The use of hyperpolarised 13 C-MRI in clinical body imaging to probe cancer metabolism

Abstract: 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 [1-13C]pyruvate. The technique increases the signal-to-noise ratio for the detection of hyperpolarised 13C-labelled metabolites by several orders of magnitude and facilitates the dynamic, noninvasive imaging of the exchange of 13C-pyruvate to 13C-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 13C-MRI with state-of-the-art multiparametric MRI is likely to reveal the unique additional information and applications offered by the technique

A method for mapping and quantifying whole organ diffusion-weighted image distortion in MR imaging of the prostate.

A computational algorithm was designed to produce a measure of DW image distortion across the prostate. This algorithm was tested and validated on virtual phantoms incorporating known degrees and distributions of distortion. A study was then carried out on DW image volumes from three sets of 10 patients who had been imaged previously. These volumes had been radiologically assessed to have, respectively, 'no distortion' or 'significant distortion' or the potential for 'significant distortion' due to susceptibility effects from hip prostheses. Prostate outlines were drawn on a T2-weighted (T2W) image 'gold-standard' volume and on an ADC image volume derived from DW images acquired over the same region. The algorithm was then applied to these outlines to quantify and map image distortion. The proposed method correctly reproduced known distortion values and distributions in virtual phantoms. It also successfully distinguished between the three groups of patients: mean distortion in 'non-distorted' image volumes, 1.942 ± 0.582 mm; 'distorted', 4.402 ± 1.098 mm; and 'hip patients' 8.083 ± 4.653 mm; P < 0.001. This work has demonstrated and validated a means of quantifying and mapping image distortion in clinical prostate MRI cases

In Vivo Cell Tracking Using PET: Opportunities and Challenges for Clinical Translation in Oncology.

Cell therapy is a rapidly evolving field involving a wide spectrum of therapeutic cells for personalised medicine in cancer. In vivo imaging and tracking of cells can provide useful information for improving the accuracy, efficacy, and safety of cell therapies. This review focuses on radiopharmaceuticals for the non-invasive detection and tracking of therapeutic cells using positron emission tomography (PET). A range of approaches for imaging therapeutic cells is discussed: Direct ex vivo labelling of cells, in vivo indirect labelling of cells by utilising gene reporters, and detection of specific antigens expressed on the target cells using antibody-based radiopharmaceuticals (immuno-PET). This review examines the evaluation of PET imaging methods for therapeutic cell tracking in preclinical cancer models, their role in the translation into patients, first-in-human studies, as well as the translational challenges involved and how they can be overcome

Effects of Multi-Shell Free Water Correction on Glioma Characterization.

Diffusion MRI is a useful tool to investigate the microstructure of brain tumors. However, the presence of fast diffusing isotropic signals originating from non-restricted edematous fluids, within and surrounding tumors, may obscure estimation of the underlying tissue characteristics, complicating the radiological interpretation and quantitative evaluation of diffusion MRI. A multi-shell regularized free water (FW) elimination model was therefore applied to separate free water from tissue-related diffusion components from the diffusion MRI of 26 treatment-naïve glioma patients. We then investigated the diagnostic value of the derived measures of FW maps as well as FW-corrected tensor-derived maps of fractional anisotropy (FA). Presumed necrotic tumor regions display greater mean and variance of FW content than other parts of the tumor. On average, the area under the receiver operating characteristic (ROC) for the classification of necrotic and enhancing tumor volumes increased by 5% in corrected data compared to non-corrected data. FW elimination shifts the FA distribution in non-enhancing tumor parts toward higher values and significantly increases its entropy (p ≤ 0.003), whereas skewness is decreased (p ≤ 0.004). Kurtosis is significantly decreased (p < 0.001) in high-grade tumors. In conclusion, eliminating FW contributions improved quantitative estimations of FA, which helps to disentangle the cancer heterogeneity

Effects of Multi-Shell Free Water Correction on Glioma Characterization.

Diffusion MRI is a useful tool to investigate the microstructure of brain tumors. However, the presence of fast diffusing isotropic signals originating from non-restricted edematous fluids, within and surrounding tumors, may obscure estimation of the underlying tissue characteristics, complicating the radiological interpretation and quantitative evaluation of diffusion MRI. A multi-shell regularized free water (FW) elimination model was therefore applied to separate free water from tissue-related diffusion components from the diffusion MRI of 26 treatment-naïve glioma patients. We then investigated the diagnostic value of the derived measures of FW maps as well as FW-corrected tensor-derived maps of fractional anisotropy (FA). Presumed necrotic tumor regions display greater mean and variance of FW content than other parts of the tumor. On average, the area under the receiver operating characteristic (ROC) for the classification of necrotic and enhancing tumor volumes increased by 5% in corrected data compared to non-corrected data. FW elimination shifts the FA distribution in non-enhancing tumor parts toward higher values and significantly increases its entropy (p ≤ 0.003), whereas skewness is decreased (p ≤ 0.004). Kurtosis is significantly decreased (p < 0.001) in high-grade tumors. In conclusion, eliminating FW contributions improved quantitative estimations of FA, which helps to disentangle the cancer heterogeneity

Enhancing the spatial resolution of hyperpolarized carbon‐13 MRI of human brain metabolism using structure guidance

Funder: Mark Foundation Institute for Cancer ResearchFunder: Cambridge Experimental Cancer Medicine CentreFunder: Alan Turing Institute; Id: http://dx.doi.org/10.13039/100012338Funder: Cantab Capital Institute for the Mathematics of InformationPurpose: Dynamic nuclear polarization is an emerging imaging method that allows noninvasive investigation of tissue metabolism. However, the relatively low metabolic spatial resolution that can be achieved limits some applications, and improving this resolution could have important implications for the technique. Methods: We propose to enhance the 3D resolution of carbon‐13 magnetic resonance imaging (13C‐MRI) using the structural information provided by hydrogen‐1 MRI (1H‐MRI). The proposed approach relies on variational regularization in 3D with a directional total variation regularizer, resulting in a convex optimization problem which is robust with respect to the parameters and can efficiently be solved by many standard optimization algorithms. Validation was carried out using an in silico phantom, an in vitro phantom and in vivo data from four human volunteers. Results: The clinical data used in this study were upsampled by a factor of 4 in‐plane and by a factor of 15 out‐of‐plane, thereby revealing occult information. A key finding is that 3D super‐resolution shows superior performance compared to several 2D super‐resolution approaches: for example, for the in silico data, the mean‐squared‐error was reduced by around 40% and for all data produced increased anatomical definition of the metabolic imaging. Conclusion: The proposed approach generates images with enhanced anatomical resolution while largely preserving the quantitative measurements of metabolism. Although the work requires clinical validation against tissue measures of metabolism, it offers great potential in the field of 13C‐MRI and could significantly improve image quality in the future

Hyperpolarized carbon 13 MRI: clinical applications and future directions in oncology

Hyperpolarized carbon 13 MRI (13C 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 13C-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 13C MRI is exchange of the hyperpolarized 13C signal from injected [1-13C]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 13C 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 13C MRI, presents key findings from human cancer studies, and explores the future clinical directions of the technique in oncology

Comparison of initial and tertiary centre second opinion reads of multiparametric magnetic resonance imaging of the prostate prior to repeat biopsy.

OBJECTIVES: To investigate the value of second-opinion evaluation of multiparametric prostate magnetic resonance imaging (MRI) by subspecialised uroradiologists at a tertiary centre for the detection of significant cancer in transperineal fusion prostate biopsy. METHODS: Evaluation of prospectively acquired initial and second-opinion radiology reports of 158 patients who underwent MRI at regional hospitals prior to transperineal MR/untrasound fusion biopsy at a tertiary referral centre over a 3-year period. Gleason score (GS) 7-10 cancer, positive predictive value (PPV) and negative (NPV) predictive value (±95 % confidence intervals) were calculated and compared by Fisher's exact test. RESULTS: Disagreement between initial and tertiary centre second-opinion reports was observed in 54 % of cases (86/158). MRIs had a higher NPV for GS 7-10 in tertiary centre reads compared to initial reports (0.89 ± 0.08 vs 0.72 ± 0.16; p = 0.04), and a higher PPV in the target area for all cancer (0.61 ± 0.12 vs 0.28 ± 0.10; p = 0.01) and GS 7-10 cancer (0.43 ± 0.12 vs 0.2 3 ± 0.09; p = 0.02). For equivocal suspicion, the PPV for GS 7-10 was 0.12 ± 0.11 for tertiary centre and 0.11 ± 0.09 for initial reads; p = 1.00. CONCLUSIONS: Second readings of prostate MRI by subspecialised uroradiologists at a tertiary centre significantly improved both NPV and PPV. Reporter experience may help to reduce overcalling and avoid overtargeting of lesions. KEY POINTS: • Multiparametric MRIs were more often called negative in subspecialist reads (41 % vs 20 %). • Second readings of prostate mpMRIs by subspecialist uroradiologists significantly improved NPV and PPV. • Reporter experience may reduce overcalling and avoid overtargeting of lesions. • Greater education and training of radiologists in prostate MRI interpretation is advised.RWTH Aachen University Hospital (Aachen, Germany), National Institute for Health Research Cambridge Biomedical Research Centre, Cancer Research UK, Engineering and Physical Sciences Research Council Imaging Centre in Cambridge and Manchester, Cambridge Experimental Cancer Medicine Centr

Intravital Imaging of Adoptive T-Cell Morphology, Mobility and Trafficking Following Immune Checkpoint Inhibition in a Mouse Melanoma Model

Efficient T-cell targeting, infiltration and activation within tumors is crucial for successful adoptive T-cell therapy. Intravital microscopy is a powerful tool for the visualization of T-cell behavior within tumors, as well as spatial and temporal heterogeneity in response to immunotherapy. Here we describe an experimental approach for intravital imaging of adoptive T-cell morphology, mobility and trafficking in a skin-flap tumor model, following immune modulation with immune checkpoint inhibitors (ICIs) targeting PD-L1 and CTLA-4. A syngeneic model of ovalbumin and mCherry-expressing amelanotic mouse melanoma was used in conjunction with adoptively transferred OT-1+ cytotoxic T-cells expressing GFP to image antigen-specific live T-cell behavior within the tumor microenvironment. Dynamic image analysis of T-cell motility showed distinct CD8+ T-cell migration patterns and morpho-dynamics within different tumor compartments in response to ICIs: this approach was used to cluster T-cell behavior into four groups based on velocity and meandering index. The results showed that most T-cells within the tumor periphery demonstrated Lévy-like trajectories, consistent with tumor cell searching strategies. T-cells adjacent to tumor cells had reduced velocity and appeared to probe the local environment, consistent with cell-cell interactions. An increased number of T-cells were detected following treatment, traveling at lower mean velocities than controls, and demonstrating reduced displacement consistent with target engagement. Histogram-based analysis of immunofluorescent images from harvested tumors showed that in the ICI-treated mice there was a higher density of CD31+ vessels compared to untreated controls and a greater infiltration of T-cells towards the tumor core, consistent with increased cellular trafficking post-treatment

Evaluating Prostate Cancer Using Fractional Tissue Composition of Radical Prostatectomy Specimens and Pre-Operative Diffusional Kurtosis Magnetic Resonance Imaging.

BACKGROUND: Evaluating tissue heterogeneity using non-invasive imaging could potentially improve prostate cancer assessment and treatment. METHODS: 20 patients with intermediate/high-risk prostate cancer underwent diffusion kurtosis imaging, including calculation of apparent diffusion (Dapp) and kurtosis (Kapp), prior to radical prostatectomy. Whole-mount tissue composition was quantified into: cellularity, luminal space, and fibromuscular stroma. Peripheral zone tumors were subdivided according to Gleason score. RESULTS: Peripheral zone tumors had increased cellularity (p<0.0001), decreased fibromuscular stroma (p<0.05) and decreased luminal space (p<0.0001). Gleason score ≥4+3 tumors had significantly increased cellularity and decreased fibromuscular stroma compared to Gleason score ≤3+4 (p<0.05). In tumors, there was a significant positive correlation between median Kapp and cellularity (ρ = 0.50; p<0.05), and a negative correlation with fibromuscular stroma (ρ = -0.45; p<0.05). In normal tissue, median Dapp had a significant positive correlation with luminal space (ρ = 0.65; p<0.05) and a negative correlation with cellularity (ρ = -0.49; p<0.05). Median Kapp and Dapp varied significantly between tumor and normal tissue (p<0.0001), but only median Kapp was significantly different between Gleason score ≥4+3 and ≤3+4 (p<0.05). CONCLUSIONS: Peripheral zone tumors have increased cellular heterogeneity which is reflected in mean Kapp, while normal prostate has a more homogeneous luminal space and cellularity better represented by Dapp.Research support from National Institute of Health Research-Cambridge Biomedical Research Centre, Cancer Research UK (C19212/A911376, C19212/A16628), Hutchinson Whampoa Limited, Addenbrooke’s Charitable Trust, and the Cancer Research UK/Engineering and Physical Sciences Research Council Imaging Centre in Cambridge and Manchester. MRI acquisition for this study funded by the Cambridge Experimental Cancer Medicine Centre and the Royal College of Surgeons of England.This is the final version of the article. It first appeared from the Public Library of Science via http://dx.doi.org/10.1371/journal.pone.015965