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

  • Fulvio Zaccagna
    Correspondence
    Corresponding author at: Division of Neuroimaging, Department of Medical Imaging, University of Toronto, 263 McCaul St 4th floor, Toronto, ON M5T 1W7, Canada.
    Affiliations
    Division of Neuroimaging, Department of Medical Imaging, University of Toronto, Toronto, Canada
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  • James T. Grist
    Affiliations
    Department of Physiology, Anatomy, and Genetics, University of Oxford, Oxford, United Kingdom

    Oxford Centre for Clinical Magnetic Resonance Research, University of Oxford, Oxford, United Kingdom

    Department of Radiology, Oxford University Hospitals NHS Foundation Trust, Oxford, United Kingdom

    Institute of Cancer and Genomic Sciences, University of Birmingham, Birmingham, United Kingdom
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  • Natale Quartuccio
    Affiliations
    Nuclear Medicine Unit, A.R.N.A.S. Ospedali Civico Di Cristina Benfratelli, Palermo, Italy
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  • Frank Riemer
    Affiliations
    Mohn Medical Imaging and Visualization Centre, University of Bergen, Bergen, Norway

    Department of Radiology, Haukeland University Hospital, Bergen, Norway
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  • Francesco Fraioli
    Affiliations
    Institute of Nuclear Medicine, University College London, London, United Kingdom

    NIHR University College London Hospitals Biomedical Research Centre, London, United Kingdom
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  • Corradina Caracò
    Affiliations
    Department of Radiology, University of Cambridge, Cambridge, United Kingdom
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  • Richard Halsey
    Affiliations
    Institute of Nuclear Medicine, University College London, London, United Kingdom

    NIHR University College London Hospitals Biomedical Research Centre, London, United Kingdom
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  • Yazeed Aldalilah
    Affiliations
    Institute of Nuclear Medicine, University College London, London, United Kingdom

    NIHR University College London Hospitals Biomedical Research Centre, London, United Kingdom

    Department of Radiology, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia
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  • Charles H. Cunningham
    Affiliations
    Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada

    Physical Sciences, Sunnybrook Research Institute, Toronto, Ontario, Canada
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  • Tarik F. Massoud
    Affiliations
    Division of Neuroimaging and Neurointervention, Department of Radiology, Stanford University School of Medicine, Stanford, USA
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  • Author Footnotes
    1 Joint senior authors.
    Luigi Aloj
    Footnotes
    1 Joint senior authors.
    Affiliations
    Department of Radiology, University of Cambridge, Cambridge, United Kingdom

    Cancer Research UK Cambridge Institute, University of Cambridge, Cambridge, United Kingdom
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  • Author Footnotes
    1 Joint senior authors.
    Ferdia A. Gallagher
    Footnotes
    1 Joint senior authors.
    Affiliations
    Department of Radiology, University of Cambridge, Cambridge, United Kingdom

    Cancer Research UK Cambridge Institute, University of Cambridge, Cambridge, United Kingdom
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  • Author Footnotes
    1 Joint senior authors.
Open AccessPublished:July 03, 2021DOI:https://doi.org/10.1016/j.ejrad.2021.109842

      Abstract

      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.

      Keywords

      1. Introduction

      Molecular imaging is a rapidly evolving area with the development of many new molecular imaging techniques and applications, ranging from hardware, novel imaging agents, acquisition protocols, and advanced image analysis approaches. Despite significant advances in the oncological management of many brain tumors, many of these continue to have a very poor prognosis with more than two-thirds of adults diagnosed with glioblastoma dying within 2 years of diagnosis, which is partly due to the high degree of morphological, metabolic, and genetic heterogeneity observed both within and between tumors [

      A.F. Tamimi, M. Juweid, Epidemiology and Outcome of Glioblastoma, in: Glioblastoma, 2017, pp. 143–153. https://doi.org/10.15586/codon.glioblastoma.2017.ch8.

      ,

      CRUK, Brain, other CNS and intracranial tumours incidence statistics | Cancer Research UK, 2019. https://www.cancerresearchuk.org/health-professional/cancer-statistics/statistics-by-cancer-type/brain-other-cns-and-intracranial-tumours/incidence#collapseTen (accessed March 24, 2019).

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      ]. The main clinical tools to probe metabolic pathways include proton magnetic resonance spectroscopy (1H MRS) and positron emission tomography (PET). PET is a very sensitive technique, providing a wide range of neurotracers to specifically image a range of metabolic pathways and provide quantitative measurement of metabolic parameters. Although MRS is less sensitive, it provides a non-invasive way of characterizing endogenous tumor metabolites, and allows for multiple metabolic pathways to be simultaneously explored without radiation exposure [
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      2-[18F]fluoro-2-deoxy-D-glucose ([18F]FDG) is a glucose analog which is transported by the transmembrane glucose transporters (GLUTs) and is phosphorylated by hexokinase in the first step of glycolysis. Owing to the physiologically high [18F]FDG uptake in normal brain tissue, tumors may present with a relatively low tumor-to-background ratio, which may hinder detection especially in low-grade brain neoplasms [
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      This review focuses on isotopic imaging of brain tumors using PET and MRI which could have a future role in neuro-oncology. It will also discuss the potential of combining molecular imaging with therapy in the form of theranostics, which is also likely to find an increasing role in future clinical practice.

      2. Current role for imaging and unmet clinical needs in neuro-oncology

      Gliomas are the most common primary brain tumors, accounting for nearly 70% of central nervous system (CNS) cancers, with glioblastoma (GBM) being the most frequent and malignant of the high grade gliomas (HGG)[

      H. Ohgaki, Epidemiology of Brain Tumors, Humana Press, 2009. https://doi.org/10.1007/978-1-60327-492-0_14.

      ]. Maximal surgical resection is often the primary aim in the management of HGGs, although there is no consensus on the role of surgery for low-grade gliomas (LGGs) [

      NICE, Brain cancers overview, National Institute for Health and Care Excellence, 2015. https://www.nice.org.uk/.

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      ]. Therefore, an accurate assessment of tumor extent is mandatory to achieve gross total resection. However, as the tumor is very infiltrative, this can often be difficult to assess using conventional MRI protocols such as: T2-weighted images (T2WI), T2 fluid-attenuated inversion recovery (FLAIR), diffusion weighted imaging (DWI), and T1-weighted images (T1WI) acquired pre- and post-gadolinium-based contrast agent administration (GBCA) [
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      ]. The prolonged progression-free survival achieved by combining 5-ALA and MRI guidance for tumor detection and delineation, underlines the potential importance of targeting hybrid imaging techniques [
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      The delineation of tumor boundaries is also of key importance for radiotherapy planning, an integral component in the treatment of brain tumors both after the initial surgery/biopsy and at recurrence, as recommended by the American Society for Radiation Oncology (ASTRO) guidelines [
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      ]. For example, tumor hypoxia is related to resistance of both radiation therapy and conventional chemotherapy and non-invasive assessment of tumor hypoxia can be used for “dose painting” or modulation of radiotherapy doses in areas of hypoxia as well as informing on the use of hypoxia-targeting drugs [
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      Non-invasive assessment of molecular biomarkers for in vivo phenotyping of gliomas is also a growing application for molecular imaging. Isocitrate dehydrogenase (IDH) has become one of the key biomarkers of underlying glioma biology and a cornerstone of the WHO brain tumor classification [
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      ]. The discovery of the importance of IDH in tumorigenesis and aggressiveness led to non-invasive methods to detect the presence of the mutation using 1H MRS. Specific mutations in IDH result in neomorphic enzyme function and the accumulation of the oncometabolite 2-hydroxglutarate (2HG). Detection of the oncometabolite 2HG in vivo indicates the presence of mutant IDH, which can be used not only to detect the mutation but also to predict therapy response earlier than morphological techniques [
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      Imaging also plays a significant role in treatment evaluation, which is currently based on the 2010 update of the RANO criteria [
      • Wen Patrick Y.
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      ]. According to those, both the T1W post GBCA and the T2W/FLAIR are used to assess interval change in size of the lesion. However, the updated RANO criteria still fall short of definitively distinguishing tumor progression, pseudoresponse (defined as decrease in contrast enhancement due to normalization of abnormally permeable tumor vessels), and pseudoprogression (defined as increased contrast enhancement after treatment which is not tumor related), resulting in uncertainties for up to 12 weeks after therapy [
      • Huang R.Y.
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      ]. Sensitive and specific methods to determine treatment evaluation are required to better define management at the earliest stage possible. Advanced imaging techniques that probe tumor biology could play a significant role in early therapy assessment and long-term follow-up in a routine clinical environment.

      3. Developments in magnetic resonance imaging (MRI) for brain tumor imaging

      MRI is the main imaging technique for assessment of patients with brain tumors. The current standard of practice in Europe is based on the recommendations of the RANO working group with significant limitations in therapy assessment within the first 3 months after treatment [
      • Wen Patrick Y.
      • Macdonald David R.
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      ].
      Several biological processes can be measured using proton MRS (1H MRS), such as lactate concentration, membrane turnover, and cellular proliferation [
      • Zhang Hui
      • Ma Li
      • Wang Qun
      • Zheng Xuan
      • Wu Chen
      • Xu Bai-nan
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      ]. However, 1H MRS requires interpretation by an experienced reader and clear thresholds for tumor grading are still a matter of debate [
      • Wang Wenzhi
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      • Lu Peiou
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      ]. Moreover, acquiring 1H MRS across the brain using multi-voxel acquisition strategies leads to lengthy scan times and presents several technical challenges such as obtaining spectra close to the skull. A further challenge with clinical field strength (≤3 T) MRS is the limited metabolic resolution leading to a restricted number of pathways that can be explored [
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      • Caprihan Arvind
      • Gasparovic Charles
      Comparative reliability of proton spectroscopy techniques designed to improve detection of J-coupled metabolites.
      ,
      • Bogner W.
      • Hangel G.
      • Esmaeili M.
      • Andronesi O.C.
      1D-spectral editing and 2D multispectral in vivo1H-MRS and1H-MRSI - Methods and applications.
      ,
      • Near J.
      • Harris A.D.
      • Juchem C.
      • Öz G.
      • Slotboom J.
      • Kreis R.
      Preprocessing, analysis and quantification in single-voxel magnetic resonance spectroscopy : experts ’ consensus recommendations.
      ].
      MRI can also be used to detect nuclei other than protons (or 1H) to explore metabolic processes in vivo. However, the signal from nuclei such as 31P, 23Na, or 13C is significantly reduced compared to protons due to lower in vivo concentrations, smaller gyromagnetic ratios, and relatively decreased nuclear polarizations. Therefore, until recently, multi-nuclei imaging with conventional MRI systems has been challenging. With the more widespread availability of higher-field (≥3 T) magnets and the improvement in coil technology and acquisition sequences, these nuclei can now be successfully imaged within a clinically practical timescale. These techniques may provide useful data to complement conventional multi-parametric MRI protocols.

      3.1 Phosphorus-31 magnetic resonance spectroscopy (31P MRS)

      Investigation of 31P MRI to detect cerebral cellular energetics dates back to the 1980s. Initial experiments with 31P MRS in preclinical models of glioma and neuroblastoma demonstrated high nucleoside triphosphate and phosphomonoesters with low peaks of phosphocreatine [
      • Hirakawa K.
      • Naruse S.
      • Higuchi T.
      • Horikawa Y.
      • Tanaka C.
      • Ebisu T.
      The investigation of experimental brain tumours using 31P-MRS and 1H-MRI.
      ]. Necrosis is typically associated with decreased nucleoside triphosphate, decreased phosphomonoesters, and increased inorganic phosphate. Hirawaka et al. subsequently postulated that non-invasive assessment of 31P could provide early assessment of therapy response before morphological changes, for instance through early increase in the inorganic phosphate concentration within the lesion [
      • Hirakawa K.
      • Naruse S.
      • Higuchi T.
      • Horikawa Y.
      • Tanaka C.
      • Ebisu T.
      The investigation of experimental brain tumours using 31P-MRS and 1H-MRI.
      ].
      Phospholipids (PL) are a key component of cellular membranes and probing PL provides information on cell replication and viability. Phosphomonoesters (PME) are precursors of PL while phosphodiesters (PDE) are products of PL catabolism. Both PME and PDE can be quantified with 31P MRS and an increase in PME has been associated with cell proliferation, tumor progression and/or recurrence in GBM [
      • Arnold D.L.
      • Emrich J.F.
      • Shoubridge E.A.
      • Villemure J.G.
      • Feindel W.
      Characterization of astrocytomas, meningiomas, and pituitary adenomas by phosphorus magnetic resonance spectroscopy.
      ]. In contrast, low grade gliomas are characterized by low proliferative rates and have lower PME levels which can potentially be used in the differential diagnosis compared to higher grade tumors [
      • Arnold D.L.
      • Emrich J.F.
      • Shoubridge E.A.
      • Villemure J.G.
      • Feindel W.
      Characterization of astrocytomas, meningiomas, and pituitary adenomas by phosphorus magnetic resonance spectroscopy.
      ]. This distinction between HGG and LGG on 31P MRS could be particularly useful for detecting areas of increased proliferation, as is present in in transforming gliomas.
      Recently, the combination of higher filed strengths, improved coil design and acquisition sequences has permitted whole-brain spectroscopic imaging (31P MRSI), paving the way for whole brain mapping of adenosine triphosphate (ATP) and phosphocreatine (PCr) [
      • Coste A.
      • Romanzetti S.
      • Le Bihan D.
      • Rabrait-Lerman C.
      • Boumezbeur F.
      In vivo 31P MRI at 7 Tesla in humans using a 3D spectrally selective SSFP sequence and TPI k-space sampling.
      ]. It also offers the possibility of spatial mapping tissue pH within brain tumors [
      • Korzowski Andreas
      • Weinfurtner Nina
      • Mueller Sebastian
      • Breitling Johannes
      • Goerke Steffen
      • Schlemmer Heinz‐Peter
      • Ladd Mark E.
      • Paech Daniel
      • Bachert Peter
      Volumetric mapping of intra- and extracellular pH in the human brain using 31P MRSI at 7T.
      ]. HGGs typically show an acidified extracellular compartment which confers a survival benefit, facilitates infiltration by creating a hostile environment for normal tissue, and promotes malignancy through induction of cancer stem cells [
      • Hjelmeland A.B.
      • Wu Q.
      • Heddleston J.M.
      • Choudhary G.S.
      • MacSwords J.
      • Lathia J.D.
      • McLendon R.
      • Lindner D.
      • Sloan A.
      • Rich J.N.
      Acidic stress promotes a glioma stem cell phenotype.
      ]. Some reports using single voxel MRS have shown mild intracellular alkalinization of astrocytomas, meningiomas and lymphomas compared to normal brain parenchyma [
      • Maintz David
      • Heindel Walter
      • Kugel Harald
      • Jaeger Richard
      • Lackner Klaus J.
      Phosphorus-31 MR spectroscopy of normal adult human brain and brain tumours.
      ,
      • Hubesch B.
      • Sappey-Marinier D.
      • Roth K.
      • Meyerhoff D.J.
      • Matson G.B.
      • Weiner M.W.
      P-31 MR spectroscopy of normal human brain and brain tumors.
      ,
      • Ha D.H.
      • Choi S.
      • Oh J.Y.
      • Yoon S.K.
      • Kang M.J.
      • Kim K.U.
      Application of 31P MR spectroscopy to the brain tumors.
      ]. A more recent report demonstrated a pH gradient from pseudonormal values within the leading edge to pronounced acidosis within the necrotic zone of a tumor [
      • Halcrow P.
      • Datta G.
      • Ohm J.E.
      • Soliman M.L.
      • Chen X.
      • Geiger J.D.
      Role of endolysosomes and pH in the pathogenesis and treatment of glioblastoma.
      ]. The ability to image the spatial distribution of pH in vivo could provide valuable insights into glioma pathophysiology, identification of areas rich in cancer stem cells as a target for therapy, as well as the potential of monitoring response to therapy. A better insight into the role of pH in gliomas could also pave the way for new treatments, such as lysosome destabilizing drugs [
      • Jensen S.S.
      • Petterson S.A.
      • Halle B.
      • Aaberg-Jessen C.
      • Kristensen B.W.
      Effects of the lysosomal destabilizing drug siramesine on glioblastoma in vitro and in vivo.
      ].

      3.2 Sodium-23 magnetic resonance imaging (23Na MRI)

      In the 1980s, Maudsley and Hilal [
      • MAUDSLEY A.A.
      • HILAL S.K.
      Biological aspects of Sodium-23 imaging.
      ] postulated that sodium MRI would distinguish features of brain tumors that could not be detected on conventional proton imaging. Following on from this work, Feinberg [
      • Feinberg D.A.
      • Crooks L.A.
      • Kaufman L.
      • Brant-Zawadzki M.
      • Posin J.P.
      • Arakawa M.
      • Watts J.C.
      • Hoenninger J.
      Magnetic resonance imaging performance: a comparison of sodium and hydrogen.
      ] demonstrated the use of the technique in brain tumor patients. Subsequent research explored the use of 23Na MRI in healthy brain and other neurological diseases, with promising results [
      • Winkler Stefan S.
      • Thomasson David M.
      • Sherwood Katherine
      • Perman William H.
      Regional T2 and sodium concentration estimates in the normal human brain by sodium-23 MR imaging at 1.5 T.
      ,
      • Hashimoto T.
      • Ikehira H.
      • Fukuda H.
      • Yamaura A.
      • Watanabe O.
      • Tateno Y.
      • Tanaka R.
      • Simon H.E.
      In vivo sodium-23 MRI in brain tumors: Evaluation of preliminary clinical experience.
      ,
      • Schuierer G.
      • Ladebeck R.
      • Barfuß H.
      • Hentschel D.
      • Huk W.J.
      Sodium-23 imaging of supratentorial lesions at 4.0 T.
      ]. Recent developments in pulse sequence design and quantification have led to a renewed interest in this technique [
      • Boada Fernando E.
      • Christensen James D.
      • Huang-Hellinger Frank R.
      • Reese Timothy G.
      • Thulborn Keith R.
      Quantitative in vivo tissue sodium concentration maps: The effects of biexponential relaxation.
      ,
      • Christensen James D.
      • Barrère Bertrand J.
      • Boada Fernando E.
      • Vevea J. Michael
      • Thulborn Keith R.
      Quantitative tissue sodium concentration mapping of normal rat brain.
      ,
      • Boada Fernando E.
      • Gillen Joseph S.
      • Shen Gary X.
      • Chang Sam Y
      • Thulborn Keith R.
      Fast three dimensional sodium imaging.
      ,
      • Boada F.E.
      • Shen G.X.
      • Chang S.Y.
      • Thulborn K.R.
      Spectrally weighted twisted projection imaging: reducing T2 signal attenuation effects in fast three-dimensional sodium imaging.
      ,
      • Riemer Frank
      • McHugh Damien
      • Zaccagna Fulvio
      • Lewis Daniel
      • McLean Mary A.
      • Graves Martin J.
      • Gilbert Fiona J.
      • Parker Geoff J.M.
      • Gallagher Ferdia A.
      Measuring tissue sodium concentration: cross-vendor repeatability and reproducibility of 23 Na-MRI across two sites.
      ]. Imaging of the sodium ion is of significant interest for brain diseases [
      • Leslie Theresa K.
      • James Andrew D.
      • Zaccagna Fulvio
      • Grist James T.
      • Deen Surrin
      • Kennerley Aneurin
      • Riemer Frank
      • Kaggie Joshua D.
      • Gallagher Ferdia A.
      • Gilbert Fiona J.
      • Brackenbury William J.
      Sodium homeostasis in the tumour microenvironment.
      ] because an increase in cellular metabolism is associated with changes in Na+/K+-ATPase activity. For example, when ATP utilization is increased in a proliferating tumor, the activity of the sodium pump may be reduced, resulting in changes in the gradient of sodium ions across the membrane [
      • Madelin G.
      • Regatte R.R.
      Biomedical applications of sodium MRI in vivo.
      ].
      In 2003, Ouwerkerk et al.[
      • Ouwerkerk Ronald
      • Bleich Karen B.
      • Gillen Joseph S.
      • Pomper Martin G.
      • Bottomley Paul A.
      Tissue sodium concentration in human brain tumors as measured with 23 Na MR imaging.
      ] demonstrated that sodium concentration is increased both in malignant tumors and in the surrounding non-enhancing FLAIR hyperintense parenchyma (Fig. 1). The signal increase was attributed to a combination of changes in the extracellular volume fraction and intracellular sodium concentration. In an attempt to disentangle the extracellular and intracellular sodium component, Nagel et al. explored the use of relaxation-weighted 23Na sequences (23NaR) to quantify the intracellular compartment [
      • Nagel Armin Michael
      • Bock Michael
      • Hartmann Christian
      • Gerigk Lars
      • Neumann Jan-Oliver
      • Weber Marc-André
      • Bendszus Martin
      • Radbruch Alexander
      • Wick Wolfgang
      • Schlemmer Heinz-Peter
      • Semmler Wolfhard
      • Biller Armin
      The potential of relaxation-weighted sodium magnetic resonance imaging as demonstrated on brain tumors.
      ]. An increased 23NaR signal intensity was observed in GBMs and in a cerebral metastasis which may relate to higher cellular proliferation as demonstrated by a strong correlation between the intracellular sodium concentration and the expression of mindbomb homolog-1 (MIB-1), a marker of proliferation rate [
      • Neder L.
      • Colli B.O.
      • Machado H.R.
      • Jr C.G.C.
      • Santos A.C.
      • Chimelli L.
      MIB-1 labeling index in astrocytic tumors–a clinicopathologic study.
      ,
      • Johannessen Anne Linn
      • Torp Sverre Helge
      The clinical value of Ki-67/MIB-1 labeling index in human astrocytomas.
      ]. Further studies have shown an increased apparent total sodium concentration and extracellular sodium concentration within tumors compared to the normal appearing white matter demonstrating the ability of 23Na MRI to distinguish different tissue compartments [
      • Madelin G.
      • Regatte R.R.
      Biomedical applications of sodium MRI in vivo.
      ,
      • Nagel Armin Michael
      • Bock Michael
      • Hartmann Christian
      • Gerigk Lars
      • Neumann Jan-Oliver
      • Weber Marc-André
      • Bendszus Martin
      • Radbruch Alexander
      • Wick Wolfgang
      • Schlemmer Heinz-Peter
      • Semmler Wolfhard
      • Biller Armin
      The potential of relaxation-weighted sodium magnetic resonance imaging as demonstrated on brain tumors.
      ,
      • Neto L.P.N.
      • Madelin G.
      • Sood T.P.
      • Wu C.
      • Kondziolka D.
      • Placantonakis D.
      • Golfinos J.G.
      • Chi A.
      • Jain R.
      Quantitative sodium imaging and gliomas : a feasibility study.
      ,
      • Madelin G.
      • Lee J.S.
      • Regatte R.R.
      • Jerschow A.
      Sodium MRI: methods and applications.
      ,
      • Biller A.
      • Pflugmann I.
      • Badde S.
      • Diem R.
      • Wildemann B.
      • Nagel A.M.
      • Jordan J.
      • Benkhedah N.
      • Kleesiek J.
      Sodium MRI in multiple sclerosis is compatible with intracellular sodium accumulation and inflammation-induced hyper-cellularity of acute brain lesions.
      ]. Moreover, 23Na MRI has been shown to correlate with the IDH mutation and could therefore act as a prognostic factor [
      • Biller A.
      • Badde S.
      • Nagel A.
      • Neumann J.-O.
      • Wick W.
      • Hertenstein A.
      • Bendszus M.
      • Sahm F.
      • Benkhedah N.
      • Kleesiek J.
      Improved brain tumor classification by sodium MR imaging: prediction of IDH mutation status and tumor progression.
      ]: for example, the ratio of 23NaR to the total sodium signal has been shown to correlate with mutant IDH expression, accurately classify glioma grade, and to predict survival [
      • Biller A.
      • Badde S.
      • Nagel A.
      • Neumann J.-O.
      • Wick W.
      • Hertenstein A.
      • Bendszus M.
      • Sahm F.
      • Benkhedah N.
      • Kleesiek J.
      Improved brain tumor classification by sodium MR imaging: prediction of IDH mutation status and tumor progression.
      ].
      Figure thumbnail gr1
      Fig. 13D 23Na-MRI of a healthy volunteer showing total sodium concentrations across brain regions from two different sites (A and B) and at two different time points (scan 1 and scan 2). Images demonstrate repeatability and reproducibility of the technique. Adapted with permission from Riemer et al.
      [
      • Riemer Frank
      • McHugh Damien
      • Zaccagna Fulvio
      • Lewis Daniel
      • McLean Mary A.
      • Graves Martin J.
      • Gilbert Fiona J.
      • Parker Geoff J.M.
      • Gallagher Ferdia A.
      Measuring tissue sodium concentration: cross-vendor repeatability and reproducibility of 23 Na-MRI across two sites.
      ]
      .
      23Na MRI has also been evaluated as an imaging biomarker for therapy evaluation in GBM combined with 3′-deoxy-3′-[18F]fluorothymidine ([18F]FLT)-PET. Laymon et al. have demonstrated that 23Na MRI and [18F]FLT-PET are complementary in assessing therapy response [
      • Laymon Charles M.
      • Oborski Matthew J.
      • Lee Vincent K.
      • Davis Denise K.
      • Wiener Erik C.
      • Lieberman Frank S.
      • Boada Fernando E.
      • Mountz James M.
      Combined imaging biomarkers for therapy evaluation in glioblastoma multiforme: Correlating sodium MRI and F-18 FLT PET on a voxel-wise basis.
      ]. More recently, Thulborn et al.[
      • Thulborn Keith R.
      • Lu Aiming
      • Atkinson Ian C.
      • Pauliah Mohan
      • Beal Kathryn
      • Chan Timothy A.
      • Omuro Antonio
      • Yamada Josh
      • Bradbury Michelle S.
      Residual tumor volume, cell volume fraction and tumor cell kill during fractionated chemoradiation therapy of human glioblastoma using quantitative sodium MR imaging.
      ] assessed the potential utility of 23Na MRI as an early biomarker of therapy response in patients undergoing fractionated chemoradiation. Using a two-compartment model, they converted the total sodium concentration maps into cell volume fraction bioscale maps from which they subsequently derived the residual tumor volume and tumor cell death component. Changes in cell volume fraction, residual tumor volume, and tumor cell death were identified during the course of the 6-week regimen but over the same period, there was little biological variation in the normal appearing tissue. However, these changes did not correlate with prognosis which may reflect the heterogeneity of GBM response treatment.

      3.3 Hyperpolarized carbon-13 magnetic resonance imaging (HP 13C MRI)

      Hyperpolarized 13C MRI is an emerging clinical technique with the potential to increase the understanding of neurological, psychiatric, and neuro-oncological conditions by probing cerebral metabolism [
      • Zaccagna F.
      • Grist J.T.
      • Deen S.S.
      • Woitek R.
      • Lechermann L.M.
      • McLean M.A.
      • Basu B.
      • Gallagher F.A.
      Hyperpolarized carbon-13 magnetic resonance spectroscopic imaging: a clinical tool for studying tumour metabolism.
      ]. The most commonly used compound in clinical studies to date has been [1-13C]pyruvate, which informs upon both oxidative and glycolytic metabolism. The hallmark of oxidative metabolism is the formation of CO2 by pyruvate dehydrogenase, which exchanges with bicarbonate. Tricarboxylic acid (TCA) cycle metabolism in mitochondria is an efficient process for ATP generation, whilst glycolytic metabolism is less energetically efficient and results in the formation of lactate through the action of lactate dehydrogenase (LDH).
      The process of hyperpolarization involves the mixing of a 13C-labelled metabolic substrate of interest with a source of free electrons known as a radical. The sample is then stored inside a sterile unit known as a ‘fluid path’ and placed inside a magnetic field (commonly 5 T for clinical applications) in a bath of liquid helium at approximately 0.8 K while undergoing irradiation with a microwave source. These conditions increase the available signal from the molecule in the order of > 10,000 fold [
      • Ardenkjaer-Larsen J.H.
      • Fridlund B.
      • Gram A.
      • Hansson G.
      • Hansson L.
      • Lerche M.H.
      • Servin R.
      • Thaning M.
      • Golman K.
      Increase in signal-to-noise ratio of > 10,000 times in liquid-state NMR.
      ]. To make use of this transient increase in signal, a bolus of super-heated water is used to dissolve the molecule-radical mix, which is then filtered to remove the radical before neutralization and cooling. The final product is then checked against quality control parameters, notably the pH of the mixture and the concentration of the molecule of interest in solution, and subsequently rapidly released into the participant within the clinical MRI scanner [
      • Grist James T
      • Miller Jack J
      • Zaccagna Fulvio
      • McLean Mary A
      • Riemer Frank
      • Matys Tomasz
      • Tyler Damian J
      • Laustsen Christoffer
      • Coles Alasdair J
      • Gallagher Ferdia A
      Hyperpolarized 13C MRI: a novel approach for probing cerebral metabolism in health and neurological disease.
      ]. Owing to the difference in chemical shift between the injected substrate and its subsequent downstream metabolites, either slice localized spectroscopy or imaging are commonly performed. Post-processing of data commonly relies either upon ratiometric (for example the lactate-to-pyruvate ratio) or model-based approaches to derive the apparent forward rate constant for the enzyme LDH (kPL)[
      • Daniels Charlie J.
      • McLean Mary A.
      • Schulte Rolf F.
      • Robb Fraser J.
      • Gill Andrew B.
      • McGlashan Nicholas
      • Graves Martin J.
      • Schwaiger Markus
      • Lomas David J.
      • Brindle Kevin M.
      • Gallagher Ferdia A.
      A comparison of quantitative methods for clinical imaging with hyperpolarized 13C-pyruvate.
      ,
      • Schulte Rolf F.
      • Sperl Jonathan I.
      • Weidl Eliane
      • Menzel Marion I.
      • Janich Martin A.
      • Khegai Oleksandr
      • Durst Markus
      • Ardenkjaer-Larsen Jan Henrik
      • Glaser Steffen J.
      • Haase Axel
      • Schwaiger Markus
      • Wiesinger Florian
      Saturation-recovery metabolic-exchange rate imaging with hyperpolarized [1-13C] pyruvate using spectral-spatial excitation.
      ,
      • Khegai O.
      • Schulte R.F.
      • Janich M.A.
      • Menzel M.I.
      • Farrell E.
      • Otto A.M.
      • Ardenkjaer-Larsen J.H.
      • Glaser S.J.
      • Haase A.
      • Schwaiger M.
      • Wiesinger F.
      Apparent rate constant mapping using hyperpolarized [1-13C]pyruvate.
      ].
      Hyperpolarized 13C MRI has been undertaken in the healthy brain and in small studies of patients with brain tumors. Initial results have demonstrated the feasibility of imaging both glycolytic and oxidative metabolism within the healthy brain [
      • Grist J.T.
      • McLean M.A.
      • Riemer F.
      • Schulte R.F.
      • Deen S.S.
      • Zaccagna F.
      • Woitek R.
      • Daniels C.J.
      • Kaggie J.D.
      • Matyz T.
      • Patterson I.
      • Slough R.
      • Gill A.B.
      • Chhabra A.
      • Eichenberger R.
      • Laurent M.-C.
      • Comment A.
      • Gillard J.H.
      • Coles A.J.
      • Tyler D.J.
      • Wilkinson I.
      • Basu B.
      • Lomas D.J.
      • Graves M.J.
      • Brindle K.M.
      • Gallagher F.A.
      Quantifying normal human brain metabolism using hyperpolarized [1–13C]pyruvate and magnetic resonance imaging.
      ,
      • Crane J.C.
      • Gordon J.W.
      • Chen H.Y.
      • Autry A.W.
      • Li Y.
      • Olson M.P.
      • Kurhanewicz J.
      • Vigneron D.B.
      • Larson P.E.Z.
      • Xu D.
      Hyperpolarized 13C MRI data acquisition and analysis in prostate and brain at University of California, San Francisco.
      ], detecting lactate and bicarbonate formation within the parenchyma (Fig. 2). The spatial variation of lactate formation across the healthy brain is well preserved across individuals and could be used to detect dysregulated metabolism in cerebral pathology [
      • Lee Casey Y.
      • Soliman Hany
      • Geraghty Benjamin J.
      • Chen Albert P.
      • Connelly Kim A.
      • Endre Ruby
      • Perks William J.
      • Heyn Chris
      • Black Sandra E.
      • Cunningham Charles H.
      Lactate topography of the human brain using hyperpolarized 13C-MRI.
      ]. Results from initial neuro-oncological studies have demonstrated lactate formation within both metastases and HGGs [
      • Park Ilwoo
      • Larson Peder E.Z.
      • Gordon Jeremy W.
      • Carvajal Lucas
      • Chen Hsin-Yu
      • Bok Robert
      • Van Criekinge Mark
      • Ferrone Marcus
      • Slater James B.
      • Xu Duan
      • Kurhanewicz John
      • Vigneron Daniel B.
      • Chang Susan
      • Nelson Sarah J.
      Development of methods and feasibility of using hyperpolarized carbon-13 imaging data for evaluating brain metabolism in patient studies.
      ,
      • Miloushev V.Z.
      • Granlund K.L.
      • Boltyanskiy R.
      • Lyashchenko S.S.K.
      • DeAngelis L.L.M.
      • Sosa E.
      • Guo Y.W.Y.
      • Chen A.P.
      • Tropp J.
      • Robb F.
      • Keshari K.K.R.
      • Member A.
      • Lyashchenko S.S.K.
      • DeAngelis L.L.M.
      • Mellinghoff I.
      • Brennan C.
      • Tabar V.
      • Yang T.
      • Holodny A.
      • Sosa R.
      • Guo Y.W.Y.
      • Keshari K.K.R.
      • Vesselin K.R.K.
      • Miloushev Z.
      • Granlund Kristin L.
      • Boltyanskiy Rostislav
      • Lyashchenko Serge K.
      • DeAngelis Lisa M.
      • Mellinghoff Ingo K.
      • Brennan Cameron W.
      • Vivian Tabar T.
      • Yang Jonathan
      • Holodny Andrei I.
      • Sosa Ramon E.
      • Guo YanWei W.
      • Chen Albert P.
      • Tro James
      Metabolic imaging of the human brain with hyperpolarized 13C pyruvate demonstrates 13C lactate production in brain tumor patients.
      ]. There have been a number of preclinical studies showing the potential for hyperpolarized MRI to demonstrate early response of brain diseases to therapeutic intervention [
      • Day Sam E.
      • Kettunen Mikko I.
      • Cherukuri Murali Krishna
      • Mitchell James B.
      • Lizak Martin J.
      • Morris H. Douglas
      • Matsumoto Shingo
      • Koretsky Alan P.
      • Brindle Kevin M.
      Detecting response of rat C6 glioma tumors to radiotherapy using hyperpolarized [1-13C]pyruvate and 13C magnetic resonance spectroscopic imaging.
      ,
      • Chaumeil Myriam M.
      • Ozawa Tomoko
      • Park IlWoo
      • Scott Kristen
      • James C. David
      • Nelson Sarah J.
      • Ronen Sabrina M.
      Hyperpolarized 13C MR spectroscopic imaging can be used to monitor Everolimus treatment in vivo in an orthotopic rodent model of glioblastoma.
      ,
      • Park J.M.
      • Recht L.D.
      • Josan S.
      • Merchant M.
      • Jang T.
      • Yen Y.-F.
      • Hurd R.E.
      • Spielman D.M.
      • Mayer D.
      Metabolic response of glioma to dichloroacetate measured in vivo by hyperpolarized 13C magnetic resonance spectroscopic imaging.
      ,
      • Park Jae Mo
      • Spielman Daniel M.
      • Josan Sonal
      • Jang Taichang
      • Merchant Milton
      • Hurd Ralph E.
      • Mayer Dirk
      • Recht Lawrence D.
      Hyperpolarized 13C-lactate to 13C-bicarbonate ratio as a biomarker for monitoring the acute response of anti-vascular endothelial growth factor (anti-VEGF) treatment.
      ,
      • Radoul Marina
      • Chaumeil Myriam M.
      • Eriksson Pia
      • Wang Alan S.
      • Phillips Joanna J.
      • Ronen Sabrina M.
      MR studies of glioblastoma models treated with dual PI3K/mTOR inhibitor and temozolomide: metabolic changes are associated with enhanced survival.
      ] with preliminary evidence of an increase in the rate constants in patients treated with bevacizumab [
      • Autry Adam W.
      • Gordon Jeremy W.
      • Chen Hsin-Yu
      • LaFontaine Marisa
      • Bok Robert
      • Van Criekinge Mark
      • Slater James B.
      • Carvajal Lucas
      • Villanueva-Meyer Javier E.
      • Chang Susan M.
      • Clarke Jennifer L.
      • Lupo Janine M.
      • Xu Duan
      • Larson Peder E.Z.
      • Vigneron Daniel B.
      • Li Yan
      Characterization of serial hyperpolarized 13C metabolic imaging in patients with glioma.
      ].
      Figure thumbnail gr2
      Fig. 2Hyperpolarized 13C-MRI in two healthy volunteers (A and B) demonstrating metabolite distribution within the healthy human brain following injection of hyperpolarized 13C-pyruvate. Adapted with permission from Grist et al.
      [
      • Grist J.T.
      • McLean M.A.
      • Riemer F.
      • Schulte R.F.
      • Deen S.S.
      • Zaccagna F.
      • Woitek R.
      • Daniels C.J.
      • Kaggie J.D.
      • Matyz T.
      • Patterson I.
      • Slough R.
      • Gill A.B.
      • Chhabra A.
      • Eichenberger R.
      • Laurent M.-C.
      • Comment A.
      • Gillard J.H.
      • Coles A.J.
      • Tyler D.J.
      • Wilkinson I.
      • Basu B.
      • Lomas D.J.
      • Graves M.J.
      • Brindle K.M.
      • Gallagher F.A.
      Quantifying normal human brain metabolism using hyperpolarized [1–13C]pyruvate and magnetic resonance imaging.
      ]
      .

      3.4 Chemical-exchange-dependent saturation transfer MRI (CEST MRI)

       Chemical-exchange-dependent saturation transfer (CEST) is based on the proton exchange between bulk water and a target molecule, either of endogenous or exogenous origin [
      • Ward K.M.
      • Aletras A.H.
      • Balaban R.S.
      A new class of contrast agents for MRI based on proton chemical exchange dependent saturation transfer (CEST).
      ]. Depending on which mobile protons are used to generate the signal, several techniques are possible with the most common being amide CEST (also known as amide proton transfer - APT), amine CEST and hydroxyl CEST [
      • Dou W.
      • Lin C.Y.E.
      • Ding H.
      • Shen Y.
      • Dou C.
      • Qian L.
      • Wen B.
      • Wu B.
      Chemical exchange saturation transfer magnetic resonance imaging and its main and potential applications in pre-clinical and clinical studies.
      ]. In neuro-oncological imaging, APT and GlucoCEST, a type of hydroxyl CEST, have been the most widely investigated [
      • Overcast W.B.
      • Davis K.M.
      • Ho C.Y.
      • Hutchins G.D.
      • Green M.A.
      • Graner B.D.
      • Veronesi M.C.
      Advanced imaging techniques for neuro-oncologic tumor diagnosis, with an emphasis on PET-MRI imaging of malignant brain tumors.
      ,
      • Zhou Jinyuan
      • Payen Jean-Francois
      • Wilson David A
      • Traystman Richard J
      • van Zijl Peter C M
      Using the amide proton signals of intracellular proteins and peptides to detect pH effects in MRI.
      ,
      • Zhou Jinyuan
      • Tryggestad Erik
      • Wen Zhibo
      • Lal Bachchu
      • Zhou Tingting
      • Grossman Rachel
      • Wang Silun
      • Yan Kun
      • Fu De-Xue
      • Ford Eric
      • Tyler Betty
      • Blakeley Jaishri
      • Laterra John
      • van Zijl Peter C M
      Differentiation between glioma and radiation necrosis using molecular magnetic resonance imaging of endogenous proteins and peptides.
      ,
      • Jiang Shanshan
      • Eberhart Charles G.
      • Lim Michael
      • Heo Hye-Young
      • Zhang Yi
      • Blair Lindsay
      • Wen Zhibo
      • Holdhoff Matthias
      • Lin Doris
      • Huang Peng
      • Qin Huamin
      • Quinones-Hinojosa Alfredo
      • Weingart Jon D.
      • Barker Peter B.
      • Pomper Martin G.
      • Laterra John
      • van Zijl Peter C.M.
      • Blakeley Jaishri O.
      • Zhou Jinyuan
      Identifying recurrent malignant glioma after treatment using amide proton transfer-weighted MR imaging: a validation study with image-guided stereotactic biopsy.
      ,
      • Park Ji Eun
      • Kim Ho Sung
      • Park Kye Jin
      • Kim Sang Joon
      • Kim Jeong Hoon
      • Smith Seth A.
      Pre-and posttreatment glioma: comparison of amide proton transfer imaging with MR spectroscopy for biomarkers of tumor proliferation.
      ,
      • Jiang S.
      • Zou T.
      • Eberhart C.G.
      • Villalobos M.A.V.
      • Zhang Y.
      • Wang Y.
      • Wang X.
      • Yu H.
      • Du Y.
      • Van Zijl P.C.M.
      Predicting IDH mutation status in grade-II gliomas using amide proton transfer-weighted (APTw) MRI.
      ,
      • Jiang Shanshan
      • Rui Qihong
      • Wang Yu
      • Heo Hye-Young
      • Zou Tianyu
      • Yu Hao
      • Zhang Yi
      • Wang Xianlong
      • Du Yongxing
      • Wen Xinrui
      • Chen Fangyao
      • Wang Jihong
      • Eberhart Charles G.
      • Zhou Jinyuan
      • Wen Zhibo
      Discriminating MGMT promoter methylation status in patients with glioblastoma employing amide proton transfer-weighted MRI metrics.
      ,
      • Xu Xiang
      • Chan Kannie W.Y.
      • Knutsson Linda
      • Artemov Dmitri
      • Xu Jiadi
      • Liu Guanshu
      • Kato Yoshinori
      • Lal Bachchu
      • Laterra John
      • McMahon Michael T.
      • van Zijl Peter C.M.
      Dynamic glucose enhanced (DGE) MRI for combined imaging of blood-brain barrier break down and increased blood volume in brain cancer.
      ,
      • Rivlin M.
      • Navon G.
      Molecular imaging of tumors by chemical exchange saturation transfer MRI of glucose analogs.
      ,
      • Xu X.
      • Sehgal A.A.
      • Yadav N.N.
      • Laterra J.
      • Blair L.
      • Blakeley J.
      • Seidemo A.
      • Coughlin J.M.
      • Pomper M.G.
      • Knutsson L.
      • van Zijl P.C.M.
      d-glucose weighted chemical exchange saturation transfer (glucoCEST)-based dynamic glucose enhanced (DGE) MRI at 3T: early experience in healthy volunteers and brain tumor patients.
      ].
      APT derives its signal from cytosolic proteins abundant in cancer cells, therefore components of gliomas show higher values than peritumoral edema or necrosis [
      • Overcast W.B.
      • Davis K.M.
      • Ho C.Y.
      • Hutchins G.D.
      • Green M.A.
      • Graner B.D.
      • Veronesi M.C.
      Advanced imaging techniques for neuro-oncologic tumor diagnosis, with an emphasis on PET-MRI imaging of malignant brain tumors.
      ,
      • Zhou Jinyuan
      • Payen Jean-Francois
      • Wilson David A
      • Traystman Richard J
      • van Zijl Peter C M
      Using the amide proton signals of intracellular proteins and peptides to detect pH effects in MRI.
      ]. Similarly, APT can be used to differentiate radiation necrosis and tumor progression [
      • Zhou Jinyuan
      • Tryggestad Erik
      • Wen Zhibo
      • Lal Bachchu
      • Zhou Tingting
      • Grossman Rachel
      • Wang Silun
      • Yan Kun
      • Fu De-Xue
      • Ford Eric
      • Tyler Betty
      • Blakeley Jaishri
      • Laterra John
      • van Zijl Peter C M
      Differentiation between glioma and radiation necrosis using molecular magnetic resonance imaging of endogenous proteins and peptides.
      ] and as an early biomarker for tumor proliferation [
      • Jiang Shanshan
      • Eberhart Charles G.
      • Lim Michael
      • Heo Hye-Young
      • Zhang Yi
      • Blair Lindsay
      • Wen Zhibo
      • Holdhoff Matthias
      • Lin Doris
      • Huang Peng
      • Qin Huamin
      • Quinones-Hinojosa Alfredo
      • Weingart Jon D.
      • Barker Peter B.
      • Pomper Martin G.
      • Laterra John
      • van Zijl Peter C.M.
      • Blakeley Jaishri O.
      • Zhou Jinyuan
      Identifying recurrent malignant glioma after treatment using amide proton transfer-weighted MR imaging: a validation study with image-guided stereotactic biopsy.
      ,
      • Park Ji Eun
      • Kim Ho Sung
      • Park Kye Jin
      • Kim Sang Joon
      • Kim Jeong Hoon
      • Smith Seth A.
      Pre-and posttreatment glioma: comparison of amide proton transfer imaging with MR spectroscopy for biomarkers of tumor proliferation.
      ]. Recent evidence suggests that APT could potentially differentiate IDH-wildtype gliomas (Fig. 3)[
      • Jiang S.
      • Zou T.
      • Eberhart C.G.
      • Villalobos M.A.V.
      • Zhang Y.
      • Wang Y.
      • Wang X.
      • Yu H.
      • Du Y.
      • Van Zijl P.C.M.
      Predicting IDH mutation status in grade-II gliomas using amide proton transfer-weighted (APTw) MRI.
      ] and detect tumor methylation status [
      • Jiang Shanshan
      • Rui Qihong
      • Wang Yu
      • Heo Hye-Young
      • Zou Tianyu
      • Yu Hao
      • Zhang Yi
      • Wang Xianlong
      • Du Yongxing
      • Wen Xinrui
      • Chen Fangyao
      • Wang Jihong
      • Eberhart Charles G.
      • Zhou Jinyuan
      • Wen Zhibo
      Discriminating MGMT promoter methylation status in patients with glioblastoma employing amide proton transfer-weighted MRI metrics.
      ].
      Figure thumbnail gr3
      Fig. 3Proton and Amide Proton Transfer (APT)-weighted MR images of a patient with an IDH-wildtype, WHO grade-II diffuse astrocytoma. The tumor (red arrows) was heterogeneously hyperintense on the T2-weigthed image, hypointense on the T1-weigthed image, with no definite enhancement after contrast injection. On the APT-weighted image, the lesion showed scattered areas of hyperintensity. The yellow arrow indicates a cystic-appearing component. Adapted with permission from Jiang et al.
      [
      • Jiang S.
      • Zou T.
      • Eberhart C.G.
      • Villalobos M.A.V.
      • Zhang Y.
      • Wang Y.
      • Wang X.
      • Yu H.
      • Du Y.
      • Van Zijl P.C.M.
      Predicting IDH mutation status in grade-II gliomas using amide proton transfer-weighted (APTw) MRI.
      ]
      .
      GlucoCEST is based on exogenously injected D-glucose to generate the CEST effect [
      • Xu Xiang
      • Chan Kannie W.Y.
      • Knutsson Linda
      • Artemov Dmitri
      • Xu Jiadi
      • Liu Guanshu
      • Kato Yoshinori
      • Lal Bachchu
      • Laterra John
      • McMahon Michael T.
      • van Zijl Peter C.M.
      Dynamic glucose enhanced (DGE) MRI for combined imaging of blood-brain barrier break down and increased blood volume in brain cancer.
      ]. Preclinical models studied at ultra-high field strength have demonstrated the potential of the technique to assess tumor blood volume and blood–brain barrier (BBB) permeability [
      • Xu Xiang
      • Chan Kannie W.Y.
      • Knutsson Linda
      • Artemov Dmitri
      • Xu Jiadi
      • Liu Guanshu
      • Kato Yoshinori
      • Lal Bachchu
      • Laterra John
      • McMahon Michael T.
      • van Zijl Peter C.M.
      Dynamic glucose enhanced (DGE) MRI for combined imaging of blood-brain barrier break down and increased blood volume in brain cancer.
      ,
      • Rivlin M.
      • Navon G.
      Molecular imaging of tumors by chemical exchange saturation transfer MRI of glucose analogs.
      ]. Recently, Xu et al. proposed a novel method to acquire GlucoCEST at clinical field strength [
      • Xu X.
      • Sehgal A.A.
      • Yadav N.N.
      • Laterra J.
      • Blair L.
      • Blakeley J.
      • Seidemo A.
      • Coughlin J.M.
      • Pomper M.G.
      • Knutsson L.
      • van Zijl P.C.M.
      d-glucose weighted chemical exchange saturation transfer (glucoCEST)-based dynamic glucose enhanced (DGE) MRI at 3T: early experience in healthy volunteers and brain tumor patients.
      ] which showed a discrepancy between the glucose enhancement and the enhancement after GBCA, suggesting that it measures tissue metabolism in addition to BBB permeability. Further optimization of the procedure is required, including the ideal mode of D-glucose injection [
      • Xu X.
      • Sehgal A.A.
      • Yadav N.N.
      • Laterra J.
      • Blair L.
      • Blakeley J.
      • Seidemo A.
      • Coughlin J.M.
      • Pomper M.G.
      • Knutsson L.
      • van Zijl P.C.M.
      d-glucose weighted chemical exchange saturation transfer (glucoCEST)-based dynamic glucose enhanced (DGE) MRI at 3T: early experience in healthy volunteers and brain tumor patients.
      ], but potentially the technique offers a novel method to study tumor metabolism.

      4. Developments in positron emission tomography (PET) for brain tumor imaging

      PET imaging may play a role in addressing several unmet clinical needs. Owing to the heterogeneous nature of brain tumors, image-guided biopsies based on morphological features may not accurately target the tumor, or precisely sample the most biologically aggressive tumor regions [
      • Jackson R.J.
      • Fuller G.N.
      • Abi-Said D.
      • Lang F.F.
      • Gokaslan Z.L.
      • Shi W.M.
      • Wildrick D.M.
      • Sawaya R.
      Limitations of stereotactic biopsy in the initial management of gliomas.
      ,
      • Vartanian A.
      • Singh S.K.
      • Agnihotri S.
      • Jalali S.
      • Burrell K.
      • Aldape K.D.
      • Zadeh G.
      GBM’s multifaceted landscape: highlighting regional and microenvironmental heterogeneity.
      ,
      • Chen W.
      Clinical applications of PET in brain tumors.
      ]. PET can provide an in vivo metabolic tumor map to guide tissue collection from the most metabolically active tumor area, allowing improved grading compared to sampling based on morphological or functional information [
      • Chen W.
      Clinical applications of PET in brain tumors.
      ,
      • Villena Martín Maikal
      • Pena Pardo Francisco José
      • Jiménez Aragón Fátima
      • Borras Moreno José María
      • García Vicente Ana María
      Metabolic targeting can improve the efficiency of brain tumor biopsies.
      ]. Guiding biopsy or treatment using metabolic changes may identify patients with a more aggressive histological or molecular tumor profile, or a higher risk of recurrence and worse outcome, who may benefit from tailored treatments and stricter imaging follow-up. Pirotte et al. demonstrated the superiority of L-[methyl-11C]-methionine ([11C]MET) over [18F]FDG in guiding tissue sampling [
      • Pirotte B.
      • Goldman S.
      • Massager N.
      • David P.
      • Wikler D.
      • Vandesteene A.
      • Salmon I.
      • Brotchi J.
      • Levivier M.
      Comparison of 18F-FDG and 11C-methionine for PET-guided stereotactic brain biopsy of gliomas.
      ]. However, the half-life of 11C is approximately 20 min, thus limiting its application to facilities with a cyclotron on site [
      • Treglia Giorgio
      • Muoio Barbara
      • Trevisi Gianluca
      • Mattoli Maria Vittoria
      • Albano Domenico
      • Bertagna Francesco
      • Giovanella Luca
      Diagnostic performance and prognostic value of PET/CT with different tracers for brain tumors: a systematic review of published meta-analyses.
      ].
      [18F]FLT is a marker of DNA synthesis and consequently, cellular proliferation. Interestingly, the volume of tumor assessed using [18F]FLT is similar to that measured using [11C]MET suggesting the possibility of using this tracer for lesion delineation [
      • Nikaki Alexandra
      • Angelidis George
      • Efthimiadou Roxani
      • Tsougos Ioannis
      • Valotassiou Varvara
      • Fountas Konstantinos
      • Prasopoulos Vasileios
      • Georgoulias Panagiotis
      18F-fluorothymidine PET imaging in gliomas: an update.
      ]. Suchorska et al. demonstrated that a smaller biological tumor volume (BTV) delineated by means of O-(2-[18F]-fluoroethyl)-L-tyrosine ([18F]FET) PET, correlates with improved progression-free survival (PFS) and overall survival (OS), suggesting that maximal PET guided-tumor resection may be beneficial [
      • Suchorska B.
      • Jansen N.L.
      • Linn J.
      • Kretzschmar H.
      • Janssen H.
      • Eigenbrod S.
      • Simon M.
      • Popperl G.
      • Kreth F.W.
      • la Fougere C.
      • Weller M.
      • Tonn J.C.
      Biological tumor volume in 18FET-PET before radiochemotherapy correlates with survival in GBM.
      ].
      6-[18F]fluoro-L-3,4-dihydroxyphenylalanine ([18F]DOPA, Fig. 4) is another promising radiotracer in neuro-oncology [
      • Piccardo Arnoldo
      • Tortora Domenico
      • Mascelli Samantha
      • Severino Mariasavina
      • Piatelli Gianluca
      • Consales Alessandro
      • Pescetto Marco
      • Biassoni Veronica
      • Schiavello Elisabetta
      • Massollo Michela
      • Verrico Antonio
      • Milanaccio Claudia
      • Garrè Maria Luisa
      • Rossi Andrea
      • Morana Giovanni
      Advanced MR imaging and (18)F-DOPA PET characteristics of H3K27M-mutant and wild-type pediatric diffuse midline gliomas.
      ]. [18F]DOPA-PET and MRS were compared by Morana et al. in 27 patients with infiltrative gliomas showing similar accuracy in differentiating gliomas from non-neoplastic lesions (accuracy of 78% for PET vs. 93% for MRS)[
      • Morana Giovanni
      • Piccardo Arnoldo
      • Puntoni Matteo
      • Nozza Paolo
      • Cama Armando
      • Raso Alessandro
      • Mascelli Samantha
      • Massollo Michela
      • Milanaccio Claudia
      • Garrè Maria Luisa
      • Rossi Andrea
      Diagnostic and prognostic value of 18F-DOPA PET and 1H-MR spectroscopy in pediatric supratentorial infiltrative gliomas: a comparative study.
      ]. More recently, Fraioli et al. compared [18F]DOPA-PET images against cross-sectional MRI in 40 patients with brain tumors investigated using hybrid PET/MRI imaging, and concluded that the combined PET/MRI approach, including use of conventional 1H sequences and contrast-enhanced perfusion-weighted imaging, improved overall tumor detection post-treatment [
      • Fraioli Francesco
      • Shankar Ananth
      • Hyare Harpreet
      • Ferrazzoli Valentina
      • Militano Vincenzo
      • Samandouras George
      • Mankad Khsitij
      • Solda Francesca
      • Zaccagna Fulvio
      • Mehdi Elnur
      • Lyasheva Maria
      • Bomanji Jamshed
      • Novruzov Fuad
      The use of multiparametric 18F-fluoro- l -3,4-dihydroxy-phenylalanine PET/MRI in post-therapy assessment of patients with gliomas.
      ].
      Figure thumbnail gr4
      Fig. 413-year-old female with a diffuse anaplastic astrocytoma of the left basal ganglia. MRI performed 1 month after initiation of radiotherapy. (A) Axial FLAIR, (B) axial T1-weighted (T1W) after injection of a gadolinium-based contrast agent (GBCA) and (C) axial fused [18F]DOPA /T1W post GBCA. FLAIR signal changes centered in the left thalamic region. The nodular bright spot represents post biopsy hemorrhage with no enhancement. [18F]DOPA-PET shows intense uptake centered at the level of the thalamic region. Follow up MRI at 8 months: (D) axial FLAIR, (E) axial T1W post GBCA and (F) axial fused [18F]DOPA/T1W post GBCA. A similar FLAIR signal abnormality is seen with the expected evolution of the previous hemorrhagic changes without contrast enhancement. The [18F]DOPA-PET demonstrated response at the original tumor site with new spread of disease along the lateral border (white arrow).
      PET imaging may also be advantageous for the early evaluation of treatment response and for the discrimination of tumor recurrence, pseudoprogression and radionecrosis [
      • Quartuccio N.
      • Laudicella R.
      • Vento A.
      • Pignata S.
      • Mattoli M.V.
      • Filice R.
      • Comis A.D.
      • Arnone A.
      • Baldari S.
      • Cabria M.
      • Cistaro A.
      The additional value of 18F-FDG PET and MRI in patients with glioma: a review of the literature from 2015 to 2020.
      ,
      • Alavi Abass
      • Barrio Jorge R.
      • Werner Thomas J.
      • Khosravi Mohsen
      • Newberg Andrew
      • Høilund-Carlsen Poul Flemming
      Suboptimal validity of amyloid imaging-based diagnosis and management of Alzheimer’s disease: why it is time to abandon the approach.
      ,

      M. Phelps, PET: Molecular Imaging and Its Biological Applications, in: 2004. https://doi.org/10.1148/radiol.2422062606.

      ]. Although an overall good performance has been described for the assessment of recurrence using [18F]FDG-PET/CT in patients with gliomas [
      • Arora Geetanjali
      • Sharma Punit
      • Sharma Anshul
      • Mishra Anil Kumar
      • Hazari Puja Panwar
      • Biswas Ahitagni
      • Garg Ajay
      • Aheer Deepak
      • Kumar Rakesh
      99mTc-methionine hybrid SPECT/CT for detection of recurrent glioma: comparison with 18F-FDG PET/CT and contrast-enhanced MRI.
      ], a relatively high rate of false negative results has been reported in LGGs [
      • Hatzoglou Vaios
      • Yang T. Jonathan
      • Omuro Antonio
      • Gavrilovic Igor
      • Ulaner Gary
      • Rubel Jennifer
      • Schneider Taylor
      • Woo Kaitlin M.
      • Zhang Zhigang
      • Peck Kyung K.
      • Beal Kathryn
      • Young Robert J.
      A prospective trial of dynamic contrast-enhanced MRI perfusion and fluorine-18 FDG PET-CT in differentiating brain tumor progression from radiation injury after cranial irradiation.
      ]. Amino acid tracers in this setting appear more effective, reaching a sensitivity of 88% (95% CI: 85–91%) and a specificity of 85% (95% CI: 80–89%), according to a recent meta-analysis of 23 studies that included a total of 889 patients [
      • Xu W.
      • Gao L.
      • Shao A.
      • Zheng J.
      • Zhang J.
      The performance of 11C-Methionine PET in the differential diagnosis of glioma recurrence.
      ].
      Radiotherapy planning may also benefit from the routine use of metabolic PET imaging to delineate PET-adapted treatment volumes reflecting metabolic activity, and to perform dose escalation [
      • Chen W.
      Clinical applications of PET in brain tumors.
      ,
      • Albert Nathalie L.
      • Weller Michael
      • Suchorska Bogdana
      • Galldiks Norbert
      • Soffietti Riccardo
      • Kim Michelle M.
      • la Fougère Christian
      • Pope Whitney
      • Law Ian
      • Arbizu Javier
      • Chamberlain Marc C.
      • Vogelbaum Michael
      • Ellingson Ben M.
      • Tonn Joerg C.
      Response assessment in neuro-oncology working group and European association for neuro-oncology recommendations for the clinical use of PET imaging in gliomas.
      ]. In a series of 26 patients followed-up for 15 months after radiotherapy, [11C]MET-PET identified areas of high risk of recurrence, suggesting the utility of incorporating this tracer into standard radiotherapy planning [
      • Lee Irwin H.
      • Piert Morand
      • Gomez-Hassan Diana
      • Junck Larry
      • Rogers Lisa
      • Hayman James
      • Ten Haken Randall K.
      • Lawrence Theodore S.
      • Cao Yue
      • Tsien Christina
      Association of 11C-methionine PET uptake with site of failure after concurrent temozolomide and radiation for primary glioblastoma multiforme.
      ]. The evaluation of hypoxia in HGGs is important to minimize resistance to radiotherapy and chemotherapy within hypoxic tumor regions. The main hypoxic radiotracer used to study brain tumors is [18F]fluoromisonidazole ([18F]FMISO). Toyonaga et al. showed hypoxic glucose metabolism to be a clinically significant prognostic factor in 32 patients with GBM using [18F]FMISO, and [18F]FDG [
      • Toyonaga Takuya
      • Yamaguchi Shigeru
      • Hirata Kenji
      • Kobayashi Kentaro
      • Manabe Osamu
      • Watanabe Shiro
      • Terasaka Shunsuke
      • Kobayashi Hiroyuki
      • Hattori Naoya
      • Shiga Tohru
      • Kuge Yuji
      • Tanaka Shinya
      • Ito Yoichi M.
      • Tamaki Nagara
      Hypoxic glucose metabolism in glioblastoma as a potential prognostic factor.
      ]. Second-generation hypoxic radiotracers with improved pharmacodynamics have been developed with the aim to improve tumor-to-background tissue localization and faster clearance from normal tissue.
      Recently, the fibroblast activation protein (FAP) expressed on cancer-associated fibroblasts has emerged as a novel target for PET imaging [
      • Windisch P.
      • Zwahlen D.R.
      • Koerber S.A.
      • Giesel F.L.
      • Debus J.
      • Haberkorn U.
      • Adeberg S.
      Clinical results of fibroblast activation protein (FAP) specific PET and implications for radiotherapy planning: systematic review.
      ]. 68Ga-labeled inhibitors of FAP, 68Ga-FAPI, have been evaluated in patients with GBM demonstrating tumor volumes that differed from those obtained using T1W MRI, suggesting potential additional information for targeting biopsy or radiotherapy planning [
      • Windisch P.
      • Röhrich M.
      • Regnery S.
      • Tonndorf-Martini E.
      • Held T.
      • Lang K.
      • Bernhardt D.
      • Rieken S.
      • Giesel F.
      • Haberkorn U.
      • Debus J.
      • Adeberg S.
      Fibroblast Activation Protein (FAP) specific PET for advanced target volume delineation in glioblastoma.
      ]. Interestingly, 68Ga-FAPI was found to be positive in IDH-wildtype GBMs and grade III/IV IDH-mutant gliomas, but not in IDH-mutant grade II gliomas [
      • Röhrich Manuel
      • Loktev Anastasia
      • Wefers Annika K.
      • Altmann Annette
      • Paech Daniel
      • Adeberg Sebastian
      • Windisch Paul
      • Hielscher Thomas
      • Flechsig Paul
      • Floca Ralf
      • Leitz Dominik
      • Schuster Julius P.
      • Huber Peter E.
      • Debus Jürgen
      • von Deimling Andreas
      • Lindner Thomas
      • Haberkorn Uwe
      IDH-wildtype glioblastomas and grade III/IV IDH-mutant gliomas show elevated tracer uptake in fibroblast activation protein-specific PET/CT.
      ]. A list of the main PET radiotracers currently used or under development for imaging brain tumors is found in Table 1.
      Table 1Some of the main PET radiotracers currently in use in neuro-oncological routine imaging (indicated with *) or with potential utility in the future. FDA approved tracers are currently in use with specific indication for brain tumor imaging. Non-FDA approved tracers are still being investigated with mounting evidence for their future use.
      RadiotracerBiological targetFDA statusEMA status
      [18F]FDG*Glucose metabolismApprovedApproved
      [11C]acetateOxidative metabolismNot approvedNot approved
      [18F]F-DOPA*Amino acid transportOrphan Drug DesignationApproved
      [11C]MET*Protein metabolism and amino acid transportNot approvedNot approved
      [18F]FETAmino acid transportOrphan Drug DesignationNot approved
      [18F]FMISOTumor hypoxiaNot approvedNot approved
      [18Ga]FAPIMarker of cancer-associated fibroblastsNot approvedNot approved

      5. Theranostics

      Brain tumors constitute a major therapeutic challenge [
      • Aldape K.
      • Brindle K.M.
      • Chesler L.
      • Chopra R.
      • Gajjar A.
      • Gilbert M.R.
      • Gottardo N.
      • Gutmann D.H.
      • Hargrave D.
      • Holland E.C.
      • Jones D.T.W.
      • Joyce J.A.
      • Kearns P.
      • Kieran M.W.
      • Mellinghoff I.K.
      • Merchant M.
      • Pfister S.M.
      • Pollard S.M.
      • Ramaswamy V.
      • Rich J.N.
      • Robinson G.W.
      • Rowitch D.H.
      • Sampson J.H.
      • Taylor M.D.
      • Workman P.
      • Gilbertson R.J.
      Challenges to curing primary brain tumours.
      ] as surgery, radiotherapy and chemotherapy have well recognized limitations and new therapeutic approaches are required. Theranostics is a broad concept referring to the use of a diagnostic agent or method to guide a therapeutic intervention, mostly relevant to the field of cancer. Radionuclide based methods are well suited for this approach because radiolabeled targeting agents can both visualize and characterize biochemical properties of tumors, while informing on the possibility of specifically delivering therapeutic radiation to the target volume sparing non-target tissues. This general concept has been applied since the 1950s when sodium iodide (131I) was first used to image and treat advanced differentiated thyroid cancers [
      • Sonenberg Martin
      • Rall Joseph E.
      The use of radioactive iodine in cancer of the thyroid.
      ]. Over the years a number of cancer-specific, highly expressed targets have emerged with clinical approval for use in neuroendocrine tumors [
      • Hennrich Ute
      • Kopka Klaus
      Lutathera®: The first FDA-and EMA-approved radiopharmaceutical for peptide receptor radionuclide therapy.
      ] and hematological malignancies [
      • Illidge Tim
      • Morschhauser Franck
      Radioimmunotherapy in follicular lymphoma.
      ].
      Several biological and molecular targets are currently under investigation for potential theranostic applications in brain tumors as combination treatments intended to provide a local radiation boost for supplementary therapeutic benefit. These targets cover the spectrum of tumor biology: metabolism, proteins or receptors overexpressed on the surface of glioma cells, markers expressed on neovasculature, proteins within the extracellular matrix, and cells within the tumor microenvironment. Consequently, a wide range of targeting agents are being investigated such as peptides and small molecules, antibodies and antibody fragments, and metabolic substrates. Imaging with these agents has largely been undertaken using PET. The therapeutic counterparts for these drugs are generally the same or very similar compounds labelled with beta-emitting, and recently alpha-emitting, radionuclides that provide a high linear energy transfer (LET) and localized absorbed dose necessary for therapeutic efficacy.
      Traditionally theranostic agents are delivered through intravenous injection, and tumor targeting is based on the biological properties of the radiolabeled agent and its ability to concentrate in the tumor due to the expression of the molecular target. Targeting gliomas offers additional challenges due to the poor diffusion of molecules from the systemic circulation into the tumor. Concurrent administration of drugs to increase BBB permeability has been attempted with limited success [
      • Prados Michael D.
      • Schold S. Clifford
      • Fine Howard A.
      • Jaeckle Kurt
      • Hochberg Fred
      • Mechtler Laszlo
      • Fetell Michael R.
      • Phuphanich Surasak
      • Feun Lynn
      • Janus Todd J.
      • Ford Kathleen
      • Graney William
      A randomized, double-blind, placebo-controlled, phase 2 study of RMP-7 in combination with carboplatin administered intravenously for the treatment of recurrent malignant glioma.
      ]. For targeted radionuclide therapy, there are several examples where the theranostic agent has been administered directly into the tumor or into an existing surgical cavity [
      • Reulen Hans-Jürgen
      • Suero Molina Eric
      • Zeidler Reinhard
      • Gildehaus Franz Josef
      • Böning Guido
      • Gosewisch Astrid
      • Stummer Walter
      Intracavitary radioimmunotherapy of high-grade gliomas: present status and future developments.
      ]. In convection enhanced delivery, hydraulic pressure provided by a pumping device attached to a catheter introduced into the tumor or surgical cavity is used to improve diffusion within the tumor [
      • Raghavan Raghu
      • Howell Roger W
      • Zalutsky Michael R
      A model for optimizing delivery of targeted radionuclide therapies into resection cavity margins for the treatment of primary brain cancers.
      ]. The aim of these strategies is to obtain higher concentrations of the agent within the tumor which should ultimately result in improved binding to the molecular target, longer retention in or around tumor cells, increased local absorbed dose, and lower systemic toxicity. Imaging of the distribution of the agent can be used to monitor distribution of radioactivity within the tumor and to estimate the tumor absorbed dose, which could potentially be modulated on a patient-by-patient basis.

      5.1 Antibody based approaches

      Monoclonal antibodies have traditionally been used as vehicles to deliver targeted radionuclide therapy. Tenascin, an extracellular matrix protein expressed on multiple cancer types, is the most investigated radioimmunotherapy target for gliomas. In the early 1990s locally administered 131I-labelled murine monoclonal antibodies against tenascin were used in a small series of patients with newly diagnosed and recurrent glioma showing 40% overall response rates [
      • Riva P.
      • Arista A.
      • Franceschi G.
      • Frattarelli M.
      • Sturiale C.
      • Riva N.
      • Casi M.
      • Rossitti R.
      Local treatment of malignant gliomas by direct infusion of specific monoclonal antibodies labeled with131I: comparison of the results obtained in recurrent and newly diagnosed tumors.
      ]. The same target was also investigated in several early phase clinical studies in the 2000s using a chimeric antibody (81C6) against tenascin labelled with 131I [
      • Reardon David A.
      • Akabani Gamal
      • Edward Coleman R.
      • Friedman Allan H.
      • Friedman Henry S.
      • Herndon James E.
      • Cokgor Ilkcan
      • McLendon Roger E.
      • Pegram Charles N.
      • Provenzale James M.
      • Quinn Jennifer A.
      • Rich Jeremy N.
      • Regalado Lorna V.
      • Sampson John H.
      • Shafman Timothy D.
      • Wikstrand Carol J.
      • Wong Terence Z.
      • Zhao Xiao-Guang
      • Zalutsky Michael R.
      • Bigner Darell D.
      Phase II trial of murine 131 I-labeled antitenascin monoclonal antibody 81C6 administered into surgically created resection cavities of patients with newly diagnosed malignant gliomas.
      ,
      • Reardon David A.
      • Akabani Gamal
      • Coleman R. Edward
      • Friedman Allan H.
      • Friedman Henry S.
      • Herndon James E.
      • McLendon Roger E.
      • Pegram Charles N.
      • Provenzale James M.
      • Quinn Jennifer A.
      • Rich Jeremy N.
      • Vredenburgh James J.
      • Desjardins Annick
      • Guruangan Sri
      • Badruddoja Michael
      • Dowell Jeanette M.
      • Wong Terence Z.
      • Zhao Xiao-Guang
      • Zalutsky Michael R.
      • Bigner Darell D.
      Salvage radioimmunotherapy with murine iodine-131-labeled antitenascin monoclonal antibody 81C6 for patients with recurrent primary and metastatic malignant brain tumors: Phase II study results.
      ] or the alpha emitter 211At [
      • Zalutsky Michael R.
      • Reardon David A.
      • Akabani Gamal
      • Coleman R. Edward
      • Friedman Allan H.
      • Friedman Henry S.
      • McLendon Roger E.
      • Wong Terence Z.
      • Bigner Darell D.
      Clinical experience with α-particle-emitting 211 At: Treatment of recurrent brain tumor patients with 211 At-labeled chimeric antitenascin monoclonal antibody 81C6.
      ]. This approach showed promising results and orphan drug designation for [131I]-81C6 was obtained in the United states in 2006, no additional steps toward approval have occurred since then. An 125I-labelled murine antibody against the epidermal growth factor receptor (EGFR) known as mAb 425 has been used for adjuvant treatment of gliomas through multiple intravenous injections, either alone or in combination with temozolomide [
      • Li Linna
      • Quang Tony S.
      • Gracely Ed J.
      • Kim Ji H.
      • Emrich Jacqueline G.
      • Yaeger Theodore E.
      • Jenrette Joseph M.
      • Cohen Steven C.
      • Black Perry
      • Brady Luther W.
      A phase II study of anti-epidermal growth factor receptor radioimmunotherapy in the treatment of glioblastoma multiforme.
      ]. This phase II study involved nearly 200 patients over 20 years and showed a survival benefit of several months in the combination arm with very limited side effects. This is one of the rare examples of successful use of a poorly penetrating Auger electron emitter such as 125I for targeted therapy and is attributed to internalization of the labeled antibody/receptor complex after binding. An additional target addressed by radioimmunotherapy with convection enhanced delivery in an early phase clinical trial is DNA histone H1 complex [
      • Shapiro William R.
      • Carpenter Susan P.
      • Roberts Karen
      • Shan Joseph S.
      131I-chTNT-1/B mAb: tumour necrosis therapy for malignant astrocytic glioma.
      ].
      Alternative immune based targeting strategies have been investigated mostly aimed at developing lower molecular weight agents that would display more favorable pharmacokinetics and diffusion. A derivative of a monoclonal antibody against the extra domain B of fibronectin (L19), a marker of tumor neoangiogenesis, has been engineered to an 80 kDa small immunoprotein (L19-SIP). Early phase clinical studies in patients with brain metastases using a systemically administered 124I-labeled derivative for PET imaging and dosimetry have been carried out to guide radioimmunotherapy with an 131I-labeled counterpart [
      • Poli Gian Luca
      • Bianchi Claudia
      • Virotta Giorgio
      • Bettini Anna
      • Moretti Renzo
      • Trachsel Eveline
      • Elia Giuliano
      • Giovannoni Leonardo
      • Neri Dario
      • Bruno Andrea
      Radretumab radioimmunotherapy in patients with brain metastasis: a 124I–L19SIP dosimetric PET study.
      ]. Along these general lines, a class of very low molecular weight antibody derivatives known as affibodies (~6 kDa) show rapid circulation times, high stability and high target affinity. Preliminary proof of concept of this approach in targeting vascular endothelial growth factor receptor (VEGFR) has been obtained in an animal model of glioma [
      • Mitran Bogdan
      • Güler Rezan
      • Roche Francis P.
      • Lindström Elin
      • Selvaraju Ram Kumar
      • Fleetwood Filippa
      • Rinne Sara S.
      • Claesson-Welsh Lena
      • Tolmachev Vladimir
      • Ståhl Stefan
      • Orlova Anna
      • Löfblom John
      Radionuclide imaging of VEGFR2 in glioma vasculature using biparatopic affibody conjugate: proof-of-principle in a murine model.
      ].

      5.2 Peptides and small molecules

      Lower molecular weight radiopharmaceuticals such as peptide-based agents (1–2 kDa) or small molecules binding to specific cell surface receptors or other proteins are proving to be very successful in theranostic applications in solid tumors outside the CNS. Most notable is the theranostic application of somatostatin analogs in neuroendocrine tumors, which has now been applied for well over two decades and is clinically approved [
      • Kong G.
      • Hicks R.J.
      Peptide receptor radiotherapy: current approaches and future directions.
      ]. These classes of ligands show better diffusion and may achieve higher concentrations in the target tissue when administered systemically compared to higher molecular weight compounds. There is histological evidence of expression of somatostatin receptors in gliomas [
      • Kiviniemi A.
      • Gardberg M.
      • Frantzén J.
      • Pesola M.
      • Vuorinen V.
      • Parkkola R.
      • Tolvanen T.
      • Suilamo S.
      • Johansson J.
      • Luoto P.
      • Kemppainen J.
      • Roivainen A.
      • Minn H.
      Somatostatin receptor subtype 2 in high-grade gliomas: PET/CT with 68Ga-DOTA-peptides, correlation to prognostic markers, and implications for targeted radiotherapy.
      ] and very high levels of expression have been demonstrated in grade 2 gliomas [
      • Lee H.
      • Suh M.
      • Choi H.
      • Ha S.
      • Paeng J.C.
      • Cheon G.J.
      • Kang K.W.
      • Lee D.S.
      A pan-cancer analysis of the clinical and genetic portraits of somatostatin receptor expressing tumor as a potential target of peptide receptor imaging and therapy.
      ]. The potential for this approach has not been fully explored in clinical studies. There is poor correlation between histologically determined somatostatin receptor expression in gliomas and uptake of [68Ga] somatostatin on PET imaging [
      • Kiviniemi A.
      • Gardberg M.
      • Frantzén J.
      • Pesola M.
      • Vuorinen V.
      • Parkkola R.
      • Tolvanen T.
      • Suilamo S.
      • Johansson J.
      • Luoto P.
      • Kemppainen J.
      • Roivainen A.
      • Minn H.
      Somatostatin receptor subtype 2 in high-grade gliomas: PET/CT with 68Ga-DOTA-peptides, correlation to prognostic markers, and implications for targeted radiotherapy.
      ]. This again indicates that diffusion and BBB permeability issues may be impairing access to the target. However, findings from a small case series suggest that local injection of the therapeutic [90Y]DOTA-TOC can provide lasting responses in progressive recurrent gliomas [
      • Schumacher T.
      • Hofer S.
      • Eichhorn K.
      • Wasner M.
      • Zimmerer S.
      • Freitag P.
      • Probst A.
      • Gratzl O.
      • Reubi J.-C.
      • Maecke H.
      • Mueller-Brand J.
      • Merlo A.
      Local injection of the 90Y-labelled peptidic vector DOTATOC to control gliomas of WHO grades II and III: An extended pilot study.
      ].
      The prostate specific membrane antigen (PSMA) is highly expressed on neovasculature of various tumors including gliomas [
      • Matsuda Masahide
      • Ishikawa Eiichi
      • Yamamoto Tetsuya
      • Hatano Kentaro
      • Joraku Akira
      • Iizumi Yuichi
      • Masuda Yosuke
      • Nishiyama Hiroyuki
      • Matsumura Akira
      Potential use of prostate specific membrane antigen (PSMA) for detecting the tumor neovasculature of brain tumors by PET imaging with 89 Zr-Df-IAB2M anti-PSMA minibody.
      ]. Preliminary evidence has shown a high target-to-background uptake ratio in PET imaging of gliomas [
      • Kunikowska Jolanta
      • Bartosz Królicki
      • Leszek Królicki
      Glioblastoma multiforme: another potential application for 68Ga-PSMA PET/CT as a guide for targeted therapy.
      ] and higher uptake in HGGs compared to LGGs [
      • Verma Priyanka
      • Malhotra Gaurav
      • Goel Atul
      • Rakshit Sutapa
      • Chandak Ashok
      • Chedda Rupal
      • Banerjee Sharmila
      • Asopa Ramesh V.
      Differential uptake of 68Ga-PSMA-HBED-CC (PSMA-11) in low-grade versus high-grade gliomas in treatment-naive patients.
      ]. There is anecdotal evidence that this approach may be relevant to treating gliomas [
      • Kumar Arunav
      • Ballal Sanjana
      • Yadav Madhav Prasad
      • ArunRaj S.T.
      • Haresh K.P.
      • Gupta Subhash
      • Damle Nishikant Avinash
      • Garg Ajay
      • Tripathi Madhavi
      • Bal Chandrasekhar
      177Lu-/68Ga-PSMA theranostics in recurrent glioblastoma multiforme: proof of concept.
      ] but dedicated clinical therapeutic trials have not been conducted.
      Intracavitary injection of radiolabeled substance P, a small peptide that binds the neurokinin-1 receptor which is highly expressed in gliomas and other cancers [
      • Hennig Ivo M.
      • Laissue Jean A.
      • Horisberger Ulla
      • Reubi Jean-Claude
      C Reubi, Substance-P receptors in human primary neoplasms: tumoral and vascular localization.
      ], has been evaluated in small case series. This peptide coupled to the chelator DOTAGA (DOTAGA-SP) was initially labeled with 111In for imaging and 90Y for therapy and applied in 12 patients in a dosimetry study [
      • Kneifel Stefan
      • Bernhardt Peter
      • Uusijärvi Helena
      • Good Stephan
      • Plasswilm Ludwig
      • Buitrago-Téllez Carlos
      • Müller-Brand Jan
      • Mäcke Helmut
      • Merlo Adrian
      Individual voxelwise dosimetry of targeted 90Y-labelled substance P radiotherapy for malignant gliomas.
      ]. Expansion of this series reported on results of therapy in 17 patients [
      • Cordier Dominik
      • Forrer Flavio
      • Kneifel Stefan
      • Sailer Martin
      • Mariani Luigi
      • Mäcke Helmut
      • Müller-Brand Jan
      • Merlo Adrian
      Neoadjuvant targeting of glioblastoma multiforme with radiolabeled DOTAGA-substance P – results from a phase I study.
      ]. More recently the same approach has been utilized for therapy with the alpha emitters 213Bi [
      • Królicki Leszek
      • Bruchertseifer Frank
      • Kunikowska Jolanta
      • Koziara Henryk
      • Królicki Bartosz
      • Jakuciński Maciej
      • Pawlak Dariusz
      • Apostolidis Christos
      • Mirzadeh Saed
      • Rola Rafał
      • Merlo Adrian
      • Morgenstern Alfred
      Safety and efficacy of targeted alpha therapy with 213 Bi-DOTA-substance P in recurrent glioblastoma.
      ] and 225Ac [
      • Królicki Leszek
      • Kunikowska Jolanta
      • Bruchertseifer Frank
      • Koziara Henryk
      • Królicki Bartosz
      • Jakuciński Maciej
      • Pawlak Dariusz
      • Rola Rafał
      • Morgenstern Alfred
      • Rosiak Elżbieta
      • Merlo Adrian
      225Ac- and 213Bi-substance P analogues for glioma therapy.
      ](Fig. 5), which have been monitored using PET imaging by co-injecting 68Ga labeled peptide. These approaches, while safe and well tolerated, require validation in terms of efficacy.
      Figure thumbnail gr5
      Fig. 5Axial (A), sagittal (B) and coronal (C) PET/CT images obtained after local co-injection of 10 MBq 68Ga-DOTA labelled Substance P (SP) with a therapeutic dose of 225Ac-DOTAGA-SP into the resection cavity of a GBM, demonstrating that the activity is concentrated within the lesion. Adapted with permission from: L. Królicki et al.
      [
      • Królicki Leszek
      • Kunikowska Jolanta
      • Bruchertseifer Frank
      • Koziara Henryk
      • Królicki Bartosz
      • Jakuciński Maciej
      • Pawlak Dariusz
      • Rola Rafał
      • Morgenstern Alfred
      • Rosiak Elżbieta
      • Merlo Adrian
      225Ac- and 213Bi-substance P analogues for glioma therapy.
      ]

      5.3 Metabolism

      Very low molecular weight metabolic substrates are rapidly diffusible and theranostic applications have been considered. While imaging applications have been relatively straightforward through standard PET labeling procedures, application of these drugs for therapy is quite challenging as there are limited possibilities for labeling these compounds with therapeutic radioisotopes without altering their biological properties. One of the few theranostic approaches attempted in the clinic is the use of iodinated phenyl alanine (IPA). [123I]IPA has been used to image gliomas [
      • Hellwig Dirk
      • Ketter Ralf
      • Romeike Bernd F.M.
      • Schaefer Andrea
      • Farmakis Georgios
      • Grgic Aleksandar
      • Moringlane Jean R.
      • Steudel Wolf-Ingo
      • Kirsch Carl-Martin
      • Samnick Samuel
      Prospective study of p-[123I]iodo-L-phenylalanine and SPECT for the evaluation of newly diagnosed cerebral lesions: Specific confirmation of glioma.
      ] and [131I]IPA has been used in combination with external beam radiotherapy in glioma patients in a small case series [
      • Verburg F.A.
      • Sweeney R.
      • Hänscheid H.
      • Dießl S.
      • Israel I.
      • Löhr M.
      • Vince G.H.
      • Flentje M.
      • Reiners C.
      • Samnick S.
      Patienten mit rezidivierendem glioblastoma multiforme Erste Erfahrungen mit p-[131I]Iod-L-phenylalanin und externen Strahlentherapie.
      ]. A phase 1–2 study addressing this approach is currently recruiting (clinicaltrials.gov, NCT03849105).

      6. Conclusion

      Molecular imaging has been evolving rapidly over the past two decades and will have a significant role in improving our understanding of brain tumor biology and metabolism, aid tumor stratification, and may foster the discovery of new treatments [
      • Aldape K.
      • Brindle K.M.
      • Chesler L.
      • Chopra R.
      • Gajjar A.
      • Gilbert M.R.
      • Gottardo N.
      • Gutmann D.H.
      • Hargrave D.
      • Holland E.C.
      • Jones D.T.W.
      • Joyce J.A.
      • Kearns P.
      • Kieran M.W.
      • Mellinghoff I.K.
      • Merchant M.
      • Pfister S.M.
      • Pollard S.M.
      • Ramaswamy V.
      • Rich J.N.
      • Robinson G.W.
      • Rowitch D.H.
      • Sampson J.H.
      • Taylor M.D.
      • Workman P.
      • Gilbertson R.J.
      Challenges to curing primary brain tumours.
      ]. The growing availability of hybrid PET/MRI systems and the possibility of obtaining multinuclear imaging opens up the possibility of using multimodal imaging to provide a wealth of information in individual patients [
      • Fraioli F.
      • Punwani S.
      Clinical and research applications of simultaneous positron emission tomography and MRI.
      ]. Advances in imaging will pave the way for better outcomes from personalized care and identification of new targets. In parallel, there are extensive research efforts in expanding theranostic applications through development of new ligands, novel approaches for drug delivery and the application of more effective radionuclides such as alpha emitters. Future neuroradiological practice will be based on the integration of a multitude of diagnostic tools but will also have an increasing role on brain tumor treatments moving towards less invasive and more targeted approaches.

      Declaration of Competing Interest

      The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

      Acknowledgements

      The researchers are supported by the NIHR Cambridge Biomedical Research Centre (BRC-1215-20014) and Cancer Research UK (CRUK). The views expressed are those of the author(s) and not necessarily those of the NIHR or the Department of Health and Social Care.

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