Publications by authors named "Fulvio Zaccagna"

57 Publications

Brain Tumor Diagnosis Using Machine Learning, Convolutional Neural Networks, Capsule Neural Networks and Vision Transformers, Applied to MRI: A Survey.

J Imaging 2022 Jul 22;8(8). Epub 2022 Jul 22.

Department of Information and Electrical Engineering and Applied Mathematics, University of Salerno, 84084 Fisciano, Italy.

Management of brain tumors is based on clinical and radiological information with presumed grade dictating treatment. Hence, a non-invasive assessment of tumor grade is of paramount importance to choose the best treatment plan. Convolutional Neural Networks (CNNs) represent one of the effective Deep Learning (DL)-based techniques that have been used for brain tumor diagnosis. However, they are unable to handle input modifications effectively. Capsule neural networks (CapsNets) are a novel type of machine learning (ML) architecture that was recently developed to address the drawbacks of CNNs. CapsNets are resistant to rotations and affine translations, which is beneficial when processing medical imaging datasets. Moreover, Vision Transformers (ViT)-based solutions have been very recently proposed to address the issue of long-range dependency in CNNs. This survey provides a comprehensive overview of brain tumor classification and segmentation techniques, with a focus on ML-based, CNN-based, CapsNet-based, and ViT-based techniques. The survey highlights the fundamental contributions of recent studies and the performance of state-of-the-art techniques. Moreover, we present an in-depth discussion of crucial issues and open challenges. We also identify some key limitations and promising future research directions. We envisage that this survey shall serve as a good springboard for further study.
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http://dx.doi.org/10.3390/jimaging8080205DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9331677PMC
July 2022

Imaging Glioblastoma Metabolism by Using Hyperpolarized [1-C]Pyruvate Demonstrates Heterogeneity in Lactate Labeling: A Proof of Principle Study.

Radiol Imaging Cancer 2022 Jul;4(4):e210076

From the Departments of Radiology (F.Z., J.T.G., J.K., F.R., R.W., A.B.G., S.D., C.J.D., S.U., M.C.L., M.L., A.F., S.H., J.H.G., T.M., M.J.G., F.A.G.), Clinical Neurosciences (R.M., C.W., S.J.P., T.S.), and Medicine (I.W.), University of Cambridge School of Clinical Medicine, Cambridge, England; Cancer Research UK Cambridge Institute (M.A.M., S.U., K.M.B.), Medical Research Council Biostatistics Unit (J.W.), and Department of Biochemistry (K.M.B.), University of Cambridge, Li Ka Shing Centre, Robinson Way, Cambridge, CB2 0RE, England; Department of Biomedical Imaging and Image-guided Therapy, Medical University of Vienna, Vienna, Austria (R.W.); GE Healthcare, Munich, Germany (R.F.S.); Department of Pathology (K.A.), Cambridge Cancer Trials Centre (A.C.), Department of Radiology (I.P., B.D.C., R.S.), and Department of Oncology (B.B., S.J.), Cambridge University Hospitals National Health Service Foundation Trust, Cambridge, England; and Population Health Sciences Institute, Newcastle University, Newcastle upon Tyne, England (J.W.).

Purpose To evaluate glioblastoma (GBM) metabolism by using hyperpolarized carbon 13 (C) MRI to monitor the exchange of the hyperpolarized C label between injected [1-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 C-hydrogen 1 head coil. Hyperpolarized [1-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 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 ( < .01). The tumor lactate-to-pyruvate (LP) ratio was not different from that in the NABP ( = .38). The LP and BP ratios in the NABP were higher than those observed previously in healthy volunteers ( < .05). Tumor lactate and bicarbonate signal intensities were strongly correlated with the pyruvate signal intensity (ρ = 0.92, < .001, and ρ = 0.66, < .001, respectively), and the LP ratio was weakly correlated with LDH-A expression in biopsy samples (ρ = 0.43, = .04). Conclusion Hyperpolarized 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. Hyperpolarized C MRI, Glioblastoma, Metabolism, Cancer, MRI, Neuro-oncology Published under a CC BY 4.0 license.
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http://dx.doi.org/10.1148/rycan.210076DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9360994PMC
July 2022

Age related increase in internal jugular vein size parallels temporal development of periventricular white matter hyperintensities.

Clin Anat 2022 Jul 2. Epub 2022 Jul 2.

Department of Medical Imaging, University of Toronto, Toronto, Canada.

Age-related white matter hyperintensities are associated with cognitive impairment and dementia. Venous insufficiency has recently been proposed as a potential mechanism for the development of periventricular white matter hyperintensities based on the neuroanatomic distribution. The current study assesses age related changes of the internal jugular veins and its association with white matter hyperintensities. A retrospective study was performed assessing patients with computed tomography angiography (CTA) and magnetic resonance imaging (MRI) within a 4-week window. The size of the internal jugular veins, straight sinus, vein of Galen and internal cerebral veins were measured on the CT angiography. A normalized neck venous ratio was developed. Burden of white matter hyperintensities were quantified on MRI using periventricular/deep Fazekas scores. Association was assessed using correlation analysis and multrivariate linear modeling, and differences between groups were assessed using t test, ANOVA or Kruskal-Wallis test, using p < 0.05 for significance. One hundred eighty-two patients were included with a mean age of 65.2 ± 16.8 (51.6% females). Age was correlated with the normalized neck venous ratio (r  = 0.25, p < 0.001), and, with both, the periventricular Fazekas (r  = 0.63, p < 0.001) and the deep Fazekas (r  = 0.57, p < 0.001) grades. The periventricular Fazekas score was positively correlated with the normalized neck venous ratio (r  = 0.21, p = 0.003), but not significant on multivariate analysis accounting for age. The internal jugular veins demonstrate age related increase in size, paralleling the progression of periventricular white matter hyperintensities. Age remains the strongest predictor of white matter hyperintensities. Further work is needed to evaluate any causal role of venous changes on white matter hyperintensities.
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http://dx.doi.org/10.1002/ca.23926DOI Listing
July 2022

Neuroplasticity Mechanisms in Frontal Brain Gliomas: A Preliminary Study.

Front Neurol 2022 3;13:867048. Epub 2022 Jun 3.

Functional and Molecular Neuroimaging Unit, IRCCS Istituto delle Scienze Neurologiche di Bologna, Bologna, Italy.

Background: Pathological brain processes may induce adaptive cortical reorganization, however, the mechanisms underlying neuroplasticity that occurs in the presence of lesions in eloquent areas are not fully explained. The aim of this study was to evaluate functional compensatory cortical activations in patients with frontal brain gliomas during a phonemic fluency task and to explore correlations with cognitive performance, white matter tracts microstructural alterations, and tumor histopathological and molecular characterization.

Methods: Fifteen patients with frontal glioma were preoperatively investigated with an MRI study on a 3T scanner and a subgroup underwent an extensive neuropsychological assessment. The hemispheric laterality index (LI) was calculated through phonemic fluency task functional MRI (fMRI) activations in the frontal, parietal, and temporal lobe parcellations. Diffusion-weighted images were acquired for all patients and for a group of 24 matched healthy volunteers. Arcuate Fasciculus (AF) and Frontal Aslant Tract (FAT) tractography was performed using constrained spherical deconvolution diffusivity modeling and probabilistic fiber tracking. All patients were operated on with a resective aim and underwent adjuvant therapies, depending on the final diagnosis.

Results: All patients during the phonemic fluency task fMRI showed left hemispheric dominance in temporal and parietal regions. Regarding frontal regions (i.e., frontal operculum) we found right hemispheric dominance that increases when considering only those patients with tumors located on the left side. These latter activations positively correlate with verbal and visuo-spatial short-term memory, and executive functions. No correlations were found between the left frontal operculum and cognitive performance. Furthermore, patients with mutation and without mutation, showed higher rightward frontal operculum fMRI activations and better cognitive performance in tests measuring general cognitive abilities, semantic fluency, verbal short-term memory, and executive functions. As for white matter tracts, we found left and right AF and FAT microstructural alterations in patients with, respectively, left-sided and right-side glioma compared to controls.

Conclusions: Compensatory cortical activation of the corresponding region in the non-dominant hemisphere and its association with better cognitive performance and more favorable histopathological and molecular tumor characteristics shed light on the neuroplasticity mechanisms that occur in the presence of a tumor, helping to predict the rate of post-operative deficit, with the final goal of improving patients'quality of life.
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http://dx.doi.org/10.3389/fneur.2022.867048DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9204970PMC
June 2022

Infra-Temporal and Pterygo-Palatine Fossae Tumors: A Frontier in Endoscopic Endonasal Surgery-Description of the Surgical Anatomy of the Approach and Report of Illustrative Cases.

Int J Environ Res Public Health 2022 05 25;19(11). Epub 2022 May 25.

Programma Neurochirurgia Ipofisi-Pituitary Unit, IRCCS Istituto delle Scienze Neurologiche di Bologna, 40139 Bologna, Italy.

Infratemporal and pterygopalatine fossae (ITF and PPF) represent two complex paramedian skull base areas, which can be defined as jewelry boxes, containing a large number of neurovascular and osteomuscular structures of primary importance. They are in close communication with many craniofacial areas, such as nasal/paranasal sinuses, orbit, middle cranial fossa, and oral cavities. Therefore, they can be involved by tumoral, infective or inflammatory lesions spreading from these spaces. Moreover, they can be the primary site of the development of some primitive tumors. For the deep-seated location of ITF and PPF lesions and their close relationship with the surrounding functional neuro-vascular structures, their surgery represents a challenge. In the last decades, the introduction of the endoscope in skull base surgery has favored the development of an innovative anterior endonasal approach for ITF and PPF tumors: the transmaxillary-pterygoid, which gives a direct and straightforward route for these areas. It has demonstrated that it is effective and safe for the treatment of a large number of benign and malignant neoplasms, located in these fossae, avoiding extensive bone drilling, soft tissue demolition, possibly unaesthetic scars, and reducing the risk of neurological deficits. However, some limits, especially for vascular tumors or lesions with lateral extension, are still present. Based on the experience of our multidisciplinary team, we present our operative technique, surgical indications, and pre- and post-operative management protocol for patients with ITF and PPF tumors.
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http://dx.doi.org/10.3390/ijerph19116413DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9180479PMC
May 2022

Hyperpolarized C-Pyruvate Metabolism as a Surrogate for Tumor Grade and Poor Outcome in Renal Cell Carcinoma-A Proof of Principle Study.

Cancers (Basel) 2022 Jan 11;14(2). Epub 2022 Jan 11.

Cancer Research UK Cambridge Centre, University of Cambridge, Cambridge CB2 0QQ, UK.

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-C]pyruvate (HP-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-C-MRI and conventional proton (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 () between C-pyruvate and 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 in ccRCC was correlated with increasing overall tumor grade (ρ = 0.92, = 0.009) and MCT1 expression (r = 0.89, = 0.016), with similar results acquired from the multi-regional analysis. Conventional H-MRI parameters did not discriminate tumor grades. The correlation between MCT1 and ccRCC grade was confirmed within a TCGA dataset ( < 0.001), where MCT1 expression was a predictor of overall and disease-free survival. In conclusion, metabolic imaging using HP-C-MRI differentiates tumor aggressiveness in ccRCC and correlates with the expression of MCT1, a predictor of survival. HP-C-MRI may non-invasively characterize metabolic phenotypes within renal cancer.
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http://dx.doi.org/10.3390/cancers14020335DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8773685PMC
January 2022

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

Diagnostics (Basel) 2021 Dec 17;11(12). Epub 2021 Dec 17.

Mohn Medical Imaging and Visualization Centre (MMIV), Department of Radiology, Haukeland University Hospital, University of Bergen, N-5021 Bergen, Norway.

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 (). 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 distribution in non-enhancing tumor parts toward higher values and significantly increases its entropy ( ≤ 0.003), whereas skewness is decreased ( ≤ 0.004). Kurtosis is significantly decreased ( < 0.001) in high-grade tumors. In conclusion, eliminating FW contributions improved quantitative estimations of , which helps to disentangle the cancer heterogeneity.
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http://dx.doi.org/10.3390/diagnostics11122385DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8700586PMC
December 2021

Advanced Computational Methods for Oncological Image Analysis.

J Imaging 2021 Nov 12;7(11). Epub 2021 Nov 12.

Saitama Prefectural University, Saitama 343-8540, Japan.

The Special Issue "Advanced Computational Methods for Oncological Image Analysis", published for the , covered original research papers about state-of-the-art and novel algorithms and methodologies, as well as applications of computational methods for oncological image analysis, ranging from radiogenomics to deep learning [...].
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http://dx.doi.org/10.3390/jimaging7110237DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8619456PMC
November 2021

Multiparametric MRI for assessment of early response to neoadjuvant sunitinib in renal cell carcinoma.

PLoS One 2021 26;16(10):e0258988. Epub 2021 Oct 26.

University of Cambridge, Cambridge, United Kingdom.

Purpose: To detect early response to sunitinib treatment in metastatic clear cell renal cancer (mRCC) using multiparametric MRI.

Method: Participants with mRCC undergoing pre-surgical sunitinib therapy in the prospective NeoSun clinical trial (EudraCtNo: 2005-004502-82) were imaged before starting treatment, and after 12 days of sunitinib therapy using morphological MRI sequences, advanced diffusion-weighted imaging, measurements of R2* (related to hypoxia) and dynamic contrast-enhanced imaging. Following nephrectomy, participants continued treatment and were followed-up with contrast-enhanced CT. Changes in imaging parameters before and after sunitinib were assessed with the non-parametric Wilcoxon signed-rank test and the log-rank test was used to assess effects on survival.

Results: 12 participants fulfilled the inclusion criteria. After 12 days, the solid and necrotic tumor volumes decreased by 28% and 17%, respectively (p = 0.04). However, tumor-volume reduction did not correlate with progression-free or overall survival (PFS/OS). Sunitinib therapy resulted in a reduction in median solid tumor diffusivity D from 1298x10-6 to 1200x10-6mm2/s (p = 0.03); a larger decrease was associated with a better RECIST response (p = 0.02) and longer PFS (p = 0.03) on the log-rank test. An increase in R2* from 19 to 28s-1 (p = 0.001) was observed, paralleled by a decrease in Ktrans from 0.415 to 0.305min-1 (p = 0.01) and a decrease in perfusion fraction from 0.34 to 0.19 (p<0.001).

Conclusions: Physiological imaging confirmed efficacy of the anti-angiogenic agent 12 days after initiating therapy and demonstrated response to treatment. The change in diffusivity shortly after starting pre-surgical sunitinib correlated to PFS in mRCC undergoing nephrectomy, however, no parameter predicted OS.

Trial Registration: EudraCtNo: 2005-004502-82.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0258988PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8547646PMC
December 2021

Dynamic biomarker and imaging changes from a phase II study of pre- and post-surgical sunitinib.

BJU Int 2022 08 2;130(2):244-253. Epub 2021 Nov 2.

Department of Oncology, Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK.

Objective: To explore translational biological and imaging biomarkers for sunitinib treatment before and after debulking nephrectomy in the NeoSun (European Union Drug Regulating Authorities Clinical Trials Database [EudraCT] number: 2005-004502-82) single-centre, single-arm, single-agent, Phase II trial.

Patients And Methods: Treatment-naïve patients with metastatic renal cell carcinoma (mRCC) received 50 mg once daily sunitinib for 12 days pre-surgically, then post-surgery on 4 week-on, 2 week-off, repeating 6-week cycles until disease progression in a single arm phase II trial. Structural and dynamic contrast-enhanced magnet resonance imaging (DCE-MRI) and research blood sampling were performed at baseline and after 12 days. Computed tomography imaging was performed at baseline and post-surgery then every two cycles. The primary endpoint was objective response rate (Response Evaluation Criteria In Solid Tumors [RECIST]) excluding the resected kidney. Secondary endpoints included changes in DCE-MRI of the tumour following pre-surgery sunitinib, overall survival (OS), progression-free survival (PFS), response duration, surgical morbidity/mortality, and toxicity. Translational and imaging endpoints were exploratory.

Results: A total of 14 patients received pre-surgery sunitinib, 71% (10/14) took the planned 12 doses. All underwent nephrectomy, and 13 recommenced sunitinib postoperatively. In all, 58.3% (seven of 12) of patients achieved partial or complete response (PR or CR) (95% confidence interval 27.7-84.8%). The median OS was 33.7 months and median PFS was 15.7 months. Amongst those achieving a PR or CR, the median response duration was 8.7 months. No unexpected surgical complications, sunitinib-related toxicities, or surgical delays occurred. Within the translational endpoints, pre-surgical sunitinib significantly increased necrosis, and reduced cluster of differentiation-31 (CD31), Ki67, circulating vascular endothelial growth factor-C (VEGF-C), and transfer constant (K , measured using DCE-MRI; all P < 0.05). There was a trend for improved OS in patients with high baseline plasma VEGF-C expression (P = 0.02). Reduction in radiological tumour volume after pre-surgical sunitinib correlated with high percentage of solid tumour components at baseline (Spearman's coefficient ρ = 0.69, P = 0.02). Conversely, the percentage tumour volume reduction correlated with lower baseline percentage necrosis (coefficient = -0.51, P = 0.03).

Conclusion: Neoadjuvant studies such as the NeoSun can safely and effectively explore translational biological and imaging endpoints.
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http://dx.doi.org/10.1111/bju.15600DOI Listing
August 2022

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

Eur J Radiol 2021 Sep 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
September 2021

Editorial for "Value of Dynamic Contrast Enhanced (DCE) MRI in Predicting Response to Foam Sclerotherapy of Venous Malformations".

J Magn Reson Imaging 2021 10 22;54(4):1117-1118. Epub 2021 May 22.

Division of Neuroimaging, Department of Medical Imaging, University of Toronto, Toronto, Ontario, Canada.

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http://dx.doi.org/10.1002/jmri.27736DOI Listing
October 2021

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

Sci Rep 2021 04 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 02 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

CT texture-based radiomics analysis of carotid arteries identifies vulnerable patients: a preliminary outcome study.

Neuroradiology 2021 Jul 3;63(7):1043-1052. Epub 2021 Jan 3.

Institute of Nuclear Medicine, University College London, London, UK.

Purpose: To assess the potential role of computed tomography (CT) texture analysis (CTTA) in identifying vulnerable patients with carotid artery atherosclerosis.

Methods: In this case-control pilot study, 12 patients with carotid atherosclerosis and a subsequent history of transient ischemic attack or stroke were age and sex matched with 12 control cases with asymptomatic carotid atherosclerosis (follow-up time 103.58 ± 9.2 months). CTTA was performed using a commercially available research software package (TexRAD) by an operator blinded to clinical data. CTTA comprised a filtration-histogram technique to extract features at different scales corresponding to spatial scale filter (fine = 2 mm, medium = 3 mm, coarse = 4 mm), followed by quantification using histogram-based statistical parameters: mean, kurtosis, skewness, entropy, standard deviation, and mean value of positive pixels. A single axial slice was selected to best represent the largest cross-section of the carotid bifurcation or the greatest degree of stenosis, in presence of an atherosclerotic plaque, on each side.

Results: CTTA revealed a statistically significant difference in skewness between symptomatic and asymptomatic patients at the medium (0.22 ± 0.35 vs - 0.18 ± 0.39, p < 0.001) and coarse (0.23 ± 0.22 vs 0.03 ± 0.29, p = 0.003) texture scales. At the fine-texture scale, skewness (0.20 ± 0.59 vs - 0.18 ± 0.58, p = 0.009) and standard deviation (366.11 ± 117.19 vs 300.37 ± 82.51, p = 0.03) were significant before correction.

Conclusion: Our pilot study highlights the potential of CTTA to identify vulnerable patients in stroke and TIA. CT texture may have the potential to act as a novel risk stratification tool in patients with carotid atherosclerosis.
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http://dx.doi.org/10.1007/s00234-020-02628-0DOI Listing
July 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

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

The use of multiparametric 18F-fluoro-L-3,4-dihydroxy-phenylalanine PET/MRI in post-therapy assessment of patients with gliomas.

Nucl Med Commun 2020 Jun;41(6):517-525

Institute of Nuclear Medicine.

Purpose: To determine the utility of F-fluoro-L-3,4-dihydroxy-phenylalanine (F-DOPA) PET/MRI versus cross-sectional MRI alone in glioma response assessment and identify whether the two techniques demonstrate different tumour features.

Methods: F-DOPA PET/MRI studies from 40 patients were analysed. Quantitative PET parameters and conventional MRI features were recorded. Tumour volume was assessed on both PET and MRI. Using dynamic susceptibility contrast perfusion-weighted imaging, maps of cerebral blood flow (CBF) and cerebral blood volume (CBV) were obtained. Within volume of tumours of tumour features and normal-appearing white matter (NAWM) drawn on MRI, standardised uptake value (SUV)max, CBF and CBV were recorded. Presence of residual active tumour was assessed by qualitative visual assessment. Receiver operating characteristic analysis was performed univariately and on parameter combination to analyse ability to determine presence/absence of disease. Reference standard for presence of viable tissue was biopsy or clinical follow-up.

Results: Median SUVmax was 3.4 for low-grade glioma (LGG) and 3.3 for high-grade glioma (HGG). There was a significant correlation between PWI parameters and WHO grade (P < 0.001), but no correlation with SUVmax. Median F-DOPA volume was 8216.88 mm for HGG and 6284.94 mm for LGG; MRI volume was 6316.57 mm and 5931.55 mm, respectively. SUVmax analysis distinguished enhancing and nonenhancing components from necrosis and NAWM and demonstrated active disease in nonenhancing regions. Visually, the modalities were concordant in 37 patients. Combining the multiparametric PET/MRI approach with all available data-enhanced detection of the presence of tumour (area under the curve 0.99, P < 0.01).

Conclusion: MRI and F-DOPA are complementary modalities for assessment of tumour burden. Matching F-DOPA and MRI in assessing residual tumour volume may better delineate the radiotherapy target volume.
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http://dx.doi.org/10.1097/MNM.0000000000001184DOI Listing
June 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

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

A critical appraisal of Monro's erroneous description of the cerebral interventricular foramina: Age-related magnetic resonance imaging spatial morphometry and a proposed new terminology.

Clin Anat 2020 Apr 22;33(3):446-457. Epub 2020 Jan 22.

Division of Neuroimaging and Neurointervention, Stanford Initiative for Multimodality neuro-Imaging in Translational Anatomy Research (SIMITAR), Department of Radiology, Stanford University School of Medicine, Stanford, California.

Anatomic connections between the cerebral lateral and third ventricles have been mischaracterized since Monro's original erroneous description of his eponymous foramina (FoMs) as being only one T-shaped passage. Accurate knowledge of the in vivo three-dimensional (3D) configuration of FoM has important clinical neuroendoscopic, neurosurgical, and neuroimaging implications. We retrospectively analyzed volumetric high-resolution brain magnetic resonance imaging of 100 normal individuals to characterize the normal spatial anatomy and morphometry for each FoM. We measured the true anatomical 3D angulations of FoMs relative to standard neuroimaging orthogonal planes, and their minimum width, depth, and distance between the medial borders of bilateral FoMs. The right and left FoMs were separate, distinct, and in a V-shaped configuration. Each FoM was a round, oval, or crescent-shaped canal-like passage with well-defined borders formed by the semicircular concavity of the ipsilateral forniceal column. The plane of FoM was angled on average 56.8° ± 9.1° superiorly from the axial plane, 22.5° ± 10.7° laterally, and 37.0° ± 6.9° anteriorly from the midsagittal plane; all these angles changing significantly with increasing age. The mean narrowest diameter of FoM was 2.8 ± 1.2 mm, and its depth was 2.5 ± 0.2 mm. Thus, the true size and orientation of FoM differs from that depicted on standard neuroimaging. Notably, in young subjects, FoM has a diameter smaller than its depth, a configuration akin to a short, small canal. We propose that the eponym "Monro" no longer be associated with this structure, and the term "foramen" be abandoned. Instead, FoM should be more appropriately renamed as the "interventricular canaliculus," or IVC, for short.
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http://dx.doi.org/10.1002/ca.23560DOI Listing
April 2020

Optic Chiasm Morphometric Changes in Multiple Sclerosis: Feasibility of a Simplified Brain Magnetic Resonance Imaging Measure of White Matter Atrophy.

Clin Anat 2019 Nov 19;32(8):1072-1081. Epub 2019 Aug 19.

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

Sophisticated volume measurements of brain structures on magnetic resonance imaging (MRI) may improve specificity in determining long-term progression of multiple sclerosis (MS), but these techniques are laborious. The optic chiasm (OC) is a white matter (WM) structure clearly visible on a routine MRI and is related to the optic nerves (ONs), which are known to atrophy in MS. We hypothesized that OC morphometric measurements would show OC atrophy in MS compared to normal patients. If so, this could help establish a novel simplified brain MRI measure of WM atrophy in MS patients. We retrospectively evaluated standard brain MRIs of 97 patients with known MS and 98 normal individuals. We electronically measured eight OC morphometrics on axial T2WIs and midsagittal T1WIs: OC width and anteroposterior (AP) diameter, diameters of each ON and optic tract (OT), and angles between the ONs or OTs. Mean OC width, AP diameter, and height in MS patients were 11.83 ± 1.25 mm (95% CI 11.58-12.09), 2.99 ± 0.65 mm (95% CI 2.85-3.12), and 2.09 ± 0.37 mm (95% CI 2-2.19), respectively. In normal individuals, they were 12.1 ± 1.4 mm (95% CI 11.78-12.34), 3.43 ± 0.63 mm (95% CI 3.3-3.58), and 2.15 ± 0.37 mm (95% CI 2.07-2.23), respectively. There were statistically significant differences between MS patients and controls for AP diameter (P = 0.000), but not for width (P = 0.204) or height (P = 0.183). The ONs were significantly smaller in MS (P < 0.0017), but not the OTs. Thus, the OC is significantly atrophied in an unstratified cohort of MS patients. Future studies may establish an MRI OC morphometric index to evaluate demyelinating disease in the brain. Clin. Anat. 32:1072-1081, 2019. © 2019 Wiley Periodicals, Inc.
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http://dx.doi.org/10.1002/ca.23446DOI Listing
November 2019

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

Post-mortem computed tomography (PMCT) radiological findings and assessment in advanced decomposed bodies.

Radiol Med 2019 Oct 28;124(10):1018-1027. Epub 2019 Jun 28.

Department of Anatomical, Histological, Forensic and Orthopaedic Sciences, Sapienza University of Rome, Viale Regina Elena 336, 00161, Rome, RM, Italy.

Purpose: The aim of the study is to report radiological findings and features in advanced decomposed bodies obtained by post-mortem computed tomography (PMCT) with autopsy correlation.

Materials And Methods: This retrospective descriptive multicentric study included 41 forensic cases examined between May 2013 and November 2016. All the bodies were PMCT-scanned prior to autopsy, and internal putrefactive state was determined using the radiological alteration index (RAI) by a radiologist with expertise in forensic radiology and a forensic pathologist trained in forensic imaging. After PMCT scans, grade of external putrefaction (GEP) was assigned during the external examination and the complete autopsy was performed by forensic pathologists.

Results: The PMCT images evaluation revealed that the RAI index was > 61 in all bodies, corresponding to a moderate-massive presence of putrefactive gas. The gas grade was > II in correspondence of the major vessels, heart cavities, liver parenchyma, vertebra L3 and subcutaneous pectoral tissues, and varied from I to III in correspondence of the kidney. Cadaveric external examination revealed the presence of advanced transformative phenomena, with a GEP3 and GEP4 in most of the cases, with body swelling, eyes and tongue protrusion, body fluids expulsion and fat liquefaction.

Conclusion: Radiological imaging by PMCT as an adjunct to autopsy in advanced decomposed bodies represents a useful tool in detecting post-mortem gas, even in very small amounts. A correct interpretation process of the PMCT data is essential to avoid images pitfalls, due to natural decomposition that can be mistaken for pathologic processes.
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http://dx.doi.org/10.1007/s11547-019-01052-6DOI Listing
October 2019

Ossification of the pterygoalar and pterygospinous ligaments: a computed tomography analysis of infratemporal fossa anatomical variants relevant to percutaneous trigeminal rhizotomy.

J Neurosurg 2019 May 10;132(6):1942-1951. Epub 2019 May 10.

5Division of Neuroimaging and Neurointervention, Department of Radiology, Stanford University School of Medicine, Stanford, California.

Objective: Ossification of pterygoalar and pterygospinous ligaments traversing the superior aspect of the infratemporal fossa results in formation of osseous bars that can obstruct percutaneous needle access to the trigeminal ganglion through the foramen ovale (FO), interfere with lateral mandibular nerve block, and impede transzygomatic surgical approaches. Presence of these ligaments has been studied on dry skulls, but description of their radiological anatomy is scarce, in particular on cross-sectional imaging. The aim of this study was to describe visualization of pterygoalar and pterygospinous bars on computed tomography (CT) and to review their prevalence and clinical significance.

Methods: The authors retrospectively reviewed 200 helical sinonasal CT scans by analyzing 0.75- to 1.0-mm axial images, maximum intensity projection (MIP) reconstructions, and volume rendered (VR) images, including views along the anticipated axis of the needle in percutaneous Hartel and submandibular approaches to the FO.

Results: Ossified pterygoalar and pterygospinous ligaments were readily identifiable on CT scans. An ossified pterygoalar ligament was demonstrated in 10 patients, including 1 individual with bilateral complete ossification (0.5%), 4 patients with unilateral complete ossification (2.0%), and 5 with incomplete unilateral ossification (2.5%). Nearly all patients with pterygoalar bars were male (90%, p < 0.01). An ossified pterygospinous ligament was seen in 35 patients, including 2 individuals with bilateral complete (1.0%), 8 with unilateral complete (4%), 8 with bilateral incomplete (4.0%), 12 with bilateral incomplete (6.0%) ossification, and 5 (2.5%) with mixed ossification (complete on one side and incomplete on the contralateral side). All pterygoalar bars interfered with a hypothetical needle access to the FO using the Hartel approach but not the submandibular approach. In contrast, 54% of complete and 24% of incomplete pterygospinous bars impeded the submandibular approach to the FO, without affecting the Hartel approach.

Conclusions: This study provides the first detailed description of cross-sectional radiological and applied surgical anatomy of pterygoalar and pterygospinous bars. Our data are clinically useful during skull base imaging to predict potential obstacles to percutaneous cannulation of the FO and assist in the choice of approach, as these two variants differentially impede the Hartel and submandibular access routes. Our results can also be useful in planning surgical approaches to the skull base through the infratemporal fossa.
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http://dx.doi.org/10.3171/2019.2.JNS182709DOI Listing
May 2019

Multi-site repeatability and reproducibility of MR fingerprinting of the healthy brain at 1.5 and 3.0 T.

Neuroimage 2019 07 25;195:362-372. Epub 2019 Mar 25.

Department of Radiology, University of Cambridge, United Kingdom.

Fully-quantitative MR imaging methods are useful for longitudinal characterization of disease and assessment of treatment efficacy. However, current quantitative MRI protocols have not been widely adopted in the clinic, mostly due to lengthy scan times. Magnetic Resonance Fingerprinting (MRF) is a new technique that can reconstruct multiple parametric maps from a single fast acquisition in the transient state of the MR signal. Due to the relative novelty of this technique, the repeatability and reproducibility of quantitative measurements obtained using MRF has not been extensively studied. Our study acquired test/retest data from the brains of nine healthy volunteers, each scanned on five MRI systems (two at 3.0 T and three at 1.5 T, all from a single vendor) located at two different centers. The pulse sequence and reconstruction algorithm were the same for all acquisitions. After registration of the MRF-derived M, 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 an excellent repeatability (CVs of 2-3% for T, 5-8% for T, 3% for normalized-M) and a good reproducibility (CVs of 3-8% for T, 8-14% for T, 5% for normalized-M) in grey and white matter.
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http://dx.doi.org/10.1016/j.neuroimage.2019.03.047DOI Listing
July 2019

Non-invasive assessment of glioma microstructure using VERDICT MRI: correlation with histology.

Eur Radiol 2019 Oct 19;29(10):5559-5566. Epub 2019 Mar 19.

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

Purpose: This prospective study evaluated the use of vascular, extracellular and restricted diffusion for cytometry in tumours (VERDICT) MRI to investigate the tissue microstructure in glioma. VERDICT-derived parameters were correlated with both histological features and tumour subtype and were also used to explore the peritumoural region.

Methods: Fourteen consecutive treatment-naïve patients (43.5 years ± 15.1 years, six males, eight females) with suspected glioma underwent diffusion-weighted imaging including VERDICT modelling. Tumour cell radius and intracellular and combined extracellular/vascular volumes were estimated using a framework based on linearisation and convex optimisation. An experienced neuroradiologist outlined the peritumoural oedema, enhancing tumour and necrosis on T2-weighted imaging and contrast-enhanced T1-weighted imaging. The same regions of interest were applied to the co-registered VERDICT maps to calculate the microstructure parameters. Pathology sections were analysed with semi-automated software to measure cellularity and cell size.

Results: VERDICT parameters were successfully calculated in all patients. The imaging-derived results showed a larger intracellular volume fraction in high-grade glioma compared to low-grade glioma (0.13 ± 0.07 vs. 0.08 ± 0.02, respectively; p = 0.05) and a trend towards a smaller extracellular/vascular volume fraction (0.88 ± 0.07 vs. 0.92 ± 0.04, respectively; p = 0.10). The conventional apparent diffusion coefficient was higher in low-grade gliomas compared to high-grade gliomas, but this difference was not statistically significant (1.22 ± 0.13 × 10 mm/s vs. 0.98 ± 0.38 × 10 mm/s, respectively; p = 0.18).

Conclusion: This feasibility study demonstrated that VERDICT MRI can be used to explore the tissue microstructure of glioma using an abbreviated protocol. The VERDICT parameters of tissue structure correlated with those derived on histology. The method shows promise as a potential test for diagnostic stratification and treatment response monitoring in the future.

Key Points: • VERDICT MRI is an advanced diffusion technique which has been correlated with histopathological findings obtained at surgery from patients with glioma in this study. • The intracellular volume fraction measured with VERDICT was larger in high-grade tumours compared to that in low-grade tumours. • The results were complementary to measurements from conventional diffusion-weighted imaging, and the technique could be performed in a clinically feasible timescale.
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http://dx.doi.org/10.1007/s00330-019-6011-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6719328PMC
October 2019

Measuring tissue sodium concentration: Cross-vendor repeatability and reproducibility of Na-MRI across two sites.

J Magn Reson Imaging 2019 10 12;50(4):1278-1284. Epub 2019 Mar 12.

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

Background: Sodium MRI ( Na-MRI)-derived biomarkers such as total sodium concentration (TSC) have the potential to provide information on tumor cellularity and the changes in tumor microstructure that occur following therapy.

Purpose: To evaluate the repeatability and reproducibility of TSC measurements in the brains of healthy volunteers, providing evidence for the technical validation of Na-MRI-derived biomarkers.

Study Type: Prospective multicenter study.

Subjects: Eleven volunteers (32 ± 6 years; eight males, three females) were scanned twice at each of two sites.

Field Strength/sequence: Comparable 3D-cones Na-MRI ultrashort echo time acquisitions at 3T.

Assessment: TSC values, quantified from calibration phantoms placed in the field of view, were obtained from white matter (WM), gray matter (GM), and cerebrospinal fluid (CSF), based on automated segmentation of coregistered H T -weighted images and hand-drawn regions of interest by two readers.

Statistical Tests: Coefficients of variation (CoVs) from mean TSC values were used to assess intrasite repeatability and intersite reproducibility.

Results: Mean GM TSC concentrations (52.1 ± 7.1 mM) were ∼20% higher than for WM (41.8 ± 6.7 mM). Measurements were highly repeatable at both sites with mean scan-rescan CoVs between volunteers and regions of 2% and 4%, respectively. Mean intersite reproducibility CoVs were 3%, 3%, and 6% for WM, GM, and CSF, respectively.

Data Conclusion: These results demonstrate technical validation of sodium MRI-derived biomarkers in healthy volunteers. We also show that comparable Na imaging of the brain can be implemented across different sites and scanners with excellent repeatability and reproducibility.

Level Of Evidence: 1 Technical Efficacy: Stage 2 J. Magn. Reson. Imaging 2019;50:1278-1284.
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http://dx.doi.org/10.1002/jmri.26705DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6767101PMC
October 2019

Evaluation of the sensitivity of Rρ MRI to pH and macromolecular density.

Magn Reson Imaging 2019 05 14;58:156-161. Epub 2019 Feb 14.

Department of Radiology, Box 218, University of Cambridge, Cambridge CB2 0QQ, United Kingdom; Cambridge University Hospitals NHS Foundation Trust, Addenbrooke's Hospital, Cambridge, United Kingdom, CB2 0QQ. Electronic address:

The tumor microenvironment is characteristically acidic and this extracellular acidosis is known to play a role in carcinogenesis and metastasis and can affect tumor chemosensitivity and radiosensitivity. Intracellular pH has been used as a possible biomarker of salvageable tissue in ischemic stroke. A non-invasive MRI-based approach for the determination and imaging of cerebral pH would be a powerful tool in cancer diagnosis and monitoring, as well as stroke treatment planning. Several pH-based MRI imaging approaches have been proposed but for these to be useful, disentangling the effects of pH from other parameters which may affect the measured MRI signal is crucial to ensure accuracy and specificity. R relaxation in the rotating frame (R) is an example of a method that has been proposed to probe pH in vivo using MRI. In this study, we have investigated the relationship between R, pH, and macromolecular density in vitro using phantoms and in human volunteers. Here we show that the rate of R relaxation (=1/T) varies with pH but only in the presence of macromolecules. At constant pH, phantom macromolecular density inversely correlated with R. R imaging of the normal human brain demonstrated regional heterogeneity with significant differences between structurally distinct regions, which are likely to be independent of pH. For example, R was higher in the basal ganglia compared to grey matter and higher in grey matter compared to white matter. We conclude that R cannot be reliably used to image tissue pH without deconvolution from the effects of local tissue macromolecular composition.
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http://dx.doi.org/10.1016/j.mri.2019.02.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6422633PMC
May 2019

Quantifying normal human brain metabolism using hyperpolarized [1-C]pyruvate and magnetic resonance imaging.

Neuroimage 2019 04 11;189:171-179. Epub 2019 Jan 11.

Department of Radiology, University of Cambridge, Cambridge, UK. Electronic address:

Hyperpolarized C Magnetic Resonance Imaging (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-C]pyruvate in the brain of healthy human volunteers for the first time. Dynamic acquisition of C images demonstrated 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) for exchange of the hyperpolarized C label between [1-C]pyruvate and the endogenous lactate pool was 0.012 ± 0.006 s and the apparent rate constant (k) for the irreversible flux of [1-C]pyruvate to [C]bicarbonate was 0.002 ± 0.002 s. Imaging also revealed that [1-C]pyruvate, [1-C]lactate and [C]bicarbonate were significantly higher in gray matter compared to white matter. Imaging normal brain metabolism with hyperpolarized [1-C]pyruvate and subsequent quantification, have important implications for interpreting pathological cerebral metabolism in future studies.
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http://dx.doi.org/10.1016/j.neuroimage.2019.01.027DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6435102PMC
April 2019
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