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INTRODUCTION Sodium MRI has been recently explored in brain tumors to potentially reveal complementary information with proton MRI about the tumor microenvironment. However, there remains limited investigation combining sodium and quantitative proton MRI techniques. This pilot study explored the associations of sodium MRI with diffusion-, pH-, and hypoxia-weighted MRI biomarkers in gliomas. METHODS Eleven patients with gliomas (n=8 IDH-wild-type; n=3 IDH-mutant) who obtained sodium, anatomical, diffusion-, pH-, and hypoxia-weighted MRI were studied. All images were obtained on a 3T Siemens Prisma with a dedicated multi-nuclear head coil. Regions-of-interest were segmented on the contrast-enhancing (CE) (n=10), FLAIR (n=11), and necrotic regions (n=9). Sodium values were normalized to the mean values of the eyes. Median sodium, apparent diffusion coefficient (ADC), ADC(L) from bimodal histogram analyses, MTRasym (acidity), and R2’ (hypoxia) values were obtained. RESULTS There was increased sodium in necrosis compared to FLAIR regions (mean difference=0.24; P/i>< 0.05) and compared to CE regions (mean difference=0.17; P/i>=0.07). There were significant positive correlations between sodium and ADC in CE (R=0.94; P/i>< 0.0001) and FLAIR regions (ρ=0.77; P/i>< 0.01), but not in necrosis (R=0.44; P/i>=0.24). There was also a significant positive correlation with ADC(L) in CE regions (R=0.90; P< 0.001) but not in FLAIR regions (ρ=0.50; P/i>=0.12). Furthermore, there was a significant positive correlation between sodium and MTRasym in necrosis (R=0.74; P/i>< 0.05) and a positive trend in CE regions (R=0.55; P=0.10). There was also a negative trend between sodium and R2’ in FLAIR regions (ρ=-0.58; P/i>=0.11). CONCLUSIONS Because ADC and ADC(L) are inversely related to cell density, increased sodium in gliomas may reflect increased extracellular space stemming from lower cell density, as sodium concentration is higher extracellularly. Positive associations between sodium and acidity as well as negative associations between sodium and hypoxia may reflect alterations in coupled sodium-pH and sodium-hypoxia homeostasis in gliomas.

In recently published work, we demonstrated that acute inhibition of the EGFR – the most frequently altered oncogene in GBM – can rapidly reduce glycolysis in a subset of GBM. To quantify this effect, we propose a new combination metabolic MR-PET imaging biomarker that combines 18F-FDG PET, DSC perfusion MRI, diffusion MRI, and pH- and oxygen-sensitive amine CEST-SAGE-EPI. Specifically, this “glycolytic index” or GI, can be defined as elevated glucose uptake (18F-FDG standard uptake value), elevated tumor acidity (MTRasym@3ppm), and lower oxygen utilization (relative cerebral metabolic rate of oxygen, rCMRO2, defined as R2’ x rCBF/rCBV from oxygen-sensitive SAGE-EPI and DSC perfusion), normalized to cell density (using ADC from diffusion MRI). In the current study, we explored the use of Tagrisso® (Osimertinib or AZD9291), which has very high brain to plasma ratios (> 1) and has proven effective in CNS metastasis of EGFR mutant lung cancer, as a potential treatment for EGFR amplified recurrent GBM. We have conducted a clinical trial (NCT03732352) to determine whether we observe similar metabolic imaging changes in EGFR mutated or amplified recurrent glioblastoma patients after treatment with osimertinib. Consistent with prior in vitro and in vivo results, treated patients exhibited a reduced glycolytic flux as indicated by reduction in 18F-FDG PET uptake (-3% change in SUV), tumor acidity (-19% change in MTRasym@3ppm) on pH-weighted CEST MRI, and glycolytic index (GI) (-25% change) in EGFR amplified recurrent GBM within 24 hours of treatment. Preliminary data suggests early change in GI correlates with and predicts both PFS (Pearson correlation, R2=0.3463, P=0.0441; Log-rank, P=0.0467) and OS (R2=0.6368, P=0.0019; Log-rank, P=0.0192). These preliminary data establish the scientific premise that a “glycolytic index” created using 18F-FDG PET, DSC perfusion, diffusion MRI, and pH- and oxygen-weighted amine CEST-SAGE-EPI may be an important tool for quantifying and visualizing glycolytic flux in GBM.

BACKGROUND Laser Interstitial Thermal Therapy (LITT) is a novel treatment for brain metastases (BMs), and data regarding radiologic changes and long-term efficacy is sparse. This study explored volumetric changes in responding and non-responding BMs and their associations with lesion-specific progression-free survival (PFS-L). METHODS Patients with BMs treated with LITT were retrospectively enrolled. 3D volumes-of-interest of the contrast-enhancing BM tissue (CE) on pre-, post-LITT, and follow-up MRI scans were obtained. BMs were followed until progression or censoring. PFS-L was determined using the modified RANO criteria to assess treatment efficacy on each lesion. RESULTS Thirty-one BMs (from 30 patients) were preliminarily analyzed. 2 BMs had no follow-up scans. Median follow-up for 29 BMs was 248 days (range 28-2200). Median time to response was 430 days (responders n=7/29), median time to progression was 176 days (progressive disease n=7/29). Pre-LITT CE volume was a predictor of PFS-L (p=0.001), with BMs> 2.5 cc being 14 times more likely to undergo progression. Differences in age and primary tumor site did not impact PFS-L, whereas PFS-L tended to be longer in females (p=0.059), and in frontal and deep grey matter BMs (p=0.11). Post-LITT CE volume was higher than pre-LITT (p< 0.0001, median increase 59%), with no significant differences among responders, stable disease, and progressive disease. In each responding BM, the CE volume shrinkage over time was described by an exponential decay (R2 ranging 0.92-1.0 and half-life ranging 16.55-204 days). All responding BMs showed a pooled exponential decay with R2=0.88 and half-life=75.6 days. CONCLUSIONS Our data suggest that smaller BMs may have improved outcomes from LITT treatment. CE volumes may increase in the early post-procedural scans, possibly due to both inflammatory changes and thermal damage. The characterization of the volumetric changes across time for responding lesions may be useful for an early detection of BMs at risk for progression.

BACKGROUND In a classic DSC perfusion sequence, T1 and T2* leakage effects compete in determining the post-bolus signal, and are influenced by tissue geometry (i.e. cell density, cell size). Different DSC sequences can be variously influenced by these effects, depending on the different degree of T1 weighting and the pre-bolus administration. Multi-echo spin-and-gradient echo (SAGE) perfusion MRI enables to disentangle T2* and T1 components that contribute to the classic DSC curve, and to simultaneously compute DSC and DCE perfusion metrics. METHODS We retrospectively selected patients with: diagnosis of primary brain tumor, availability of SAGE-based DSC perfusion and DWI datasets, availability of histopathological images from targeted biopsies located within contrast-enhancing tissue. Post-processing allowed to distinguish the pure T2* component from the pure T1 component, and to perform a DCE analysis on the latter. Quantitative perfusion MRI measurements were then evaluated with respect to underlying histopathology. RESULTS Histopathological images were available for 22 targeted biopsies (across 10 patients) meeting the inclusion criteria. The following novel MRI quantitative maps were successfully computed voxelwise: ΔR2* at steady state (reflecting T2* leakage effects), ΔR1 at steady state (reflecting T1 leakage effects), transverse relaxivity at tracer equilibrium (TRATE, reflecting the combination of T2* and T1 leakage effects). In addition, Ve and ktrans were computed from the DCE analysis, and the percentage of signal recovery (PSR) was computed from the second echo of the multi-echo DSC (comparable to a classic single-echo DSC sequence). CONCLUSIONS Histopathological validation will assess the usefulness of these novel multi-echo derived quantitative maps for the non-invasive prediction of tumor microstructure. This would be particularly relevant for: 1) differential diagnosis between brain tumors with different cell size and cell density (e.g. lymphoma vs glioblastoma); 2) treatment response assessment (as pre-existing studies proved that cell shrinkage is an early event in treatment response).

BACKGROUND The blood brain barrier (BBB) is a major obstacle to the delivery of chemotherapy to the CNS. Regadenoson is an FDA approved adenosine A2 agonist used for cardiac stress tests. In murine models, it transiently increases BBB permeability to a 70KD dextran. This multi-institutional, NIH funded, Adult Brain Tumor Consortium trial was designed to discover a dose of regadenoson that substantially increases vascular permeability in normal appearing white matter (NAWM) where drug delivery is particularly challenging. METHODS Adults ages 18-45 with supratentorial gliomas at low-risk for regadenoson complications were recruited (n = 7). One patient was treated at each of seven dose levels (from 0.05 to 1.4 mg) that are known to be safe in humans. The primary outcome measure is change in vascular permeability via dynamic contrast enhanced (DCE) perfusion MRI estimates of Ktrans. The primary outcome measure was a 10-fold higher Ktrans in NAWM than reported in literature (Ktrans > 0.04 min-1). Contrast-enhanced T1 subtraction map estimates of change in contrast enhancement and other measurements in normal brain and non-enhancing tumor were quantified. RESULTS Ktrans measures in NAWM averaged 1.13x10-3 ± 0.44x10-3 (SEM) min-1, lower than the target of 0.04 min-1. Normalized, contrast enhanced T1-weighted MR signal intensity in NAWM increased an average of 74.0 ± 22.4% min-1 (SEM) min-1, which was significantly higher than zero (P = 0.0163). Data available from this limited sample failed to meet the target goal in Ktrans increase or change in contrast enhancing signal intensity. CONCLUSION Administration of regadenoson at seven different doses did not significantly elevate Ktrans for gadolinium in NAWM. This data suggests that single doses of regadenoson are unlikely to substantially increase the delivery of therapeutic agents in non-enhancing brain tissue. This trial design is appropriate for further human testing of other regadenoson schedules and other novel approaches aimed at transiently modifying BBB permeability.

Preoperative prediction of isocitrate dehydrogenase mutation status is clinically meaningful, but remains challenging. This study aimed to predict the isocitrate dehydrogenase (IDH) status of gliomas by using the machine learning voxel-wise clustering method of multiparametric physiologic and metabolic magnetic resonance imaging (MRI) and to show the association of the created cluster labels with the glucose metabolism status of the tumors. Sixty-nine patients with diffuse glioma were scanned by pH-sensitive MRI, diffusion-weighted imaging, fluid-attenuated inversion recovery, and contrast-enhanced T1-weighted imaging at 3 T. An unsupervised two-level clustering approach, including the generation of a self-organizing map followed by the K-means clustering, was used for voxel-wise feature extraction from the acquired images. The logarithmic ratio of the labels in each class within tumor regions was applied to a support vector machine to differentiate IDH mutation status. Bootstrapping and leave-one-out cross-validation were used to calculate the area under the curve (AUC) of receiver operating characteristic curves, accuracy, sensitivity, and specificity for evaluating performance. Targeted biopsies were performed for 14 patients to explore the relationship between clustered labels and the expression of key glycolytic proteins determined using immunohistochemistry. The highest prediction performance to differentiate IDH status was found for 10-class clustering, with a mean AUC, accuracy, sensitivity, and specificity of 0.94, 0.91, 0.90, and 0.91, respectively. The tissues with labels 7 + 8 + 9 + 10 showed high expression levels of hypoxia-inducible factor 1-alpha, glucose transporter 3, and hexokinase 2, which are typical of IDH wild-type glioma, whereas those with labels 1 showed low expression of these proteins. Our machine learning model successfully predicted the IDH mutation status of gliomas, and the resulting clusters properly reflected the metabolic status of the tumors.

Hypoxia and tissue acidosis are two key features of the glioma microenvironment, both associated with a more aggressive phenotype through promotion of invasion, angiogenesis, and resistance to a vast number of therapies. In the current study, we demonstrate that higher levels of acidity and hypoxia in glioma are associated with worse prognosis by using simultaneous pH- and oxygen-sensitive amine chemical exchange saturation transfer spin-and-gradient echo echo-planar imaging (CEST-SAGE-EPI). A total of 159 histologically confirmed adult glioma patients (WHO grade II: N = 42; grade III: N = 38; grade IV, N = 79) were retrospectively evaluated. All patients were scanned with a custom amine CEST-SAGE-EPI MRI pulse sequence at 3T. Magnetization transfer ratio asymmetry (MTRasym) at 3ppm was used as a measure of relative acidity, R2’ was used as a surrogate of hypoxia, and their product MTRasym×R2' was used to quantify the degree of both acidity and hypoxia. Cox regression was performed to evaluate prognostic factors for OS and PFS. Univariate results suggested higher hypoxia, R2' (HR = 1.44, p = 0.0002), and higher combined measure of acidity and hypoxia, MTRasym×R2' (HR = 1.14, p = 0.0008), were associated with a shorter OS. When considering age, treatment status, and IDH mutation status as covariates, R2' and MTRasym×R2' remained significantly associated with patient OS (R2': HR = 1.27, p = 0.045; MTRasym×R2': HR = 1.17, p = 0.002). Within the treatment naïve patients, tumor acidity MTRasym, was also associated with OS (HR = 3.72, p = 0.003). R2' and MTRasym×R2' were significantly associated with PFS, both using univariate (R2': p < 0.0001; MTRasym×R2': p < 0.0001) and multivariate analyses including clinical factors (R2': p = 0.010; MTRasym×R2': p < 0.0001). In summary, tumor acidity and hypoxia measured using pH- and oxygen-sensitive metabolic MRI are significant prognostic factors in glioma.

The current study tested the hypotheses that (1) pH-weighted MRI measurements of tumor acidity reflect glycolytic activity in human gliomas, (2) that tumor acidity, and thus glycolytic activity, differs between human IDH mutant (mIDH) and wild type gliomas, and (3) that an increase in tumor acidity, suggestive of increased glycolytic activity, occurs after inhibition of mutant IDH enzyme activity and reduction in 2HG, an oncometabolite. To test these hypotheses, we employed a custom pH-weighted amine chemical exchange saturation transfer echoplanar (CEST-EPI) technique in 152 patients with IDH mutant or wildtype glioma prior to surgery and 11 patients before and after treatment with AG120 or AG881 enrolled at our institution in a phase 1 perioperative study in patients with recurrent, non-enhancing, IDH mutant low-grade gliomas (NCT03343197). Results from image-guided biopsies in more than 100 patients demonstrated a significant correlation between MTRasym at 3ppm, a measure of tumor acidity from pH-weighted amine CEST-EPI, and expression of key glycolytic proteins including GLUT3 (R2=0.2188,P=0.0105), HK2 (R2=0.1788,P=0.0314), LDHA (R2=0.1111,P=0.0071), and MCT1 (R2=0.1228,P=0.0039) as well as ex vivo extracellular flux analysis estimates of ATP consumption from glycolysis (R2=0.6684,P=0.0021). Data suggests a significantly lower acidity (MTRasym@3ppm) within non-enhancing tumor in IDH mutant gliomas when compared to IDH wild type gliomas (P< 0.0001). Patients in a phase 1 perioperative study showed a shift toward higher tumor acidity (i.e. higher glycolytic activity) following inhibition of IDH based on 2HG suppression in resected tumors, but at levels below that of IDH wild type gliomas. Levels of 2HG within the tumor after IDH inhibition were inversely correlated with post-treatment tumor acidity (R2=0.6342, P=0.0180). Overall, results suggest mIDH gliomas have low levels of glycolytic activity, and successful inhibition of the mutant IDH enzyme results in reduction in 2HG and a measurable metabolic shift toward elevated glycolysis as evidenced using pH-weighted molecular MRI.

Diffusion magnetic resonance imaging (MRI) estimates of the apparent diffusion coefficient (ADC) has been revealed to be useful for predicting treatment response in patients with glioblastoma (GBM), with an increase in ADC indicating tumor cell death. The aim of the current study was to investigate whether quantitative changes in diffusion MRI after treatment with immune checkpoint inhibitors (ICI) could predict OS in patients with recurrent GBM. A total of 61 patients were included in this retrospective study with the following inclusion criteria: (i) diagnosis of recurrent GBM treated either with pembrolizumab or nivolumab and (ii) availability of diffusion data in pre- and post-ICI MRI. Tumor volume and median relative apparent diffusion coefficient (rADC) within enhancing tumor with respect to normal-appearing white matter were calculated. Median OS for all patients was 7.6 months (range, 1.0–30.6 months). Results showed that higher post-treatment rADC was associated with significantly longer OS (median, 372 days for rADC ≧ 1.42 versus 211 days for rADC < 1.42; P = 0.01, log-rank test), whereas tumor volume and pre-treatment rADC were not significantly associated with OS. Cox regression analysis revealed post-treatment rADC significantly influences OS (P = 0.02, univariate analysis), even after controlling for age, sex, and IDH status (P = 0.007, multivariate analysis), and additionally controlling for whether surgery was performed after ICI treatment (P = 0.049, multivariate analysis). In conclusion, a high post-treatment rADC may be an early imaging biomarker for identifying OS benefit in recurrent GBM patients receiving ICI treatment.

Ensuring optimal quality of life and functioning is a clinical priority in treating glioma survivors. Cognitive function and mood symptoms are prevalent in this population after treatment and it’s reasonable to consider these as significant contributors to patients’ functioning at work and in daily life. However, it’s unclear the degree to which these symptoms contribute to such outcomes. To address this question, we examined the relationships between cognitive tests (i.e., a neuropsychological battery) and mood measures (i.e., the Beck Depression Inventory-II, and the Beck Anxiety Inventory) and work and daily functioning (i.e., Work Productivity and Activity Impairment Questionnaire). Partial correlation of cognitive tests and regression models also included age and IQ (i.e., Test of Premorbid Functioning). Of the 11 participants who were currently working, worse work productivity was significantly associated with worse processing speed (Stroop color naming r=-.74,p=.03, Stroop color word r=-.78,p=.02). Similarly, worse ability in daily activities was also associated with worse processing speed and executive function (Stroop color naming, r=-.52,p=.04; Stroop color word, r=-.55,p=.03; Trails B, r=-.53,p=.03). Greater depression symptoms were strongly correlated with both worse work productivity (r=.83,p=.002), and worse ability in daily activities (r=.55,p=.01). Depression symptoms were generally uncorrelated with cognitive scores. In linear regression models that included both depression symptoms and cognitive scores, only depression emerged as a significant predictor of work productivity and ability to conduct daily activities. In sum, glioma survivors face multiple threats to work and daily functioning by way of tumor and treatment related symptoms. Our analyses suggest that both cognitive function and mood symptoms are important to consider in optimizing functioning, but depression appears to vastly outweigh cognitive function in this regard. These preliminary findings highlight the importance of careful attention to these symptoms in survivorship and point to future research directions elaborating on these relationships.

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 (MTR(asym)) at 3 ppm and oxygen-sensitive measure of R(2)’ 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 MTR(asym) at 3 ppm, R(2)’, and MTR(asym)xR(2)’ (P = 0.007, P = 0.003, and P = 0.001, respectively). MTR(asym)xR(2)’ could identify IDH1 mutant gliomas with a high sensitivity (81.0%) and specificity (81.3%). HIF1α was positively correlated with MTR(asym) at 3 ppm, R(2)’ and MTR(asym)xR(2)’ in IDH1 wild type (r = 0.610, P = 0.003; r = 0.667, P = 0.008; r = 0.635, P = 0.006), but only MTR(asym)xR(2)’ 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 (MTR(asym)xR(2)’) can differentiate IDH1 mutation status and is correlated with tumor acidity and hypoxia.

Advanced multimodality treatments have led to improved survival and quality of life for patients with diffuse gliomas, and widespread functional reorganization has been reported to be associated with improved cognitive function. However, investigation of morphological alterations in patients with diffuse gliomas has been problematic, largely due to the tumor resection cavities. This pilot study has overcome these challenges and aims to characterize the relationship between structural plasticity and cognitive function in survivors of diffuse gliomas. High-resolution T1 weighted images were collected from 24 patients with diffuse gliomas (mean age 44.5 ± 11.5) who had completed their treatment within the previous ten years. Interregional correlations of cortical thickness were computed to establish morphometric correlation networks (MCN) for twelve cognitively impaired and twelve non-impaired glioma patients, as well as correlated with self-reported cognitive impairment. Our findings demonstrated that both cognitively impaired (σ=1.5979) and non-impaired (σ=1.3683) glioma patients have a small world architecture in disrupted morphological networks. Although the left fusiform (p=0.0409), left inferior (p=0.0209), and temporal (p=0.0173) gyri were observed to be thicker in non-impaired patients, the robustness of their morphological network was weak and easily vulnerable to pathological attacks and neurological deterioration. Furthermore, regions such as the superior temporal gyrus (p=0.0126) and rostral middle frontal gyrus (p=0.0148) were not only identified as predominant nodes in the MCN of patients but were also found to have greater gray matter thickness, which is associated with better FACT-cognitive function. Together, these results support our hypothesis that a widespread morphological network is altered in survivors of diffuse gliomas. Predominant regions obtained by topological analysis may lead to reliable imaging biomarkers that help evaluate patients’ cognition and ability to function.

VB-111 is a non-replicating adenovirus carrying a pro-apoptotic transgene for TNFR1/Fas under the control of a modified murine promoter to pre-proendothelin 1. The transgene is expressed only in angiogenic endothelial cells, and therefore VB-111 results in targeted apoptosis of neovascular vessels. The current study characterizes the quantitative radiographic results and impact on OS in phase 2 and 3 trials of recurrent glioblastoma (GBM) patients treated with VB-111 with or without bevacizumab (BV) or BV monotherapy. MRI data from a phase 2 (NCT01260506) and randomized, double arm, controlled phase 3 (GLOBE; NCT02511405) trial of VB-111 in recurrent GBM were used in current study: Arm A) VB-111 monotherapy until progression followed by combination VB-111 and bevacizumab (BV) (“Primed Combination”; Phase 2; N=24); Arm B) VB-111 in combination with BV (“Unprimed Combination”; Phase 3; N=124); Arm C) BV monotherapy (“Control”; Phase 3; N=120). Contrast enhanced T1-weighted digital subtraction was used to quantify tumor volume at all time points. Baseline tumor volume was prognostic for OS in all treatment groups when controlling for therapy and age (Cox, P< 0.001, HR=1.02). In patients with smaller tumors (< 25mL), the “primed combination” cohort (Arm A) from the phase 2 trial had a significant OS advantage compared to both upfront combination of VB-111 and BV (Arm B; P=0.0094, HR=0.53; median OS = 7 vs. 15mo) as well as BV alone (Arm C; P=0.025, HR=0.58; median OS=8.5 vs. 15mo). Patients with a radiographic response (>65% reduction) had a significant survival difference from non-responders when controlling for age, baseline tumor volume, and treatment arm (P=0.0014, HR=0.58). Responders to VB-111 monotherapy or combination therapy after priming with VB-111 exhibited characteristic, expansive areas of necrosis in areas of initial disease.

Alterations in the PI3K pathway are found in the majority of malignant gliomas, but lack of efficacy has caused investigators to question the viability of this target, particularly due to lack of brain penetration. GDC-0084 was specifically optimized to penetrate the brain, targeting both PI3K and mTOR. Since these two targets alter tumor vascularity and metabolism, respectively, we hypothesized that multi-parametric MR-PET could be used to quantify the response, estimate pharmacokinetic (PK) parameters, and predict progression-free survival (PFS) in patients with recurrent malignant gliomas. In this first-in-man, multicenter, phase I, dose-escalation study (NCT01547546), we show in 47 patients that the measured maximum concentration (Cmax) of GDC0084 was associated with a decrease in enhancing tumor volume (P=0.0287) and an increase in fractional anisotropy (FA) (P=0.0418). Post-treatment tumor volume, 18F-FDG uptake, Ktrans, and relative cerebral blood volume (rCBV) were all correlated with Cmax. A linear combination of change in 18F-FDG PET uptake, apparent diffusion coefficient (ADC), FA, Ktrans, vp, and rCBV were able to estimate both Cmax (R2=0.4113, P< 0.0001) and drug exposure (AUC) (R2=0.3481, P< 0.0001). Using this composite multi-parametric MR-PET imaging response biomarker to predict PK, patients with an estimated Cmax >0.1 uM and AUC > 1.25 uM*hr demonstrated significantly longer PFS compared with patients with a lower estimated concentration and exposure (P=0.0039 and P=0.0296, respectively). Results from the current study suggest composite biomarkers created from multi-parametric MR-PET imaging targeting metabolic and/or physiologic processes specific to the drug mechanism of action may be useful for subsequent evaluation of treatment efficacy for larger phase II-III studies.

Author(s): Ellingson, Benjamin M; Aftab, Dana T; Schwab, Gisela M; Hessel, Colin; Harris, Robert J; Woodworth, Davis C; Leu, Kevin; Chakhoyan, Ararat; Raymond, Catalina; Drappatz, Jan; de Groot, John; Prados, Michael D; Reardon, David A; Schiff, David; Chamberlain, Marc; Mikkelsen, Tom; Desjardins, Annick; Holland, Jaymes; Ping, Jerry; Weitzman, Ron; Wen, Patrick Y; Cloughesy, Timothy F | Abstract: Background:To overcome challenges with traditional response assessment in anti-angiogenic agents, the current study uses T1 subtraction maps to quantify volumetric radiographic response in monotherapy with cabozantinib, an orally bioavailable tyrosine kinase inhibitor with activity against vascular endothelial growth factor receptor 2 (VEGFR2), hepatocyte growth factor receptor (MET), and AXL, in an open-label, phase II trial in patients with recurrent glioblastoma (GBM) (NCT00704288). Methods:A total of 108 patients with adequate imaging data and confirmed recurrent GBM were included in this retrospective study from a phase II multicenter trial of cabozantinib monotherapy (XL184-201) at either 100 mg (N = 87) or 140 mg (N = 21) per day. Contrast enhanced T1-weighted digital subtraction maps were used to define volume of contrast-enhancing tumor at baseline and subsequent follow-up time points. Volumetric radiographic response (g65% reduction in contrast-enhancing tumor volume from pretreatment baseline tumor volume sustained for more than 4 wk) was tested as an independent predictor of overall survival (OS). Results:Volumetric response rate for all therapeutic doses was 38.9% (41.4% and 28.6% for 100 mg and 140 mg doses, respectively). A log-linear association between baseline tumor volume and OS (P = 0.0006) and a linear correlation between initial change in tumor volume and OS (P = 0.0256) were observed. A significant difference in OS was observed between responders (median OS = 20.6 mo) and nonresponders (median OS = 8.0 mo) (hazard ratio [HR] = 0.3050, P l 0.0001). Multivariable analyses showed that continuous measures of baseline tumor volume (HR = 1.0233, P l 0.0001) and volumetric response (HR = 0.2240, P l 0.0001) were independent predictors of OS. Conclusions:T1 subtraction maps provide value in determining response in recurrent GBM treated with cabozantinib and correlated with survival benefit.

PURPOSE: To determine clinically relevant MRI features of various metastatic brain lesions using classical and advanced post-processing techniques of both diffusion and perfusion-weighted MR images. METHODS: One hundred twenty-three brain metastases including breast (27), non-small cell lung cancer (NSCLC, 43) and other (44) were retrospectively assessed prior to radiation treatment with standard anatomical, diffusion and perfusion-weighted MRI. A total of 346 individual lesions were manually segmented. Complementary to tumor volume, apparent diffusion coefficients (ADC) and relative cerebral volume (rCBV) measurements, an independent component analysis (ICA) was performed with dynamic susceptibility contrast (DSC) in order to assess arterio-venous components and their overlap region relative to tumor volume and time to peak of T2* signal from each component. RESULTS: Results suggests that no differences are observable for either ADC or rCBV features (median value) across metastatic subtypes. Interestingly, ICA-derived arterial component was higher in breast and NSCLC compared to other patients, while the venous component was higher in breast compared to all other groups. No difference in the overlap component was observed between groups. Within the other group, we found that overlap has higher volume than venous and arterial components. For other group, the difference between arterial and venous components was as well significant. Median time to peak of arterial and venous components were 8.4s and 12.6s with no differences between lesion types. Additionally, the overlap component was positively related to rCBV in all groups. However, no correlation was found for arterial and venous components with respect to rCBV values. CONCLUSIONS: Advanced ICA-derived component analysis demonstrates perfusion differences in metastatic brain lesions not observable with classical ADC and optimized rCBV post-processing approaches.