Positron Emission Tomography-Magnetic Resonance Imaging in the Evaluation of Brain Tumors: Current Status and Future Prospects

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Positron emission tomography/magnetic resonance imaging (PET/MRI) in the Evaluation of Brain Tumors: Current status and future Prospects Nghi Nguyen MD, Jesse Montagnese DO, Lisa R. Rogers DO, Leo Wolansky MD

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Seminar in Roentgenology

Cite this article as: Nghi Nguyen MD, Jesse Montagnese DO, Lisa R. Rogers DO, Leo Wolansky MD, Positron emission tomography/magnetic resonance imaging (PET/MRI) in the Evaluation of Brain Tumors: Current status and future Prospects, Seminar in Roentgenology, http://dx.doi.org/10.1053/j.ro.2014.07.001 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting galley proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

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Title: Positron Emission Tomography/Magnetic Resonance Imaging (PET/MRI) in the Evaluation of Brain Tumors: Current Status and Future Prospects Authors: Nghi Nguyen, MD; Jesse Montagnese, DO; Lisa R. Rogers, DO; Leo Wolansky, MD From the Departments of Radiology (N.N., J.M., L.W.) and Neurology (L.R.), University Hospitals Case Medical Center, Case Western Reserve University School of Medicine, 11100 Euclid Avenue, Cleveland, OH 44106.

Please address correspondence to Leo Wolansky, MD, Department of Radiology, University Hospitals Case Medical Center, 11100 Euclid Avenue, Cleveland, OH 44106; email: [email protected]

Abstract Various designs of positron emission tomography/magnetic resonance imaging (PET/MRI) systems have been recently introduced into clinical practice, which have overcome technical challenges concerning the fusion of PET and MRI. This review summarizes the literature on the use of PET and MRI as well as addresses the potential benefit and contributions of hybrid PET/MRI in neuro-oncology. Multiple functional parameters derived from this novel technology are appealing as imaging biomarkers because of its noninvasive nature, complementary information and quantitative capability. There is a need for the development of time efficient acquisition protocols that tailor the various clinical indications as well as systematic evaluation in standardized, multi-center clinical trials. There are grounds for cautious optimism that hybrid PET/MRI will become a valuable imaging tool for the detection and characterization of brain tumors as well as for monitoring the response to therapy.

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INTRODUCTION Epidemiology and types of CNS tumors Brain neoplasms can be classified as primary brain tumors and secondary metastatic tumors arising from extracranial malignancies. The latter are encountered more frequently than the former. According to the American Cancer Society, more than 100,000 people die each year due to symptomatic brain metastases while an estimated 12,760 people, among the 20,500 newly-diagnosed primary brain tumors, die [1]. The most common tumors to metastasize to the brain are carcinoma of the breast, lung, colon and kidney, followed by melanoma. Roughly half of brain metastases are single and half are multiple. Although primary brain tumors can occur at any age, there are two age peaks, one in adults between 40 and 70 years, and one in children between 3 and 12 years. Primary brain tumors are rare in adults and account for only 3% of all new cancer cases; however, up to 20% of newly diagnosed cancers in childhood are brain tumors [2]. The most common site for primary brain tumors depends upon patient age. In adults, two thirds of tumors arise in the supratentorial compartment; the opposite is true for pediatric brain tumors, in which two thirds arise in the infratentorial compartment. The World Health Organization provides a classification and grading system of brain tumors that is accepted and in use worldwide [3]. The most common adult primary brain tumors arise from neuroepithelial tissue. The most common of these is astrocytoma, of which there are four grades: grade 1 (pilocytic astrocytoma), grade 2 (diffuse/fibrillary

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astrocytoma), grade 3 (anaplastic astrocytoma), and grade 4 (glioblastoma multiforme). A less common glioma, but one of considerable clinical relevance because of the comparatively improved response to treatment and long term survival as compared with astrocytoma, is the oligodendroglioma, of which there are two grades; grade 2 and grade 3 (anaplastic oligodendroglioma). Other common primary brain tumors in adults include those of the meninges (typically meningioma, of which there are three grades), cranial nerves (e.g. schwannoma), and benign tumors of the sellar region. Less common are tumors of hematopoietic origin (lymphoma) and germ cells. CNS lymphoma may be primary or secondary, with primary CNS lymphoma accounting for 6.6% of all primary brain tumors in adults. The most common pediatric primary brain tumors include medulloblastoma, an embryonal tumor which typically arises in the fourth ventricle, ependymoma, and glioma. The majority of adult and pediatric primary brain tumors require surgery for histological confirmation and for therapeutic debulking. Aside from some low grade tumors, the majority of brain tumors are subsequently treated with radiation therapy and/or chemotherapy.

Technological advancements in functional hybrid imaging Contrast-enhanced MRI is a well-established imaging modality in the clinical and research setting. It has numerous clinical applications and is the gold standard in neuroimaging due to its superb anatomical details [4]. Although much of the information obtained from magnetic resonance imaging (MRI) is morphologic in nature, biochemical

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composition influences even the most fundamental pulse sequences. Furthermore, advanced MRI techniques, such as diffusion-weighted MRI (DWI), MR spectroscopy (MRS) and perfusion MRI (pMRI) provide improved biochemical characterization of tissues; thus, morphologic and functional MRI are complementary allowing both anatomical and molecular imaging capabilities [5]. Besides computed tomography (CT) and MRI, advances in multimodality imaging such as positron-emission-tomography/computed-tomography (PET/CT) have significantly improved patient care, particularly in oncology. Since its introduction in 2000, PET/CT imaging has become widely used and made enormous contribution to the diagnosis, staging, and treatment monitoring in cancer patients [6, 7]. In brain imaging, PET and PET/CT imaging using various radiopharmaceuticals have also proven to be helpful. It is expected that PET/MRI will provide more clinically relevant information than PET or PET/CT in neuroimaging because MRI provides superb soft tissue contrast and functional imaging capabilities. Integrated whole-body PET/MRI systems are now commercially available and expected to change the medical imaging field by providing optimal anatomic-metabolic image information. In 2010, Philips Healthcare installed the first sequential PET/MRI system (Ingenuity TF PET/MRI, Philips Healthcare) at Mount Sinai Medical Center, New York [8]. At our institution, Case Western Reserve University/University Hospitals Case Medical Center in Cleveland, the Ingenuity TF PET/MRI was installed in 2011 and has been used since for both clinical service and research. In this review, we describe our first clinical experience with PET/MRI in neuroimaging and discuss the current status as well as perspectives of integrated PET/MRI.

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Co-registration of PET and MRI images Co-registration (fusion) of brain PET and MRI images is used with increasing frequency to achieve better anatomical localization and characterization of PET lesions. Image fusion of separate PET and MRI data can be carried out with help of various commercial and free software programs. The accuracy of co-registration is high with an error as low as 2 mm in the brain, making co-registration of PET and MRI brain images a viable option in clinical practice [9]. In a retrospective study of 47 patients with brain tumors that were previously treated with stereotactic radiosurgery, the co-registration of PET and MRI data resulted in an increase in sensitivity for tumor recurrence from 65% to 86% while maintaining the specificity at 80% [10]. There are however, a number of limitations. 1) In many cases, the PET examination and MRI examination are performed on different days, so the tumor biology may have changed between the scans, resulting in suboptimal correlation of PET and MRI. 2) Some patients will have the scans performed at different departments that may not share a common picture archiving and communication system (PACS); consequently, the combined interpretation of the two modalities may not be practical. 3) Despite the fact that image fusion software is now available for clinical use, most comprehensive and user-friendly software packages will require a software purchase, which may limit its widespread clinical use overall. 4) Because the PET and MRI images are acquired separately, the imaging protocols of PET and MRI are not optimized for each other, and as a result, simple differences in matrix size, slice thickness, head position, as well as imaging planes may complicate accurate correlation. 5) The interpretation of PET and MRI images may be inconsistent

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because the MRI scan may be read separately without the knowledge of the PET scan and vice versa.

PET/MRI SCANNER DESIGNS Siemens Medical Solutions The industry saw the market niche for integrated PET/MRI, soon after marketing of PET/CT systems was successful. The first integrated PET/MRI system (“BrainPET/MRI”) dedicated for brain imaging was introduced by Siemens Medical Solutions in 2007 [11-13]. The system consists of an MR-compatible PET system that is inserted into a modified whole-body MR scanner with 3 Tesla magnet (Magnetom Trio). Several technical difficulties have been resolved to allow a simultaneous acquisition of PET and MRI. For PET, conventional photomultiplier tubes are replaced by avalanche photodiodes to allow for magnetic field compatibility. Appropriate shielding of PET components located inside the MRI system has been achieved to minimize interference with the radiofrequency and gradient fields of the MRI. In 2010, Siemens introduced the first whole-body PET/MRI (“Biograph mMR”) which allows a simultaneous acquisition of MRI and PET because the two systems are fully integrated within the same gantry. The advantages of this scanner design include the low risk of patient motion affecting image quality and co-registration. Most important benefit however lies in the simultaneous acquisition of PET and MRI, allowing unmatched temporal and spatial correlation between PET and MRI, particularly by means of dynamic imaging and allowing translational neurologic and psychiatric

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research. The setup of the PET scanner inside the MRI system has additional advantage of partial volume correction and motion correction of PET data based on MRI information. Brain imaging using the whole-body PET/MRI results in less favorable spatial resolution compared to the dedicated BrainPET/MRI, but the former has a larger bore and enables imaging of the body.

Philips Healthcare Philips Healthcare has a sequential approach in the PET/MRI design. Their Ingenuity TF PET/MRI system is a hybrid of the Gemini TF PET scanner with time-of-flight technology and the Achieva 3 T MRI scanner that is housed in a single room. The gantry of the two scanners is approximately 4.2 m apart; the scanner table is in the middle between the two scanners and rotates 180° for scanning with MRI vs. PET. Technically, this approach is less challenging to achieve compared to the simultaneous PET/MRI system from Siemens. Although a simultaneous acquisition is not possible with this system design, the PET and MR images are automatically co-registered. The main advantages of the Ingenuity TF PET/MRI lie in the cost saving from the simple scanner design and high image quality of PET using time-of-flight technology as well as the preserved MR image quality due to minimal PET interference with the magnetic field of the MRI [14].

GE Healthcare

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As with Philips Healthcare, GE Healthcare has pursued a sequential but tri-modality system that allows MRI scanning (Discovery MR750w at 3 Tesla) in one room and PET/CT scanning (Discovery PET/CT with time-of-flight technology) in an adjacent room. A two-room setup is required for this scanner system configuration. The patient is transferred between the two scanners on a hover table. The advantage of the sequential design over the simultaneous design lies mainly in reduced cost as well as the flexible use of PET/CT, MRI or both. Other advantages include preserved MRI image quality due to the minimal interference of the PET system with the MRI magnetic field and the robust attenuation correction of PET using CT data instead of MRI information [15].

DIAGNOSTIC VALUE OF SEPARATE MRI AND PET MRI Contrast-enhanced MRI MRI has become the gold standard for non-invasive imaging of brain tumors [4]. It provides great structural details and enables the detection and localization of brain lesions to submillimeter resolution. T2-weighted and Fluid-attenuated inversion-recovery (FLAIR) sequences, based on the fast spin-echo technology are standard in brain imaging because these display high sensitivity to edema, a common denominator of most cerebral pathology, being manifest as hyperintensity. Although highly sensitive [4], FLAIR signal hyperintensity (Fig. 1) is not particularly specific for a brain tumor. Contrast enhancement adds some degree of specificity in the diagnosis of high-grade gliomas

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(grades III and IV). Tumor contrast enhancement is largely due to leakage of gadolinium (Gd) chelate into the interstitium because of blood-brain-barrier (BBB) breakdown, which is usually related to neovascularization and necrosis. Contrast enhancement is also not entirely specific being seen in other malignant tumors, e.g., primary CNS lymphomas and metastases. Furthermore, enhancement can be seen with benign tumors, such as meningiomas, pilocytic astrocytomas and hemangioblastomas as well as many non-neoplastic processes, abscesses, acute demyelination , and subacute infarction. The diagnostic accuracy of conventional MRI in the diagnosis of malignant brain tumor is approximately 86% [16], so surgical biopsy or resection is carried out in most cases to provide histological diagnosis. There are also limitations to histological diagnosis, e.g. sampling errors in surgical biopsies due to tumor heterogeneity, which may result in undergrading of the tumor, or due to tissue sampling at the edge of a lesion, which may be difficult to differentiate a low-grade glioma (Fig. 1A-C) from reactive gliosis. Despite continued progress in imaging, MRI is often not able to detect areas of microscopic tumor infiltration, which frequently renders gliomas incurable.

Diffusion-weighted Imaging (DWI) DWI utilizes the microscopic mobility of water, classic Brownian motion, to detect biologic abnormalities. Parameters such as apparent diffusion coefficient (ADC) derived from DWI are appealing as biomarkers because of the noninvasive nature, not requiring intravenous contrast infusion; but are nevertheless quantitative and rapid, being easily incorporated into the routine MRI examination. Diffusivity is inversely correlated with

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cellularity, with reduced diffusivity (diminished ADC signal) often correlating with higher grade (hypercellular) tumor (Fig. 1), which can aid in staging intracranial neoplasm, particularly glioma. Specifically, the use of ADC histograms has shown promising results in the grading of gliomas particularly when focusing on the lower diffusivity peak, corresponding to the non-necrotic portion of the tumor [17]. Furthermore, ADC has been used to assess brain tumor response to therapy and to predict survival, particularly in patients with high grade gliomas [18]. Insert Fig. 1

Proton MR Spectroscopy (MRS) MRS allows non-invasive measurement of metabolites in brain tumors, with most neoplasms demonstrating increased Choline (Cho) and reduced N-acetylaspartic acid (NAA) and creatine (Cr) – Fig. 2. MRS can help differentiate tumor grade and aid in differentiation of recurrent neoplasm from radiation change. Furthermore, it could be used to guide biopsies and define radiotherapy targets as well as to monitor patients after treatment [19]. However, clinical application is hampered by technical factors, e.g. standardization of data acquisition across different scanning systems and the effect of field strength variations because of voxel measurements in spatially heterogeneous tumors. As a result, MRS may be unreliable for lesions less than 2 cm in diameter or for lesions close to bone, cerebrospinal fluid or fat because of signal contaminations, e.g. base of skull and retro-orbital region. The field heterogeneity is amplified in the patients who have ferromagnetic surgical hardware for craniotomy flap fixation overlying the

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cerebral lesion. In addition, MRS is time consuming and labor intensive, often requiring compromise in terms of lesion coverage, especially using single-voxel technique. Consequently, the measured data may not reflect the biology in other parts of the tumor. This consideration is particularly important in high-grade gliomas, which are heterogeneous due to cystic degeneration and necrosis. In contrast, multi-voxel spectroscopy can provide greater tumor coverage and display regional differences within a tumor, but the signal to noise ratio and associated quality of the spectra are significantly worse than single voxel spectroscopy. Thus, multi-voxel spectroscopy is technically demanding, less reproducible and more difficult for quantitative evaluation [17]. Insert Fig. 2 Perfusion-weighted MRI Perfusion-weighted MRI allows an evaluation and quantification of cerebral hemodynamics. Three technical approaches are being used clinically. The first two of these require IV contrast infusion and are known as dynamic contrast enhanced MRI (DCE-MRI). The first of these is based on T1 relaxation enhancement during serial imaging and is typically referred to as DCE-T1 or by the shortened, deceptively nonspecific name “DCE.” The second technique makes use of the magnetic susceptibility (T2*) effect of the contrast bolus induced tissue heterogeneity. This is referred to as dynamic susceptibility contrast MRI (DSC-MRI). These techniques provide information about tissue perfusion and permeability and are increasingly used in tumor grading, pre-treatment planning as well as assessing therapeutic response,

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particularly in the setting of antiangiogenic therapy [20-22]. The regional cerebral blood volume (rCBV) derived from the DSC data, either as an absolute measure or a ratio with the contralateral “normal’’ white matter have been shown to correlate with microvascular density and with tumor grade in that maximum regional cerebral blood volume (rCBV) values of low-grade gliomas are significantly lower than those of highgrade gliomas (Fig. 3). Recent data also suggests that rCBV is helpful in predicting progression in gliomas, both low-grade gliomas treated conservatively [23] as well as low-grade and high-grade gliomas prior to as well as after surgery [24]. However, there are still significant limitations particularly regarding the lack of specificity. Arterial spin labelling (ASL) is an emerging technique that allows perfusion measurements (rCBF) without the need of contrast agent and is based on flow saturation, the blood being labeled magnetically as part of the imaging sequence [25]. ASL has been shown to have higher rCBF in glioblastoma than grade II and III gliomas; these findings correlate with the higher rCBV derived from DSC-MRI as well [25].

Functional MRI (fMRI) fMRI is another innovative MR technique for measuring brain activity. It works by detecting the changes in blood oxygen levels in response to neural activity and resulting changes in blood flow due to autoregulation (blood-oxygen-level-dependent or BOLD). fMRI can be used to produce activation maps showing which parts of the brain are involved in the particular mental process. The method is most accurate at delineating brain regions associated with motor tasks [26]. BOLD–fMRI is valuable in the

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preoperative planning of brain tumor surgery, especially if the tumor is in close proximity to eloquent functional brain centers.

PET Imaging F-18 FDG PET Molecular imaging with PET has gained significant interest over the years because it has the potential to image a wide range of biochemical processes that are critical for the understanding of pathophysiology of neoplasms, and thereby can play a major role in drug development and monitoring of targeted treatments. Although there are certain advantages for the use of newer radiotracers, F-18 FDG is the most commonly used radiotracer because of its overall acceptable diagnostic accuracy, low cost and widespread availability as well as favorable half-life (110 minutes). FDG-PET is being used in more than 90% of cancers for staging, restaging and assessing therapy response. The goal of FDG PET is to detect increased glucose metabolism in tumors. There is however a high metabolic activity in normal gray matter, mostly reflecting physiological state of neuronal activity. This high FDG uptake in normal brain tissue often limits the delineation of tumor from normal brain metabolic activity. As a result, only 3-6% of low-grade gliomas and 21-47% of high-grade gliomas show increased FDG metabolism [27, 28]. It is therefore highly recommended to interpret FDG PET images in conjunction with anatomical images, such as CT and MRI. Metastases from various extracranial malignancies may have variable FDG uptake [29]. In a retrospective study conducted on 104 neurologically asymptomatic patients for

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initial lung cancer staging, FDG PET/CT detected only 7.7% of brain metastases as opposed to 21.2% with brain MRI [29]. Therefore, FDG PET or PET/CT is usually not recommended to screen for brain metastasis [29]. Standard uptake value (SUV) is a semi-quantitative parameter of metabolic activity and can provide more precise diagnosis than visual interpretation, and the relative change in SUV is very helpful in characterizing treatment response. The use of SUV however has some limitations, particularly if the brain tumor is located in an area of high physiologic brain uptake. As an alternative, activity ratios (SUV ratio) to the contralateral brain or to the adjacent white matter have been used to better characterize the brain lesions. The increased FDG uptake in brain tumors correlates well with the degree of malignancy (Fig. 3, Fig. 6). Di Chiro et al. [30] found in a study of 23 patients that all 10 high-grade (III and IV) gliomas demonstrated high glucose metabolism (7.4 ± 3.5 mg/100g per min) whereas the 13 low-grade gliomas (I and II) showed lower uptake (4.0 ± 1.8 mg/100g per min). Besides tumor grading, FDG PET provides valuable information about prognosis. In studies with high grade gliomas, a high metabolic activity was associated with a mean/median survival time of 5-7 months compared to 19-33 months for those with low metabolic activity [31, 32]. Insert Fig. 3 It is evident that FDG PET has positive clinical value in predicting tumor response and may be used to assess early treatment response and to aid the therapeutic management of brain tumors [33, 34]. The differential diagnosis of post-treatment radiation change and residual or recurrent tumor remains a challenging task in clinical

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practice. The effect of radiation change and necrosis is particularly notable in patients with high-grade tumors treated in “standard of care” combination chemoradiation (Temozolomide). The diagnostic accuracy of FDG PET in differentiating post-radiation change (Fig. 4) from viable tumor (Fig. 2) varies significantly, with a sensitivity of 8186% and a specificity of 40-90% [35]. Insert Fig. 4

Non-FDG PET There is an increasing interest in applying other PET radiotracers to avoid the shortcomings of FDG PET. The integration of novel radiotracers, such as C-11 methionine (MET), and F-18 fluorothymidine (FLT), enables an enhanced evaluation of tumor pathophysiology and metabolism, resulting in improved accuracy for CNS tumor diagnosis and follow-up. The following section will provide an overview of some of the commonly used non-FDG radiotracers in the literature. Based on its favorable half-life of 110 min, F-18 is the most practical isotope for radiolabeling; C-11with a half-life 20 min is being used mainly in clinical research settings where on-site cyclotrons are available. At the time of this writing, FDG is the only radiotracer currently FDA approved for clinical use, although many of them are being studied as Investigational New Drug Applications (INDs). The ability to develop PET tracers for specific molecular targets is potentially important and a large number of them are in development [36]. Besides FDG, the radiolabeled amino acids C-11 Methionine (MET) and F-18 fluoroethyl-tyrosine (FET) are the most commonly used PET tracers for brain tumors. The

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most significant advantage of using radiolabeled amino acids over FDG is the relatively low uptake of amino acids by normal brain tissue. The high uptake in gliomas therefore results in good lesion-to-background ratio so that the tumor can be detected more easily. As the building blocks of proteins, amino acids serve well as a target for molecular imaging. As a component of many metabolic cycles, the metabolism of amino acids is up-regulated in cells with increased proliferative activity, such as in cancer. This makes it attractive for researchers to develop radiotracers labeling PET isotopes with amino acids for tumor imaging. The uptake mechanism for the most commonly used amino acid radiotracers (MET, FET) is mainly explained by the transport via specific amino acid transporters although a small amount of the radiotracer may be further metabolized or incorporated into protein synthesis within the cell [37]. Certain amino acids radiotracers are being used more common than others depending on the ease of biochemical compounding, the availability of an on-site cyclotron and clinical indication as well as cost consideration. MET is the most popular amino acid radiotracer in neurooncology although its use is limited to PET centers with on-site cyclotron. Its popularity is largely due to the relatively simple steps of production. FET is newer than MET and has the advantage of longer half-life (110 min) and wider availability, obviating the need for an on-site cyclotron. FLT is an analog to the nucleoside thymidine and was developed as a PET radiotracer to assess cellular proliferation. The phosphorylated FLT within the cell reflects cell proliferation and correlates strongly with thymidine incorporation into the DNA. The actual incorporation of FLT into the DNA is however low, and the majority of the phosphorylated FLT is trapped in the cytosol [38, 39]. As a biomarker for cell

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proliferation, FLT has the tremendous potential in monitoring and treatment response assessment. This is demonstrated in a study of 19 patients treated with bevacizumab and irinotecan. Comparative studies between MET and FET have shown similar results in gliomas [40, 41]. Because amino acid radiotracers easily diffuse into the brain tissue, a disruption of the BBB is not required for the increased metabolism in brain tumors. Consequently, amino acid radiotracers enable imaging of both low-grade tumors without BBB leakage and high-grade tumors with BBB leakage. The sensitivity and specificity of MET PET and FET PET is in the range of 70-90% each [42, 43]. C-11 Choline is a natural amine that enters the cells and is involved in the synthesis of the cell membrane. Given the increased cell proliferation of tumor cells, there is also increased cell membrane turnover; therefore, choline can serve as a marker for phospholipid synthesis. Comparative studies have shown that C-11 choline is superior to FDG PET in delineating the extent of tumor [39, 44]. The uptake of C-11 choline is reported to be 3-4 times higher in glioblastomas than in normal brain tissue, and the uptake in low-grade tumors remains low and is comparable with the non-neoplastic lesions [45, 46]. Hypoxia in malignant gliomas represents a significant risk for resistance to both radiation and chemotherapy, and is associated with a more aggressive tumor phenotype and worse prognosis. Diagnostic imaging with hypoxia markers such as 18Ffluoromisonidazole (FMISO) enables the quantification of hypoxia in tumors and

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provides valuable information for prognosis, treatment planning and response to therapy [47, 48].

POTENTIAL DIAGNOSTIC VALUE OF HYBRID PET/MRI Functional imaging plays an important role in aiding the clinical management of patients with brain tumors. Multi-parametric imaging with hybrid PET/MRI is now available at some imaging centers, enabling an in-depth studying of pathophysiologic processes at a molecular level. Intuitively, the different functional data derived from multimodal imaging will enhance diagnostic confidence and accuracy. However, the era of PET/MRI has just started, and much more work lies ahead to demonstrate its clinical potential, particularly compared with currently available modalities of MRI and PET/CT as well as co-registration of individual MRI and PET data. To date, the literature on the use of hybrid PET/MRI in neuro-oncology is limited to a few reports [11-13]. These studies were carried out on the dedicated BrainPET/MRI system which is being used in a few imaging centers. It is expected that future PET/MRI applications and investigations will be primarily done using the whole-body PET/MRI systems that are being offered by the three major vendors Siemens, Philips and GE. It will take several more years before a good amount of research data is available on the use of hybrid PET/MRI. Researchers at the University of Tuebingen were the first to report on the use of hybrid PET/MRI in human brain [11, 13]. Using the BrainPET/MRI system, the tumor delineation in the seven patients undergoing MET PET was compatible between

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PET/MRI and PET/CT [13]. They performed Ga-68 DOTATOC PET in eight patients as well for the diagnosis of meningioma. Six of eight patients were found to have comparable lesions between PET/MRI and PET/CT, whereas an additional lesion was suggested in the remaining two patients [13]. This study was however mainly an image quality evaluation, in which the authors shared their initial clinical experience on a simultaneous PET/MRI system, and the clinical indications were wide, ranging from meningiomas, head and neck tumors to astrocytomas. Comprehensive studies evaluating the clinical value of hybrid PET/MRI are under way and the results are to be expected for the coming years. In the following section, the current literature on the use of separate MRI and PET scanning with subsequent image fusion is reviewed and the clinical and research potential of hybrid PET/MRI is discussed.

Tumor grading and prognosis Gliomas may consist of different parts that are heterogeneous in terms of tumor grading. Thus, low- and high-grade areas may be present within the same tumor. Although MRI is the modality of choice to detect intracerebral neoplasms, the inherent heterogeneity of gliomas may not be sufficiently depicted by conventional MRI, particularly in non-enhancing gliomas (Fig. 1A-C). To date, several studies combining single modalities of functional MRI and PET have been reported in the literature [25, 49]. In a prospective study of 61 patients with WHO grade II-IV gliomas, Weber at al. [23] wanted to answer the question whether the use of various functional imaging modalities would lead to similar target areas for biopsy. Using an extensive array of

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functional MRI (Na-23-, MRS, ASL, DCE and DSC, DW) in combination with FDG- and FLT-PET, they found that FLT-PET, DSC-, DW- and DCE-MRI as well as MRS correctly identified all three non-enhancing grade III lesions and showed no significant tumor heterogeneity in all 15 grade II gliomas. Tumor grading correlated well with semiquantitative parameters of tumor vascularity and proliferation. In the majority of the cases (>80%), areas of increased FLT uptake matched with that of choline peak on MRS [25]. Tumors with the same histopathological diagnosis can behave in very different ways. Novel biomarkers of prognosis can aid treatment strategy, moving towards personalized treatments. Functional imaging can serve as noninvasive biomarkers of prognosis, which commonly mirrors the biomarkers found for grading. In a study that included 189 patients with grade II glioma, high rCBV at DSC-MRI predicted a short time to disease progression and poor clinical outcome [24]. In a retrospective study including 187 patients with high-grade gliomas, Majos et al. [50] established that MRS at diagnosis could identify patients with poor prognosis, depending on spectral characteristics such as low myo-inositol levels and high levels of mobile lipids. In a retrospective study, the mean and minimum ADC were found to be significantly lower in patients with progressive, compared with stable, high-grade gliomas at 2 years [18]. Using FET-PET, the combination with MR morphology has been found to be a significant prognostic predictor for patients with newly diagnosed low-grade gliomas [51]. Baseline FET uptake and a circumscribed versus a diffuse growth pattern on MRI were highly significant predictors for patients’ course and outcome. One could envision that multiparametric PET/MRI could enhance our knowledge of both prognostic and predictive

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outcome. Multi-parametric PET/MRI has the potential to evolve into a valuable tool for research, potentially important for the understanding of tumor microenvironment and drug development.

Biopsy guidance Often, brain tumors exhibit different degrees of anaplasia in different tumor parts. Thus, surgical biopsies, especially when taken stereotactically, may miss the most malignant tumor area and therefore underestimate the tumor grade. Although surgical resection is a key intervention in many patients, including adults with low-grade and high-grade gliomas, biopsy is still important in some cases, such as in patients with diffuse tumors and those tumors in which extensive surgery would pose a significant risk to life. In addition to providing noninvasive diagnosis, functional imaging can be used to guide biopsy in large complex lesions in which there is a risk that the tissue obtained may not be representative of the highest grade within the tumor (Fig. 5). Insert Fig. 5 Weber et al. [25] conducted a study of 61 patients using MRS, DWI, ASL, DCE-T1, DSC, 23Na-MRI as well as FLT and FDG PET. These authors showed that target areas for vascularity, cellularity and proliferation were similar among the various functional parameters. In areas without tumor necrosis, there was a good agreement between markers of cell proliferation (increased choline at MRS and FLT uptake at PET) and cellularity (low ADC values, increased FDG uptake) as well as microcirculation and angiogenesis (elevated rCBV and rCBF). Functional MRI also showed similar hot spots

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compared with those observed with PET. Widhalm et al. [49] showed in a study of 32 patients using co-registration of MRS and MET PET that areas of positive MRS and PET for anaplasia overlapped  50% in 18/21 cases and <50% in 3/21 cases. MRI and PET appear to complement each other in the characterization of tumor tissue, contributing to image guided biopsy. The question remains whether hybrid PET/MRI will be able to enhance the characterization of tumor heterogeneity further compared with the co-registration of separate MRI and PET examinations.

Treatment planning In PET, measuring the uptake of amino acids by using either MET or FET has been shown to be a more reliable in brain tumors compared with F-18 FDG [28, 37]. Studies that fuse MRI and MET-PET images have shown that MET-PET may delineate areas of active tumor not apparent at contrast-enhanced MRI [52, 53]. Tsien et al. [52] has shown that the MET-PET uptake extended beyond the gadolinium-enhanced MRI target volume in 22 of 32 patients that had positive pre-treatment MET-PET findings, and that the area of increased MET uptake was visible 0.8 to 3 cm beyond the T1 contrast enhancement in 69% of cases [52]. FLT PET, which is known to be actively taken up into dividing cells, has an excellent lesion-to-background ratio, and studies measuring FLT uptake have shown that it correlates well with tissue markers of proliferation. It has been shown however that FLT could underestimate the extent of the tumors in half of the cases, even if areas of

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increased FLT metabolism were larger than those visualized at MRI when using imageguided biopsies [54]. FET-PET and MRI have been correlated for gross tumor volume (GTV) delineation. The size and geometric location of the GTVs, as defined by the biological tumor volumes, were different in a majority of the 17 evaluated patients [55]. Recently, other authors have proposed to integrate FET PET for target volume definition as part of the contouring process to avoid larger incongruence between anatomic and biological imaging techniques [56]. Retrospective co-registration of PET and functional MR images (e.g. perfusion and diffusion maps) using mutual anatomic information is challenging and may be prone to inaccuracy due to the lack of appropriate anatomical landmarks. Consequently, the accuracy of multi-parametric data analysis based on image co-registration would be suboptimal, rendered inadequate for treatment planning. Hybrid PET/MRI on the other hand provides excellent image registration and seems most appropriate for guiding treatment planning. Potentially, tumor delineation obtained through hybrid PET/MRI will be able to guide the boost for dose painting as well [57]. The combined use of FET PET with MRI, particularly BOLD-MRI, may be helpful in correlating the extent of tumor with the mapping of eloquent cortex, thus, contributing to improved surgical outcome. As technology advances, it will become increasingly feasible to integrate multi-parameter PET/MRI into the pre-treatment planning.

Response to therapy assessment for clinical trials

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The assessment of treatment response is different depending on the situation. Standard of care is tailored for patient management. Response assessment for clinical trials uses strict predetermined definitions of response. In early phase clinical trial where “proof on concept” is tested the definition of response will typically be very different from that used for a phase 3, registrational, multicenter, blinded trial. Because patients with uncommon tumors need to be drawn from a wide geographic area, the technical demands of imaging need to be minimized. A lowest common denominator approach is used so that patient data from time point to time point can be pooled with that of other patients. For this reason Macdonald Criteria [58], the imaging component of which are based entirely on bidimensional measurement of enhancing tumor size were the standard for approximately 20 years. Under this system, a decrease in enhancing area by 50% or more was considered a partial response (PR) and an increase in area of at least 25% (or a new lesion) was defined as progressive disease (PD). In 2010, Patrick Wen et al. [59] published a revision of these entitled Response Assessment in Neuro-oncology (RANO) which introduced evaluation of the nonenhancing tumor as seen on FLAIR as a criterion for progressive disease (PD) but still relied predominantly on bidimensional measurement of enhancement, using the same thresholds. These are likely to be revised, albeit slowly, allowing for universality of technique. In contrast to this, early phase trials are very suited to PET-MRI. In this setting, a new agent that has unknown efficacy for a particular indication, is tested for some form of favorable effect, decreased FDG uptake, decreased CBV, change in diffusivity. Having demonstrated some sort of effect, the therapeutic agent can then be further investigated with the costly randomized trials.

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The limits of morphologic MRI in treatment response assessment are well known. For example, in patients treated with Avastin (bevacizumab), a humanized monoclonal antibody against vascular endothelial growth factor combined with irinotecan [60], the rapid normalization of tumor vasculature seen as initial disappearance of contrast enhancement and surrounding vasogenic edema may be falsely regarded as tumor response, which eventually reverse when the drugs are discontinued. As a solution, multi-parametric PET/MRI may serve best as surrogate end point for trials, which can be used to reliably to distinguish patients who will respond favorably to therapy from those who will not. Recent literature suggests a potential role of dynamic FET-PET in predicting treatment failure to bevacizumab and irinotecan in patients with recurrent malignant gliomas, and FET-PET combined with MRI made significant contribution to clinical management in these patients [61]. In a prospective study of 19 patients treated with bevacizumab and irinotecan for recurrent gliomas, Chen at al. [38] showed that responders, defined as 25% or more interval decrease in SUV, survived 3 times as long as non-responders (10.8 vs 3.4 months) and concluded that FLT PET was a better predictor of overall survival compared with MRI. Although FLT has been successfully used for early response to therapy assessment [62, 63], the uptake mechanism and specifically, the component of tracer transport into the cell vs. metabolic trapping is not well understood [62, 64]. Hybrid imaging combining FLT PET with permeability parameters of functional MRI may help contribute to a better understanding of FLT PET uptake mechanism. The dynamic heterogeneity of high-grade gliomas reflects the complexity of the underlying genotype, which changes over time, beginning very early in response to

26 

chemo-radiation. Delivering boost doses selectively to the highly aggressive areas of high-grade gliomas may help overcome radio-resistance. However, as conventional radiotherapy planning is anatomically defined and tumor morphology remains has not changed much during the early course of treatment, an early assessment the radiotherapy, e.g. within 3-4 weeks of chemo-radiation, could also be a difficult task. The current trend is to combine imaging as an integrated multimodality technique. Thus, the use of hybrid PET/MRI represents a unique opportunity to assess chemo-radiation early on. As a gold standard for CBF, a study with oxygen-15 water may complement the perfusion measurements using quantitative MRI techniques. For example, DCE-MRI is an acceptable marker of perfusion, but perfusion depends on several factors including the permeability of the capillary bed, surface area of the capillary bed, CBF and CBV [65]; it is therefore difficult to determine which of these factors is or are changing during the course of a therapy. Hybrid PET/MRI will allow unique opportunities for cross validation of multi-parametric imaging and the comprehensive understanding of perfusion environment within the brain tumors. In this regard, a PET/MRI system could be powerful in enabling the study of fundamental physiology of CBV, CBF, metabolic rate of oxygen and oxygen extraction fraction across imaging modalities. Malignant gliomas often show areas with hypoxic tissue, which may be associated with radiotherapy resistance. There will be great opportunities to investigate to correlate hypoxia at PET such as FMISO with the measurements of neovascularization in tumors using functional MRI in clinical trials [47, 66]. In this context, new PET radiotracers binding to integrins, such as RGD peptides [67], may serve as a marker for neovascularization and hold the potential to be used in combination with functional MRI.

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Identifying active tumor after treatment Radiation therapy is an integral part for the treatment of gliomas having shown to increase median overall survival. Radiation treatment is not without risk however, and is associated with radiation injury. Difficulties in differentiating recurrence from radiation injury may complicate the patient care. Pseudoprogression and radiation necrosis are seen in 20-47% of cases and represent the typical pitfalls of false positive interpretation of anatomical and molecular imaging [68]. Nearly one-half of high grade glioma patients will develop increased enhancement and edema suspicious for progressive disease on the first MRI following the completing standard of care radiotherapy. Approximately onehalf of these cases, if followed with no further treatment will resolve spontaneously and therefore are considered “pseudoprogression.” This phenomenon has been more frequently associated with tumor marker O6-methylguanine–DNA methyltransferase (MGMT) promoter methylation and even hypothesized to be a sign of tumoricidal efficacy [69]. Considering these factors, RANO criteria [59] explicitly single out this period of high risk of up to 12 weeks following completion of radiation before the MRI diagnosis of tumor recurrence within the high dose radiation region is considered reliable and have recommended cautious observation with monthly scanning during this period (assuming clinical stability). Increasing evidence suggests that various advanced imaging methods, are capable of distinguishing active tumors from pseudoprogression and radiation necrosis (Fig. 4) in that active tumors usually show high rCBV (particularly high rCBV ratio compared with

28 

normal brain when corrected for leakage with preloading dose and baseline subtraction). Fink et al. [70] found a mean ratio of 3.62 ± 0.65 for progressing tumor and 1.31 ± 0.5 for postradiation change. DCE-T1 pMRI has also shown promise with rapid enhancement being typical of progressive disease from tumor (Fig. 5). Narang et al. [71] used the maximum slope of the initial vascular phase (MSIVP) to distinguish radiation change (mean 8.06 signal/sec) from recurrent/progressive tumor (mean 15.78 signal/sec) and found normalized MSIVP to have 95% sensitivity and 78% specificity for radiation change (Fig. 4). Furthermore, on MRS, active tumors typically display high levels of choline [72-74] – Fig. 2. A study in 26 adults with glioma showed that MRS and perfusion MRI were more accurate than MRI and FDG–PET for discriminating tumor recurrence, grade increase and radiation necrosis [75]. The combination of multiple imaging modalities has been suggested to be more powerful than a single modality approach for differentiating between treatment necrosis and tumor recurrence (Fig. 6). Floeth et al. [76] reported that the accuracy to detect tumor recurrence increased from 68% to 97% when MRI was used in combination with FET-PET and MRS. Insert Fig. 6

Pediatric neuro-oncology Patient exposure to radiation from radiotracer administration and ionizing radiation from CT is a major concern in pediatric care because of the risk of developing secondary cancer [77, 78]. The survival of children with cancer has increased dramatically over the past decades. Therefore, the development of secondary cancers is subject of increasing

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concern and it is desirable to minimize the radiation exposure to children. The possibility to substitute a CT examination with an MRI examination is a major benefit in children [79]. In addition, integrated PET/MRI clearly provides the benefit of a one-stop-shop examination and helps cutting imaging time, improving patient compliance and reducing sedation time for the examination. Advanced MRI plays an important role in aiding the diagnosis and management of children with brain tumors. Studies have shown potential of MRS in characterizing cerebellar tumor types (pilocytic astrocytoma, medulloblastoma and ependymoma) [80]. Quantitative measurements using either DCE- or DSC-MRI may be challenging in children [81]. ASL does not require injection of contrast agent and therefore has an appeal in children [82]. Regarding PET, only a few clinical trials are available in children with brain tumors. The assessment of tumor grading with amino acids has been found to be less reliable in children than in adults [83]. Counterintuitively, the glucose metabolism in low-grade tumors such as pilocytic astrocytomas and gangliogliomas may be high whereas uptake may be low in a high-grade medulloblastoma [83]. Similar to glucose metabolism, the amino acid uptake may overlap broadly between low-grade and high-grade tumors [84]. Pirotte et al. [85] evaluated the impact of PET in 55 pediatric patients with incidentally diagnosed brain lesions and imaged 13 children with FDG PET and 42 children with MET PET. PET and MR images were then assessed together. The authors found a high sensitivity and specificity of PET for brain tumors. PET was able to contribute to the selection of the appropriate treatment strategy (surgery vs. conservative treatment) compared with MRI. Overall, the surgical risk of treating non-neoplastic lesions was

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reduced, and the correct decision for surgical treatment in a malignant lesion was improved. Combined with MRI, the potential of amino acids PET to determine the site of stereotactic biopsy or for image-guided surgical resection of infiltrative low-grade brain tumors has been demonstrated in children [86]. The presence of amino acid uptake early after surgery would indicate residual tumor when findings at MRI were ambiguous [87]. Comparative studies are however required prior to adopting PET/MR imaging in routine pediatric oncology. It is important to define specific acquisition protocols for specific time points of the disease for each indication to achieve the optimal imaging outcome and to know when to perform MRI with functional imaging alone and when to add PET scanning.

ADVANTAGES OF HYBRID PET/MRI x

The combination of functional MRI and PET in an integrated PET/MRI scanner will help resolve the diagnostic shortcomings of MRI and PET alone.

x

The functional information from PET can be improved upon by the inherent spatial registration of anatomical MRI. Moreover, cross-validations of functional MRI with PET will extend our understanding of tumor phenotype, microenvironment and metabolism. Potentially, the joint findings from hybrid PET/MRI may have considerable impact in aspects of patient care ranging from diagnosis, biopsy guidance to treatment planning and response to therapy evaluation of brain tumors.

x

Hybrid PET/MRI is expected to be more quantitative and accurate than either method alone. Certain brain tumors or aspects of brain tumor may be best

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characterized with hybrid PET/MRI. These advantages may be mainly due to the benefits of multi-parametric cross-validation, allowing close temporal and spatial correlation between MRI and PET parameters. x

Many new therapies are currently entering development as a result of increased understanding of the molecular and genetic pathways controlling cellular function. Hybrid PET/MRI may play in important role in the drug development and validation, providing accurate in vivo correlation of structural and functional components of cancer biology.

x

In pediatric patients, the switch from PET/CT scanning to PET/MRI scanning has significant advantages, not at least due to the reduction in radiation exposure and the enhanced soft tissue contrast gained with the MRI.

x

As a one-stop-shop, hybrid PET/MRI helps save time for the patients compared to the combination of single modalities, acquired at different time and potentially dates. This will have also great impact on patient compliance and medical care.

CHALLENGES FOR PET/MRI The advantages of PET/MRI are clear, but a lot challenges remain in terms of cost, acquisition protocol, image analysis and interpretation.

Acquisition protocols We have performed more than 200 PET/MRI examinations at our institution (over 50 of the brain) and gained valuable experience in adopting this novel technology for both

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research and patient care. At our institution, our brain tumor protocol includes standard T1, T2, FLAIR, DWI, and contrast enhanced T1-weighted imaging. In addition, we obtain pMRI consisting of a combination of a 5 cc Gadolinium injection for DCE-T1 weighted pMRI lasting approximately 5 minutes, followed by DSC pMRI using 15 cc. pMRI data is integrated off-line using commercially available perfusion software (Olea Medical Solutions Inc. 1955 Massachusetts Avenue, Suite 12 & 14, Cambridge, MA 02140). DCE-T1 KTRANS maps and DSC rCBV-corrected pMRI maps are routinely sent to PACS and in addition, the images are reviewed off-line by the neuroradiologist to interrogate particular regions of interest. DCE-T1 and DSC signal intensity (SI)-time curves are then reviewed. MRS is tailored to the lesion in question but most typically consists of multi-voxel and single-voxel techniques as well as chemical shift imaging. Finally, FDG-PET activity is coregistered with the MRI images and two radiologists, one from neuroradiology and one from nuclear medicine review the integrated studies.

Image analysis and interpretation With the expected complexity of multi-parametric data, the challenges of data reconstruction and analysis as well as storage grow significantly. Various software vendors are working on solutions to optimize image analysis and display. Attention to study design, implementation, and image analysis are required to achieve maximal benefits out of hybrid PET/MRI. Scanning parameters should be standardized to allow

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for accurate and reproducible quantification, and the selected parameters should ideally be achieved across PET/MRI platforms to allow meaningful comparison of results.

SUMMARY We envision a significant role for multi-parametric PET/MRI in neuro-oncology, both clinical and research. This applies to the initial diagnosis and characterization of brain tumors. In addition, as patient survival increases with the advent of new treatment techniques and regimen, hybrid PET/MRI will have many opportunities to demonstrate its strengths in the evaluation of treatment response and differential diagnosis of remaining viable tumor and post-treatment inflammation. If PET/MRI performs well compared with MRI, PET/CT or both using image co-registration, and considering the steady improvement hardware and software, there is no doubt that PET/MRI will find its permanent place in functional neuroimaging. Acknowledgements: We wish to thank Andrew Sher, Christian Rubbert, and Jose L. Vercher-Conejero, MD

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Figure 1 A-C Post-biopsy baseline, A) Gd-T1, B) FLAIR, C) ADC; D-F 6 month F-U, D) Gd-T1, E) FLAIR, F) ADC: Patient with nonenhancing left opercular FLAIR hyperintense white matter lesion consistent with fibrillary astrocytoma (WHO Grade II) (A, B). Increased diffusivity on ADC typical of low-grade glioma (long arrow, C). Several months after radiation therapy, follow-up MRI demonstrated new enhancing left nodule (D) with progressive abnormal FLAIR signal (E) and associated hypointensity on ADC indicating diffusion restriction in the region corresponding with the enhancing nodule (short arrow in F). Associated diffusion restriction is often seen with high grade (hypercellular) neoplasm, although second peak with increased diffusivity can be seen with frankly necrotic regions of tumor (not shown).  

Figure 2: MRS of same patient as Figure 1. Single voxel spectrum from lesion (A) displays elevated absolute choline (Cho) in comparison with control region of normal hemisphere (B). Lesion also displays decreased NAA and Cho/NAA ratio of 3.6. Spectroscopy findings are typical of high-grade neoplasm.  

Figure 3: A-C 6 month F-U, A) Gd-T1, B) 18F-FDG PET, C) 18F-FDG PET-MR; D-F 8 month F-U, D) Gd-T1, E) DSC rCBV map, F) DCE-T1 Ktransmap: Same patient as in Figure 1 & 2 with enhancing left opercular nodule (A) which displays hypermetabolism on PET (short arrow in B) & PET-MR (C) on a background of radiation induced dimished FDG uptake (long arrow in B). Interval progressive enhancement of left frontal lesion (D). DSC perfusion (rCBV) map with associated increased perfusion (red area in E) At this time the corrected rCBV measured 10.8 mL/100 gm brain compared to 1.9 in the contralateral normal white matter (5.7:1 ratio) . DCE permeability Ktrans map with increased permeability (F). FDG avidity, increased perfusion, and permeability are typical of high grade neoplasm. Subsequent biopsy confirmed that tumor had upgraded to anaplastic astrocytoma (WHO Grade III).

Figure 4:

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A) Gd-T1, B) 18F-FDG PET-MR, C) 18F-FDG PET, D) DSC pMRI rCBV map, E) DCE T1 Time - concentration curve, F) Gd-T1 at follow-up. Enhancement in the right frontal centrum semiovale and periventricular white matter (short arrow in A) in this patient with prior history of right frontal oligodendroglioma (WHO Grade II) s/p resection and chemoradiation therapy. Diffusely diminished cortical FDG activity in the right frontal lobe related to radiation change (B, long arrow in C). No significant FDG uptake in the ill-defined enhancing lesion (C, faint hyperintensity in B due to overlay of Gd enhancement). Lack of FDG activity matches area lacking significantly increased perfusion (D) with low rCBV ratio compared to the contralateral normal appearing white matter with slow enhancement on the time - concentration DCE-T1 curve (red curve in E) compared with control white matter (green curve in E). Findings are consistent with radiation necrosis. Patient was treated with hyperbaric oxygen and follow-up MRI 10 months later (F) demonstrates near complete resolution of ill-defined enhancement. 

Figure 5: A) Gd-T1, B) 18F-FDG PET, C) 18F-FDG PET-MR, D) DSC pMRI rCBV map, E) DCE-T1 enhancement time - concentration curve Patient with prior right occipital glioblastoma (WHO Grade IV) status post resection and chemoradiation therapy with new ill-defined heterogeneous enhancement along margins of the resection cavity (A). FDG PET (B) and fused PET/MR images (C), demonstrate areas of hypermetabolism laterally, representing viable neoplasm (long arrow in B) with relative photopenia representing predominantly radiation necrosis (short arrow in B). DSC rCBV map demonstrates correlation with PET with a similar pattern of increased perfusion (white arrow in D). DCE-T1 time – concentration curve displays steep upslope (E).

Figure 6: Patient with metastatic breast adenocarcinoma with prior gamma knife radiosurgery with Gd enhancing lesions of cerebellar vermis (A-E) and right occipital lobe (F-I)/ A) Gd-T1, B) DSC pMRI rCBV map, C) DCE-T1 Ktransmap, D) 18F-FDG PET, E) 18F-FDG PET-MR, F) Gd-T1, G) DSC pMRI rCBV map, H) 18F-FDG PET, I) 18FFDG PET-MR.

The vermian nodule (A-E) demonstrates increased rCBV (white arrow in B) and increased permeability (orange arrow in C) with FDG hypermetabolism within the right aspect of the lesion (arrow in D, E), consistent with of neoplasm. Subsequent surgical resection yielded metastatic adenocarcinoma.

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The right occipital nodule (F-I) is poorly characterized on the rCBV (G) map due to juxtacortical location. PET/MR shows corresponding focal cortical photopenia (arrows in H,I). PET/MR findings are more suggestive of radiation change. Stability over time was demonstrated.  

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