Advanced MR Techniques for Preoperative Glioma Characterization: Part 2.

Preoperative clinical MRI protocols for gliomas, brain tumors with dismal outcomes due to their infiltrative properties, still rely on conventional structural MRI, which does not deliver information on tumor genotype and is limited in the delineation of diffuse gliomas. The GliMR COST action wants to raise awareness about the state of the art of advanced MRI techniques in gliomas and their possible clinical translation. This review describes current methods, limits, and applications of advanced MRI for the preoperative assessment of glioma, summarizing the level of clinical validation of different techniques. In this second part, we review magnetic resonance spectroscopy (MRS), chemical exchange saturation transfer (CEST), susceptibility-weighted imaging (SWI), MRI-PET, MR elastography (MRE), and MR-based radiomics applications. The first part of this review addresses dynamic susceptibility contrast (DSC) and dynamic contrast-enhanced (DCE) MRI, arterial spin labeling (ASL), diffusion-weighted MRI, vessel imaging, and magnetic resonance fingerprinting (MRF). EVIDENCE LEVEL: 3. TECHNICAL EFFICACY: Stage 2.

Multi-Site Concordance of Diffusion-Weighted Imaging Quantification for Assessing Prostate Cancer Aggressiveness.

BACKGROUND: Diffusion-weighted imaging (DWI) is commonly used to detect prostate cancer, and a major clinical challenge is differentiating aggressive from indolent disease. PURPOSE: To compare 14 site-specific parametric fitting implementations applied to the same dataset of whole-mount pathologically validated DWI to test the hypothesis that cancer differentiation varies with different fitting algorithms. STUDY TYPE: Prospective. POPULATION: Thirty-three patients prospectively imaged prior to prostatectomy. FIELD STRENGTH/SEQUENCE: 3 T, field-of-view optimized and constrained undistorted single-shot DWI sequence. ASSESSMENT: Datasets, including a noise-free digital reference object (DRO), were distributed to the 14 teams, where locally implemented DWI parameter maps were calculated, including mono-exponential apparent diffusion coefficient (MEADC), kurtosis (K), diffusion kurtosis (DK), bi-exponential diffusion (BID), pseudo-diffusion (BID*), and perfusion fraction (F). The resulting parametric maps were centrally analyzed, where differentiation of benign from cancerous tissue was compared between DWI parameters and the fitting algorithms with a receiver operating characteristic area under the curve (ROC AUC). STATISTICAL TEST: Levene's test, P < 0.05 corrected for multiple comparisons was considered statistically significant. RESULTS: The DRO results indicated minimal discordance between sites. Comparison across sites indicated that K, DK, and MEADC had significantly higher prostate cancer detection capability (AUC range = 0.72-0.76, 0.76-0.81, and 0.76-0.80 respectively) as compared to bi-exponential parameters (BID, BID*, F) which had lower AUC and greater between site variation (AUC range = 0.53-0.80, 0.51-0.81, and 0.52-0.80 respectively). Post-processing parameters also affected the resulting AUC, moving from, for example, 0.75 to 0.87 for MEADC varying cluster size. DATA CONCLUSION: We found that conventional diffusion models had consistent performance at differentiating prostate cancer from benign tissue. Our results also indicated that post-processing decisions on DWI data can affect sensitivity and specificity when applied to radiological-pathological studies in prostate cancer. LEVEL OF EVIDENCE: 1 TECHNICAL EFFICACY: Stage 3.

Human Fetal Tissue from Elective Abortions in Research and Medicine: Science, Ethics, and the Law.

Since the U.S. Supreme Court issued its landmark decision in 1973 to legalize abortion, over 60 million preborn have been killed by elective abortion. While alive in the womb, these preborn are abandoned and not protected under current law. But once aborted, their body parts are a highly esteemed and prized commodity amongst certain members of the scientific community. Moral discourse is disregarded for the sake of science. The public have been lulled and lured into believing that this practice must continue in order to understand and develop cures for some of the most debilitating diseases of our day. But they are mistaken. This practice is not necessary, especially in light of numerous noncontroversial alternatives. Here, we expose and consider the false and misleading claims regarding human fetal tissue (HFT) in research from scientific, legal, and ethical points of view. We endeavor deeply to understand the depth of the injustice in this practice and what forces promote and maintain it; and by revealing and understanding these forces, we set forth how these inhumane practices can be ended. An accurate portrayal of the history of HFT use in research is provided, along with a close examination of the current state of this practice under existing laws. The serious societal implications are also discussed, which will worsen beyond comprehension if these practices are allowed to continue. The timeliness of this information cannot be overstated, and a thorough understanding is paramount for anyone who desires to know the facts about HFT in research and medicine and its detrimental impact for humanity.

Spatial discrimination of glioblastoma and treatment effect with histologically-validated perfusion and diffusion magnetic resonance imaging metrics.

The goal of this study is to spatially discriminate tumor from treatment effect (TE), within the contrast-enhancing lesion, for brain tumor patients at all stages of treatment. To this end, the diagnostic accuracy of MRI-derived diffusion and perfusion parameters to distinguish pure TE from pure glioblastoma (GBM) was determined utilizing spatially-correlated biopsy samples. From July 2010 through June 2015, brain tumor patients who underwent pre-operative DWI and DSC-MRI and stereotactic image-guided biopsy were considered for inclusion in this IRB-approved study. MRI-derived parameter maps included apparent diffusion coefficient (ADC), normalized cerebral blood flow (nCBF), normalized and standardized relative cerebral blood volume (nRCBV, sRCBV), peak signal-height (PSR) and percent signal-recovery (PSR). These were co-registered to the Stealth MRI and median values extracted from the spatially-matched biopsy regions. A ROC analysis accounting for multiple subject samples was performed, and the optimal threshold for distinguishing TE from GBM determined for each parameter. Histopathologic diagnosis of pure TE (n = 10) or pure GBM (n = 34) was confirmed in tissue samples from 15 consecutive subjects with analyzable data. Perfusion thresholds of sRCBV (3575; SN/SP% = 79.4/90.0), nRCBV (1.13; SN/SP% = 82.1/90.0), and nCBF (1.05; SN/SP% = 79.4/80.0) distinguished TE from GBM (P < 0.05), whereas ADC, PSR, and PH could not (P > 0.05). The thresholds for CBF and CBV can be applied to lesions with any admixture of tumor or treatment effect, enabling the identification of true tumor burden within enhancing lesions. This approach overcomes current limitations of averaging values from both tumor and TE for quantitative assessments.

The effect of low b-values on the intravoxel incoherent motion derived pseudodiffusion parameter in liver.

PURPOSE: To examine the effect of low b-values (0 < b < 50 s/mm(2)) on the calculation of the intravoxel incoherent motion (IVIM) derived pseudodiffusion parameter in the normal liver. METHODS: Simulations were performed to examine the effects of adding low b-values on the pseudodiffusion parameter. Low b-values were cumulatively added to the distribution and the IVIM signal was generated with varying pseudodiffusion values. The signal was fit with the IVIM model after the addition of Gaussian noise, and the simulated values were compared with the true values. In addition, the livers of eight control subjects were imaged using respiratory-triggered DWI. Pseudodiffusion was calculated with and without low b-values and compared. RESULTS: Pseudodiffusion tended to be underestimated when low b-values were not included in the b-value distribution as predicted by simulations and confirmed with in vivo imaging. The number of outlier values was also reduced as more low b-values were added. CONCLUSION: In conclusion, this study showed pseudodiffusion in the liver tended to be underestimated when too few low b-values (0 < b < 50 s/mm(2)) were included in the distribution. Therefore, it is recommended to include at least two low b-values when performing liver IVIM studies.

Location of brain tumor intersecting white matter tracts predicts patient prognosis.

Brain tumor cells invade adjacent normal brain along white matter (WM) bundles of axons. We therefore hypothesized that the location of tumor intersecting WM tracts would be associated with differing survival. This study introduces a method, voxel-wise survival analysis (VSA), to determine the relationship between the location of brain tumor intersecting WM tracts and patient prognosis. 113 primary glioblastoma (GBM) patients were retrospectively analyzed for this study. Patient specific tumor location, defined by contrast-enhancement, was combined with diffusion tensor imaging derived tractography to determine the location of axons intersecting tumor enhancement (AXITEs). VSA was then used to determine the relationship between the AXITE location and patient survival. Tumors intersecting the right anterior thalamic radiation (ATR), right inferior fronto-occipital fasciculus (IFOF), right and left cortico-spinal tract (CST), and corpus callosum (CC) were associated with decreased overall survival. Tumors intersecting the CST, body of the CC, right ATR, posterior IFOF, and inferior longitudinal fasciculus are associated with decreased progression-free survival (PFS), while tumors intersecting the right genu of the CC and anterior IFOF are associated with increased PFS. Patients with tumors intersecting the ATR, IFOF, CST, or CC had significantly improved survival prognosis if they were additionally treated with bevacizumab. This study demonstrates the usefulness of VSA by locating AXITEs associated with poor prognosis in GBM patients. This information should be included in patient-physician conversations, therapeutic strategy, and clinical trial design.

Comprehensive characterization of glioblastoma tumor tissues for biomarker identification using mass spectrometry-based label-free quantitative proteomics.

Cancer is a complex disease; glioblastoma (GBM) is no exception. Short survival, poor prognosis, and very limited treatment options make it imperative to unravel the disease pathophysiology. The critically important identification of proteins that mediate various cellular events during disease is made possible with advancements in mass spectrometry (MS)-based proteomics. The objective of our study is to identify and characterize proteins that are differentially expressed in GBM to better understand their interactions and functions that lead to the disease condition. Further identification of upstream regulators will provide new potential therapeutic targets. We analyzed GBM tumors by SDS-PAGE fractionation with internal DNA markers followed by liquid chromatography-tandem mass spectrometry (MS). Brain tissue specimens obtained for clinical purposes during epilepsy surgeries were used as controls, and the quantification of MS data was performed by label-free spectral counting. The differentially expressed proteins were further characterized by Ingenuity Pathway Analysis (IPA) to identify protein interactions, functions, and upstream regulators. Our study identified several important proteins that are involved in GBM progression. The IPA revealed glioma activation with z score 2.236 during unbiased core analysis. Upstream regulators STAT3 and SP1 were activated and CTNNα was inhibited. We verified overexpression of several proteins by immunoblot to complement the MS data. This work represents an important step towards the identification of GBM biomarkers, which could open avenues to identify therapeutic targets for better treatment of GBM patients. The workflow developed represents a powerful and efficient method to identify biomarkers in GBM.

Effect of contrast leakage on the detection of abnormal brain tumor vasculature in high-grade glioma.

Abnormal brain tumor vasculature has recently been highlighted by a dynamic susceptibility contrast (DSC) MRI processing technique. The technique uses independent component analysis (ICA) to separate arterial and venous perfusion. The overlap of the two, i.e. arterio-venous overlap or AVOL, preferentially occurs in brain tumors and predicts response to anti-angiogenic therapy. The effects of contrast agent leakage on the AVOL biomarker have yet to be established. DSC was acquired during two separate contrast boluses in ten patients undergoing clinical imaging for brain tumor diagnosis. Three components were modeled with ICA, which included the arterial and venous components. The percentage of each component as well as a third component were determined within contrast enhancing tumor and compared. AVOL within enhancing tumor was also compared between doses. The percentage of enhancing tumor classified as not arterial or venous and instead into a third component with contrast agent leakage apparent in the time-series was significantly greater for the first contrast dose compared to the second. The amount of AVOL detected within enhancing tumor was also significantly greater with the second dose compared to the first. Contrast leakage results in large signal variance classified as a separate component by the ICA algorithm. The use of a second dose mitigates the effect and allows measurement of AVOL within enhancement.

Practical guidance to identify and troubleshoot suboptimal DSC-MRI results.

Relative cerebral blood volume (rCBV) derived from dynamic susceptibility contrast (DSC) perfusion MR imaging (pMRI) has been shown to be a robust marker of neuroradiological tumor burden. Recent consensus recommendations in pMRI acquisition strategies have provided a pathway for pMRI inclusion in diverse patient care centers, regardless of size or experience. However, even with proper implementation and execution of the DSC-MRI protocol, issues will arise that many centers may not easily recognize or be aware of. Furthermore, missed pMRI issues are not always apparent in the resulting rCBV images, potentiating inaccurate or missed radiological diagnoses. Therefore, we gathered from our database of DSC-MRI datasets, true-to-life examples showcasing the breakdowns in acquisition, postprocessing, and interpretation, along with appropriate mitigation strategies when possible. The pMRI issues addressed include those related to image acquisition and postprocessing with a focus on contrast agent administration, timing, and rate, signal-to-noise quality, and susceptibility artifact. The goal of this work is to provide guidance to minimize and recognize pMRI issues to ensure that only quality data is interpreted.

Application of Delta T1 maps for quantitative and objective assessment of extent of resection and survival prediction in glioblastoma.

Background and Objectives: Gross-total resection (GTR) and low residual tumor volume (RTV) have been associated with increased survival in glioblastoma. Largely due to the subjectivity involved, the determination of GTR and RTV remains difficult in the postoperative setting. In response, the objective of this study is to evaluate the clinical efficacy of an easy-to-use MRI metric, called delta T1 (dT1), to quantify extent of resection (EOR) and RTV, in comparison to radiologist impression, to predict overall survival (OS) in glioblastoma patients. Methods: 59 patients who underwent resection of glioblastoma were retrospectively identified. Delta T1 (dT1) images, automatically created from the difference between calibrated post- and pre-contrast T1-weighted images, were used to quantify EOR and RTV. Kaplan-Meier survival estimates were determined for EOR categories, an RTV cutoff of 5cm3 and radiologist interpretation of EOR. Multivariate Cox proportional hazard regression analysis was used to evaluate RTV and EOR along with effects related to sex, KPS, MGMT, and age on OS. Results: Kaplan-Meier analysis revealed a statistically significant difference in median OS for a dT1-determined RTV cutoff of 5 cm3 (P=.0024, HR=2.18 (1.232-3.856)), but not for radiological impression (P=0.666) or dT1-determined EOR (P=0.0803), which was limited to a comparison between partial and subtotal resections. Furthermore, when covariates were accounted for in multivariate Cox regression, significant differences in OS were retained for dT1-determined RTV. Additionally, a significantly strong yet short-term effect of MGMT methylation status on OS was revealed for each RTV and EOR model. Conclusion: The utility of dT1 maps to quantify EOR and RTV in glioblastoma and predict survival, suggests an emerging role for dT1s with relevance for intraoperative MRI, neuro-navigation and postoperative disease surveillance.

Identification of a single-dose, low flip angle based CBV threshold for fractional tumor burden (FTB) mapping in recurrent glioblastoma.

BACKGROUND AND PURPOSE: DSC-MRI can be used to generate fractional tumor burden (FTB) maps, via application of relative CBV thresholds, to spatially differentiate glioblastoma recurrence from post treatment radiation effects (PTRE). Image-localized histopathology was previously used to validate FTB maps derived from a reference DSC-MRI protocol using preload, a moderate flip angle (MFA, 60°) and post-processing leakage correction. Recently, a DSC-MRI protocol with a low flip angle (LFA, 30°) with no preload was shown to provide leakage-corrected RCBV equivalent to the reference protocol. This study aims to identify the RCBV thresholds for the LFA protocol that generate the most accurate FTB maps, concordant with those obtained from the reference MFA protocol. MATERIALS AND METHODS: Fifty-two patients with grade IV GBM who had prior surgical resection and received chemotherapy and radiotherapy were included in the study. Two sets of DSC-MRI data were collected sequentially first using LFA protocol with no preload, which served as the preload for the subsequent MFA protocol. Standardized relative CBV maps (sRCBV) were obtained for each patient and co-registered with the anatomical post-contrast T1-weighted images. The reference MFA-based FTB maps were computed using previously published sRCBV thresholds (1.0 and 1.56). An ROC analysis was conducted to identify the optimal, voxelwise LFA sRCBV thresholds, and the sensitivity, specificity, and accuracy of the LFA-based FTB maps were computed with respect to the MFA-based reference. RESULTS: The mean sRCBV values of tumors across patients exhibited strong agreement (CCC = 0.99) between the two protocols. Using the ROC analysis, the optimal lower LFA threshold that accurately distinguishes PTRE from tumor recurrence was found to be 1.0 (sensitivity: 87.77%; specificity: 90.22%), equivalent to the ground truth. To identify aggressive tumor regions, the ROC analysis identified an upper LFA threshold of 1.37 (sensitivity: 90.87%; specificity: 91.10%) for the reference MFA threshold of 1.56. CONCLUSION: For LFA-based FTB maps, a sRCBV threshold of 1.0 and 1.37 can differentiate PTRE from recurrent tumor. FTB maps aids in surgical planning, guiding pathological diagnosis and treatment strategies in the recurrent setting. This study further confirms the reliability of single-dose LFA-based DSC-MRI. ABBREVIATIONS: LFA = low flip angle; MFA = moderate flip angle; sRCBV = standardized relative cerebral blood volume; FTB = fractional tumor burden; PTRE = post treatment radiation effects; ROC = receiver operating characteristics; CCC = concordance correlation coefficient.

Multiphasic modification of intrinsic functional connectivity of the rat brain during increasing levels of propofol.

The dose-dependent effects of anesthetics on brain functional connectivity are incompletely understood. Resting-state functional magnetic resonance imaging (rsfMRI) is widely used to assess the functional connectivity in humans and animals. Propofol is an anesthetic agent with desirable characteristics for functional neuroimaging in animals but its dose-dependent effects on rsfMRI functional connectivity have not been determined. Here we tested the hypothesis that brain functional connectivity undergoes specific changes in distinct neural networks at anesthetic depths associated with loss of consciousness. We acquired spontaneous blood oxygen level-dependent (BOLD) signals simultaneously with electroencephalographic (EEG) signals from rats under steady-state, intravenously administered propofol at increasing doses from light sedation to deep anesthesia (20, 40, 60, 80, and 100 mg/kg/h IV). Power spectra and burst suppression ratio were calculated from the EEG to verify anesthetic depth. Functional connectivity was determined from the whole brain correlation of BOLD data in regions of interest followed by a segmentation of the correlation maps into anatomically defined regional connectivity. We found that propofol produced multiphasic, dose dependent changes in functional connectivity of various cortical and subcortical networks. Cluster analysis predicted segregation of connectivity into two cortical and two subcortical clusters. In one cortical cluster (somatosensory and parietal), the early reduction in connectivity was followed by transient reversal; in the other cluster (sensory, motor and cingulate/retrosplenial), this rebound was absent. The connectivity of the subcortical cluster (brainstem, hippocampal and caudate) was strongly reduced, whereas that of another (hypothalamus, medial thalamus and n. basalis) did not. Subcortical connectivity increased again in deep anesthesia associated with EEG burst suppression. Regional correlation analysis confirmed the breakdown of connectivity within and between specific cortical and subcortical networks with deepening propofol anesthesia. Cortical connectivity was suppressed before subcortical connectivity at a critical propofol dose associated with loss of consciousness.

Effects of perfusion on diffusion changes in human brain tumors.

PURPOSE: To characterize the influence of perfusion on the measurement of diffusion changes over time when ADC is computed using standard two-point methods. MATERIALS AND METHODS: Functional diffusion maps (FDMs), which depict changes in diffusion over time, were compared with rCBV changes in patients with brain tumors. The FDMs were created by coregistering and subtracting ADC maps from two time points and categorizing voxels where ADC significantly increased (iADC), decreased (dADC), or did not change (ncADC). Traditional FDMs (tFDMs) were computed using b = 0,1000 s/mm(2). Flow-compensated FDMs (fcFDMs) were calculated using b = 500,1000 s/mm(2). Perfusion's influence on FDMs was determined by evaluating changes in rCBV in areas where the ADC change significantly differed between the two FDMs. RESULTS: The mean ΔrCBV in voxels that changed from iADC (dADC) on the tFDM to ncADC on the fcFDM was significantly greater (less) than zero. In addition, mean ΔrCBV in iADC (dADC) voxels on the tFDM was significantly higher (lower) than in iADC (dADC) voxels on the fcFDM. CONCLUSION: The ability to accurately identify changes in diffusion on traditional FDMs is confounded in areas where perfusion and diffusion changes are colocalized. Flow-compensated FDMs, which use only non-zero b-values, should therefore be the standard approach.

Early post-bevacizumab change in rCBV from DSC-MRI identifies pseudoresponse in recurrent glioblastoma: Results from ACRIN 6677/RTOG 0625.

Background: Progressive enhancement predicted poor survival in ACRIN 6677/RTOG 0625, a multi-center trial of bevacizumab with irinotecan or temozolomide in recurrent glioblastoma, but pseudoresponse likely limited enhancement-based survival prognostication in T1 non-progressors. We aimed to determine whether early change in cerebral blood volume from baseline (ΔCBV) could further stratify the T1 non-progressors according to overall (OS) and progression-free (PFS) survival. Methods: 37/123 enrolled patients had DSC-MRI, including 13, 15, and 8 patients without 2D-T1 progression at 2, 8, and 16 weeks post-treatment initiation, respectively. Mean CBV normalized to white matter (nRCBV) and mean standardized CBV (sRCBV) were extracted from enhancing tumor. ROC curves were derived for ΔCBV using six-month PFS and one-year OS as reference standards. Kaplan-Meier survival estimates and log-rank test compared PFS and OS for both ΔCBV (increase vs. decrease) and T1 response status (stable vs. decreasing enhancement). Results: PFS and OS were significantly worse for increasing CBV at 2 weeks (p=0.003 and p=0.002 for nRCBV, and p=0.03 and p=0.03 for sRCBV, respectively), but not for 2D-T1 patients with stable vs. decreasing enhancement (p=0.44 and p=0.86, respectively). ΔCBV at week 2 was also a good prognostic marker for OS-1 and PFS-6 using ROC analysis. By contrast, 2D-T1 response status at weeks 2, 8, and 16 was not associated with PFS-6. ΔCBV at 16 weeks (p=0.008 for sRCBV) but not 8 weeks (p=0.74 for nRCBV and p=0.56 for sRCBV) was associated with significant difference in median survival, but no difference in survival was observed for 2D-T1 patients with stable vs. decreasing enhancement at 8 weeks (p=0.69) or 16 weeks (p=0.21). At 16 weeks, OS did not differ significantly between 2D-T1 progressors and 2D-T1 non-progressors with increasing CBV (median survival 3.3 months post week 16 scan vs. 9.2 months, respectively; p=0.13), suggesting that 2D-T1 non-progressors with increasing CBV may have a prognosis like that of 2D-T1 progressors. Conclusion: After 2 weeks of anti-angiogenic therapy, ΔCBV in 2D-T1 non-progressors significantly prognosticated PFS and OS, whereas 2D-T1 response status did not, identifying a subpopulation that benefits from bevacizumab. Combining 2D-T1 progression and ΔCBV may yield a response assessment paradigm with 3-tiered OS stratification.

Magnetic resonance imaging-derived relative cerebral blood volume characteristics in a case of pathologically confirmed neurocysticercosis: illustrative case.

BACKGROUND: Neurocysticercosis (NCC) is a parasitic infection of the brain caused by ingesting water or food contaminated with tapeworm eggs. When it presents as a solitary mass, differentiation from a primary brain tumor on imaging can be difficult. Magnetic resonance imaging (MRI)-derived relative cerebral blood volume (rCBV) is a newer imaging technique used to identify areas of neovascularization in tumors, which may advance the differential diagnosis. OBSERVATIONS: A 25-year-old male presented after a seizure. Computed tomography (CT) and MRI demonstrated a partially enhancing lesion with microcalcifications and vasogenic edema. Follow-up rCBV assessment demonstrated mild hyperperfusion and/or small vessels at the lesional margins consistent with either an intermediate grade glioma or infection. Given the radiological equipoise, surgical accessibility, and differential diagnosis including primary neoplasm, metastatic disease, NCC, and abscess, resection was pursued. The calcified mass was excised en bloc and was confirmed as larval-stage NCC. LESSONS: CT or MRI may not always provide sufficient information to distinguish NCC from brain tumors. Although reports have suggested that rCBV may aid in identifying NCC, here the authors describe a case of pathologically confirmed NCC in which preoperative, qualitative, standardized rCBV findings raised concern for a primary neoplasm. This case documents the first standardized rCBV values reported in a pathologically confirmed case of NCC in the United States.

Potent in vivo efficacy of oral gallium maltolate in treatment-resistant glioblastoma.

Background: Treatment-resistant glioblastoma (trGBM) is an aggressive brain tumor with a dismal prognosis, underscoring the need for better treatment options. Emerging data indicate that trGBM iron metabolism is an attractive therapeutic target. The novel iron mimetic, gallium maltolate (GaM), inhibits mitochondrial function via iron-dependent and -independent pathways. Methods: In vitro irradiated adult GBM U-87 MG cells were tested for cell viability and allowed to reach confluence prior to stereotactic implantation into the right striatum of male and female athymic rats. Advanced MRI at 9.4T was carried out weekly starting two weeks after implantation. Daily oral GaM (50mg/kg) or vehicle were provided on tumor confirmation. Longitudinal MRI parameters were processed for enhancing tumor ROIs in OsiriX 8.5.1 (lite) with Imaging Biometrics Software (Imaging Biometrics LLC). Statistical analyses included Cox proportional hazards regression models, Kaplan-Meier survival plots, linear mixed model comparisons, and t-statistic for slopes comparison as indicator of tumor growth rate. Results: In this study we demonstrate non-invasively, using longitudinal MRI surveillance, the potent antineoplastic effects of GaM in a novel rat xenograft model of trGBM, as evidenced by extended suppression of tumor growth (23.56 mm3/week untreated, 5.76 mm3/week treated, P < 0.001), a blunting of tumor perfusion, and a significant survival benefit (median overall survival: 30 days untreated, 56 days treated; P < 0.001). The therapeutic effect was confirmed histologically by the presence of abundant cytotoxic cellular swelling, a significant reduction in proliferation markers (P < 0.01), and vessel normalization characterized by prominent vessel pruning, loss of branching, and uniformity of vessel lumina. Xenograft tumors in the treatment group were further characterized by an absence of an invasive edge and a significant reduction in both, MIB-1% and mitotic index (P < 0.01 each). Transferrin receptor and ferroportin expression in GaM-treated tumors illustrated cellular iron deprivation. Additionally, treatment with GaM decreased the expression of pro-angiogenic markers (von Willebrand Factor and VEGF) and increased the expression of anti-angiogenic markers, such as Angiopoietin-2. Conclusion: Monotherapy with the iron-mimetic GaM profoundly inhibits trGBM growth and significantly extends disease-specific survival in vivo.

A cross-sectional study to test equivalence of low- versus intermediate-flip angle dynamic susceptibility contrast MRI measures of relative cerebral blood volume in patients with high-grade gliomas at 1.5 Tesla field strength.

Introduction: 1.5 Tesla (1.5T) remain a significant field strength for brain imaging worldwide. Recent computer simulations and clinical studies at 3T MRI have suggested that dynamic susceptibility contrast (DSC) MRI using a 30° flip angle ("low-FA") with model-based leakage correction and no gadolinium-based contrast agent (GBCA) preload provides equivalent relative cerebral blood volume (rCBV) measurements to the reference-standard acquisition using a single-dose GBCA preload with a 60° flip angle ("intermediate-FA") and model-based leakage correction. However, it remains unclear whether this holds true at 1.5T. The purpose of this study was to test this at 1.5T in human high-grade glioma (HGG) patients. Methods: This was a single-institution cross-sectional study of patients who had undergone 1.5T MRI for HGG. DSC-MRI consisted of gradient-echo echo-planar imaging (GRE-EPI) with a low-FA without preload (30°/P-); this then subsequently served as a preload for the standard intermediate-FA acquisition (60°/P+). Both normalized (nrCBV) and standardized relative cerebral blood volumes (srCBV) were calculated using model-based leakage correction (C+) with IBNeuro™ software. Whole-enhancing lesion mean and median nrCBV and srCBV from the low- and intermediate-FA methods were compared using the Pearson's, Spearman's and intraclass correlation coefficients (ICC). Results: Twenty-three HGG patients composing a total of 31 scans were analyzed. The Pearson and Spearman correlations and ICCs between the 30°/P-/C+ and 60°/P+/C+ acquisitions demonstrated high correlations for both mean and median nrCBV and srCBV. Conclusion: Our study provides preliminary evidence that for HGG patients at 1.5T MRI, a low FA, no preload DSC-MRI acquisition can be an appealing alternative to the reference standard higher FA acquisition that utilizes a preload.

Integrated molecular and multiparametric MRI mapping of high-grade glioma identifies regional biologic signatures.

Sampling restrictions have hindered the comprehensive study of invasive non-enhancing (NE) high-grade glioma (HGG) cell populations driving tumor progression. Here, we present an integrated multi-omic analysis of spatially matched molecular and multi-parametric magnetic resonance imaging (MRI) profiling across 313 multi-regional tumor biopsies, including 111 from the NE, across 68 HGG patients. Whole exome and RNA sequencing uncover unique genomic alterations to unresectable invasive NE tumor, including subclonal events, which inform genomic models predictive of geographic evolution. Infiltrative NE tumor is alternatively enriched with tumor cells exhibiting neuronal or glycolytic/plurimetabolic cellular states, two principal transcriptomic pathway-based glioma subtypes, which respectively demonstrate abundant private mutations or enrichment in immune cell signatures. These NE phenotypes are non-invasively identified through normalized K2 imaging signatures, which discern cell size heterogeneity on dynamic susceptibility contrast (DSC)-MRI. NE tumor populations predicted to display increased cellular proliferation by mean diffusivity (MD) MRI metrics are uniquely associated with EGFR amplification and CDKN2A homozygous deletion. The biophysical mapping of infiltrative HGG potentially enables the clinical recognition of tumor subpopulations with aggressive molecular signatures driving tumor progression, thereby informing precision medicine targeting.

Evaluation of combined bevacizumab plus irinotecan therapy in brain tumors using magnetic resonance imaging measures of relative cerebral blood volume.

Frequently, bevacizumab is combined with chemotherapeutics such as irinotecan, motivated by studies showing improved clinical outcomes compared with historical controls. However, no systematic studies have been performed to determine if and how these drugs should be combined for optimal therapeutic response. The purpose of this study was to characterize the temporal combinations of bevacizumab and irinotecan by measuring the contrast-agent enhanced tumor volumes and relative cerebral blood volume using dynamic susceptibility contrast imaging. The studies, performed in the U87 brain tumor model, show a vascular normalization window with bevacizumab monotherapy and are consistent with clinical indications of no additional benefit in the addition of irinotecan to bevacizumab therapy.

High-Grade Glioma Treatment Response Monitoring Biomarkers: A Position Statement on the Evidence Supporting the Use of Advanced MRI Techniques in the Clinic, and the Latest Bench-to-Bedside Developments. Part 1: Perfusion and Diffusion Techniques.

Objective: Summarize evidence for use of advanced MRI techniques as monitoring biomarkers in the clinic, and highlight the latest bench-to-bedside developments. Methods: Experts in advanced MRI techniques applied to high-grade glioma treatment response assessment convened through a European framework. Current evidence regarding the potential for monitoring biomarkers in adult high-grade glioma is reviewed, and individual modalities of perfusion, permeability, and microstructure imaging are discussed (in Part 1 of two). In Part 2, we discuss modalities related to metabolism and/or chemical composition, appraise the clinic readiness of the individual modalities, and consider post-processing methodologies involving the combination of MRI approaches (multiparametric imaging) or machine learning (radiomics). Results: High-grade glioma vasculature exhibits increased perfusion, blood volume, and permeability compared with normal brain tissue. Measures of cerebral blood volume derived from dynamic susceptibility contrast-enhanced MRI have consistently provided information about brain tumor growth and response to treatment; it is the most clinically validated advanced technique. Clinical studies have proven the potential of dynamic contrast-enhanced MRI for distinguishing post-treatment related effects from recurrence, but the optimal acquisition protocol, mode of analysis, parameter of highest diagnostic value, and optimal cut-off points remain to be established. Arterial spin labeling techniques do not require the injection of a contrast agent, and repeated measurements of cerebral blood flow can be performed. The absence of potential gadolinium deposition effects allows widespread use in pediatric patients and those with impaired renal function. More data are necessary to establish clinical validity as monitoring biomarkers. Diffusion-weighted imaging, apparent diffusion coefficient analysis, diffusion tensor or kurtosis imaging, intravoxel incoherent motion, and other microstructural modeling approaches also allow treatment response assessment; more robust data are required to validate these alone or when applied to post-processing methodologies. Conclusion: Considerable progress has been made in the development of these monitoring biomarkers. Many techniques are in their infancy, whereas others have generated a larger body of evidence for clinical application.