 3% of that through PDH. A hyperpolarized [1- 13 C]alanine signal was also detected, but this was localized to extracranial muscle tissue in keeping with skeletal alanine aminotransferase (ALT) activity. The results demonstrate the potential of hyperpolarized 13 C-MRI to assess cerebral and extracerebral [1- 13 C]pyruvate metabolism in addition to LDH and PDH activity. Non-invasive measurements of brain pH could be particularly important in assessing cerebral pathology given the wide range of disease processes that alter acid-base balance., (© 2024 The Author(s). NMR in Biomedicine published by John Wiley & Sons Ltd.)

Introduction: Localised renal masses are an increasing burden on healthcare due to the rising number of cases. However, conventional imaging cannot reliably distinguish between benign and malignant renal masses, and renal mass biopsies are unable to characterise the entirety of the tumour due to sampling error, which may lead to delayed treatment or overtreatment. There is an unmet clinical need to develop novel imaging techniques to characterise renal masses more accurately. Renal tumours demonstrate characteristic metabolic reprogramming, and novel MRI methods have the potential to detect these metabolic perturbations, which may therefore aid accurate characterisation. Here, we present our study protocol for the investigation of the differential biology of benign and malignant renal masses using advanced MRI techniques (IBM-Renal)., Methods and Analysis: IBM-Renal is a multiarm, single-centre, non-randomised, feasibility study with the aim to provide preliminary evidence for the potential role of the novel MRI techniques to phenotype localised renal lesions. 30 patients with localised renal masses will be recruited to three imaging arms, with 10 patients in each: (1) hyperpolarised [1- 13 C]-pyruvate MRI, (2) deuterium metabolic imaging (DMI) and (3) sodium MRI. The diagnosis will be made on samples acquired at biopsy or at surgery. The primary objective is the technical development of the novel MRI techniques, with the ultimate aim to understand whether these can identify differences between benign and malignant tumours, while the secondary objectives aim to assess how complementary the techniques are, and if they provide additional information. The exploratory objective is to link imaging findings with clinical data and molecular analyses for the biological validation of the novel MRI techniques., Ethics and Dissemination: This study was ethically approved (UK REC HRA: 22/EE/0136; current protocol version 2.1 dated 11 August 2022). The plans for dissemination include presentations at conferences, publications in scientific journals, a doctoral thesis and patient and public involvement., Trial Registration Number: NCT06016075., Competing Interests: Competing interests: GDS has received educational grants from Pfizer, AstraZeneca and Intuitive Surgical; consultancy fees from Pfizer, MSD, EUSA Pharma and CMR Surgical; Travel expenses from MSD and Pfizer; Speaker fees from Pfizer; Clinical lead (urology) National Kidney Cancer Audit and Topic Advisor for the NICE kidney cancer guideline. SJW is a founder and director of Pinto Medical Consultancy. FAG has research grants from GlaxoSmithKline and AstraZeneca, research support from GE Healthcare and has consulted for AstraZeneca on behalf of the University of Cambridge. All other authors have no competing interests., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY. Published by BMJ.)

Purpose: To develop a highly accelerated multi-echo spin-echo method, TEMPURA, for reducing the acquisition time and/or increasing spatial resolution for kidney T 2 mapping., Methods: TEMPURA merges several adjacent echoes into one k-space by either combining independent echoes or sharing one echo between k-spaces. The combined k-space is reconstructed based on compressed sensing theory. Reduced flip angles are used for the refocusing pulses, and the extended phase graph algorithm is used to correct the effects of indirect echoes. Two sequences were developed: a fast breath-hold sequence; and a high-resolution sequence. The performance was evaluated prospectively on a phantom, 16 healthy subjects, and two patients with different types of renal tumors., Results: The fast TEMPURA method reduced the acquisition time from 3-5 min to one breath-hold (18 s). Phantom measurements showed that fast TEMPURA had a mean absolute percentage error (MAPE) of 8.2%, which was comparable to a standardized respiratory-triggered sequence (7.4%), but much lower than a sequence accelerated by purely k-t undersampling (21.8%). High-resolution TEMPURA reduced the in-plane voxel size from 3 × 3 to 1 × 1 mm 2 , resulting in improved visualization of the detailed anatomical structure. In vivo T 2 measurements demonstrated good agreement (fast: MAPE = 1.3%-2.5%; high-resolution: MAPE = 2.8%-3.3%) and high correlation coefficients (fast: R = 0.85-0.98; high-resolution: 0.82-0.96) with the standardized method, outperforming k-t undersampling alone (MAPE = 3.3-4.5%, R = 0.57-0.59)., Conclusion: TEMPURA provides fast and high-resolution renal T 2 measurements. It has the potential to improve clinical throughput and delineate intratumoral heterogeneity and tissue habitats at unprecedented spatial resolution., (© 2024 The Authors. Magnetic Resonance in Medicine published by Wiley Periodicals LLC on behalf of International Society for Magnetic Resonance in Medicine.)

Hyperpolarised magnetic resonance imaging (HP- 13 C-MRI) has shown promise as a clinical tool for detecting and characterising prostate cancer. Here we use a range of spatially resolved histological techniques to identify the biological mechanisms underpinning differential [1- 13 C]lactate labelling between benign and malignant prostate, as well as in tumours containing cribriform and non-cribriform Gleason pattern 4 disease. Here we show that elevated hyperpolarised [1- 13 C]lactate signal in prostate cancer compared to the benign prostate is primarily driven by increased tumour epithelial cell density and vascularity, rather than differences in epithelial lactate concentration between tumour and normal. We also demonstrate that some tumours of the cribriform subtype may lack [1- 13 C]lactate labelling, which is explained by lower epithelial lactate dehydrogenase expression, higher mitochondrial pyruvate carrier density, and increased lipid abundance compared to lactate-rich non-cribriform lesions. These findings highlight the potential of combining spatial metabolic imaging tools across scales to identify clinically significant metabolic phenotypes in prostate cancer., (© 2024. The Author(s).)

Objective. A model-based alternating reconstruction coupling fitting, termed Model-based Alternating Reconstruction COupling fitting (MARCO), is proposed for accurate and fast magnetic resonance parameter mapping. Approach. MARCO utilizes the signal model as a regularization by minimizing the bias between the image series and the signal produced by the suitable signal model based on iteratively updated parameter maps when reconstructing. The technique can incorporate prior knowledge of both image series and parameters by adding sparsity constraints. The optimization problem is decomposed into three subproblems and solved through three alternating steps involving reconstruction and nonlinear least-square fitting, which can produce both contrast-weighted images and parameter maps simultaneously. Main results. The algorithm is applied to T 2 mapping with extended phase graph algorithm integrated and validated on undersampled multi-echo spin-echo data from both phantom and in vivo sources. Compared with traditional compressed sensing and model-based methods, the proposed approach yields more accurate T The proposed method provides a basic framework for quantitative MR relaxometry, theoretically applicable to all quantitative MR relaxometry. It has the potential to improve the diagnostic utility of quantitative imaging techniques.2 maps with more details at high acceleration factors. Significance. The proposed method provides a basic framework for quantitative MR relaxometry, theoretically applicable to all quantitative MR relaxometry. It has the potential to improve the diagnostic utility of quantitative imaging techniques., (© 2024 Institute of Physics and Engineering in Medicine.)

Background: Clinical imaging tools to probe aggressiveness of renal masses are lacking, and T2-weighted imaging as an integral part of magnetic resonance imaging protocol only provides qualitative information. We developed high-resolution and accelerated T2 mapping methods based on echo merging and using k-t undersampling and reduced flip angles (TEMPURA) and tested their potential to quantify differences between renal tumour subtypes and grades., Methods: Twenty-four patients with treatment-naïve renal tumours were imaged: seven renal oncocytomas (RO); one eosinophilic/oncocytic renal cell carcinoma; two chromophobe RCCs (chRCC); three papillary RCCs (pRCC); and twelve clear cell RCCs (ccRCC). Median, kurtosis, and skewness of T2 were quantified in tumours and in the normal-adjacent kidney cortex and were compared across renal tumour subtypes and between ccRCC grades., Results: High-resolution TEMPURA depicted the tumour structure at improved resolution compared to conventional T2-weighted imaging. The lowest median T2 values were present in pRCC (high-resolution, 51 ms; accelerated, 45 ms), which was significantly lower than RO (high-resolution; accelerated, p = 0.012) and ccRCC (high-resolution, p = 0.019; accelerated, p = 0.008). ROs showed the lowest kurtosis (high-resolution, 3.4; accelerated, 4.0), suggestive of low intratumoural heterogeneity. Lower T2 values were observed in higher compared to lower grade ccRCCs (grades 2, 3 and 4 on high-resolution, 209 ms, 151 ms, and 106 ms; on accelerated, 172 ms, 160 ms, and 102 ms, respectively), with accelerated TEMPURA showing statistical significance in comparison (p = 0.037)., Conclusions: Both high-resolution and accelerated TEMPURA showed marked potential to quantify differences across renal tumour subtypes and between ccRCC grades., Trial Registration: ClinicalTrials.gov, NCT03741426 . Registered on 13 November 2018., Relevance Statement: The newly developed T 2 mapping methods have improved resolution, shorter acquisition times, and promising quantifiable readouts to characterise incidental renal masses., (© 2024. The Author(s).)

Hyperpolarization techniques significantly enhance the sensitivity of magnetic resonance (MR) and thus present fascinating new directions for research and applications with in vivo MR imaging and spectroscopy (MRI/S). Hyperpolarized 13 C MRI/S, in particular, enables real-time non-invasive assessment of metabolic processes and holds great promise for a diverse range of clinical applications spanning fields like oncology, neurology, and cardiology, with a potential for improving early diagnosis of disease, patient stratification, and therapy response assessment. Despite its potential, technical challenges remain for achieving clinical translation. This paper provides an overview of the discussions that took place at the international workshop "New Horizons in Hyperpolarized 13 C MRI," in March 2023 at the Bavarian Academy of Sciences and Humanities, Munich, Germany. The workshop covered new developments, as well as future directions, in topics including polarization techniques (particularly focusing on parahydrogen-based methods), novel probes, considerations related to data acquisition and analysis, and emerging clinical applications in oncology and other fields., (© 2023. The Author(s).)

While radical prostatectomy remains the mainstay of prostate cancer (PCa) treatment, 20 to 40% of patients develop postsurgical biochemical recurrence (BCR). A particularly challenging clinical cohort includes patients with intermediate-risk disease whose risk stratification would benefit from advanced approaches that complement standard-of-care diagnostic tools. Here, we show that imaging tumor lactate using hyperpolarized 13 C MRI and spatial metabolomics identifies BCR-positive patients in two prospective intermediate-risk surgical cohorts. Supported by spatially resolved tissue analysis of established glycolytic biomarkers, this study provides the rationale for multicenter trials of tumor metabolic imaging as an auxiliary tool to support PCa treatment decision-making., Competing Interests: Competing interests statement:G.H., J.R., S.T.B., and R.J.A.G. are AstraZeneca employees.

Hyperpolarized carbon 13 MRI ( 13 C MRI) is a novel imaging approach that can noninvasively probe tissue metabolism in both normal and pathologic tissues. The process of hyperpolarization increases the signal acquired by several orders of magnitude, allowing injected 13 C-labeled molecules and their downstream metabolites to be imaged in vivo, thus providing real-time information on kinetics. To date, the most important reaction studied with hyperpolarized 13 C MRI is exchange of the hyperpolarized 13 C signal from injected [1- 13 C]pyruvate with the resident tissue lactate pool. Recent preclinical and human studies have shown the role of several biologic factors such as the lactate dehydrogenase enzyme, pyruvate transporter expression, and tissue hypoxia in generating the MRI signal from this reaction. Potential clinical applications of hyperpolarized 13 C MRI in oncology include using metabolism to stratify tumors by grade, selecting therapeutic pathways based on tumor metabolic profiles, and detecting early treatment response through the imaging of shifts in metabolism that precede tumor structural changes. This review summarizes the foundations of hyperpolarized 13 C MRI, presents key findings from human cancer studies, and explores the future clinical directions of the technique in oncology. Keywords: Hyperpolarized Carbon 13 MRI, Molecular Imaging, Cancer, Tissue Metabolism © RSNA, 2023.

Objectives: Dynamic contrast-enhanced MR images can be analyzed through the application of a wide range of kinetic models. This process is prone to variability and a lack of standardization that can affect the measured metrics. There is a need for customized digital reference objects (DROs) for the validation of DCE-MRI software packages that undertake kinetic model analysis. DROs are currently available only for a small subset of the kinetic models commonly applied to DCE-MRI data. This work aimed to address this gap., Methods: Code was written in the MATLAB programming environment to generate customizable DROs. This modular code allows the insertion of a plug-in to describe the kinetic model to be tested. We input our generated DROs into three commercial and open-source analysis packages and assessed the agreement of kinetic model parameter values output with the 'ground-truth' values used in the DRO generation., Results: For the five kinetic models tested, the concordance correlation coefficient values were >98%, indicating excellent agreement of the results with 'ground-truth'., Conclusions: Testing our DROs on three independent software packages produced concordant results, strongly suggesting our DRO generation code is correct. This implies that our DROs can be used to validate other third party software for the kinetic model analysis of DCE-MRI data., Advances in Knowledge: This work extends published work of others to allow customized generation of test objects for any applied kinetic model and allows the incorporation of B 1 mapping into the DRO for application at higher field strengths.

Hyperpolarised [1- 13 C]pyruvate MRI (HP- 13 C-MRI) is an emerging metabolic imaging technique that has shown promise for evaluating prostate cancer (PCa) aggressiveness. Accurate tumour delineation on HP- 13 C-MRI is vital for quantitative assessment of the underlying tissue metabolism. However, there is no consensus on the optimum method for segmenting HP- 13 C-MRI, and whole-mount pathology (WMP) as the histopathological gold-standard is only available for surgical patients. Although proton MRI can be used for tumour delineation, this approach significantly underestimates tumour volume, and metabolic tumour segmentation based on HP- 13 C-MRI could provide an important functional metric of tumour volume. In this study, we quantified metabolism using HP- 13 C-MRI and segmentation approaches based on WMP maps, 1 H-MRI-derived T 2 -weighted imaging (T2WI), and HP- 13 C-MRI-derived total carbon signal-to-noise ratio maps (TC-SNR) with an SNR threshold of 5.0. 13 C-labelled pyruvate SNR, lactate SNR, TC-SNR, and the pyruvate-to-lactate exchange rate constant (k PL ) were significantly higher when measured using the TC-SNR-guided approach, which also corresponded to a significantly higher tumour epithelial expression on RNAscope imaging of the enzyme catalysing pyruvate-to-lactate metabolism (lactate dehydrogenase (LDH)). However, linear regression and Bland-Altman analyses demonstrated a strong linear relationship between all three segmentation approaches, which correlated significantly with RNA-scope-derived epithelial LDH expression. These results suggest that standard-of-care T2WI and TC-SNR maps could be used as clinical reference tools for segmenting localised PCa on HP- 13 C-MRI in the absence of the WMP gold standard. The TC-SNR-guided approach could be used clinically to target biopsies towards highly glycolytic tumour areas and therefore to sample aggressive disease with higher precision. KEY POINTS: • T2WI- and TC-SNR-guided segmentations can be used in all PCa patients and do not explicitly require WMP maps. • Agreement between the three segmentation approaches is biologically validated by their strong relationship with epithelial LDH mRNA expression. • The TC-SNR-guided approach can potentially be used to identify occult disease on 1 H-MRI and target the most glycolytically active regions., (© 2022. The Author(s).)

MRI is a widely available clinical tool for cancer diagnosis and treatment monitoring. MRI provides excellent soft tissue imaging, using a wide range of contrast mechanisms, and can non-invasively detect tissue metabolites. These approaches can be used to distinguish cancer from normal tissues, to stratify tumor aggressiveness, and to identify changes within both the tumor and its microenvironment in response to therapy. In this review, the role of MRI in immunotherapy monitoring will be discussed and how it could be utilized in the future to address some of the unique clinical questions that arise from immunotherapy. For example, MRI could play a role in identifying pseudoprogression, mixed response, T cell infiltration, cell tracking, and some of the characteristic immune-related adverse events associated with these agents. The factors to be considered when developing MRI imaging biomarkers for immunotherapy will be reviewed. Finally, the advantages and limitations of each approach will be discussed, as well as the challenges for future clinical translation into routine clinical care. Given the increasing use of immunotherapy in a wide range of cancers and the ability of MRI to detect the microstructural and functional changes associated with successful response to immunotherapy, the technique has great potential for more widespread and routine use in the future for these applications., Competing Interests: Competing interests: The authors declare the following competing interests: DL has research support from AstraZeneca. PGC has received speaker fees and Advisory Board Honoraria from Bristol Myers Squibb, Merck Sharp & Dohme, Novartis and Pierre Fabre. FAG has research support from GE Healthcare, grants from GlaxoSmithKline, and has consulted for AstraZeneca on behalf of the University of Cambridge., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY. Published by BMJ.)

Purpose To evaluate glioblastoma (GBM) metabolism by using hyperpolarized carbon 13 ( 13 C) MRI to monitor the exchange of the hyperpolarized 13 C label between injected [1- 13 C]pyruvate and tumor lactate and bicarbonate. Materials and Methods In this prospective study, seven treatment-naive patients (age [mean ± SD], 60 years ± 11; five men) with GBM were imaged at 3 T by using a dual-tuned 13 C-hydrogen 1 head coil. Hyperpolarized [1- 13 C]pyruvate was injected, and signal was acquired by using a dynamic MRI spiral sequence. Metabolism was assessed within the tumor, in the normal-appearing brain parenchyma (NABP), and in healthy volunteers by using paired or unpaired t tests and a Wilcoxon signed rank test. The Spearman ρ correlation coefficient was used to correlate metabolite labeling with lactate dehydrogenase A (LDH-A) expression and some immunohistochemical markers. The Benjamini-Hochberg procedure was used to correct for multiple comparisons. Results The bicarbonate-to-pyruvate (BP) ratio was lower in the tumor than in the contralateral NABP ( P < .01). The tumor lactate-to-pyruvate (LP) ratio was not different from that in the NABP ( P = .38). The LP and BP ratios in the NABP were higher than those observed previously in healthy volunteers ( P < .05). Tumor lactate and bicarbonate signal intensities were strongly correlated with the pyruvate signal intensity (ρ = 0.92, P < .001, and ρ = 0.66, P < .001, respectively), and the LP ratio was weakly correlated with LDH-A expression in biopsy samples (ρ = 0.43, P = .04). Conclusion Hyperpolarized 13 C MRI demonstrated variation in lactate labeling in GBM, both within and between tumors. In contrast, bicarbonate labeling was consistently lower in tumors than in the surrounding NABP. Keywords: Hyperpolarized 13 C MRI, Glioblastoma, Metabolism, Cancer, MRI, Neuro-oncology Supplemental material is available for this article. Published under a CC BY 4.0 license.

Objectives: To investigate the relationship between magnetization transfer (MT) imaging and tissue macromolecules in high-grade serous ovarian cancer (HGSOC) and whether MT ratio (MTR) changes following neoadjuvant chemotherapy (NACT)., Methods: This was a prospective observational study. 12 HGSOC patients were imaged before treatment. MTR was compared to quantified tissue histology and immunohistochemistry. For a subset of patients ( n = 5), MT imaging was repeated after NACT. The Shapiro-Wilk test was used to assess for normality of data and Spearman's rank-order or Pearson's correlation tests were then used to compare MTR with tissue quantifications. The Wilcoxon signed-rank test was used to assess for changes in MTR after treatment., Results: Treatment-naïve tumour MTR was 21.9 ± 3.1% (mean ± S.D.). MTR had a positive correlation with cellularity, rho = 0.56 ( p < 0.05) and a negative correlation with tumour volume, ρ = -0.72 ( p = 0.01). MTR did not correlate with the extracellular proteins, collagen IV or laminin ( p = 0.40 and p = 0.90). For those patients imaged before and after NACT, an increase in MTR was observed in each case with mean MTR 20.6 ± 3.1% (median 21.1) pre-treatment and 25.6 ± 3.4% (median 26.5) post-treatment ( p = 0.06)., Conclusion: In treatment-naïve HGSOC, MTR is associated with cellularity, possibly reflecting intracellular macromolecular concentration. MT may also detect the HGSOC response to NACT, however larger studies are required to validate this finding., Advances in Knowledge: MTR in HGSOC is influenced by cellularity. This may be applied to assess for cell changes following treatment., Competing Interests: Competing interests: The authors have no conflicts of interest to declare., (© 2022 The Authors. Published by the British Institute of Radiology.)

Hyperpolarised magnetic resonance imaging (HP  13 C-MRI) is an emerging clinical technique to detect [1- 13 C]lactate production in prostate cancer (PCa) following intravenous injection of hyperpolarised [1- 13 C]pyruvate. Here we differentiate clinically significant PCa from indolent disease in a low/intermediate-risk population by correlating [1- 13 C]lactate labelling on MRI with the percentage of Gleason pattern 4 (%GP4) disease. Using immunohistochemistry and spatial transcriptomics, we show that HP  13 C-MRI predominantly measures metabolism in the epithelial compartment of the tumour, rather than the stroma. MRI-derived tumour [1- 13 C]lactate labelling correlated with epithelial mRNA expression of the enzyme lactate dehydrogenase (LDHA and LDHB combined), and the ratio of lactate transporter expression between the epithelial and stromal compartments (epithelium-to-stroma MCT4). We observe similar changes in MCT4, LDHA, and LDHB between tumours with primary Gleason patterns 3 and 4 in an independent TCGA cohort. Therefore, HP  13 C-MRI can metabolically phenotype clinically significant disease based on underlying metabolic differences in the epithelial and stromal tumour compartments., (© 2022. The Author(s).)

Differentiating aggressive clear cell renal cell carcinoma (ccRCC) from indolent lesions is challenging using conventional imaging. This work prospectively compared the metabolic imaging phenotype of renal tumors using carbon-13 MRI following injection of hyperpolarized [1- 13 C]pyruvate (HP- 13 C-MRI) and validated these findings with histopathology. Nine patients with treatment-naïve renal tumors (6 ccRCCs, 1 liposarcoma, 1 pheochromocytoma, 1 oncocytoma) underwent pre-operative HP- 13 C-MRI and conventional proton ( 1 H) MRI. Multi-regional tissue samples were collected using patient-specific 3D-printed tumor molds for spatial registration between imaging and molecular analysis. The apparent exchange rate constant ( k PL ) between 13 C-pyruvate and 13 C-lactate was calculated. Immunohistochemistry for the pyruvate transporter (MCT1) from 44 multi-regional samples, as well as associations between MCT1 expression and outcome in the TCGA-KIRC dataset, were investigated. Increasing k PL in ccRCC was correlated with increasing overall tumor grade (ρ = 0.92, p H-MRI parameters did not discriminate tumor grades. The correlation between MCT1 and ccRCC grade was confirmed within a TCGA dataset ( p < 0.001), where MCT1 expression was a predictor of overall and disease-free survival. In conclusion, metabolic imaging using HP- 1 C-MRI differentiates tumor aggressiveness in ccRCC and correlates with the expression of MCT1, a predictor of survival. HP- p < 0.001), where MCT1 expression was a predictor of overall and disease-free survival. In conclusion, metabolic imaging using HP- 13 C-MRI differentiates tumor aggressiveness in ccRCC and correlates with the expression of MCT1, a predictor of survival. HP- 13 C-MRI may non-invasively characterize metabolic phenotypes within renal cancer.

Hyperpolarized 13 C-MRI is an emerging tool for probing tissue metabolism by measuring 13 C-label exchange between intravenously injected hyperpolarized [1- 13 C]pyruvate and endogenous tissue lactate. Here, we demonstrate that hyperpolarized 13 C-MRI can be used to detect early response to neoadjuvant therapy in breast cancer. Seven patients underwent multiparametric 1 H-MRI and hyperpolarized 13 C-MRI before and 7-11 days after commencing treatment. An increase in the lactate-to-pyruvate ratio of approximately 20% identified three patients who, following 5-6 cycles of treatment, showed pathological complete response. This ratio correlated with gene expression of the pyruvate transporter MCT1 and lactate dehydrogenase A ( LDHA ), the enzyme catalyzing label exchange between pyruvate and lactate. Analysis of approximately 2,000 breast tumors showed that overexpression of LDHA and the hypoxia marker CAIX was associated with reduced relapse-free and overall survival. Hyperpolarized 13 C-MRI represents a promising method for monitoring very early treatment response in breast cancer and has demonstrated prognostic potential. SIGNIFICANCE: Hyperpolarized carbon-13 MRI allows response assessment in patients with breast cancer after 7-11 days of neoadjuvant chemotherapy and outperformed state-of-the-art and research quantitative proton MRI techniques., (©2021 The Authors; Published by the American Association for Cancer Research.)

Background: Immune checkpoint inhibitors are now standard of care treatment for many cancers. Treatment failure in metastatic melanoma is often due to tumor heterogeneity, which is not easily captured by conventional CT or tumor biopsy. The aim of this prospective study was to investigate early microstructural and functional changes within melanoma metastases following immune checkpoint blockade using multiparametric MRI., Methods: Fifteen treatment-naïve metastatic melanoma patients (total 27 measurable target lesions) were imaged at baseline and following 3 and 12 weeks of treatment on immune checkpoint inhibitors using: T 2 -weighted imaging, diffusion kurtosis imaging, and dynamic contrast-enhanced MRI. Treatment timepoint changes in tumor cellularity, vascularity, and heterogeneity within individual metastases were evaluated and correlated to the clinical outcome in each patient based on Response Evaluation Criteria in Solid Tumors V.1.1 at 1 year., Results: Differential tumor growth kinetics in response to immune checkpoint blockade were measured in individual metastases within the same patient, demonstrating significant intertumoral heterogeneity in some patients. Early detection of tumor cell death or cell loss measured by a significant increase in the apparent diffusivity (D app ) (p<0.05) was observed in both responding and pseudoprogressive lesions after 3 weeks of treatment. Tumor heterogeneity, as measured by apparent diffusional kurtosis (K app ), was consistently higher in the pseudoprogressive and true progressive lesions, compared with the responding lesions throughout the first 12 weeks of treatment. These preceded tumor regression and significant tumor vascularity changes (K trans , v e , and v p ) detected after 12 weeks of immunotherapy (p<0.05)., Conclusions: Multiparametric MRI demonstrated potential for early detection of successful response to immune checkpoint inhibitors in metastatic melanoma., Competing Interests: Competing interests: No conflict of interest to declare with respect to the content of this work. AL, MS, LB, and J-ML are employees of AstraZeneca UK., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY. Published by BMJ.)

Metabolic reprogramming is one of the hallmarks of cancer and includes the Warburg effect, which is exhibited by many tumours. This can be exploited by positron emission tomography (PET) as part of routine clinical cancer imaging. However, an emerging and alternative method to detect altered metabolism is carbon-13 magnetic resonance imaging (MRI) following injection of hyperpolarised [1- 13 C]pyruvate. The technique increases the signal-to-noise ratio for the detection of hyperpolarised 13 C-labelled metabolites by several orders of magnitude and facilitates the dynamic, noninvasive imaging of the exchange of 13 C-pyruvate to 13 C-lactate over time. The method has produced promising preclinical results in the area of oncology and is currently being explored in human imaging studies. The first translational studies have demonstrated the safety and feasibility of the technique in patients with prostate, renal, breast and pancreatic cancer, as well as revealing a successful response to treatment in breast and prostate cancer patients at an earlier stage than multiparametric MRI. This review will focus on the strengths of the technique and its applications in the area of oncological body MRI including noninvasive characterisation of disease aggressiveness, mapping of tumour heterogeneity, and early response assessment. A comparison of hyperpolarised 13 C-MRI with state-of-the-art multiparametric MRI is likely to reveal the unique additional information and applications offered by the technique.

Sodium magnetic resonance imaging (MRI) is a powerful, non-invasive technique to assess sodium distribution within the kidney. Here we undertook pre-clinical and clinical studies to quantify the corticomedullary sodium gradient in healthy individuals and in a porcine model of diuresis. The results demonstrated that sodium MRI could detect spatial differences in sodium biodistribution across the kidney. The sodium gradient of the kidney changed significantly after diuresis in the pig model and was independent of blood electrolyte measurements. Thus, rapid sodium MRI can be used to dynamically quantify sodium biodistribution in the porcine and human kidney., (Copyright © 2020 International Society of Nephrology. Published by Elsevier Inc. All rights reserved.)

Purpose: To compare hyperpolarized carbon 13 ( 13 C) MRI with dynamic contrast material-enhanced (DCE) MRI in the detection of early treatment response in breast cancer., Materials and Methods: In this institutional review board-approved prospective study, a woman with triple-negative breast cancer (age, 49 years) underwent 13 C MRI after injection of hyperpolarized [1-carbon 13 { 13 C}]-pyruvate and DCE MRI at 3 T at baseline and after one cycle of neoadjuvant therapy. The 13 C-labeled lactate-to-pyruvate ratio derived from hyperpolarized 13 C MRI and the pharmacokinetic parameters transfer constant ( K trans ) and washout parameter ( k ep ) derived from DCE MRI were compared before and after treatment., Results: Exchange of the 13 C label between injected hyperpolarized [1- 13 C]-pyruvate and the endogenous lactate pool was observed, catalyzed by the enzyme lactate dehydrogenase. After one cycle of neoadjuvant chemotherapy, a 34% reduction in the 13 C-labeled lactate-to-pyruvate ratio resulted in correct identification of the patient as a responder to therapy, which was subsequently confirmed via a complete pathologic response. However, DCE MRI showed an increase in mean K trans (31%), which could be incorrectly interpreted as a poor response to treatment.k ep (31%), which could be incorrectly interpreted as a poor response to treatment., Conclusion: Hyperpolarized 13 C MRI enabled successful identification of breast cancer response after one cycle of neoadjuvant chemotherapy and may improve response prediction when used in conjunction with multiparametric proton MRI.Published under a CC BY 4.0 license., (2020 by the Radiological Society of North America, Inc.)

Our purpose is to investigate the feasibility of imaging tumor metabolism in breast cancer patients using 13 C magnetic resonance spectroscopic imaging (MRSI) of hyperpolarized 13 C label exchange between injected [1- 13 C]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 13 C MRSI was performed following injection of hyperpolarized [1- 13 C]pyruvate. Expression of lactate dehydrogenase A (LDHA), which catalyzes 13 C 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 13 C 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- 13 C]pyruvate metabolism in breast cancer is feasible and demonstrated significant intertumoral and intratumoral metabolic heterogeneity, where lactate labeling correlated with MCT1 expression and hypoxia., Competing Interests: Competing interest statement: A research agreement is in place between GE Healthcare and K.M.B. and F.A.G., (Copyright © 2020 the Author(s). Published by PNAS.)

Background: There has been recent interest in nonproton MRI including hyperpolarized carbon-13 ( 13 C) imaging. Prostate cancer has been shown to have a higher tissue sodium concentration (TSC) than normal tissue. Sodium ( 23 Na) and 13 C nuclei have a frequency difference of only 1.66 MHz at 3T, potentially enabling 23 Na imaging with a 13 C-tuned coil and maximizing the metabolic information obtained from a single study., Purpose: To compare TSC measurements from a 13 C-tuned endorectal coil to those quantified with a dedicated 23 Na-tuned coil., Study Type: Prospective., Population: Eight patients with biopsy-proven, intermediate/high risk prostate cancer imaged prior to prostatectomy., Sequence: 3T MRI with separate dual-tuned 1 H/ 23 Na and 1 H/ 13 C endorectal receive coils to quantify TSC., Assessment: Regions-of-interest for TSC quantification were defined for normal peripheral zone (PZ), normal transition zone (TZ), and tumor, with reference to histopathology maps., Statistical Tests: Two-sided Wilcoxon rank sum with additional measures of correlation, coefficient of variation, and Bland-Altman plots to assess for between-test differences., Results: Mean TSC for normal PZ and TZ were 39.2 and 33.9 mM, respectively, with the 23 Na coil and 40.1 and 36.3 mM, respectively, with the 13 C coil (P = 0.22 and P = 0.11 for the intercoil comparison, respectively). For tumor tissue, there was no statistical difference between the overall mean tumor TSC measured with the 23 Na coil (41.8 mM) and with the 13 C coil (46.6 mM; P = 0.38). Bland-Altman plots showed good repeatability for tumor TSC measurements between coils, with a reproducibility coefficient of 9 mM; the coefficient of variation between the coils was 12%. The Pearson correlation coefficient for TSC between coils for all measurements was r = 0.71 (r 2 = 0.51), indicating a strong positive linear relationship. The mean TSC within PZ tumors was significantly higher compared with normal PZ for both the 23 Na coil (45.4 mM; P = 0.02) and the 13 C coil (49.4 mM; P = 0.002)., Data Conclusion: We demonstrated the feasibility of using a carbon-tuned coil to quantify TSC, enabling dual metabolic information from a single coil. This approach could make the acquisition of both 23 Na-MRI and 13 C-MRI feasible in a single clinical imaging session., Level of Evidence: 2 Technical Efficacy: Stage 2 J. Magn. Reson. Imaging 2020;51:90-97., (© 2019 International Society for Magnetic Resonance in Medicine.)

This study assessed the feasibility of using diffusion kurtosis imaging (DKI) as a measure of tissue heterogeneity and proliferation to predict the response of high grade serous ovarian cancer (HGSOC) to neoadjuvant chemotherapy (NACT). Seventeen patients with HGSOC were imaged at 3 T and had biopsy samples taken prior to any treatment. The patients were divided into two groups: responders and non-responders based on Response Evaluation Criteria In Solid Tumours (RECIST) criteria. The following imaging metrics were calculated: apparent diffusion coefficient (ADC), apparent diffusion (D app ) and apparent kurtosis (K app ). Tumour cellularity and proliferation were quantified using histology and Ki-67 immunohistochemistry. Mean K app before therapy was higher in responders compared to non-responders: 0.69 ± 0.13 versus 0.51 ± 0.11 respectively, P = 0.02. Tumour cellularity correlated positively with K app (rho = 0.50, P = 0.04) and negatively with both ADC (rho = -0.72, P = 0.001) and D app (rho = -0.80, P < 0.001). Ki-67 expression correlated with K app (rho = 0.53, P = 0.03) but not with ADC or D app . In conclusion, K app was found to be a potential predictive biomarker of NACT response in HGSOC, which suggests that DKI is a promising clinical tool for use oncology and radiology that should be evaluated further in future larger studies.

Multiparametric magnetic resonance imaging (MRI) can be used to characterize many cancer subtypes including ovarian cancer. Quantitative mapping of MRI relaxation values, such as T 1 and T 2 -weighted images. However, quantitative MRI relaxation mapping methods often involve long scan times due to sequentially measuring many parameters. Magnetic resonance fingerprinting (MRF) is a new method that enables fast quantitative MRI by exploiting the transient signals caused by the variation of pseudorandom sequence parameters. These transient signals are then matched to a simulated dictionary of T 1 values to create quantitative maps. The ability of MRF to simultaneously measure multiple parameters, could represent a new approach to characterizing cancer and assessing treatment response. This feasibility study investigates MRF for simultaneous T 2 , and relative proton density (rPD) mapping using ovarian cancer as a model system.T 1 and T 2 values to create quantitative maps. The ability of MRF to simultaneously measure multiple parameters, could represent a new approach to characterizing cancer and assessing treatment response. This feasibility study investigates MRF for simultaneous T 1 , T 2 , and relative proton density (rPD) mapping using ovarian cancer as a model system.

The aim of this study was to assess the feasibility of rapid sodium MRI ( 23 Na-MRI) for the imaging of peritoneal cancer deposits in high grade serous ovarian cancer (HGSOC) and to evaluate the relationship of 23 Na-MRI with tumour cellularity. 23 Na-MRI was performed at 3 T on twelve HGSOC patients using a 3D-cones acquisition technique. Tumour biopsies specimens were collected after imaging and cellularity was measured from histology. Total 23 Na-MRI scan time for each patient was approximately 11 min. At an isotropic resolution of 5.6 mm, signal-to-noise ratios (SNRs) of 82.2 ± 15.3 and 15.1 ± 7.1 (mean ± standard deviation) were achieved for imaging of tumour tissue sodium concentration (TSC) and intracellular weighted sodium concentration (IWS) respectively. Tumour TSC and IWS concentrations were: 56.8 ± 19.1 mM and 30.8 ± 9.2 mM respectively and skeletal muscle TSC and IWS concentrations were 33.2 ± 16.3 mM and 20.5 ± 9.9 mM respectively. There were significant sodium concentration differences between cancer and skeletal muscle, Wilcoxon signed-rank test, P  <  0.001 for TSC and P  =  0.01 for IWS imaging. Tumour cellularity displayed a strong negative correlation with TSC, Spearman's rho = -0.92, P  <  0.001, but did not correlate with IWS. This study demonstrates that 23 Na-MRI using 3D-cones can rapidly assess sodium concentration in peritoneal deposits of HGSOC and that TSC may serve as a biomarker of tumour cellularity.

Hyperpolarized 13 C Magnetic Resonance Imaging ( 13 C-MRI) provides a highly sensitive tool to probe tissue metabolism in vivo and has recently been translated into clinical studies. We report the cerebral metabolism of intravenously injected hyperpolarized [1- 13 C]pyruvate in the brain of healthy human volunteers for the first time. Dynamic acquisition of 13 C images demonstrated 13 C-labeling of both lactate and bicarbonate, catalyzed by cytosolic lactate dehydrogenase and mitochondrial pyruvate dehydrogenase respectively. This demonstrates that both enzymes can be probed in vivo in the presence of an intact blood-brain barrier: the measured apparent exchange rate constant (k PL ) for exchange of the hyperpolarized 13 C label between [1- 13 C]pyruvate and the endogenous lactate pool was 0.012 ± 0.006 s -1 and the apparent rate constant (k PB ) for the irreversible flux of [1- 13 C]pyruvate to [ 13 C]bicarbonate was 0.002 ± 0.002 s -1 . Imaging also revealed that [1- 13 C]pyruvate, [1- 13 C]lactate and [ 13 C]bicarbonate were significantly higher in gray matter compared to white matter. Imaging normal brain metabolism with hyperpolarized [1- 13 C]pyruvate and subsequent quantification, have important implications for interpreting pathological cerebral metabolism in future studies., (Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.)

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.

Objectives: The aim of this study was to measure the tissue sodium concentration (TSC) within tumors and normal prostate in prostate cancer patients, using prostatectomy as pathological criterion standard., Materials and Methods: Fifteen patients with biopsy-proven, magnetic resonance imaging (MRI) visible, intermediate- or high-risk prostate cancer underwent a dedicated research sodium MRI, before treatment with radical prostatectomy. All participants signed written informed consent for this institutional review board-approved prospective study. 3 T MRI acquired using a dedicated multinuclear clamshell transmit coil and a bespoke dual-tuned H/Na endorectal receive coil, with intracellular-sodium imaging acquired using inversion recovery sequences; a phantom-based calibration enabled quantitative sodium maps. Regions of interest were defined for normal peripheral zone (PZ) and transition zone (TZ) and tumor regions, referenced from histopathology maps. A 1-way analysis of variance compared normal and tumor tissue, using Tukey test for multiple comparisons., Results: Two patients were excluded due to artifact; software error resulted in 1 further intracellular-sodium failure. Fifteen tumors were detected (13 PZ, 2 TZ) in 13 patients: Gleason 3 + 3 (n = 1), 3 + 4 (6), 3 + 5 (2), 4 + 3 (5), 4 + 5 (1). Both mean TSC and intracellular-sodium were significantly higher in normal PZ (39.2 and 17.5 mmol/L, respectively) versus normal TZ (32.9 and 14.7; P < 0.001 and P = 0.02). Mean TSC in PZ tumor (45.0 mmol/L) was significantly higher than both normal PZ and TZ tissue (P < 0.001). Intracellular sodium in PZ tumors (19.9 mmol/L) was significantly higher than normal TZ (P < 0.001) but not normal PZ (P = 0.05). Mean TSC and intracellular-sodium was lower in Gleason ≤3 + 4 tumors (44.4 and 19.5 mmol/L, respectively) versus ≥4 + 3 (45.6 and 20.2), but this was not significant (P = 0.19 and P = 0.29)., Conclusions: Tissue sodium concentration and intracellular sodium concentrations of prostate tumors were quantified, with PZ tumors demonstrating a significantly increased TSC.

Purpose: To determine whether, in patients with Hodgkin lymphoma (HL) or non-Hodgkin lymphoma (NHL), [ 18 F]FDG PET/MR can capture treatment effects within the first week after treatment initiation, and whether changes in glucose metabolism and cell density occur simultaneously., Methods: Patients with histologically proven HL or NHL were included in this prospective IRB-approved study. Patients underwent [ 18 F]FDG PET/MR before, and then 48-72 h after (follow-up 1, FU-1) and 1 week after (FU-2) initiation of the first cycle of their respective standard chemotherapy (for HL) or immunochemotherapy (for NHL). Standardized [ 18 F]FDG uptake values (SUVmax, SUVmean) and apparent diffusion coefficients (ADCmin, ADCmean) based on diffusion-weighted MRI, and metabolic and morphological tumour volumes (MTV, VOL) were assessed at each time-point. Multilevel analyses with an unstructured covariance matrix, and pair-wise post-hoc tests were used to test for significant changes in SUVs, ADCs, MTVs and VOLs between the three time-points., Results: A total of 58 patients (11 with HL and 47 with NHL) with 166 lesions were analysed. Lesion-based mean rates of change in SUVmax, SUVmean, ADCmin, ADCmean, MTV and VOL between baseline and FU-1 were -46.8%, -33.3%, +20.3%, +14%, -46% and -12.8%, respectively, and between baseline and FU-2 were -65.1%, -49%, +50.7%, +32.4%, -61.1% and -24.2%, respectively. These changes were statistically significant (P < 0.01) except for the change in VOL between baseline and FU-1 (P = 0.079)., Conclusion: In lymphoma patients, [ 18 F]FDG PET/MR can capture treatment-induced changes in glucose metabolism and cell density as early as 48-72 h after treatment initiation.

Aim: To determine the significance and need for investigation of incidental prostatic uptake in men undergoing 18 F-labelled fluorodeoxyglucose ( 18 F-FDG) positron emission tomography/computed tomography (PET/CT) for other indications., Methods: Hospital databases were searched over a 5-year period for patients undergoing both PET/CT and prostate magnetic resonance imaging (MRI). For the initial analysis, the prostate was divided into six sectors and suspicious or malignant sectors were identified using MRI and histopathology reports respectively. Maximum and mean 18 F-FDG standardised uptake values were measured in each sector by an investigator blinded to the MRI and histopathology findings. Two age-matched controls were selected per case. Results were analysed using a paired t- test and one-way ANOVA. For the second analysis, PET/CT reports were searched for prostatic uptake reported incidentally and these patients were followed up., Results: Over a 5-year period, 15 patients underwent both PET/CT and MRI and had biopsy-proven prostate cancer. Malignant prostatic sectors had a trend to higher 18 F-FDG uptake than benign sectors, however this was neither clinically nor statistically significant (3.13 ± 0.58 vs 2.86 ± 0.68, P > 0.05). 18 F-FDG uptake showed no correlation with the presence or histopathological grade of tumour. 18 F-FDG uptake in cases with prostate cancer was comparable to that from age-matched controls. Forty-six (1.6%) of 2846 PET/CTs over a 5-year period reported incidental prostatic uptake. Of these, 18 (0.6%) were investigated by PSA, 9 (0.3%) were referred to urology, with 3 (0.1%) undergoing MRI and/or biopsy. No cases of prostate cancer were diagnosed in patients with incidental 18 F-FDG uptake in our institute over a 5-year period., Conclusion: 18 F-FDG uptake overlaps significantly between malignant and benign prostatic conditions. Subsequent patient management was not affected by the reporting of incidental focal prostatic uptake in this cohort., Competing Interests: Conflict-of-interest statement: The authors have no competing interests.

Background: To assess if transperineal prostate (TP) biopsy affects th e outcome of robotic-assisted laparoscopic prostatectomy (RALP), with particular reference to perioperative complications, oncological results and functional outcomes in the early postoperative setting., Methods: We identified 61 men who had undergone RALP after TP biopsies, from June 2012 to June 2014 and a control group of 120 men who had undergone RALP after conventional TRUS biopsy in the same period. Data was compared from the pre-operative biopsy, peri- and postoperative period, procedural outcomes including histological, oncological and functional outcomes between the groups., Results: The groups had comparable demographics, with matched median ages and PSA levels. There was a higher incidence of Gleason 6 disease detected in the TRUS group (P=0.01). Mean operative time (146 minutes TRUS vs. 158 minutes TP, P=0.133), blood loss (250 mL TRUS vs. 288 mL TP, P=0.462) and intraoperative complications were not significantly different between groups. Median length of stay (1 day) and median catheter duration (7 days) were identical in both cohorts. PSA failure rate at 6 months was similar (11.7% TRUS vs. 9.8% TP, P=0.904). There were no differences in functional outcomes (potency or continence) between groups at 6 month s follow-up., Conclusions: RALP is safe after TP biopsy with no adverse impact on oncological or short-term functional outcomes.

Objectives: Pancreatic cancer (PCa) is treatable by surgery when detected at an early stage. Non-invasive imaging methods able to detect both established tumours and their precursor lesions are needed to select patients for surgery. We investigated here whether pancreatic preneoplasia could be detected prior to the development of invasive cancers in genetically engineered mouse models of PCa using metabolic imaging., Design: The concentrations of alanine and lactate and the activities of lactate dehydrogenase (LDH) and alanine aminotransferase (ALT) were measured in extracts prepared from the pancreas of animals at different stages of disease progression; from pancreatitis, through tissue with predominantly low-grade and then high-grade pancreatic intraepithelial neoplasia and then tumour. (13)C magnetic resonance spectroscopic imaging ((13)C-MRSI) was used to measure non-invasively changes in (13)C labelling of alanine and lactate with disease progression, following injection of hyperpolarised [1-(13)C]pyruvate., Results: Progressive decreases in the alanine/lactate concentration ratio and ALT/LDH activity ratio with disease progression were accompanied by a corresponding decrease in the [1-(13)C]alanine/[1-(13)C]lactate signal ratio observed in (13)C-MRSI images of the pancreas., Conclusions: Metabolic imaging with hyperpolarised [1-(13)C]pyruvate enables detection and monitoring of the progression of PCa precursor lesions. Translation of this MRI technique to the clinic has the potential to improve the management of patients at high risk of developing PCa., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/)

Objective: The purpose of this study was to investigate the ability of the apparent diffusion coefficient (ADC) ratio of tumor to normal prostate tissue to overcome inherent variability based on choice of b values, with whole-mount histopathologic analysis as the reference standard for tumor identification., Materials and Methods: Thirty-nine patients with prostate cancer underwent 3-T MRI, including DWI with b values of 0, 150, 750, and 1000 s/mm(2). ADC maps were derived from four b value combinations. Histologically derived ROIs were defined for prostate tumor and benign prostate tissue to generate a ratio. The concordance correlation coefficient was used to evaluate agreement and reproducibility at different b values. Bland-Altman plots were used to evaluate the pattern of relative measurement difference between b value combinations. The relationship between ADC values and Gleason score was tested by Spearman rank correlation., Results: ADC values varied depending on the b value combination selected. The concordance correlation coefficient was higher for ADC ratios (0.883; 95% CI, 0.816-0.927) compared with absolute ADC values for normal tissue (0.873; 95% CI, 0.799-0.921) and tumor (0.792; 95% CI, 0.688-0.864). The ADC ratio concordance correlation coefficient for transition zone tumors was considerably higher than that for the peripheral zone in all cases. Bland-Altman analysis showed higher variation for ADC maps incorporating a b value of zero for both ratio and absolute values. There was a stronger inverse relationship to Gleason score for ADC ratios (rho, -0.354 to -0.456) compared with absolute ADC values (rho, -0.117 to -0.379)., Conclusion: The use of a simple ratio of prostate tumor ADC to normal tissue ADC improved the concordance between different b value combinations and could provide a more robust means of assessing restricted diffusion in the prostate.

Objective: The purpose of this study was to prospectively evaluate the value of diffusion-weighted MRI (DWI) for the assessment of extracapsular extension (ECE) in patients with prostate cancer., Subjects and Methods: Between November 2010 and April 2012, 40 patients with intermediate- to high-risk prostate cancer were prospectively recruited. MR images were obtained at 3 T with a phased-array coil. Two independent readers scored the T2-weighted images alone and then in combination with DW images. ROIs were drawn on the apparent diffusion coefficient (ADC) maps, and histogram-derived values were calculated. Whole-mount histopathologic examination was the standard of reference. Reader performance was analyzed, and differences in patient characteristics and histogram-based ADC values, according to ECE status, were evaluated., Results: ECE was present in 23 of 40 (58%) patients and 23 of 43 (53%) tumors. The sensitivity for side-specific ECE detection significantly increased, from 0.22 to 0.44 for reader 1 and 0.33 to 0.82 for reader 2 (both p < 0.05) without a significant change in specificity for either reader with the addition of DWI and ADC mapping. The positive and negative predictive values for both readers also increased. The ADC parameters of median and 10th and 25th centiles showed a statistically significant difference between tumors with and those without ECE (p < 0.05)., Conclusion: The addition of DWI and ADC mapping to T2-weighted MRI improved the accuracy of preoperative detection of ECE. Median and 10th and 25th centile ADC values were significantly associated with the presence of ECE and may be useful in the pretreatment assessment of patients with prostate cancer.

Acute kidney injury (AKI) is a common and important medical problem, affecting 10% of hospitalized patients, and it is associated with significant morbidity and mortality. The most frequent cause of AKI is acute tubular necrosis (ATN). Current imaging techniques and biomarkers do not allow ATN to be reliably differentiated from important differential diagnoses, such as acute glomerulonephritis (GN). We investigated whether (13)C magnetic resonance spectroscopic imaging (MRSI) might allow the noninvasive diagnosis of ATN. (13)C MRSI of hyperpolarized [1,4-(13)C(2)]fumarate and pyruvate was used in murine models of ATN and acute GN (NZM2410 mice with lupus nephritis). A significant increase in [1,4-(13)C(2)]malate signal was identified in the kidneys of mice with ATN early in the disease course before the onset of severe histological changes. No such increase in renal [1,4-(13)C(2)]malate was observed in mice with acute GN. The kidney [1-(13)C]pyruvate/[1-(13)C]lactate ratio showed substantial variability and was not significantly decreased in animals with ATN or increased in animals with GN. In conclusion, MRSI of hyperpolarized [1,4-(13)C(2)]fumarate allows the detection of early tubular necrosis and its distinction from glomerular inflammation in murine models. This technique may have the potential to identify a window of therapeutic opportunity in which emerging therapies might be applied to patients with ATN, reducing the need for acute dialysis with its attendant morbidity and cost.

Objective: The purpose of this article is to establish the range of normal splenic stiffness in healthy volunteers using MR elastography (MRE) and to investigate any correlation with physiologic parameters and driver position., Subjects and Methods: Sixteen volunteers (mean [+/- SD] age, 37 +/- 9 years) with no history of gastrointestinal, hepatobiliary, or cardiovascular disease were recruited. The MRI protocol included T2-weighted axial and gradient-echo MRE sequences using steady-state 60-Hz excitation. Two MRE acquisitions were performed, one with the driver placed on the right side of the abdomen and the other with the driver placed on the left side. Volunteers' body mass index (BMI), arterial mean blood pressure, age, spleen volume, and liver stiffness were also determined. Two radiologists independently measured the spleen stiffness on the MRE inversion images. The correlations between spleen stiffness and BMI, arterial mean blood pressure, age, spleen volume, and liver stiffness were quantified., Results: Sixteen volunteers underwent MRE. With the driver placed on the right side of the abdomen, the mean splenic stiffness was 3,565 +/- 586 Pa (range, 2,353-4,442 Pa); with the driver on the left side of the abdomen, the mean splenic stiffness was significantly (p < 0.004) different (4,255 +/- 625 Pa; range, 3,194-5,581 Pa). No significant correlation was found between spleen stiffness and BMI, arterial mean blood pressure, age, spleen volume, and liver stiffness (all p > 0.05), Conclusion: These preliminary results in a small number of healthy volunteers show that spleen stiffness is not significantly correlated with BMI, arterial mean blood pressure, spleen volume, or liver stiffness. A significant difference was observed using different driver positions.

Dynamic nuclear polarization of (13)C-labeled cell substrates has been shown to massively increase their sensitivity to detection in NMR experiments. The sensitivity gain is sufficiently large that if these polarized molecules are injected intravenously, their spatial distribution and subsequent conversion into other cell metabolites can be imaged. We have used this method to image the conversion of fumarate to malate in a murine lymphoma tumor in vivo after i.v. injection of hyperpolarized [1,4-(13)C(2)]fumarate. In isolated lymphoma cells, the rate of labeled malate production was unaffected by coadministration of succinate, which competes with fumarate for transport into the cell. There was, however, a correlation with the percentage of cells that had lost plasma membrane integrity, suggesting that the production of labeled malate from fumarate is a sensitive marker of cellular necrosis. Twenty-four hours after treating implanted lymphoma tumors with etoposide, at which point there were significant levels of tumor cell necrosis, there was a 2.4-fold increase in hyperpolarized [1,4-(13)C(2)]malate production compared with the untreated tumors. Therefore, the formation of hyperpolarized (13)C-labeled malate from [1,4-(13)C(2)]fumarate appears to be a sensitive marker of tumor cell death in vivo and could be used to detect the early response of tumors to treatment. Given that fumarate is an endogenous molecule, this technique has the potential to be used clinically.

Dynamic nuclear polarization (DNP) is an emerging technique for increasing the sensitivity of (13)C MR spectroscopy (MRS). [5-(13)C(1)]Glutamine was hyperpolarized using this technique by up to 5%, representing a 6000-fold increase in sensitivity. The conversion of hyperpolarized glutamine to glutamate by mitochondrial glutaminase was demonstrated using (13)C-MRS measurements in cultured human hepatoma cells (HepG2). These results represent the first step in developing an imaging technique for detecting glutamine metabolism in vivo. Furthermore, since glutamine utilization has been correlated with cell proliferation, the study suggests a new technique for detecting changes in tumor cell proliferation., ((c) 2008 Wiley-Liss, Inc.)