Publications by authors named "Ferdia A Gallagher"

86 Publications

3D deformable registration of longitudinal abdominopelvic CT images using unsupervised deep learning.

Comput Methods Programs Biomed 2021 Jul 8;208:106261. Epub 2021 Jul 8.

Department of Radiology, University of Cambridge, CB2 0QQ Cambridge, United Kingdom; Cancer Research UK Cambridge Centre, University of Cambridge, CB2 0RE Cambridge, United Kingdom; Department of Biomedical Imaging and Image-guided Therapy, Medical University Vienna, 1090 Vienna, Austria.

Background And Objectives: Deep learning is being increasingly used for deformable image registration and unsupervised approaches, in particular, have shown great potential. However, the registration of abdominopelvic Computed Tomography (CT) images remains challenging due to the larger displacements compared to those in brain or prostate Magnetic Resonance Imaging datasets that are typically considered as benchmarks. In this study, we investigate the use of the commonly used unsupervised deep learning framework VoxelMorph for the registration of a longitudinal abdominopelvic CT dataset acquired in patients with bone metastases from breast cancer.

Methods: As a pre-processing step, the abdominopelvic CT images were refined by automatically removing the CT table and all other extra-corporeal components. To improve the learning capabilities of the VoxelMorph framework when only a limited amount of training data is available, a novel incremental training strategy is proposed based on simulated deformations of consecutive CT images in the longitudinal dataset. This devised training strategy was compared against training on simulated deformations of a single CT volume. A widely used software toolbox for deformable image registration called NiftyReg was used as a benchmark. The evaluations were performed by calculating the Dice Similarity Coefficient (DSC) between manual vertebrae segmentations and the Structural Similarity Index (SSIM).

Results: The CT table removal procedure allowed both VoxelMorph and NiftyReg to achieve significantly better registration performance. In a 4-fold cross-validation scheme, the incremental training strategy resulted in better registration performance compared to training on a single volume, with a mean DSC of 0.929±0.037 and 0.883±0.033, and a mean SSIM of 0.984±0.009 and 0.969±0.007, respectively. Although our deformable image registration method did not outperform NiftyReg in terms of DSC (0.988±0.003) or SSIM (0.995±0.002), the registrations were approximately 300 times faster.

Conclusions: This study showed the feasibility of deep learning based deformable registration of longitudinal abdominopelvic CT images via a novel incremental training strategy based on simulated deformations.
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http://dx.doi.org/10.1016/j.cmpb.2021.106261DOI Listing
July 2021

Imaging and treatment of brain tumors through molecular targeting: Recent clinical advances.

Eur J Radiol 2021 Jul 3;142:109842. Epub 2021 Jul 3.

Department of Radiology, University of Cambridge, Cambridge, United Kingdom; Cancer Research UK Cambridge Institute, University of Cambridge, Cambridge, United Kingdom.

Molecular imaging techniques have rapidly progressed over recent decades providing unprecedented in vivo characterization of metabolic pathways and molecular biomarkers. Many of these new techniques have been successfully applied in the field of neuro-oncological imaging to probe tumor biology. Targeting specific signaling or metabolic pathways could help to address several unmet clinical needs that hamper the management of patients with brain tumors. This review aims to provide an overview of the recent advances in brain tumor imaging using molecular targeting with positron emission tomography and magnetic resonance imaging, as well as the role in patient management and possible therapeutic implications.
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http://dx.doi.org/10.1016/j.ejrad.2021.109842DOI Listing
July 2021

The DANTE trial protocol: a randomised phase III trial to evaluate the Duration of ANti-PD-1 monoclonal antibody Treatment in patients with metastatic mElanoma.

BMC Cancer 2021 Jul 1;21(1):761. Epub 2021 Jul 1.

Sheffield Teaching Hospitals NHS Foundation Trust , Sheffield, UK.

Background: Immunotherapy is revolutionising the treatment of patients diagnosed with melanoma and other cancers. The first immune checkpoint inhibitor, ipilimumab (targeting cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4)), showed a survival advantage over standard chemotherapy. Subsequently the anti-programmed cell death protein 1 (PD-1) antibodies, nivolumab and pembrolizumab were shown to be more effective than ipilimumab. Ipilimumab combined with nivolumab gives an incremental gain in overall survival compared with nivolumab alone but increases the risk of severe, potentially life-threatening toxicities. In contrast to ipilimumab monotherapy, anti-PD-1 antibodies are licensed to be continued until disease progression. Follow-up of patients recruited to the first trials evaluating 2 years of pembrolizumab showed that three-quarters of responding patients continue responding after stopping treatment. Suggestive of early response, we hypothesised that continuing anti-PD-1 treatment beyond 1 year in progression-free patients may be unnecessary and so designed the DANTE trial.

Methods: DANTE is a multicentre, randomised, phase III, non-inferiority trial to evaluate the duration of anti-PD-1 therapy in patients with metastatic (unresectable stage III and stage IV) melanoma. It uses a two-stage recruitment strategy, registering patients before they complete 1 year of first-line anti-PD-1 +/- CTLA-4 therapy and randomising eligible patients who have received 12 months of treatment and are progression-free at 1 year. At randomisation, 1208 patients are assigned (1:1) to either 1) continue anti-PD-1 treatment until disease progression/ unacceptable toxicity/ for at least 2 years in the absence of disease progression/ unacceptable toxicity or 2) to stop treatment. Randomisation stratifies for baseline prognostic factors. The primary outcome is progression-free survival at 3, 6, 9 and 12 months and then, 6-monthly for up to 4-years. Secondary outcomes collected at all timepoints include overall survival, response-rate and duration and safety, with quality of life and cost-effectiveness outcomes collected 3-monthly for up to 18-months. Sub-studies include a qualitative analysis of patient acceptance of randomisation and sample collection to inform future translational studies into response/ toxicity biomarkers.

Discussion: DANTE is a unique prospective trial investigating the optimal duration of anti-PD-1 therapy in metastatic melanoma patients. Outcomes will inform future use of these high burden drugs.

Trial Registration: ISRCTN15837212 , 31 July 2018.
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http://dx.doi.org/10.1186/s12885-021-08509-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8246129PMC
July 2021

Combined Na and C imaging at 3.0 Tesla using a single-tuned large FOV birdcage coil.

Magn Reson Med 2021 09 2;86(3):1734-1745. Epub 2021 May 2.

Department of Radiology, University of Cambridge, Cambridge, United Kingdom.

Purpose: An unmet need in carbon-13 ( C)-MRI is a transmit system that provides uniform excitation across a large FOV and can accommodate patients of wide-ranging body habitus. Due to the small difference between the resonant frequencies, sodium-23 ( Na) coil developments can inform C coil design while being simpler to assess due to the higher naturally abundant Na signal. Here we present a removable Na birdcage, which also allows operation as a C abdominal coil.

Methods: We demonstrate a quadrature-driven 4-rung Na birdcage coil of 50 cm in length for both Na and C abdominal imaging. The coil transmit efficiencies and maps were compared to a linearly driven C Helmholtz-based (clamshell) coil. SNR was investigated with Na and C data using an 8-channel C receive array within the Na birdcage.

Results: The Na birdcage longitudinal FOV was > 40 cm, whereas the C clamshell was < 32 cm. The transmit efficiency of the birdcage at the Na frequency was 0.65 µT/sqrt(W), similar to the clamshell for C. However, the coefficient of variation of Na- was 16%, nearly half that with the C clamshell. The 8-channel C receive array combined with the Na birdcage coil generated a greater than twofold increase in Na-SNR from the central abdomen compared with the birdcage alone.

Discussion: This Na birdcage coil has a larger FOV and improved uniformity when compared to the widely used clamshell coil design while also providing similar transmit efficiency. The coil has the potential to be used for both Na and C imaging.
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http://dx.doi.org/10.1002/mrm.28772DOI Listing
September 2021

Investigating the relationship between diffusion kurtosis tensor imaging (DKTI) and histology within the normal human brain.

Sci Rep 2021 Apr 23;11(1):8857. Epub 2021 Apr 23.

Department of Radiology, University of Cambridge School of Clinical Medicine, University of Cambridge, Cambridge Biomedical Campus, Box 218, Cambridge, CB2 0QQ, UK.

Measurements of water diffusion with MRI have been used as a biomarker of tissue microstructure and heterogeneity. In this study, diffusion kurtosis tensor imaging (DKTI) of the brain was undertaken in 10 healthy volunteers at a clinical field strength of 3 T. Diffusion and kurtosis metrics were measured in regions-of-interest on the resulting maps and compared with quantitative analysis of normal post-mortem tissue histology from separate age-matched donors. White matter regions showed low diffusion (0.60 ± 0.04 × 10 mm/s) and high kurtosis (1.17 ± 0.06), consistent with a structured heterogeneous environment comprising parallel neuronal fibres. Grey matter showed intermediate diffusion (0.80 ± 0.02 × 10 mm/s) and kurtosis (0.82 ± 0.05) values. An important finding is that the subcortical regions investigated (thalamus, caudate and putamen) showed similar diffusion and kurtosis properties to white matter. Histological staining of the subcortical nuclei demonstrated that the predominant grey matter was permeated by small white matter bundles, which could account for the similar kurtosis to white matter. Quantitative histological analysis demonstrated higher mean tissue kurtosis and vector standard deviation values for white matter (1.08 and 0.81) compared to the subcortical regions (0.34 and 0.59). Mean diffusion on DKTI was positively correlated with tissue kurtosis (r = 0.82, p < 0.05) and negatively correlated with vector standard deviation (r = -0.69, p < 0.05). This study demonstrates how DKTI can be used to study regional structural variations in the cerebral tissue microenvironment and could be used to probe microstructural changes within diseased tissue in the future.
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http://dx.doi.org/10.1038/s41598-021-87857-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8065051PMC
April 2021

Assessing robustness of carotid artery CT angiography radiomics in the identification of culprit lesions in cerebrovascular events.

Sci Rep 2021 Feb 10;11(1):3499. Epub 2021 Feb 10.

Department of Medicine, University of Cambridge, Cambridge, UK.

Radiomics, quantitative feature extraction from radiological images, can improve disease diagnosis and prognostication. However, radiomic features are susceptible to image acquisition and segmentation variability. Ideally, only features robust to these variations would be incorporated into predictive models, for good generalisability. We extracted 93 radiomic features from carotid artery computed tomography angiograms of 41 patients with cerebrovascular events. We tested feature robustness to region-of-interest perturbations, image pre-processing settings and quantisation methods using both single- and multi-slice approaches. We assessed the ability of the most robust features to identify culprit and non-culprit arteries using several machine learning algorithms and report the average area under the curve (AUC) from five-fold cross validation. Multi-slice features were superior to single for producing robust radiomic features (67 vs. 61). The optimal image quantisation method used bin widths of 25 or 30. Incorporating our top 10 non-redundant robust radiomics features into ElasticNet achieved an AUC of 0.73 and accuracy of 69% (compared to carotid calcification alone [AUC: 0.44, accuracy: 46%]). Our results provide key information for introducing carotid CT radiomics into clinical practice. If validated prospectively, our robust carotid radiomic set could improve stroke prediction and target therapies to those at highest risk.
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http://dx.doi.org/10.1038/s41598-021-82760-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7876096PMC
February 2021

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

Br J Cancer 2021 Mar 28;124(7):1187-1198. Epub 2021 Jan 28.

Department of Radiology, University of Cambridge, Cambridge, UK.

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-C]pyruvate. The technique increases the signal-to-noise ratio for the detection of hyperpolarised C-labelled metabolites by several orders of magnitude and facilitates the dynamic, noninvasive imaging of the exchange of C-pyruvate to 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 C-MRI with state-of-the-art multiparametric MRI is likely to reveal the unique additional information and applications offered by the technique.
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http://dx.doi.org/10.1038/s41416-020-01224-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8007617PMC
March 2021

The role of [ Ga]Ga-DOTATATE PET/CT in wild-type KIT/PDGFRA gastrointestinal stromal tumours (GIST).

EJNMMI Res 2021 Jan 14;11(1). Epub 2021 Jan 14.

Department of Endocrinology, Cambridge University Hospitals Foundation Trust, Cambridge, CB2 0QQ, UK.

Background: [ Ga]Ga-DOTATATE PET/CT is now recognised as the most sensitive functional imaging modality for the diagnosis of well-differentiated neuroendocrine tumours (NET) and can inform treatment with peptide receptor radionuclide therapy with [Lu]Lu-DOTATATE. However, somatostatin receptor (SSTR) expression is not unique to NET, and therefore, [ Ga]Ga-DOTATATE PET/CT may have oncological application in other tumours. Molecular profiling of gastrointestinal stromal tumours that lack activating somatic mutations in KIT or PDGFRA or so-called 'wild-type' GIST (wtGIST) has demonstrated that wtGIST and NET have overlapping molecular features and has encouraged exploration of shared therapeutic targets, due to a lack of effective therapies currently available for metastatic wtGIST.

Aims: To investigate (i) the diagnostic role of [ Ga]Ga-DOTATATE PET/CT; and, (ii) to investigate the potential of this imaging modality to guide treatment with [Lu]Lu-DOTATATE in patients with wtGIST.

Methods: [ Ga]Ga-DOTATATE PET/CT was performed on 11 patients with confirmed or metastatic wtGIST and one patient with a history of wtGIST and a mediastinal mass suspicious for metastatic wtGIST, who was subsequently diagnosed with a metachronous mediastinal paraganglioma. Tumour expression of somatostatin receptor subtype 2 (SSTR2) using immunohistochemistry was performed on 54 tumour samples including samples from 8/12 (66.6%) patients who took part in the imaging study and 46 tumour samples from individuals not included in the imaging study.

Results: [ Ga]Ga-DOTATATE PET/CT imaging was negative, demonstrating that liver metastases had lower uptake than background liver for nine cases (9/12 cases, 75%) and heterogeneous uptake of somatostatin tracer was noted for two cases (16.6%) of wtGIST. However, [ Ga]Ga-DOTATATE PET/CT demonstrated intense tracer uptake in a synchronous paraganglioma in one case and a metachronous paraganglioma in another case with wtGIST.

Conclusions: Our data suggest that SSTR2 is not a diagnostic or therapeutic target in wtGIST. [ Ga]Ga-DOTATATE PET/CT may have specific diagnostic utility in differentiating wtGIST from other primary tumours such as paraganglioma in patients with sporadic and hereditary forms of wtGIST.
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http://dx.doi.org/10.1186/s13550-021-00747-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7809083PMC
January 2021

Characterization and correction of center-frequency effects in X-nuclear eddy current compensations on a clinical MR system.

Magn Reson Med 2021 05 4;85(5):2370-2376. Epub 2020 Dec 4.

GE Healthcare, Munich, Germany.

Purpose: The aim of the study was to investigate whether incorrectly compensated eddy currents are the source of persistent X-nuclear spectroscopy and imaging artifacts, as well as methods to correct this.

Methods: Pulse-acquire spectra were collected for H and X-nuclei ( Na or P) using the minimum TR permitted on a 3T clinical MRI system. Data were collected in 3 orientations (axial, sagittal, and coronal) with the spoiler gradient at the end of the TR applied along the slice direction for each. Modifications to system calibration files to tailor eddy current compensation for each X-nucleus were developed and applied, and data were compared with and without these corrections for: slice-selective MRS (for Na and P), 2D spiral trajectories (for C), and 3D cones trajectories (for Na).

Results: Line-shape distortions characteristic of eddy currents were demonstrated for X-nuclei, which were not seen for H. The severity of these correlated with the amplitude of the eddy current frequency compensation term applied by the system along the axis of the applied spoiler gradient. A proposed correction to eddy current compensation, taking account of the gyromagnetic ratio, was shown to dramatically reduce these distortions. The same correction was also shown to improve data quality of non-Cartesian imaging (2D spiral and 3D cones trajectories).

Conclusion: A simple adaptation of the default compensation for eddy currents was shown to eliminate a range of artifacts detected on X-nuclear spectroscopy and imaging.
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http://dx.doi.org/10.1002/mrm.28607DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7898706PMC
May 2021

Correlating Radiomic Features of Heterogeneity on CT with Circulating Tumor DNA in Metastatic Melanoma.

Cancers (Basel) 2020 Nov 24;12(12). Epub 2020 Nov 24.

Department of Radiology, University of Cambridge, Cambridge CB2 0QQ, UK.

Clinical imaging methods, such as computed tomography (CT), are used for routine tumor response monitoring. Imaging can also reveal intratumoral, intermetastatic, and interpatient heterogeneity, which can be quantified using radiomics. Circulating tumor DNA (ctDNA) in the plasma is a sensitive and specific biomarker for response monitoring. Here we evaluated the interrelationship between circulating tumor DNA mutant allele fraction (ctDNA), obtained by targeted amplicon sequencing and shallow whole genome sequencing, and radiomic measurements of CT heterogeneity in patients with stage IV melanoma. ctDNA and radiomic observations were obtained from 15 patients with a total of 70 CT examinations acquired as part of a prospective trial. 26 of 39 radiomic features showed a significant relationship with log(ctDNA). Principal component analysis was used to define a radiomics signature that predicted ctDNA independent of lesion volume. This radiomics signature and serum lactate dehydrogenase were independent predictors of ctDNA. Together, these results suggest that radiomic features and ctDNA may serve as complementary clinical tools for treatment monitoring.
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http://dx.doi.org/10.3390/cancers12123493DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7759931PMC
November 2020

Three dimensional MRF obtains highly repeatable and reproducible multi-parametric estimations in the healthy human brain at 1.5T and 3T.

Neuroimage 2021 02 19;226:117573. Epub 2020 Nov 19.

IRCCS Stella Maris, Pisa, Italy; Imago7 Foundation, Pisa, Italy. Electronic address:

Magnetic resonance fingerprinting (MRF) is highly promising as a quantitative MRI technique due to its accuracy, robustness, and efficiency. Previous studies have found high repeatability and reproducibility of 2D MRF acquisitions in the brain. Here, we have extended our investigations to 3D MRF acquisitions covering the whole brain using spiral projection k-space trajectories. Our travelling head study acquired test/retest data from the brains of 12 healthy volunteers and 8 MRI systems (3 systems at 3 T and 5 at 1.5 T, all from a single vendor), using a study design not requiring all subjects to be scanned at all sites. The pulse sequence and reconstruction algorithm were the same for all acquisitions. After registration of the MRF-derived PD T and T maps to an anatomical atlas, coefficients of variation (CVs) were computed to assess test/retest repeatability and inter-site reproducibility in each voxel, while a General Linear Model (GLM) was used to determine the voxel-wise variability between all confounders, which included test/retest, subject, field strength and site. Our analysis demonstrated a high repeatability (CVs 0.7-1.3% for T1, 2.0-7.8% for T, 1.4-2.5% for normalized PD) and reproducibility (CVs of 2.0-5.8% for T, 7.4-10.2% for T, 5.2-9.2% for normalized PD) in gray and white matter. Both repeatability and reproducibility improved when compared to similar experiments using 2D acquisitions. Three-dimensional MRF obtains highly repeatable and reproducible estimations of T and T, supporting the translation of MRF-based fast quantitative imaging into clinical applications.
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http://dx.doi.org/10.1016/j.neuroimage.2020.117573DOI Listing
February 2021

CXCR4 inhibition in human pancreatic and colorectal cancers induces an integrated immune response.

Proc Natl Acad Sci U S A 2020 11 30;117(46):28960-28970. Epub 2020 Oct 30.

Cancer Research UK Cambridge Institute, University of Cambridge, Cambridge, CB2 ORE, UK.

Inhibition of the chemokine receptor CXCR4 in combination with blockade of the PD-1/PD-L1 T cell checkpoint induces T cell infiltration and anticancer responses in murine and human pancreatic cancer. Here we elucidate the mechanism by which CXCR4 inhibition affects the tumor immune microenvironment. In human immune cell-based chemotaxis assays, we find that CXCL12-stimulated CXCR4 inhibits the directed migration mediated by CXCR1, CXCR3, CXCR5, CXCR6, and CCR2, respectively, chemokine receptors expressed by all of the immune cell types that participate in an integrated immune response. Inhibiting CXCR4 in an experimental cancer medicine study by 1-wk continuous infusion of the small-molecule inhibitor AMD3100 (plerixafor) induces an integrated immune response that is detected by transcriptional analysis of paired biopsies of metastases from patients with microsatellite stable colorectal and pancreatic cancer. This integrated immune response occurs in three other examples of immune-mediated damage to noninfected tissues: Rejecting renal allografts, melanomas clinically responding to anti-PD1 antibody therapy, and microsatellite instable colorectal cancers. Thus, signaling by CXCR4 causes immune suppression in human pancreatic ductal adenocarcinoma and colorectal cancer by impairing the function of the chemokine receptors that mediate the intratumoral accumulation of immune cells.
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http://dx.doi.org/10.1073/pnas.2013644117DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7682333PMC
November 2020

Magnetic resonance fingerprinting of the pancreas at 1.5 T and 3.0 T.

Sci Rep 2020 10 16;10(1):17563. Epub 2020 Oct 16.

Department of Radiology, University of Cambridge, Cambridge Biomedical Campus, Box 218, Cambridge, CB2 0QQ, UK.

Magnetic resonance imaging of the pancreas is increasingly used as an important diagnostic modality for characterisation of pancreatic lesions. Pancreatic MRI protocols are mostly qualitative due to time constraints and motion sensitivity. MR Fingerprinting is an innovative acquisition technique that provides qualitative data and quantitative parameter maps from a single free-breathing acquisition with the potential to reduce exam times. This work investigates the feasibility of MRF parameter mapping for pancreatic imaging in the presence of free-breathing exam. Sixteen healthy participants were prospectively imaged using MRF framework. Regions-of-interest were drawn in multiple solid organs including the pancreas and T and T values determined. MRF T and T mapping was performed successfully in all participants (acquisition time:2.4-3.6 min). Mean pancreatic T values were 37-43% lower than those of the muscle, spleen, and kidney at both 1.5 and 3.0 T. For these organs, the mean pancreatic T values were nearly 40% at 1.5 T and < 12% at 3.0 T. The feasibility of MRF at 1.5 T and 3 T was demonstrated in the pancreas. By enabling fast and free-breathing quantitation, MRF has the potential to add value during the clinical characterisation and grading of pathological conditions, such as pancreatitis or cancer.
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http://dx.doi.org/10.1038/s41598-020-74462-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7567885PMC
October 2020

Multi-site clonality analysis uncovers pervasive heterogeneity across melanoma metastases.

Nat Commun 2020 08 27;11(1):4306. Epub 2020 Aug 27.

Experimental Cancer Genetics, The Wellcome Sanger Institute, Hinxton, Cambridgeshire, UK.

Metastatic melanoma carries a poor prognosis despite modern systemic therapies. Understanding the evolution of the disease could help inform patient management. Through whole-genome sequencing of 13 melanoma metastases sampled at autopsy from a treatment naïve patient and by leveraging the analytical power of multi-sample analyses, we reveal evidence of diversification among metastatic lineages. UV-induced mutations dominate the trunk, whereas APOBEC-associated mutations are found in the branches of the evolutionary tree. Multi-sample analyses from a further seven patients confirmed that lineage diversification was pervasive, representing an important mode of melanoma dissemination. Our analyses demonstrate that joint analysis of cancer cell fraction estimates across multiple metastases can uncover previously unrecognised levels of tumour heterogeneity and highlight the limitations of inferring heterogeneity from a single biopsy.
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http://dx.doi.org/10.1038/s41467-020-18060-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7453196PMC
August 2020

Three-Dimensional Printed Molds for Image-Guided Surgical Biopsies: An Open Source Computational Platform.

JCO Clin Cancer Inform 2020 08;4:736-748

Cancer Research UK, Cambridge Institute, University of Cambridge, Cambridge, United Kingdom.

Purpose: Spatial heterogeneity of tumors is a major challenge in precision oncology. The relationship between molecular and imaging heterogeneity is still poorly understood because it relies on the accurate coregistration of medical images and tissue biopsies. Tumor molds can guide the localization of biopsies, but their creation is time consuming, technologically challenging, and difficult to interface with routine clinical practice. These hurdles have so far hindered the progress in the area of multiscale integration of tumor heterogeneity data.

Methods: We have developed an open-source computational framework to automatically produce patient-specific 3-dimensional-printed molds that can be used in the clinical setting. Our approach achieves accurate coregistration of sampling location between tissue and imaging, and integrates seamlessly with clinical, imaging, and pathology workflows.

Results: We applied our framework to patients with renal cancer undergoing radical nephrectomy. We created personalized molds for 6 patients, obtaining Dice similarity coefficients between imaging and tissue sections ranging from 0.86 to 0.96 for tumor regions and between 0.70 and 0.76 for healthy kidneys. The framework required minimal manual intervention, producing the final mold design in just minutes, while automatically taking into account clinical considerations such as a preference for specific cutting planes.

Conclusion: Our work provides a robust and automated interface between imaging and tissue samples, enabling the development of clinical studies to probe tumor heterogeneity on multiple spatial scales.
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http://dx.doi.org/10.1200/CCI.20.00026DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7469624PMC
August 2020

Hyperpolarized C MRI of Tumor Metabolism Demonstrates Early Metabolic Response to Neoadjuvant Chemotherapy in Breast Cancer.

Radiol Imaging Cancer 2020 07 31;2(4):e200017. Epub 2020 Jul 31.

Departments of Radiology (R.W., A.B.G., J.T.G., A.J.P., S.U., F.Z., M.L., M.C.L., S.H., A.F., L.B., L.R., E.S., M.J.G., F.J.G., F.A.G.), Oncology (J.K., H.B., E.H., B.B., R.B., J.E.A., C.C.), and Biochemistry (K.M.B.), the Cambridge Breast Cancer Research Unit (E.P., J.K., H.B., E.H., R.B., J.E.A., C.C.), University of Cambridge, Cambridge, England; Departments of Radiology (A.J.P., I.P., R.S., M.J.G., F.J.G., F.A.G.) and Histopathology (E.P.), Addenbrooke's Hospital, Cambridge University Hospitals NHS Foundation Trust, Cambridge, England; Cancer Research UK Cambridge Centre, Cambridge, England (R.W., M.A.M., E.P., T.T., L.B., L.R., E.S., J.E.A., C.C., K.M.B., F.A.G.); Department of Biomedical Imaging and Image-guided Therapy, Medical University of Vienna, Waehringer Guertel 18-20, Vienna 1090, Austria (R.W., L.B.); Cancer Research UK Cambridge Institute, University of Cambridge, Li Ka Shing Centre, Cambridge, England (M.A.M., T.T., C.C., K.M.B.); and RAPID Biomedical, Rimpar, Germany (T.L.).

Purpose: To compare hyperpolarized carbon 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 C MRI after injection of hyperpolarized [1-carbon 13 {C}]-pyruvate and DCE MRI at 3 T at baseline and after one cycle of neoadjuvant therapy. The C-labeled lactate-to-pyruvate ratio derived from hyperpolarized C MRI and the pharmacokinetic parameters transfer constant ( ) and washout parameter ( ) derived from DCE MRI were compared before and after treatment.

Results: Exchange of the C label between injected hyperpolarized [1-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 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 (132%) and mean (31%), which could be incorrectly interpreted as a poor response to treatment.

Conclusion: Hyperpolarized 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.
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http://dx.doi.org/10.1148/rycan.2020200017DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7398116PMC
July 2020

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

Front Immunol 2020 22;11:1514. Epub 2020 Jul 22.

Cancer Research UK Cambridge Centre, Cambridge, United Kingdom.

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.
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http://dx.doi.org/10.3389/fimmu.2020.01514DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7387409PMC
April 2021

Detection limit of Zr-labeled T cells for cellular tracking: an in vitro imaging approach using clinical PET/CT and PET/MRI.

EJNMMI Res 2020 Jul 14;10(1):82. Epub 2020 Jul 14.

Department of Radiology, University of Cambridge, Cambridge, UK.

Purpose: Tracking cells in vivo using imaging can provide non-invasive information to understand the pharmacology, efficacy, and safety of novel cell therapies. Zirconium-89 (t = 78.4 h) has recently been used to synthesize [Zr]Zr(oxinate) for cell tracking using positron emission tomography (PET). This work presents an in vitro approach to estimate the detection limit for in vivo PET imaging of Jurkat T cells directly labeled with [Zr]Zr(oxinate) utilizing clinical PET/CT and PET/MRI.

Methods: Jurkat T cells were labeled with varying concentrations of [Zr]Zr(oxinate) to generate different cell-specific activities (0.43-31.91 kBq/10 cells). Different concentrations of labeled cell suspensions (10, 10, and 10 cells) were seeded on 6-well plates and into a 3 × 3 cubic-well plate with 1 cm cubic wells as a gel matrix. Plates were imaged on clinical PET/CT and PET/MRI scanners for 30 min. The total activity in each well was determined by drawing volumes of interest over each well on PET images. The total cell-associated activity was measured using a well counter and correlated with imaging data. Simulations for non-specific signal were performed to model the effect of non-specific radioactivity on detection.

Results: Using this in vitro model, the lowest cell number that could be visualized on 6-well plate images was 6.8 × 10, when the specific activity was 27.8 kBq/10 cells. For the 3 × 3 cubic-well, a plate of 3.3 × 10 cells could be detected on images with a specific activity of 15.4 kBq/10 cells.

Conclusion: The results show the feasibility of detecting [Zr]Zr(oxinate)-labeled Jurkat T cells on clinical PET systems. The results provide a best-case scenario, as in vivo detection using PET/CT or PET/MRI will be affected by cell number, specific activity per cell, the density of cells within the target volume, and non-specific signal. This work has important implications for cell labeling studies in patients, particularly when using radiosensitive cells (e.g., T cells), which require detection of low cell numbers while minimizing radiation dose per cell.
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http://dx.doi.org/10.1186/s13550-020-00667-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7360010PMC
July 2020

Visualization of sodium dynamics in the kidney by magnetic resonance imaging in a multi-site study.

Kidney Int 2020 11 22;98(5):1174-1178. Epub 2020 Jun 22.

MR Research Centre, Department of Clinical Medicine, Aarhus University, Aarhus, Denmark.

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.
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http://dx.doi.org/10.1016/j.kint.2020.04.056DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7652549PMC
November 2020

The emerging role of cell surface receptor and protein binding radiopharmaceuticals in cancer diagnostics and therapy.

Nucl Med Biol 2021 01 12;92:53-64. Epub 2020 Jun 12.

Department of Radiology, University of Cambridge, Cambridge, United Kingdom; Cancer Research UK Cambridge Centre, Cambridge, United Kingdom.

Targeting specific cell membrane markers for both diagnostic imaging and radionuclide therapy is a rapidly evolving field in cancer research. Some of these applications have now found a role in routine clinical practice and have been shown to have a significant impact on patient management. Several molecular targets are being investigated in ongoing clinical trials and show promise for future implementation. Advancements in molecular biology have facilitated the identification of new cancer-specific targets for radiopharmaceutical development.
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http://dx.doi.org/10.1016/j.nucmedbio.2020.06.005DOI Listing
January 2021

ctDNA monitoring using patient-specific sequencing and integration of variant reads.

Sci Transl Med 2020 06;12(548)

Cambridge University Hospitals NHS Foundation Trust, Cambridge CB2 0QQ, UK.

Circulating tumor-derived DNA (ctDNA) can be used to monitor cancer dynamics noninvasively. Detection of ctDNA can be challenging in patients with low-volume or residual disease, where plasma contains very few tumor-derived DNA fragments. We show that sensitivity for ctDNA detection in plasma can be improved by analyzing hundreds to thousands of mutations that are first identified by tumor genotyping. We describe the INtegration of VAriant Reads (INVAR) pipeline, which combines custom error-suppression methods and signal-enrichment approaches based on biological features of ctDNA. With this approach, the detection limit in each sample can be estimated independently based on the number of informative reads sequenced across multiple patient-specific loci. We applied INVAR to custom hybrid-capture sequencing data from 176 plasma samples from 105 patients with melanoma, lung, renal, glioma, and breast cancer across both early and advanced disease. By integrating signal across a median of >10 informative reads, ctDNA was routinely quantified to 1 mutant molecule per 100,000, and in some cases with high tumor mutation burden and/or plasma input material, to parts per million. This resulted in median area under the curve (AUC) values of 0.98 in advanced cancers and 0.80 in early-stage and challenging settings for ctDNA detection. We generalized this method to whole-exome and whole-genome sequencing, showing that INVAR may be applied without requiring personalized sequencing panels so long as a tumor mutation list is available. As tumor sequencing becomes increasingly performed, such methods for personalized cancer monitoring may enhance the sensitivity of cancer liquid biopsies.
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http://dx.doi.org/10.1126/scitranslmed.aaz8084DOI Listing
June 2020

Creating a clinical platform for carbon-13 studies using the sodium-23 and proton resonances.

Magn Reson Med 2020 10 13;84(4):1817-1827. Epub 2020 Mar 13.

Department of Radiology, University of Cambridge, Cambridge, United Kingdom.

Purpose: Calibration of hyperpolarized C-MRI is limited by the low signal from endogenous carbon-containing molecules and consequently requires C-enriched external phantoms. This study investigated the feasibility of using either Na-MRI or H-MRI to calibrate the C excitation.

Methods: Commercial C-coils were used to estimate the transmit gain and center frequency for C and Na resonances. Simulations of the transmit B profile of a Helmholtz loop were performed. Noise correlation was measured for both nuclei. A retrospective analysis of human data assessing the use of the H resonance to predict [1- C]pyruvate center frequency was also performed. In vivo experiments were undertaken in the lower limbs of 6 pigs following injection of hyperpolarized C-pyruvate.

Results: The difference in center frequencies and transmit gain between tissue Na and [1- C]pyruvate was reproducible, with a mean scale factor of 1.05179 ± 0.00001 and 10.4 ± 0.2 dB, respectively. Utilizing the H water peak, it was possible to retrospectively predict the C-pyruvate center frequency with a standard deviation of only 11 Hz sufficient for spectral-spatial excitation-based studies.

Conclusion: We demonstrate the feasibility of using the Na and H resonances to calibrate the C transmit B using commercially available C-coils. The method provides a simple approach for in vivo calibration and could improve clinical workflow.
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http://dx.doi.org/10.1002/mrm.28238DOI Listing
October 2020

Hyperpolarized C MRI: A novel approach for probing cerebral metabolism in health and neurological disease.

J Cereb Blood Flow Metab 2020 06 10;40(6):1137-1147. Epub 2020 Mar 10.

Department of Radiology, University of Cambridge, Cambridge, UK.

Cerebral metabolism is tightly regulated and fundamental for healthy neurological function. There is increasing evidence that alterations in this metabolism may be a precursor and early biomarker of later stage disease processes. Proton magnetic resonance spectroscopy (H-MRS) is a powerful tool to non-invasively assess tissue metabolites and has many applications for studying the normal and diseased brain. However, the technique has limitations including low spatial and temporal resolution, difficulties in discriminating overlapping peaks, and challenges in assessing metabolic flux rather than steady-state concentrations. Hyperpolarized carbon-13 magnetic resonance imaging is an emerging clinical technique that may overcome some of these spatial and temporal limitations, providing novel insights into neurometabolism in both health and in pathological processes such as glioma, stroke and multiple sclerosis. This review will explore the growing body of pre-clinical data that demonstrates a potential role for the technique in assessing metabolism in the central nervous system. There are now a number of clinical studies being undertaken in this area and this review will present the emerging clinical data as well as the potential future applications of hyperpolarized C magnetic resonance imaging in the brain, in both clinical and pre-clinical studies.
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http://dx.doi.org/10.1177/0271678X20909045DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7238376PMC
June 2020

Noninvasive In Vivo Assessment of Cardiac Metabolism in the Healthy and Diabetic Human Heart Using Hyperpolarized C MRI.

Circ Res 2020 03 5;126(6):725-736. Epub 2020 Feb 5.

From the Oxford Centre for Clinical Magnetic Resonance Research, Radcliffe Department of Medicine (O.J.R., A.A., J.J.J.J.M., J.Y.C.L., A.J.M.L., M.A.P., C.T., S.N., D.J.T.), University of Oxford, United Kingdom.

Rationale: The recent development of hyperpolarized 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 (P-magnetic resonance spectroscopy), and lipid content (H-magnetic resonance spectroscopy) in the fasted state. In a subset (5 T2DM, 5 control), hyperpolarized [1-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-C]pyruvate via PDH (pyruvate dehydrogenase, [C]bicarbonate), lactate dehydrogenase ([1-C]lactate), and alanine transaminase ([1-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; =0.013). In addition, a significant increase in metabolic flux through PDH was observed after the oral glucose challenge (<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 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.
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http://dx.doi.org/10.1161/CIRCRESAHA.119.316260DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7077975PMC
March 2020

Feasibility of Quantitative Magnetic Resonance Fingerprinting in Ovarian Tumors for T and T Mapping in a PET/MR Setting.

IEEE Trans Radiat Plasma Med Sci 2019 Jul 15;3(4):509-515. Epub 2019 Mar 15.

Department of Radiology, University of Cambridge, Cambridge CB2 0QQ, U.K.; Cambridge University Hospitals, NHS Foundation Trust, Addenbrooke's Hospital, Cambridge, U.K.

Multiparametric magnetic resonance imaging (MRI) can be used to characterize many cancer subtypes including ovarian cancer. Quantitative mapping of MRI relaxation values, such as and mapping, is promising for improving tumor assessment beyond conventional qualitative - and -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 and 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 , , and relative proton density (rPD) mapping using ovarian cancer as a model system.
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http://dx.doi.org/10.1109/TRPMS.2019.2905366DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7025887PMC
July 2019

Radiomics of computed tomography and magnetic resonance imaging in renal cell carcinoma-a systematic review and meta-analysis.

Eur Radiol 2020 Jun 14;30(6):3558-3566. Epub 2020 Feb 14.

Department of Radiology, School of Clinical Medicine, University of Cambridge, Cambridge, UK.

Objectives: (1) To assess the methodological quality of radiomics studies investigating histological subtypes, therapy response, and survival in patients with renal cell carcinoma (RCC) and (2) to determine the risk of bias in these radiomics studies.

Methods: In this systematic review, literature published since 2000 on radiomics in RCC was included and assessed for methodological quality using the Radiomics Quality Score. The risk of bias was assessed using the Quality Assessment of Diagnostic Accuracy Studies tool and a meta-analysis of radiomics studies focusing on differentiating between angiomyolipoma without visible fat and RCC was performed.

Results: Fifty-seven studies investigating the use of radiomics in renal cancer were identified, including 4590 patients in total. The average Radiomics Quality Score was 3.41 (9.4% of total) with good inter-rater agreement (ICC 0.96, 95% CI 0.93-0.98). Three studies validated results with an independent dataset, one used a publically available validation dataset. None of the studies shared the code, images, or regions of interest. The meta-analysis showed moderate heterogeneity among the included studies and an odds ratio of 6.24 (95% CI 4.27-9.12; p < 0.001) for the differentiation of angiomyolipoma without visible fat from RCC.

Conclusions: Radiomics algorithms show promise for answering clinical questions where subjective interpretation is challenging or not established. However, the generalizability of findings to prospective cohorts needs to be demonstrated in future trials for progression towards clinical translation. Improved sharing of methods including code and images could facilitate independent validation of radiomics signatures.

Key Points: • Studies achieved an average Radiomics Quality Score of 10.8%. Common reasons for low Radiomics Quality Scores were unvalidated results, retrospective study design, absence of open science, and insufficient control for multiple comparisons. • A previous training phase allowed reaching almost perfect inter-rater agreement in the application of the Radiomics Quality Score. • Meta-analysis of radiomics studies distinguishing angiomyolipoma without visible fat from renal cell carcinoma show moderate diagnostic odds ratios of 6.24 and moderate methodological diversity.
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http://dx.doi.org/10.1007/s00330-020-06666-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7248043PMC
June 2020

Imaging breast cancer using hyperpolarized carbon-13 MRI.

Proc Natl Acad Sci U S A 2020 01 21;117(4):2092-2098. Epub 2020 Jan 21.

Medical Genomics Research, Illumina, Great Abington, Cambridge CB21 6DF, United Kingdom.

Our purpose is to investigate the feasibility of imaging tumor metabolism in breast cancer patients using C magnetic resonance spectroscopic imaging (MRSI) of hyperpolarized C label exchange between injected [1-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 C MRSI was performed following injection of hyperpolarized [1-C]pyruvate. Expression of lactate dehydrogenase A (LDHA), which catalyzes 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 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 ( = 0.903, = 0.005) and MCT 1 ( = 0.85, = 0.032) and HIF1α expression ( = 0.83, = 0.043). Imaging of hyperpolarized [1-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.
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http://dx.doi.org/10.1073/pnas.1913841117DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6995024PMC
January 2020

Removing rician bias in diffusional kurtosis of the prostate using real-data reconstruction.

Magn Reson Med 2020 06 18;83(6):2243-2252. Epub 2019 Nov 18.

Department of Radiology, School of Clinical Medicine, University of Cambridge, Cambridge, United Kingdom.

Purpose: To compare prostate diffusional kurtosis imaging (DKI) metrics generated using phase-corrected real data with those generated using magnitude data with and without noise compensation (NC).

Methods: Diffusion-weighted images were acquired at 3T in 16 prostate cancer patients, measuring 6 b-values (0-1500 s/mm ), each acquired with 6 signal averages along 3 diffusion directions, with noise-only images acquired to allow NC. In addition to conventional magnitude averaging, phase-corrected real data were averaged in an attempt to reduce rician noise-bias, with a range of phase-correction low-pass filter (LPF) sizes (8-128 pixels) tested. Each method was also tested using simulations. Pixelwise maps of apparent diffusion (D) and apparent kurtosis (K) were calculated for magnitude data with and without NC and phase-corrected real data. Average values were compared in tumor, normal transition zone (NTZ), and normal peripheral zone (NPZ).

Results: Simulations indicated LPF size can strongly affect K metrics, where 64-pixel LPFs produced accurate metrics. Relative to metrics estimated from magnitude data without NC, median NC K were lower (P < 0.0001) by 6/11/8% in tumor/NPZ/NTZ, 64-LPF real-data K were lower (P < 0.0001) by 4/10/7%, respectively.

Conclusion: Compared with magnitude data with NC, phase-corrected real data can produce similar K, although the choice of phase-correction LPF should be chosen carefully.
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http://dx.doi.org/10.1002/mrm.28080DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7065237PMC
June 2020

Fumarate Metabolic Signature for the Detection of Reed Syndrome in Humans.

Clin Cancer Res 2020 01 21;26(2):391-396. Epub 2019 Oct 21.

Department of Medical Genetics, University of Cambridge and NIHR Cambridge Biomedical Research Centre and Cancer Research UK Cambridge Centre, Cambridge, United Kingdom.

Purpose: Inherited pathogenic variants in genes encoding the metabolic enzymes succinate dehydrogenase (SDH) and fumarate hydratase predispose to tumor development through accumulation of oncometabolites (succinate and fumarate, respectively; ref. 1). Noninvasive detection of tumor succinate by proton magnetic resonance spectroscopy (H-MRS) has been reported in SDH-deficient tumors, but the potential utility of this approach in the management of patients with hereditary leiomyomatosis and renal cell cancer syndrome or Reed syndrome is unknown.

Experimental Design: Magnetic resonance spectroscopy (H-MRS) was performed on three cases and correlated with germline genetic results and tumor IHC when available.

Results: Here, we have demonstrated a proof of principle that H-MRS can provide a noninvasive diagnosis of hereditary leiomyomatosis and renal cell cancer syndrome or Reed syndrome through detection of fumarate accumulation .

Conclusions: This study demonstrates that detection of fumarate could be employed as a functional biomarker.
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http://dx.doi.org/10.1158/1078-0432.CCR-19-1729DOI Listing
January 2020

Sodium homeostasis in the tumour microenvironment.

Biochim Biophys Acta Rev Cancer 2019 12 23;1872(2):188304. Epub 2019 Jul 23.

Department of Biology, University of York, Heslington, York YO10 5DD, UK; York Biomedical Research Institute, University of York, Heslington, York YO10 5DD, UK. Electronic address:

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.
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http://dx.doi.org/10.1016/j.bbcan.2019.07.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7115894PMC
December 2019
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