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Purpose: To examine whether the rate of change in maximum 18 F-FDOPA PET uptake and the rate of change in non-enhancing tumor volume could predict malignant transformation and residual overall survival (OS) in low grade glioma (LGG) patients who received serial 18 F-FDOPA PET and MRI scans., Methods: 27 LGG patients with ≥ 2 18 F-FDOPA PET and MRI scans between 2003 and 2016 were included. The rate of change in FLAIR volume (uL/day) and maximum normalized 18 F-FDOPA specific uptake value (nSUV max /month), were compared between histological and molecular subtypes. General linear models (GLMs) were used to integrate clinical information with MR-PET measurements to predict malignant transformation. Cox univariate and multivariable regression analyses were performed to identify imaging and clinical risk factors related to OS., Results: A GLM using patient age, treatment, the rate of change in FLAIR and 18 F-FDOPA nSUV max could predict malignant transformation with > 67% sensitivity and specificity (AUC = 0.7556, P = 0.0248). A significant association was observed between OS and continuous rates of change in PET uptake (HR = 1.0212, P = 0.0034). Cox multivariable analysis confirmed that continuous measures of the rate of change in PET uptake was an independent predictor of OS (HR = 1.0242, P = 0.0033); however, stratification of patients based on increasing or decreasing rate of change in FLAIR (HR = 2.220, P = 0.025), PET uptake (HR = 2.148, P = 0.0311), or both FLAIR and PET (HR = 2.354, P = 0.0135) predicted OS., Conclusions: The change in maximum normalized 18 F-FDOPA PET uptake, with or without clinical information and rate of change in tumor volume, may be useful for predicting the risk of malignant transformation and estimating residual survival in patients with LGG.

Background and Purpose: Post-radiation treatment effects (pseudoprogression/radionecrosis) may bias MRI-based tumor response evaluation. To understand these changes specifically after high doses of radiotherapy, we analyzed MRIs of patients enrolled in the INTRAGO study (NCT02104882), a phase I/II dose-escalation trial of intraoperative radiotherapy (20-40 Gy) in glioblastoma., Methods: INTRAGO patients were evaluated and compared to control patients who received standard therapy with focus on contrast enhancement patterns/volume, T2 lesion volume, and mean rCBV., Results: Overall, 11/15 (73.3%) INTRAGO patients (median age 60 years) were included. Distant failure was observed in 7/11 (63.6%) patients, local tumor recurrence in one patient (9.1%). On the first follow-up MRI all but one patient demonstrated enhancement of varying patterns around the resection cavity which were: in 2/11 (18.2%) patients thin and linear, in 7/11 (63.6%) combined linear and nodular, and in 1/11 (9.1%) voluminous, indistinct, and mesh-like. In the course of treatment, most patients developed the latter two patterns (8/11 [72.7%]). INTRAGO patients demonstrated more often combined linear and nodular and/or voluminous, indistinct, mesh-like components (8/11 [72.7%]) in comparison to control patients (3/12 [25%], P = 0.02). INTRAGO patients demonstrated significantly increasing enhancing lesion (P = 0.001) and T2 lesion volumes (P < 0.001) in the longitudinal non-parametric analysis in comparison to the control group. rCBV showed no significant differences between both groups., Conclusions: High doses of radiotherapy to the tumor cavity result in more pronounced enhancement patterns/volumes and T2 lesion volumes. These results will be useful for the response evaluation of patients exposed to high doses of radiotherapy in future studies., (Copyright © 2019 Elsevier Masson SAS. All rights reserved.)

The advent of immunotherapy using immune checkpoint inhibitors (ICIs) and targeted therapy (TT) has dramatically improved the prognosis of various cancer types. However, following ICI therapy or TT-either alone (especially ICI) or in combination with radiotherapy-imaging findings on anatomical contrast-enhanced MRI can be unpredictable and highly variable, and are often difficult to interpret regarding treatment response and outcome. This review aims at summarizing the imaging challenges related to TT and ICI monotherapy as well as combined with radiotherapy in patients with brain metastases, and to give an overview on advanced imaging techniques which potentially overcome some of these imaging challenges. Currently, major evidence suggests that imaging parameters especially derived from amino acid PET, perfusion-/diffusion-weighted MRI, or MR spectroscopy may provide valuable additional information for the differentiation of treatment-induced changes from brain metastases recurrence and the evaluation of treatment response., (© The Author(s) 2019. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Recent advancements in neuroimaging and machine learning have significantly improved our ability to diagnose and categorize isocitrate dehydrogenase (IDH)-wildtype glioblastoma, a disease characterized by notable tumoral heterogeneity, which is crucial for effective treatment. Neuroimaging techniques, such as diffusion tensor imaging and magnetic resonance radiomics, provide noninvasive insights into tumor infiltration patterns and metabolic profiles, aiding in accurate diagnosis and prognostication. Machine learning algorithms further enhance glioblastoma characterization by identifying distinct imaging patterns and features, facilitating precise diagnoses and treatment planning. Integration of these technologies allows for the development of image-based biomarkers, potentially reducing the need for invasive biopsy procedures and enabling personalized therapy targeting specific pro-tumoral signaling pathways and resistance mechanisms. Although significant progress has been made, ongoing innovation is essential to address remaining challenges and further improve these methodologies. Future directions should focus on refining machine learning models, integrating emerging imaging techniques, and elucidating the complex interplay between imaging features and underlying molecular processes. This review highlights the pivotal role of neuroimaging and machine learning in glioblastoma research, offering invaluable noninvasive tools for diagnosis, prognosis prediction, and treatment planning, ultimately improving patient outcomes. These advances in the field promise to usher in a new era in the understanding and classification of IDH-wildtype glioblastoma., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the Congress of Neurological Surgeons.)

Background: Isocitrate dehydrogenase 1 (IDH1) mutant gliomas are thought to have distinct metabolic characteristics, including a blunted response to hypoxia and lower glycolytic flux. We hypothesized that non-invasive quantification of abnormal metabolic behavior in human IDH1 mutant gliomas could be performed using a new pH- and oxygen-sensitive molecular MRI technique., Methods: Simultaneous pH- and oxygen-sensitive MRI was obtained at 3T using amine CEST-SAGE-EPI. The pH-dependent measure of the magnetization transfer ratio asymmetry (MTRasym) at 3 ppm and oxygen-sensitive measure of R2' were quantified in 90 patients with gliomas. Additionally, stereotactic, image-guided biopsies were performed in 20 patients for a total of 52 samples. The association between imaging measurements and hypoxia-inducible factor 1 alpha (HIF1α) expression was identified using Pearson correlation analysis., Results: IDH1 mutant gliomas exhibited significantly lower MTRasym at 3 ppm, R2', and MTRasymxR2' (P = 0.007, P = 0.003, and P = 0.001, respectively). MTRasymxR2' could identify IDH1 mutant gliomas with a high sensitivity (81.0%) and specificity (81.3%). HIF1α was positively correlated with MTRasym at 3 ppm, R2' and MTRasymxR2' in IDH1 wild type (r = 0.610, P = 0.003; r = 0.667, P = 0.008; r = 0.635, P = 0.006), but only MTRasymxR2' in IDH1 mutant gliomas (r = 0.727, P = 0.039)., Conclusions: IDH1 mutant gliomas have distinct metabolic and microenvironment characteristics compared with wild type gliomas. An imaging biomarker combining tumor acidity and hypoxia (MTRasymxR2') can differentiate IDH1 mutation status and is correlated with tumor acidity and hypoxia., (© The Author(s) 2019. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background and Purpose: Acidification of the tumor microenvironment from abnormal metabolism along with angiogenesis to meet metabolic demands are both hallmarks of malignant brain tumors; however, the interdependency of tumor acidity and vascularity has not been explored. Therefore, our aim was to investigate the association between pH-sensitive amine chemical exchange saturation transfer echoplanar imaging (CEST-EPI) and relative cerebral blood volume (CBV) measurements obtained from dynamic susceptibility contrast (DSC) perfusion MRI in patients with gliomas., Materials and Methods: In this retrospective study, 90 patients with histologically confirmed gliomas were scanned between 2015 and 2018 (median age, 50.3 years; male/female ratio = 59:31). pH-weighting was obtained using chemical exchange saturation transfer echo-planar imaging estimation of the magnetization transfer ratio asymmetry at 3 ppm, and CBV was estimated using DSC-MR imaging. The voxelwise correlation and patient-wise median value correlation between the magnetization transfer ratio asymmetry at 3 ppm and CBV within T2-hyperintense lesions and contrast-enhancing lesions were evaluated using the Pearson correlation analysis., Results: General colocalization of elevated perfusion and high acidity was observed in tumors, with local intratumor heterogeneity. For patient-wise analysis, median CBV and magnetization transfer ratio asymmetry at 3 ppm within T2-hyperintense lesions were significantly correlated ( R = 0.3180, P = .002), but not in areas of contrast enhancement ( P = .52). The positive correlation in T2-hyperintense lesions remained within high-grade gliomas ( R = 0.4128, P = .001) and in isocitrate dehydrogenase wild-type gliomas ( R = 0.4300, P = .002), but not in World Health Organization II or in isocitrate dehydrogenase mutant tumors. Both magnetization transfer ratio asymmetry at 3 ppm and the voxelwise correlation between magnetization transfer ratio asymmetry and CBV were higher in high-grade gliomas compared with low-grade gliomas in T2-hyperintense tumors (magnetization transfer ratio asymmetry, P = .02 ; Pearson correlation, P = .01). The same trend held when comparing isocitrate dehydrogenase wild-type gliomas and isocitrate dehydrogenase mutant gliomas (magnetization transfer ratio asymmetry, P = .04; Pearson correlation, P = .01)., Conclusions: A positive linear correlation between CBV and acidity in areas of T2-hyperintense, nonenhancing tumor, but not enhancing tumor, was observed across patients. Local heterogeneity was observed within individual tumors., (© 2019 by American Journal of Neuroradiology.)

Purpose: The objective of the current study was to explore the efficacy of using pH-weighted amine CEST-EPI as a potential non-invasive imaging biomarker for treatment response and/or failure in recurrent GBM patients treated with bevacizumab., Method: A total of 11 patients with recurrent GBM treated with bevacizumab were included in this prospective study. CEST-EPI, perfusion MRI, and standardized anatomic MRI were obtained in patients before and after bevacizumab administration. CEST-EPI measures of magnetization transfer ratio asymmetry (MTR asym ) at 3 ppm were used for pH-weighted imaging contrast. Multiple measures were examined for their association with progression-free survival (PFS)., Result: Tumor acidity, measured with MTR asym at 3 ppm, was significantly reduced in both contrast enhancing and non-enhancing tumor after bevacizumab (p = 0.0002 and p < 0.00001, respectively). The reduction in tumor acidity in both contrast enhancing and non-enhancing tumor was linearly correlated with PFS (p = 0.044 and p = 0.00026, respectively). In 9 of the 11 patients, areas of residual acidity were localized to areas of tumor recurrence, typically around 2 months prior to radiographic progression. Univariate (p = 0.006) and multivariate Cox regression controlling for age (p = 0.009) both indicated that change in tumor acidity (ΔMTR asym at 3 ppm) was a significant predictor of PFS., Conclusions: This pilot study suggests pH-weighted amine CEST MRI may have value as a non-invasive, early imaging biomarker for bevacizumab treatment response and failure. Early decreases MTR asym at 3.0 ppm in recurrent GBM after bevacizumab may be associated with better PFS. Residual or emerging regions of acidity may colocalize to the site of tumor recurrence.

To evaluate the association between a vessel size index (VSI MRI ) derived from dynamic susceptibility contrast (DSC) perfusion imaging using a custom spin-and-gradient echo echoplanar imaging (SAGE-EPI) sequence and quantitative estimates of vessel morphometry based on immunohistochemistry from image-guided biopsy samples. The current study evaluated both relative cerebral blood volume (rCBV) and VSI MRI in eleven patients with high-grade glioma (7 WHO grade III and 4 WHO grade IV). Following 26 MRI-guided glioma biopsies in these 11 patients, we evaluated tissue morphometry, including vessel density and average radius, using an automated procedure based on the endothelial cell marker CD31 to highlight tumor vasculature. Measures of rCBV and VSI MRI were then compared to histological measures. We demonstrate good agreement between VSI measured by MRI and histology; VSI MRI  = 13.67 μm and VSI Histology  = 12.60 μm, with slight overestimation of VSI MRI in grade III patients compared to histology. rCBV showed a moderate but significant correlation with vessel density (r = 0.42, p = 0.03), and a correlation was also observed between VSI MRI and VSI Histology (r = 0.49, p = 0.01). The current study supports the hypothesis that vessel size measures using MRI accurately reflect vessel caliber within high-grade gliomas, while traditional measures of rCBV are correlated with vessel density and not vessel caliber.

Objectives: To determine whether repeated administration of the macrocyclic gadolinium-based contrast agent (GBCA) gadobutrol in children is associated with T1-weighted hyperintensity within the dentate nucleus, an imaging surrogate for gadolinium deposition., Methods: With institutional review board approval, we identified a cohort of eight patients aged 18 years or younger who underwent at least four gadobutrol-enhanced magnetic resonance imaging (MRI) examinations of the brain from 2013 to 2017. For comparison, we identified a cohort of 19 patients who underwent at least four gadopentetate dimeglumine-enhanced MRI examinations. For each examination, both dentate nuclei were contoured on unenhanced images; the mean dentate-to-pons signal intensity (DN-P SI) ratio was calculated. DN-P SI ratios from the first and last MRI exams were compared using Wilcoxon signed ranks tests and linear regression analyses., Results: In the gadobutrol cohort, there was no significant change in the mean DN-P SI ratio from the first to the last scan (1.02 vs 1.02, p = 1.00). In the gadopentetate dimeglumine cohort, there was a significant increase in the mean DN-P SI ratio from the first to the last scan (1.05 vs 1.13, p = 0.003). After controlling for potentially confounding variables, the change in DN-P SI ratio from the first to the last scan was significantly lower for patients in the gadobutrol group than in the gadopentetate dimeglumine group (β = -0.08, p = 0.04)., Conclusions: Repeated administration of the macrocyclic GBCA gadobutrol in children was not associated with T1-weighted dentate hyperintensity, while the repeated administration of the linear GBCA gadopentetate dimeglumine was associated with T1-weighted dentate hyperintensity, presumably due to gadolinium deposition., Key Points: • Gadolinium-based contrast agents are routinely used in magnetic resonance imaging. • Repeated administration of the macrocyclic agent gadobutrol in children was not associated with T1-weighted dentate hyperintensity.

Purpose: To introduce a new pH-sensitive and oxygen-sensitive MRI technique using amine proton CEST echo spin-and-gradient echo (SAGE) EPI (CEST-SAGE-EPI)., Methods: pH-weighting was obtained using CEST estimations of magnetization transfer ratio asymmetry (MTR asym ) at 3 ppm, and oxygen-weighting was obtained using R2' measurements. Glutamine concentration, pH, and relaxation rates were varied in phantoms to validate simulations and estimate relaxation rates. The values of MTR asym and R2' in normal-appearing white matter, T 2 hyperintensity, contrast enhancement, and macroscopic necrosis were measured in 47 gliomas., Results: Simulation and phantom results confirmed an increase in MTR asym with decreasing pH. The CEST-SAGE-EPI estimates of R 2 , R2*, and R2' varied linearly with gadolinium diethylenetriamine penta-acetic acid concentration (R 2  = 6.2 mM -1 ·sec -1 and R2* = 6.9 mM -1 ·sec -1 ). The CEST-SAGE-EPI and Carr-Purcell-Meiboom-Gill estimates of R 2 (R 2  = 0.9943) and multi-echo gradient-echo estimates of R2* (R 2  = 0.9727) were highly correlated. T 2 lesions had lower R2' and higher MTR asym compared with normal-appearing white matter, suggesting lower hypoxia and high acidity, whereas contrast-enhancement tumor regions had elevated R2' and MTR asym , indicating high hypoxia and acidity., Conclusion: The CEST-SAGE-EPI technique provides simultaneous pH-sensitive and oxygen-sensitive image contrasts for evaluation of the brain tumor microenvironment. Advantages include fast whole-brain acquisition, in-line B 0 correction, and simultaneous estimation of CEST effects, R 2 , R2*, and R2' at 3 T., (© 2018 International Society for Magnetic Resonance in Medicine.)

Background: In the current study we used contrast-enhanced T1 subtraction maps to test whether early changes in enhancing tumor volume are prognostic for overall survival (OS) in newly diagnosed glioblastoma (GBM) patients treated with chemoradiation with or without bevacizumab (BV)., Methods: Seven hundred ninety-eight patients (404 BV and 394 placebo) with newly diagnosed GBM in the AVAglio trial (NCT00943826) had baseline MRI scans available, while 337 BV-treated and 269 placebo-treated patients had >4 MRI scans for response evaluation. The volume of contrast-enhancing tumor was quantified and used for subsequent analyses., Results: A decrease in tumor volume during chemoradiation was associated with a longer OS in the placebo group (hazard ratio [HR] = 1.578, P < 0.0001) but not BV-treated group (HR = 1.135, P = 0.4889). Results showed a higher OS in patients on the placebo arm with a sustained decrease in tumor volume using a post-chemoradiation baseline (HR = 1.692, P = 0.0005), and a trend toward longer OS was seen in BV-treated patients (HR = 1.264, P = 0.0724). Multivariable Cox regression confirmed that sustained response or stable disease was prognostic for OS (HR = 0.7509, P = 0.0127) when accounting for age (P = 0.0002), KPS (P = 0.1516), postsurgical tumor volume (P < 0.0001), O6-methylguanine-DNA methyltransferase status (P < 0.0001), and treatment type (P = 0.7637) using the post-chemoradiation baseline., Conclusions: The post-chemoradiation timepoint is a better baseline for evaluating efficacy in newly diagnosed GBM. Early progression during the maintenance phase is consequential in predicting OS, supporting the use of progression-free survival rates as a meaningful surrogate for GBM.

Purpose: To quantify changes and prognostic value of diffusion MRI measurements obtained using mono-exponential, diffusion kurtosis imaging (DKI) and stretched exponential (SE) models prior and after chemoradiation in newly diagnosed glioblastoma (GBM)., Methods: Diffusion-weighted images (DWIs) were acquired in twenty-three patients following surgery, prior chemoradiation and within 7 days following completion of treatment, using b-values ranging from 0 to 5000s/mm 2 . Mono-exponential diffusion (apparent diffusion coefficient: ADC), isotropic (non-directional) DKI model with apparent diffusivity (Dapp) and kurtosis (Kapp) estimates as well as SE model with distributed-diffusion coefficient (DDC) and mean intra-voxel heterogeneity (α) were computed for all patients prior and after chemoradiation. Median values were calculated for normal appearing white matter (NAWM) and contrast-enhancing tumor (CET). The magnitudes of diffusion change prior and after chemoradiation were used to predict overall survival (OS)., Results: Diffusivity in NAWM was consistent for all diffusion measures during chemoradiation, while diffusivity measurements (ADC, Dapp and DDC) within CET changed significantly. A strong positive correlation existed between ADC, Dapp, and DDC measurements prior to chemoradiation; however, this association was weak following chemoradiation, suggesting a more complex microstructural environment after cytotoxic therapy. When combined with baseline tumor volume and MGMT status, age and ADC changes added significant prognostic values, whereas more complex diffusion models did not show significant value in predicting OS., Conclusions: Despite increased tissue complexity following chemoradiation, advanced diffusion models have longer acquisition times, provide largely comparable measures of diffusivity, and do not appear to provide additional prognostic value compared to mono-exponential ADC maps.

Magnetic resonance imaging is integral to the care of patients with high-grade gliomas. Anatomic detail can be acquired with conventional structural imaging, but newer approaches also add capabilities to interrogate image-derived physiologic and molecular characteristics of central nervous system neoplasms. These advanced imaging techniques are increasingly employed to generate biomarkers that better reflect tumor burden and therapy response. The following is an overview of current strategies based on advanced magnetic resonance imaging that are used in the assessment of high-grade glioma patients with an emphasis on how novel imaging biomarkers can potentially advance patient care.

Amine chemical exchange saturation transfer (CEST) echoplanar imaging (EPI) provides unique pH and amino acid MRI contrast, enabling sensitive detection of altered microenvironment properties in various diseases. However, CEST contrast is sensitive to static magnetic field (B 0 ) inhomogeneities. Here we propose 2 new B 0 correction algorithms for use in correcting pH-weighted amine CEST EPI based on k-means clustering and Lorentzian fitting of CEST data: the iterative downsampling estimation using Lorentzian fitting and the 2-stage Lorentzian estimation with 4D polynomial fitting. Higher quality images of asymmetric magnetization transfer ratio (MTR asym ) at 3.0 ppm could be obtained with the proposed algorithms than with the existing B 0 correction methods. In particular, the proposed methods are shown to improve the intertissue consistency, interpatient consistency, and tumor region signal-to-noise ratio of MTR asym at 3.0 ppm images, with nonexcessive computation time., Competing Interests: Conflict of Interest: The authors have no conflict of interest to declare.

Background and Purpose: Our aim was to evaluate whether serial administration of the macrocyclic gadolinium-based contrast agent gadoteridol in children is associated with T1-weighted hyperintensity within the dentate nucleus, an imaging surrogate for gadolinium deposition., Materials and Methods: We identified a retrospective cohort of 10 patients younger than 18 years of age who underwent between 4 and 8 gadoteridol-enhanced MR imaging examinations of the brain from 2016 to 2017. For comparison, we identified a retrospective cohort of 9 pediatric patients who each underwent 6 gadodiamide-enhanced MR imaging examinations. For each examination, both dentate nuclei were contoured on unenhanced images and the mean dentate-to-pons signal intensity ratio was calculated. Dentate-to-pons signal intensity ratios from the first and last scans were compared using paired t tests., Results: In the gadoteridol group, there was no significant change in the mean dentate-to-pons signal intensity ratio from the first to the last scan (0.99 versus 0.99, P = .59). In the gadodiamide group, there was a significant increase in the mean dentate-to-pons signal intensity ratio from the first to the last scan (0.99 versus 1.10, P = .001)., Conclusions: Repeat administration of the macrocyclic gadolinium-based contrast agent gadoteridol in children was not associated with T1-weighted dentate hyperintensity, while the repeat administration of the linear gadolinium-based contrast agent gadodiamide was associated with T1-weighted dentate hyperintensity, presumably due to gadolinium deposition., (© 2018 by American Journal of Neuroradiology.)

Background: In the current study, we pooled imaging data in newly diagnosed glioblastoma (GBM) patients from international multicenter clinical trials, single institution databases, and multicenter clinical trial consortiums to identify the relationship between postoperative residual enhancing tumor volume and overall survival (OS)., Methods: Data from 1511 newly diagnosed GBM patients from 5 data sources were included in the current study: (i) a single institution database from UCLA (N = 398; Discovery); (ii) patients from the Ben and Cathy Ivy Foundation for Early Phase Clinical Trials Network Radiogenomics Database (N = 262 from 8 centers; Confirmation); (iii) the chemoradiation placebo arm from an international phase III trial (AVAglio; N = 394 from 120 locations in 23 countries; Validation); (iv) the experimental arm from AVAglio examining chemoradiation plus bevacizumab (N = 404 from 120 locations in 23 countries; Exploratory Set 1); and (v) an Alliance (N0874) phase I/II trial of vorinostat plus chemoradiation (N = 53; Exploratory Set 2). Postsurgical, residual enhancing disease was quantified using T1 subtraction maps. Multivariate Cox regression models were used to determine influence of clinical variables, O6-methylguanine-DNA methyltransferase (MGMT) status, and residual tumor volume on OS., Results: A log-linear relationship was observed between postoperative, residual enhancing tumor volume and OS in newly diagnosed GBM treated with standard chemoradiation. Postoperative tumor volume is a prognostic factor for OS (P < 0.01), regardless of therapy, age, and MGMT promoter methylation status., Conclusion: Postsurgical, residual contrast-enhancing disease significantly negatively influences survival in patients with newly diagnosed GBM treated with chemoradiation with or without concomitant experimental therapy.

Purpose: To assess the safety and efficacy of upfront treatment using bortezomib combined with standard radiation therapy (RT) and temozolomide (TMZ), followed by adjuvant bortezomib and TMZ for ≤24 cycles, in patients with newly diagnosed glioblastoma multiforme (GBM)., Methods and Materials: Twenty-four patients with newly diagnosed GBM were enrolled. The patients received standard external beam regional RT with concurrent TMZ beginning 3 to 6 weeks after surgery, followed by adjuvant TMZ and bortezomib for ≤24 cycles or until tumor progression. During RT, bortezomib was given at 1.3 mg/m 2 on days 1, 4, 8, 11, 29, 32, 36, and 39. After RT, bortezomib was given at 1.3 mg/m 2 on days 1, 4, 8, and 11 every 4 weeks., Results: No unexpected adverse events occurred from the addition of bortezomib. The efficacy analysis showed a median progression-free survival (PFS) of 6.2 months (95% confidence interval [CI] 3.7-8.8), with promising PFS rates at ≥18 months compared with historical norms (25.0% at 18 and 24 months; 16.7% at 30 months). In terms of overall survival (OS), the median OS was 19.1 months (95% CI 6.7-31.4), with improved OS rates at ≥12 months (87.5% at 12, 50.0% at 24, 34.1% at 36-60 months) compared with the historical norms. The median PFS was 24.7 months (95% CI 8.5-41.0) in 10 MGMT methylated and 5.1 months (95% CI 3.9-6.2) in 13 unmethylated patients. The estimated median OS was 61 months (95% CI upper bound not reached) in the methylated and 16.4 months (95% CI 11.8-21.0) in the unmethylated patients., Conclusions: The addition of bortezomib to current standard radiochemotherapy in newly diagnosed GBM patients was tolerable. The PFS and OS rates appeared promising, with more benefit to MGMT methylated patients. Further clinical investigation is warranted in a larger cohort of patients., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Magnetic resonance imaging (MRI) is the cornerstone for evaluating patients with brain masses such as primary and metastatic tumors. Important challenges in effectively detecting and diagnosing brain metastases and in accurately characterizing their subsequent response to treatment remain. These difficulties include discriminating metastases from potential mimics such as primary brain tumors and infection, detecting small metastases, and differentiating treatment response from tumor recurrence and progression. Optimal patient management could be benefited by improved and well-validated prognostic and predictive imaging markers, as well as early response markers to identify successful treatment prior to changes in tumor size. To address these fundamental needs, newer MRI techniques including diffusion and perfusion imaging, MR spectroscopy, and positron emission tomography (PET) tracers beyond traditionally used 18-fluorodeoxyglucose are the subject of extensive ongoing investigations, with several promising avenues of added value already identified. These newer techniques provide a wealth of physiologic and metabolic information that may supplement standard MR evaluation, by providing the ability to monitor and characterize cellularity, angiogenesis, perfusion, pH, hypoxia, metabolite concentrations, and other critical features of malignancy. This chapter reviews standard and advanced imaging of brain metastases provided by computed tomography, MRI, and amino acid PET, focusing on potential biomarkers that can serve as problem-solving tools in the clinical management of patients with brain metastases., (Copyright © 2018 Elsevier B.V. All rights reserved.)

DSC perfusion MR imaging in brain tumors requires a trade-off between spatial and temporal resolution, resulting in less spatial coverage to meet the temporal resolution requirements for accurate relative CBV estimation. DSC-MR imaging could potentially benefit from the advantages associated with simultaneous multi-slice imaging, including increased spatiotemporal resolution. In the current article, we demonstrate how simultaneous multi-slice EPI can be used to improve DSC-MR imaging spatiotemporal resolution in patients with glioblastoma., (© 2018 by American Journal of Neuroradiology.)

Purpose: Differentiating WHO grade I-III of meningioma by non-invasive imaging is challenging. This study investigated the potential of MR arterial spin labeling (ASL) to establish tumor grade in meningioma patients., Material and Methods: Pseudo-continuous ASL with 3D background suppressed gradient and spin echo (GRASE) was acquired on 54 patients with newly diagnosed or recurrent intracranial meningioma. Perfusion patterns characterized in CBF color maps were independently evaluated by three neuroradiologists blinded to patient history, and correlated with tumor grade from histo-pathological review., Results: Three perfusion patterns could be discerned by visual evaluation of CBF maps. Pattern 1 consisted of homogeneous hyper-perfusion of the entire tumor; pattern 2 demonstrated heterogeneous hyper-perfusion; pattern 3 showed no substantial hyper-perfusion. Evaluation of the perfusion patterns was highly concordant among the three readers (Kendall W=0.9458, P<0.0001). Pattern 1 was associated with WHO Grade I meningioma of (P<0.0001). Patterns 2 and 3 were predictive of WHO Grade II and III meningioma (P<0.0001), with an odds ratio (OR, versus pattern 1) of 49.6 (P<0.01) in a univariate analysis, and an OR of 186.4 (P<0.01) in a multivariate analysis., Conclusion: Qualitative evaluation of ASL CBF maps can help differentiate benign (WHO Grade I) from higher grade (WHO Grade II and III) intracranial meningiomas, potentially impacting therapeutic strategy., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Purpose: Anti-VEGF therapies remain controversial in the treatment of recurrent glioblastoma (GBM). In the current study, we demonstrate that recurrent GBM patients with a specific diffusion MR imaging signature have an overall survival (OS) advantage when treated with cediranib, bevacizumab, cabozantinib, or aflibercept monotherapy at first or second recurrence. These findings were validated using a separate trial comparing bevacizumab with lomustine. Experimental Design: Patients with recurrent GBM and diffusion MRI from the monotherapy arms of 5 separate phase II clinical trials were included: (i) cediranib (NCT00035656); (ii) bevacizumab (BRAIN Trial, AVF3708g; NCT00345163); (iii) cabozantinib (XL184-201; NCT00704288); (iv) aflibercept (VEGF Trap; NCT00369590); and (v) bevacizumab or lomustine (BELOB; NTR1929). Apparent diffusion coefficient (ADC) histogram analysis was performed prior to therapy to estimate "ADC L ," the mean of the lower ADC distribution. Pretreatment ADC L , enhancing volume, and clinical variables were tested as independent prognostic factors for OS. Results: The coefficient of variance (COV) in double baseline ADC L measurements was 2.5% and did not significantly differ ( P = 0.4537). An ADC L threshold of 1.24 μm 2 /ms produced the largest OS differences between patients (HR ∼ 0.5), and patients with an ADC L > 1.24 μm 2 /ms had close to double the OS in all anti-VEGF therapeutic scenarios tested. Training and validation data confirmed that baseline ADC L was an independent predictive biomarker for OS in anti-VEGF therapies, but not in lomustine, after accounting for age and baseline enhancing tumor volume. Conclusions: Pretreatment diffusion MRI is a predictive imaging biomarker for OS in patients with recurrent GBM treated with anti-VEGF monotherapy at first or second relapse. Clin Cancer Res; 23(19); 5745-56. ©2017 AACR ., (©2017 American Association for Cancer Research.)

The wide variety of treatment options that exist for glioblastoma, including surgery, ionizing radiation, anti-neoplastic chemotherapies, anti-angiogenic therapies, and active or passive immunotherapies, all may alter aspects of vascular permeability within the tumor and/or normal parenchyma. These alterations manifest as changes in the degree of contrast enhancement or T2-weighted signal hyperintensity on standard anatomic MRI scans, posing a potential challenge for accurate radiographic response assessment for identifying anti-tumor effects. The current review highlights the challenges that remain in differentiating true disease progression from changes due to radiation therapy, including pseudoprogression and radionecrosis, as well as immune or inflammatory changes that may occur as either an undesired result of cytotoxic therapy or as a desired consequence of immunotherapies.

The value of perfusion and diffusion-weighted MRI in differentiating histological subtypes according to the 2007 WHO glioma classification scheme (i.e. astrocytoma vs. oligodendroglioma) and genetic subtypes according to the 2016 WHO reclassification (e.g. 1p/19q co-deletion and IDH1 mutation status) in WHO grade II and III diffuse gliomas remains controversial. In the current study, we describe unique perfusion and diffusion MR signatures between histological and genetic glioma subtypes. Sixty-five patients with 2007 histological designations (astrocytomas and oligodendrogliomas), 1p/19q status (+ = intact/- = co-deleted), and IDH1 mutation status (MUT/WT) were included in this study. In all patients, median relative cerebral blood volume (rCBV) and apparent diffusion coefficient (ADC) were estimated within T2 hyperintense lesions. Bootstrap hypothesis testing was used to compare subpopulations of gliomas, separated by WHO grade and 2007 or 2016 glioma classification schemes. A multivariable logistic regression model was also used to differentiate between 1p19q + and 1p19q - WHO II-III gliomas. Neither rCBV nor ADC differed significantly between histological subtypes of pure astrocytomas and pure oligodendrogliomas. ADC was significantly different between molecular subtypes (p = 0.0016), particularly between IDH WT and IDH MUT /1p19q + (p = 0.0013). IDH MUT /1p19q + grade III gliomas had higher median ADC; IDH WT grade III gliomas had higher rCBV with lower ADC; and IDH MUT /1p19q - had intermediate rCBV and ADC values, similar to their grade II counterparts. A multivariable logistic regression model was able to differentiate between IDH WT and IDH MUT WHO II and III gliomas with an AUC of 0.84 (p < 0.0001, 74% sensitivity, 79% specificity). Within IDH MUT WHO II-III gliomas, a separate multivariable logistic regression model was able to differentiate between 1p19q + and 1p19q - WHO II-III gliomas with an AUC of 0.80 (p = 0.0015, 64% sensitivity, 82% specificity). ADC better differentiated between genetic subtypes of gliomas according to the 2016 WHO guidelines compared to the classification scheme outlined in the 2007 WHO guidelines based on histological features of the tissue. Results suggest a combination of rCBV, ADC, T2 hyperintense volume, and presence of contrast enhancement together may aid in non-invasively identifying genetic subtypes of diffuse gliomas.

Objective: For patients with high-grade glioma on clinical trials it is important to accurately assess time of disease progression. However, differentiation between pseudoprogression (PsP) and progressive disease (PD) is unreliable with standard magnetic resonance imaging (MRI) techniques. Dynamic susceptibility contrast perfusion MRI (DSC-MRI) can measure relative cerebral blood volume (rCBV) and may help distinguish PsP from PD., Methods: A subset of patients with high-grade glioma on a phase II clinical trial with temozolomide, paclitaxel poliglumex, and concurrent radiation were assessed. Nine patients (3 grade III, 6 grade IV), with a total of 19 enhancing lesions demonstrating progressive enhancement (≥25% increase from nadir) on postchemoradiation conventional contrast-enhanced MRI, had serial DSC-MRI. Mean leakage-corrected rCBV within enhancing lesions was computed for all postchemoradiation time points., Results: Of the 19 progressively enhancing lesions, 10 were classified as PsP and 9 as PD by biopsy/surgery or serial enhancement patterns during interval follow-up MRI. Mean rCBV at initial progressive enhancement did not differ significantly between PsP and PD (2.35 vs. 2.17; P=0.67). However, change in rCBV at first subsequent follow-up (-0.84 vs. 0.84; P=0.001) and the overall linear trend in rCBV after initial progressive enhancement (negative vs. positive slope; P=0.04) differed significantly between PsP and PD., Conclusions: Longitudinal trends in rCBV may be more useful than absolute rCBV in distinguishing PsP from PD in chemoradiation-treated high-grade gliomas with DSC-MRI. Further studies of DSC-MRI in high-grade glioma as a potential technique for distinguishing PsP from PD are indicated.

Background: The prognostic significance of baseline contrast enhancing tumor prior to second- or third-line therapy in recurrent glioblastoma (GBM) for overall survival (OS) remains controversial, particularly in the context of repeated surgical resection and/or use of anti-angiogenic therapy. In the current study, we examined recurrent GBM patients from both single and multicenter clinical trials to test whether baseline enhancing tumor volume, including central necrosis, is a significant prognostic factor for OS in recurrent GBM., Methods: Included were 497 patients with recurrent GBM from 4 data sources: 2 single-center sites (University of Toronto, University of California Los Angeles) and 2 phase II multicenter trials (AVF3708G, Bevacizumab ± Irinotecan, NCT00345163; XL184-201, Cabozantinib, NCT00704288). T1 subtraction maps were used to define volume of contrast enhancing tumor, including central necrosis. Cox multivariable and univariate analyses were used to evaluate the relationship between tumor volume prior to second- or third-line therapy and OS., Results: Both continuous measures of baseline tumor volume and tumors dichotomized into large (≥15cc) and small (<15cc) tumors were significant predictors of OS (P<.0001), independently of age and treatment. Univariate analysis demonstrated significant OS differences (P<.05) between large (≥15cc) and small (<15cc) tumors in patients under all therapeutic scenarios. Only patients treated with cabozantinib who previously failed anti-angiogenic therapy did not show an OS dependence on baseline tumor volume., Conclusions: Baseline tumor volume is a significant prognostic factor in recurrent GBM. Clinical trial treatment arms must have a balanced distribution of tumor size, and tumor size should be considered when interpreting therapeutic efficacy., (© The Author(s) 2016. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Routine diagnostics and treatment monitoring of brain tumors is usually based on contrast-enhanced MRI. However, the capacity of conventional MRI to differentiate tumor tissue from posttherapeutic effects following neurosurgical resection, chemoradiation, alkylating chemotherapy, radiosurgery, and/or immunotherapy may be limited. Metabolic imaging using PET can provide relevant additional information on tumor metabolism, which allows for more accurate diagnostics especially in clinically equivocal situations. This review article focuses predominantly on the amino acid PET tracers 11 C-methyl-l-methionine (MET), O -(2-[ 18 F]fluoroethyl)-l-tyrosine (FET) and 3,4-dihydroxy-6-[ 18 F]-fluoro-l-phenylalanine (FDOPA) and summarizes investigations regarding monitoring of brain tumor therapy.

Acidity within the extracellular milieu is a hallmark of cancer. There is a current need for fast, high spatial resolution pH imaging techniques for clinical evaluation of cancers, including gliomas. Chemical exchange saturation transfer (CEST) MRI targeting fast-exchanging amine protons can be used to obtain high-resolution pH-weighted images, but conventional CEST acquisition strategies are slow. There is also a need for more accurate MR simulations to better understand the effects of amine CEST pulse sequence parameters on pH-weighted image contrast. In the current study we present a simulation of amine CEST contrast specific for a newly developed CEST echoplanar imaging (EPI) pulse sequence. The accuracy of the simulations was validated by comparing the exchange rates and Z-spectrum under a variety of conditions using physical phantoms of glutamine with different pH values. The effects of saturation pulse shapes, pulse durations, pulse train lengths, repetition times, and relaxation rates of bulk water and exchangeable amine protons on the CEST signal were explored for normal-appearing white matter (NAWM), glioma, and cerebrospinal fluid. Last, 18 patients with WHO II-IV gliomas were evaluated. Results showed that the Z-spectrum was highly dependent on saturation pulse shape, repetition time, saturation amplitude, magnetic field strength, and T 2 within bulk water; however, the Z-spectrum was only minimally influenced by saturation pulse duration and the specific relaxation rates of amine protons. Results suggest that a Gaussian saturation pulse train consisting of 3 × 100 ms pulses using the minimum allowable repetition time is optimal for achieving over 90% available contrast across all tissues. Results also demonstrate that high saturation pulse amplitude and scanner field strength (>3 T) are necessary for adequate endogenous pH-weighted amine CEST contrast. pH-weighted amine CEST contrast increased with increasing tumor grade, with glioblastoma showing significantly higher contrast compared with WHO II or III gliomas., (Copyright © 2016 John Wiley & Sons, Ltd.)

Purpose: To evaluate a leakage correction algorithm for T 1 and T2* artifacts arising from contrast agent extravasation in dynamic susceptibility contrast magnetic resonance imaging (DSC-MRI) that accounts for bidirectional contrast agent flux and compare relative cerebral blood volume (CBV) estimates and overall survival (OS) stratification from this model to those made with the unidirectional and uncorrected models in patients with recurrent glioblastoma (GBM)., Materials and Methods: We determined median rCBV within contrast-enhancing tumor before and after bevacizumab treatment in patients (75 scans on 1.5T, 19 scans on 3.0T) with recurrent GBM without leakage correction and with application of the unidirectional and bidirectional leakage correction algorithms to determine whether rCBV stratifies OS., Results: Decreased post-bevacizumab rCBV from baseline using the bidirectional leakage correction algorithm significantly correlated with longer OS (Cox, P = 0.01), whereas rCBV change using the unidirectional model (P = 0.43) or the uncorrected rCBV values (P = 0.28) did not. Estimates of rCBV computed with the two leakage correction algorithms differed on average by 14.9%., Conclusion: Accounting for T 1 and T2* leakage contamination in DSC-MRI using a two-compartment, bidirectional rather than unidirectional exchange model might improve post-bevacizumab survival stratification in patients with recurrent GBM. J. Magn. Reson. Imaging 2016;44:1229-1237., (© 2016 International Society for Magnetic Resonance in Medicine.)

Dynamic susceptibility contrast (DSC) MR imaging, a perfusion-weighted MR imaging technique typically used in neuro-oncologic applications for estimating the relative cerebral blood volume within brain tumors, has demonstrated much potential for determining prognosis, predicting therapeutic response, and assessing early treatment response of gliomas. This review highlights recent developments using DSC-MR imaging and emphasizes the need for technical standardization and validation in prospective studies in order for this technique to become incorporated into standard-of-care imaging for patients with brain tumors., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Background and Purpose: Menière disease and idiopathic sudden sensorineural hearing loss can have overlapping clinical presentation and may have similar pathophysiology. Prior studies using postcontrast 3D-FLAIR MR imaging suggest abnormal blood-labyrinth barrier permeability in both conditions, but the 2 diseases have not been directly compared by using the same imaging techniques. We hypothesized that delayed postcontrast 3D-FLAIR MR imaging would show differences in blood-labyrinth barrier permeability between Menière disease and idiopathic sudden sensorineural hearing loss., Materials and Methods: Patients with unilateral Menière disease ( n = 32) and unilateral idiopathic sudden sensorineural hearing loss ( n = 11) imaged with delayed postcontrast 3D-FLAIR MR imaging were retrospectively studied. Signal intensities of the medulla and perilymph of the cochlear basal turns of both ears in each patient were measured in a blinded fashion. Cochlea/medulla ratios were calculated for each ear as a surrogate for blood-labyrinth barrier permeability. The ears were segregated by clinical diagnosis., Results: Cochlea/medulla ratio was higher in symptomatic ears of patients with Menière disease (12.6 ± 7.4) than in patients with idiopathic sudden sensorineural hearing loss (5.7 ± 2.0) and asymptomatic ears of patients with Menière disease (8.0 ± 3.1), indicating increased blood-labyrinth barrier permeability in Menière disease ears. The differences in cochlea/medulla ratio between symptomatic and asymptomatic ears were significantly higher in Menière disease than in idiopathic sudden sensorineural hearing loss. Asymptomatic ears in patients with Menière disease showed higher cochlea/medulla ratio than symptomatic and asymptomatic ears in patients with idiopathic sudden sensorineural hearing loss., Conclusions: Increased cochlea/medulla ratio indicates increased blood-labyrinth barrier permeability in Menière disease compared with idiopathic sudden sensorineural hearing loss. Increased cochlea/medulla ratio in asymptomatic ears of patients with Menière disease also suggests an underlying systemic cause of Menière disease and may provide a pathophysiologic biomarker., (© 2016 by American Journal of Neuroradiology.)

Background: Little is known about the natural growth characteristics of untreated glioblastoma before surgical or therapeutic intervention, because patients are rapidly treated after preliminary radiographic diagnosis. Understanding the growth characteristics of uninhibited human glioblastoma may be useful for characterizing changes in response to therapy. Thus, the objective of the current study was to explore tumor growth dynamics in a cohort of patients with untreated glioblastoma before surgical or therapeutic intervention., Methods: Ninety-five patients with glioblastoma who had measurable enhancing disease on >2 magnetic resonance imaging scans before surgery were identified. Tumor growth rates were quantified in 4 different ways (the percentage change per day, the absolute rate of change per day, the estimated volumetric doubling time, and the radial expansion rate) using 3 different approaches (bidirectional product, enhancing disease, and total lesion volume)., Results: The median volumetric doubling time was 21.1 days, the percentage change in tumor volume was 2.1% per day, and the rate of change in total lesion volume was 0.18 cc per day. The length of follow-up between magnetic resonance imaging examinations should be >28 days to detect progressive disease with high specificity. Small initial tumor sizes (<3 cm in greatest dimension) are biased toward a large percentage change at follow-up., Conclusions: Presurgical, treatment-naive glioblastoma growth dynamics can be estimated in a variety of ways with similar results. The percentage changes in tumor size and volume depend on baseline tumor size and the time interval between scans. Cancer 2016;122:1718-27. © 2016 American Cancer Society., (© 2016 American Cancer Society.)

Aside from bidimensional measurements from conventional contrast-enhanced MRI, there are no validated or FDA-qualified imaging biomarkers for high-grade gliomas. However, advanced functional MRI techniques, including perfusion- and diffusion-weighted MRI, have demonstrated much potential for determining prognosis, predicting therapeutic response, and assessing early treatment response. They may also prove useful for differentiating pseudoprogression from true progression after temozolomide chemoradiation and pseudoresponse from true response after anti-angiogenic therapy. This review will highlight recent developments using these techniques and emphasize the need for technical standardization and validation in prospective studies in order for these methods to become incorporated into standard-of-care imaging for brain tumor patients., (© The Author(s) 2015. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Purpose: The RANO criteria have not been assessed using outcome data from prospective trials. We examined the radiologic data of patients with recurrent glioblastoma from the randomized phase II trial (AVF3708g) to determine the effect of including T2/FLAIR evaluation as per RANO criteria on measurements of objective response rates (ORRs) and progression-free survival (PFS) compared with assessment based on contrast enhancement (Macdonald criteria)., Experimental Design: The ORRs and median PFS were determined using the RANO criteria and compared with those obtained using the Macdonald criteria. Landmark analyses were performed at 2, 4, and 6 months, and Cox proportional hazard models were used to determine the associations between OR and progression with subsequent survival., Results: The ORRs were 0.331 [95% confidence interval (CI), 0.260-0.409] and 0.393 (95% CI, 0.317-0.472) by RANO and Macdonald criteria, respectively (P < 0.0001). The median PFS was 4.6 months (95% CI, 4.1-5.5) using RANO criteria, compared with 6.4 months (95% CI, 5.5-7.1) as determined by Macdonald criteria (P = 0.01). At 2-, 4-, and 6-month landmarks, both OR status and PFS determined by either RANO or Macdonald criteria were predictive of overall survival [OS; hazard ratios for 4-month landmark (OR HR = 1.93, P = 0.0012; PFS HR, 4.23, P < 0.0001)]., Conclusions: The inclusion of T2/FLAIR assessment resulted in statistically significant differences in median PFS and ORRs compared with assessment of solely enhancing tumor (Macdonald criteria), although OR and PFS determined by both RANO and Macdonald criteria correlated with OS., (©2015 American Association for Cancer Research.)

Central nervous system (CNS) involvement by rheumatoid arthritis (RA) in the form of rheumatoid meningitis (RM) is rare and most commonly occurs in the setting of longstanding severe RA. Due to a wide range of clinical presentations and nonspecific laboratory findings, it presents a diagnostic challenge often requiring brain biopsy. Only a few histopathologically confirmed cases have been described in the literature. Our aim is to describe two cases of RM and review the literature. The first case is of a previously healthy 37-year-old man who presented with severe headaches and focal neurologic deficits. Magnetic resonance imaging demonstrated abnormal leptomeningeal enhancement in the left frontal and parietal sulci. The second case is of a 62-year-old woman with a history of mild chronic joint pain who presented with confusion, personality changes and seizures. Both patients ultimately underwent brain biopsy which demonstrated RM on pathologic examination. Administration of corticosteroids resulted in significant clinical improvement in both cases. To our knowledge, our unusual case of RM in the young man is the fifth reported case of rheumatoid meningitis in a patient with no prior history of RA. Such an atypical presentation makes diagnosis even more difficult and highlights the need for awareness of this entity in the diagnostic consideration of a patient presenting with unexplained neurologic symptoms. Our literature review underscores the clinical and pathologic heterogeneity of CNS involvement in RA., (© 2015 Japanese Society of Neuropathology.)

Imaging is integral to the management of patients with brain tumors. Conventional structural imaging provides exquisite anatomic detail but remains limited in the evaluation of molecular characteristics of intracranial neoplasms. Quantitative and physiologic biomarkers derived from advanced imaging techniques have been increasingly utilized as problem-solving tools to identify glioma grade and assess response to therapy. This chapter provides a comprehensive overview of the imaging strategies used in the clinical assessment of patients with gliomas and describes how novel imaging biomarkers have the potential to improve patient management., (© 2016 Elsevier B.V. All rights reserved.)

Background: Interstitial tissue acidosis resulting from abnormal perfusion and metabolism is a hallmark of cancer. The current study demonstrates that chemical exchange saturation transfer (CEST) MRI can be used as a noninvasive pH-weighted molecular imaging technique by targeting the chemical exchange between amine protons and protons in extracellular bulk water., Methods: First, the sensitivity of amine CEST was validated in phantoms under a variety of conditions, including different magnetic field strengths, amino acid concentrations, and pH values. Amine CEST was compared with histology in both a preclinical GL261 intracranial glioma model at 7T and human patients at 3T. The association between physiologic and pH-weighted MRI was explored, along with the ability to predict time to progression to radiochemotherapy in 20 glioblastoma patients., Results: z-Spectral asymmetry increased at 3 ppm (amine range) on CEST MRI with decreasing pH within the range observed in tumors for both 3T and 7T scanners. Lesions with acidic signatures showed active tumor and pseudopalisading tumor on histology and showed elevated FDOPA PET uptake, lactate on MR spectroscopy, and perfusion abnormalities. Patients with acidic lesions after surgery or stable/growing acidic lesions had a shorter time to progression following radiochemotherapy compared with patients with lesions demonstrating relatively low acidity (P < .001)., Conclusion: Results suggest pH-weighted MRI may provide new insight into brain tumor physiology beyond traditional imaging technologies., (© The Author(s) 2015. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

The most common type of primary brain tumor is malignant glioma. Despite intensive therapeutic efforts, the majority of these neoplasms remain incurable. Imaging techniques are important for initial tumor detection and comprise indispensable tools for monitoring treatment. Structural imaging using contrast-enhanced MRI is the method of choice for brain tumor surveillance, but its capacity to differentiate tumor from nonspecific tissue changes can be limited, particularly with posttreatment gliomas. Metabolic imaging using positron-emission-tomography (PET) can provide relevant additional information, which may allow for better assessment of tumor burden in ambiguous cases. Specific PET tracers have addressed numerous molecular targets in the last decades, but only a few have achieved relevance in routine clinical practice. At present, PET studies using radiolabeled amino acids appear to improve clinical decision-making as these tracers can offer better delineation of tumor extent as well as improved targeting of biopsies, surgical interventions, and radiation therapy. Amino acid PET imaging also appears useful for distinguishing glioma recurrence or progression from postradiation treatment effects, particularly radiation necrosis and pseudoprogression, and provides information on histological grading and patient prognosis. In the last decade, the tracers O-(2-[(18)F]fluoroethyl)-L-tyrosine (FET) and 3,4-dihydroxy-6-[(18)F]-fluoro-L-phenylalanine (FDOPA) have been increasingly used for these indications. This review article focuses on these tracers and summarizes their recent applications for patients with brain tumors. Current uses of tracers other than FET and FDOPA are also discussed, and the most frequent practical questions regarding PET brain tumor imaging are reviewed., (© The Author(s) 2015. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Immunotherapy is a promising area of therapy in patients with neuro-oncological malignancies. However, early-phase studies show unique challenges associated with the assessment of radiological changes in response to immunotherapy reflecting delayed responses or therapy-induced inflammation. Clinical benefit, including long-term survival and tumour regression, can still occur after initial disease progression or after the appearance of new lesions. Refinement of the response assessment criteria for patients with neuro-oncological malignancies undergoing immunotherapy is therefore warranted. Herein, a multinational and multidisciplinary panel of neuro-oncology immunotherapy experts describe immunotherapy Response Assessment for Neuro-Oncology (iRANO) criteria based on guidance for the determination of tumour progression outlined by the immune-related response criteria and the RANO working group. Among patients who demonstrate imaging findings meeting RANO criteria for progressive disease within 6 months of initiating immunotherapy, including the development of new lesions, confirmation of radiographic progression on follow-up imaging is recommended provided that the patient is not significantly worse clinically. The proposed criteria also include guidelines for the use of corticosteroids. We review the role of advanced imaging techniques and the role of measurement of clinical benefit endpoints including neurological and immunological functions. The iRANO guidelines put forth in this Review will evolve successively to improve their usefulness as further experience from immunotherapy trials in neuro-oncology accumulate., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Background: Management of language difficulties is an important aspect of clinical care for glioma patients, and accurately identifying the possible language deficits in patients based on lesion location would be beneficial to clinicians. To that end, we examined the relationship between lesion presence and language performance on tests of receptive language and expressive language using a highly specific voxel-based lesion-symptom mapping (VLSM) approach in glioma patients., Methods: 98 adults with primary glioma, who were pre-surgical candidates, were administered seven neurocognitive tests within the domains of receptive language and expressive language. The association between language performance and lesion presence was examined using VLSM. Statistical parametric maps were created for each test, and composite maps for both receptive language and expressive language were created to display the significant voxels common to all tests within these language domains., Results: We identified clusters of voxels with a significant relationship between lesion presence and language performance. All tasks were associated with several white matter pathways. The receptive language tasks were additionally all associated with regions primarily within the lateral temporal lobe and medial temporal lobe. In contrast, the expressive language tasks shared little overlap, despite each task being independently associated with large anatomic areas., Conclusions: Our findings identify the key anatomic structures involved in language functioning in adult glioma patients using an innovative lesion analysis technique and suggest that expressive language abilities may be more task-dependent and distributed than receptive language abilities.

Purpose: Evaluation of nonenhancing tumor (NET) burden is an important yet challenging part of brain tumor response assessment. This study focuses on using dual-echo turbo spin-echo MRI as a means of quickly estimating tissue T2, which can be used to objectively define NET burden., Experimental Design: A series of experiments were performed to establish the use of T2 maps for defining NET burden. First, variation in T2 was determined using the American College of Radiology (ACR) water phantoms in 16 scanners evaluated over 3 years. Next, the sensitivity and specificity of T2 maps for delineating NET from other tissues were examined. Then, T2-defined NET was used to predict survival in separate subsets of patients with glioblastoma treated with radiotherapy, concurrent radiation, and chemotherapy, or bevacizumab at recurrence., Results: Variability in T2 in the ACR phantom was 3% to 5%. In training data, ROC analysis suggested that 125 ms < T2 < 250 ms could delineate NET with a sensitivity of >90% and specificity of >65%. Using this criterion, NET burden after completion of radiotherapy alone, or concurrent radiotherapy, and chemotherapy was shown to be predictive of survival (Cox, P < 0.05), and the change in NET volume before and after bevacizumab therapy in recurrent glioblastoma was also a predictive of survival (P < 0.05)., Conclusions: T2 maps using dual-echo data are feasible, stable, and can be used to objectively define NET burden for use in brain tumor characterization, prognosis, and response assessment. The use of effective T2 maps for defining NET burden should be validated in a randomized, clinical trial., (©2015 American Association for Cancer Research.)

A recent joint meeting was held on January 30, 2014, with the US Food and Drug Administration (FDA), National Cancer Institute (NCI), clinical scientists, imaging experts, pharmaceutical and biotech companies, clinical trials cooperative groups, and patient advocate groups to discuss imaging endpoints for clinical trials in glioblastoma. This workshop developed a set of priorities and action items including the creation of a standardized MRI protocol for multicenter studies. The current document outlines consensus recommendations for a standardized Brain Tumor Imaging Protocol (BTIP), along with the scientific and practical justifications for these recommendations, resulting from a series of discussions between various experts involved in aspects of neuro-oncology neuroimaging for clinical trials. The minimum recommended sequences include: (i) parameter-matched precontrast and postcontrast inversion recovery-prepared, isotropic 3D T1-weighted gradient-recalled echo; (ii) axial 2D T2-weighted turbo spin-echo acquired after contrast injection and before postcontrast 3D T1-weighted images to control timing of images after contrast administration; (iii) precontrast, axial 2D T2-weighted fluid-attenuated inversion recovery; and (iv) precontrast, axial 2D, 3-directional diffusion-weighted images. Recommended ranges of sequence parameters are provided for both 1.5 T and 3 T MR systems., (© The Author(s) 2015. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)