Brigatinib in NF2-Related Schwannomatosis with Progressive Tumors.

BACKGROUND: NF2-related schwannomatosis (NF2-SWN, formerly called neurofibromatosis type 2) is a tumor predisposition syndrome that is manifested by multiple vestibular schwannomas, nonvestibular schwannomas, meningiomas, and ependymomas. The condition is relentlessly progressive with no approved therapies. On the basis of preclinical activity of brigatinib (an inhibitor of multiple tyrosine kinases) in NF2-driven nonvestibular schwannoma and meningioma, data were needed on the use of brigatinib in patients with multiple types of progressive NF2-SWN tumors. METHODS: In this phase 2 platform trial with a basket design, patients who were 12 years of age or older with NF2-SWN and progressive tumors were treated with oral brigatinib at a dose of 180 mg daily. A central review committee evaluated one target tumor and up to five nontarget tumors in each patient. The primary outcome was radiographic response in target tumors. Key secondary outcomes were safety, response rate in all tumors, hearing response, and patient-reported outcomes. RESULTS: A total of 40 patients (median age, 26 years) with progressive target tumors (10 vestibular schwannomas, 8 nonvestibular schwannomas, 20 meningiomas, and 2 ependymomas) received treatment with brigatinib. After a median follow-up of 10.4 months, the percentage of tumors with a radiographic response was 10% (95% confidence interval [CI], 3 to 24) for target tumors and 23% (95% CI, 16 to 30) for all tumors; meningiomas and nonvestibular schwannomas had the greatest benefit. Annualized growth rates decreased for all tumor types during treatment. Hearing improvement occurred in 35% (95% CI, 20 to 53) of eligible ears. Exploratory analyses suggested a decrease in self-reported pain severity during treatment (-0.013 units per month; 95% CI, -0.002 to -0.029) on a scale from 0 (no pain) to 3 (severe pain). No grade 4 or 5 treatment-related adverse events were reported. CONCLUSIONS: Brigatinib treatment resulted in radiographic responses in multiple tumor types and clinical benefit in a heavily pretreated cohort of patients with NF2-SWN. (Funded by the Children's Tumor Foundation and others; INTUITT-NF2 ClinicalTrials.gov number, NCT04374305.).

dCas9/CRISPR-based methylation of O-6-methylguanine-DNA methyltransferase enhances chemosensitivity to temozolomide in malignant glioma.

BACKGROUND: Malignant glioma carries a poor prognosis despite current therapeutic modalities. Standard of care therapy consists of surgical resection, fractionated radiotherapy concurrently administered with temozolomide (TMZ), a DNA-alkylating chemotherapeutic agent, followed by adjuvant TMZ. O-6-methylguanine-DNA methyltransferase (MGMT), a DNA repair enzyme, removes alkylated lesions from tumor DNA, thereby promoting chemoresistance. MGMT promoter methylation status predicts responsiveness to TMZ; patients harboring unmethylated MGMT (~60% of glioblastoma) have a poorer prognosis with limited treatment benefits from TMZ. METHODS: Via lentiviral-mediated delivery into LN18 glioma cells, we employed deactivated Cas9-CRISPR technology to target the MGMT promoter and enhancer regions for methylation, as mediated by the catalytic domain of the methylation enzyme DNMT3A. Methylation patterns were examined at a clonal level in regions containing Differentially Methylation Regions (DMR1, DMR2) and the Methylation Specific PCR (MSP) region used for clinical assessment of MGMT methylation status. Correlative studies of genomic and transcriptomic effects of dCas9/CRISPR-based methylation were performed via Illumina 850K methylation array platform and bulk RNA-Seq analysis. RESULTS: We used the dCas9/DNMT3A catalytic domain to achieve targeted MGMT methylation at specific CpG clusters in the vicinity of promoter, enhancer, DMRs and MSP regions. Consequently, we observed MGMT downregulation and enhanced glioma chemosensitivity in survival assays in vitro, with minimal off-target effects. CONCLUSION: dCas9/CRISPR is a viable method of epigenetic editing, using the DNMT3A catalytic domain. This study provides initial proof-of-principle for CRISPR technology applications in malignant glioma, laying groundwork for subsequent translational studies, with implications for future epigenetic editing-based clinical applications.

Imaging as an early biomarker to predict sensitivity to everolimus for progressive NF2-related vestibular schwannoma.

PURPOSE: NF2-related schwannomatosis (NF2) is characterized by bilateral vestibular schwannomas (VS) often causing hearing and neurologic deficits, with currently no FDA-approved drug treatment. Pre-clinical studies highlighted the potential of mTORC1 inhibition in delaying schwannoma progression. We conducted a prospective open-label, phase II study of everolimus for progressive VS in NF2 patients and investigated imaging as a potential biomarker predicting effects on growth trajectory. METHODS: The trial enrolled 12 NF2 patients with progressive VS. Participants received oral everolimus daily for 52 weeks. Brain imaging was obtained quarterly. As primary endpoint, radiographic response (RR) was defined as ≥ 20% decrease in target VS volume. Secondary endpoints included other tumors RR, hearing outcomes, drug safety and quality of life (QOL). RESULTS: Eight participants completed the trial and four discontinued the drug early due to significant volumetric VS progression. After 52 weeks of treatment, the median annual VS growth rate decreased from 77.2% at baseline to 29.4%. There was no VS RR and 3 of 8 (37.5%) participants had stable disease. Decreased or unchanged VS volume after 3 months of treatment was predictive of stabilization at 12 months. Seven of eight participants had stable hearing during treatment except one with a decline in word recognition score. Ten of twelve participants reported only minimal changes to their QOL scores. CONCLUSIONS: Volumetric imaging at 3 months can serve as an early biomarker to predict long-term sensitivity to everolimus treatment. Everolimus may represent a safe treatment option to decrease the growth of NF2-related VS in patients who have stable hearing and neurological condition. TRN: NCT01345136 (April 29, 2011).

Cancer Predisposition Syndromes in Neuro-oncology.

Although most primary central and peripheral nervous system (NS) tumors occur sporadically, there are a subset that may arise in the context of a cancer predisposition syndrome. These syndromes occur due to a pathogenic mutation in a gene that normally functions as a tumor suppressor. With increased understanding of the molecular pathogenesis of these tumors, more people have been identified with a cancer predisposition syndrome. Identification is crucial, as this informs surveillance, diagnosis, and treatment options. Moreover, relatives can also be identified through genetic testing. Although there are many cancer predisposition syndromes that increase the risk of NS tumors, in this review, we focus on three of the most common cancer predisposition syndromes, neurofibromatosis type 1, neurofibromatosis type 2, and tuberous sclerosis complex type 1 and type 2, emphasizing the clinical manifestations, surveillance guidelines, and treatment options.

Amine-weighted chemical exchange saturation transfer magnetic resonance imaging in brain tumors.

Amine-weighted chemical exchange saturation transfer (CEST) magnetic resonance imaging (MRI) is particularly valuable as an amine- and pH-sensitive imaging technique in brain tumors, targeting the intrinsically high concentration of amino acids with exchangeable amine protons and reduced extracellular pH in brain tumors. Amine-weighted CEST MRI contrast is dependent on the glioma genotype, likely related to differences in degree of malignancy and metabolic behavior. Amine-weighted CEST MRI may provide complementary value to anatomic imaging in conventional and exploratory therapies in brain tumors, including chemoradiation, antiangiogenic therapies, and immunotherapies. Continual improvement and clinical testing of amine-weighted CEST MRI has the potential to greatly impact patients with brain tumors by understanding vulnerabilities in the tumor microenvironment that may be therapeutically exploited.

NCCN Guidelines® Insights: Central Nervous System Cancers, Version 2.2022.

The NCCN Guidelines for Central Nervous System (CNS) Cancers focus on management of the following adult CNS cancers: glioma (WHO grade 1, WHO grade 2-3 oligodendroglioma [1p19q codeleted, IDH-mutant], WHO grade 2-4 IDH-mutant astrocytoma, WHO grade 4 glioblastoma), intracranial and spinal ependymomas, medulloblastoma, limited and extensive brain metastases, leptomeningeal metastases, non-AIDS-related primary CNS lymphomas, metastatic spine tumors, meningiomas, and primary spinal cord tumors. The information contained in the algorithms and principles of management sections in the NCCN Guidelines for CNS Cancers are designed to help clinicians navigate through the complex management of patients with CNS tumors. Several important principles guide surgical management and treatment with radiotherapy and systemic therapy for adults with brain tumors. The NCCN CNS Cancers Panel meets at least annually to review comments from reviewers within their institutions, examine relevant new data from publications and abstracts, and reevaluate and update their recommendations. These NCCN Guidelines Insights summarize the panel's most recent recommendations regarding molecular profiling of gliomas.

Multi-nuclear sodium, diffusion, and perfusion MRI in human gliomas.

PURPOSE: There is limited knowledge about the associations between sodium and proton MRI measurements in brain tumors. The purpose of this study was to quantify intra- and intertumoral correlations between sodium, diffusion, and perfusion MRI in human gliomas. METHODS: Twenty glioma patients were prospectively studied on a 3T MRI system with multinuclear capabilities. Three mutually exclusive tumor volumes of interest (VOIs) were segmented: contrast-enhancing tumor (CET), T2/FLAIR hyperintense non-enhancing tumor (NET), and necrosis. Median and voxel-wise associations between apparent diffusion coefficient (ADC), normalized relative cerebral blood volume (nrCBV), and normalized sodium measurements were quantified for each VOI. RESULTS: Both relative sodium concentration and ADC were significantly higher in areas of necrosis compared to NET (P = 0.003 and P = 0.008, respectively) and CET (P = 0.02 and P = 0.02). Sodium concentration was higher in CET compared to NET (P = 0.04). Sodium and ADC were higher in treated compared to treatment-naïve gliomas within NET (P = 0.006 and P = 0.01, respectively), and ADC was elevated in CET (P = 0.03). Median ADC and sodium concentration were positively correlated across patients in NET (r = 0.77, P < 0.0001) and CET (r = 0.84, P < 0.0001), but not in areas of necrosis (r = 0.45, P = 0.12). Median nrCBV and sodium concentration were negatively correlated across patients in areas of NET (r=-0.63, P = 0.003). Similar associations were observed when examining voxel-wise correlations within VOIs. CONCLUSION: Sodium MRI is positively correlated with proton diffusion MRI measurements in gliomas, likely reflecting extracellular water. Unique areas of multinuclear MRI contrast may be useful in future studies to understand the chemistry of the tumor microenvironment.

Simultaneous quantification of perfusion, permeability, and leakage effects in brain gliomas using dynamic spin-and-gradient-echo echoplanar imaging MRI.

OBJECTIVE: To determine the feasibility and biologic correlations of dynamic susceptibility contrast (DSC), dynamic contrast enhanced (DCE), and quantitative maps derived from contrast leakage effects obtained simultaneously in gliomas using dynamic spin-and-gradient-echo echoplanar imaging (dynamic SAGE-EPI) during a single contrast injection. MATERIALS AND METHODS: Thirty-eight patients with enhancing brain gliomas were prospectively imaged with dynamic SAGE-EPI, which was processed to compute traditional DSC metrics (normalized relative cerebral blood flow [nrCBV], percentage of signal recovery [PSR]), DCE metrics (volume transfer constant [Ktrans], extravascular compartment [ve]), and leakage effect metrics: ΔR2,ss* (reflecting T2*-leakage effects), ΔR1,ss (reflecting T1-leakage effects), and the transverse relaxivity at tracer equilibrium (TRATE, reflecting the balance between ΔR2,ss* and ΔR1,ss). These metrics were compared between patient subgroups (treatment-naïve [TN] vs recurrent [R]) and biological features (IDH status, Ki67 expression). RESULTS: In IDH wild-type gliomas (IDHwt-i.e., glioblastomas), previous exposure to treatment determined lower TRATE (p = 0.002), as well as higher PSR (p = 0.006), Ktrans (p = 0.17), ΔR1,ss (p = 0.035), ve (p = 0.006), and ADC (p = 0.016). In IDH-mutant gliomas (IDHm), previous treatment determined higher Ktrans and ΔR1,ss (p = 0.026). In TN-gliomas, dynamic SAGE-EPI metrics tended to be influenced by IDH status (p ranging 0.09-0.14). TRATE values above 142 mM-1s-1 were exclusively seen in TN-IDHwt, and, in TN-gliomas, this cutoff had 89% sensitivity and 80% specificity as a predictor of Ki67 > 10%. CONCLUSIONS: Dynamic SAGE-EPI enables simultaneous quantification of brain tumor perfusion and permeability, as well as mapping of novel metrics related to cytoarchitecture (TRATE) and blood-brain barrier disruption (ΔR1,ss), with a single contrast injection. CLINICAL RELEVANCE STATEMENT: Simultaneous DSC and DCE analysis with dynamic SAGE-EPI reduces scanning time and contrast dose, respectively alleviating concerns about imaging protocol length and gadolinium adverse effects and accumulation, while providing novel leakage effect metrics reflecting blood-brain barrier disruption and tumor tissue cytoarchitecture. KEY POINTS: • Traditionally, perfusion and permeability imaging for brain tumors requires two separate contrast injections and acquisitions. • Dynamic spin-and-gradient-echo echoplanar imaging enables simultaneous perfusion and permeability imaging. • Dynamic spin-and-gradient-echo echoplanar imaging provides new image contrasts reflecting blood-brain barrier disruption and cytoarchitecture characteristics.

The Future Glioblastoma Clinical Trials Landscape: Early Phase 0, Window of Opportunity, and Adaptive Phase I-III Studies.

PURPOSE OF REVIEW: Innovative clinical trial designs for glioblastoma (GBM) are needed to expedite drug discovery. Phase 0, window of opportunity, and adaptive designs have been proposed, but their advanced methodologies and underlying biostatistics are not widely known. This review summarizes phase 0, window of opportunity, and adaptive phase I-III clinical trial designs in GBM tailored to physicians. RECENT FINDINGS: Phase 0, window of opportunity, and adaptive trials are now being implemented for GBM. These trials can remove ineffective therapies earlier during drug development and improve trial efficiency. There are two ongoing adaptive platform trials: GBM Adaptive Global Innovative Learning Environment (GBM AGILE) and the INdividualized Screening trial of Innovative GBM Therapy (INSIGhT). The future clinical trials landscape in GBM will increasingly involve phase 0, window of opportunity, and adaptive phase I-III studies. Continued collaboration between physicians and biostatisticians will be critical for implementing these trial designs.

Caregiver survey in glioblastoma focused on cognitive dysfunction: development and results from a multicenter study.

Aim: To develop a cognitive dysfunction (CD) focused questionnaire to evaluate caregiver burden in glioblastoma. Materials & methods: The survey was developed from stakeholder consultations and a pilot study, and disseminated at eight US academic cancer centers. Caregivers self-reported caring for an adult with glioblastoma and CD. Results: The 89-item survey covered demographics, CD symptoms and caregiver burden domains. Among 185 caregivers, most were white, educated females and reported memory problems as the most common CD symptom. An exposure-effect was observed, with increase in number of CD symptoms significantly associated with greater caregiver burden. Conclusion: This questionnaire could guide caregiver interventions and be adapted for use longitudinally, in community cancer settings, and in patients with brain metastases.

Glioblastoma (GBM) is a very aggressive brain cancer. People who have GBM have trouble remembering things and are unable to do things they used to do. These changes can be very hard. Researchers are trying to better understand what it is like for people who take care of people with GBM (or caregivers). In this study, researchers created a new survey for caregivers. The survey included questions about what caregivers see happening in their loved one with GBM. Caregivers said that memory problems were common. Also, when the patient had more problems the caregiver had a harder time, too. Researchers hope to improve the survey and use it in the future for more studies.

The dopamine receptor antagonist trifluoperazine prevents phenotype conversion and improves survival in mouse models of glioblastoma.

Glioblastoma (GBM) is the deadliest adult brain cancer, and all patients ultimately succumb to the disease. Radiation therapy (RT) provides survival benefit of 6 mo over surgery alone, but these results have not improved in decades. We report that radiation induces a glioma-initiating cell phenotype, and we have identified trifluoperazine (TFP) as a compound that interferes with this phenotype conversion. TFP causes loss of radiation-induced Nanog mRNA expression, and activation of GSK3 with consecutive posttranslational reduction in p-Akt, Sox2, and ß-catenin protein levels. TFP did not alter the intrinsic radiation sensitivity of glioma-initiating cells (GICs). Continuous treatment with TFP and a single dose of radiation reduced the number of GICs in vivo and prolonged survival in syngeneic and patient-derived orthotopic xenograft (PDOX) mouse models of GBM. Our findings suggest that the combination of a dopamine receptor antagonist with radiation enhances the efficacy of RT in GBM by preventing radiation-induced phenotype conversion of radiosensitive non-GICs into treatment-resistant, induced GICs (iGICs).

Caregiver burden by treatment and clinical characteristics of patients with glioblastoma.

BACKGROUND: Glioblastoma is an incurable disease with a poor prognosis. For caregivers of people with glioblastoma, the burden of care can be high. Patients often present with different clinical characteristics, which may impact caregiver burden in different ways. This study aimed to evaluate associations between patient clinical characteristics and caregiver burden/quality of life (QoL). METHODS: Caregiver-patient dyads were enrolled at 7 academic cancer centers in the United States. Eligible caregiver participants were self-reported as the primary caregiver of an adult living with glioblastoma and completed a caregiver burden survey. Eligible patients were age ≥ 18 years at glioblastoma diagnosis and alive when their respective caregiver entered the study, with the presence of cognitive dysfunction confirmed by the caregiver. Data were analyzed with descriptive statistics and multivariable analyses. RESULTS: The final cohort included 167 dyads. Poor patient performance status resulted in patient difficulty with mental tasks, more caregiving tasks, and increased caregiving time. Language problems were reported in patients with left-sided lesions. Patient confusion was negatively associated with all caregiver domains: emotional health, social health, general health, ability to work, confidence in finances, and overall QoL. Better caregiver QoL was observed in patients with frontal lobe lesions versus non-frontal lobe lesions. CONCLUSION: This study reinforced that patient performance status is a critical clinical factor that significantly affects caregiver burden, caregiving tasks, and caregiver time. Additionally, patient confusion affects multiple facets of caregiver burden/QoL. These results could be used to support guided intervention for caregiver support, customized to the patient experience.

Preferential tumor localization in relation to 18F-FDOPA uptake for lower-grade gliomas.

PURPOSE: Although tumor localization and 3,4-dihydroxy-6-18F-fluoro-L-phenylalanine (FDOPA) uptake may have an association, preferential tumor localization in relation to FDOPA uptake is yet to be investigated in lower-grade gliomas (LGGs). This study aimed to identify differences in the frequency of tumor localization between FDOPA hypometabolic and hypermetabolic LGGs using a probabilistic radiographic atlas. METHODS: Fifty-one patients with newly diagnosed LGG (WHO grade II, 29; III, 22; isocitrate dehydrogenase wild-type, 21; mutant 1p19q non-codeleted,16; mutant codeleted, 14) who underwent FDOPA positron emission tomography (PET) were retrospectively selected. Semiautomated tumor segmentation on FLAIR was performed. Patients with LGGs were separated into two groups (FDOPA hypometabolic and hypermetabolic LGGs) according to the normalized maximum standardized uptake value of FDOPA PET (a threshold of the uptake in the striatum) within the segmented regions. Spatial normalization procedures to build a 3D MRI-based atlas using each segmented region were validated by an analysis of differential involvement statistical mapping. RESULTS: Superimposition of regions of interest showed a high number of hypometabolic LGGs localized in the frontal lobe, while a high number of hypermetabolic LGGs was localized in the insula, putamen, and temporal lobe. The statistical mapping revealed that hypometabolic LGGs occurred more frequently in the superior frontal gyrus (close to the supplementary motor area), while hypermetabolic LGGs occurred more frequently in the insula. CONCLUSION: Radiographic atlases revealed preferential frontal lobe localization for FDOPA hypometabolic LGGs, which may be associated with relatively early detection.

Relative oxygen extraction fraction (rOEF) MR imaging reveals higher hypoxia in human epidermal growth factor receptor (EGFR) amplified compared with non-amplified gliomas.

PURPOSE: Epidermal growth factor receptor (EGFR) amplification promotes gliomagenesis and is linked to lack of oxygen within the tumor microenvironment. Using hypoxia-sensitive spin-and-gradient echo echo-planar imaging and perfusion MRI, we investigated the influence of EGFR amplification on tissue oxygen availability and utilization in human gliomas. METHODS: This study included 72 histologically confirmed EGFR-amplified and non-amplified glioma patients. Reversible transverse relaxation rate (R2'), relative cerebral blood volume (rCBV), and relative oxygen extraction fraction (rOEF) were calculated for the contrast-enhancing and non-enhancing tumor regions. Using Student t test or Wilcoxon rank-sum test, median R2', rCBV, and rOEF were compared between EGFR-amplified and non-amplified gliomas. ROC analysis was performed to assess the ability of imaging characteristics to discriminate EGFR amplification status. Overall survival (OS) was determined using univariate and multivariate cox models. Kaplan-Meier survival curves were plotted and compared using the log-rank test. RESULTS: EGFR amplified gliomas exhibited significantly higher median R2' and rOEF than non-amplified gliomas. ROC analysis suggested that R2' (AUC = 0.7190; P = 0.0048) and rOEF (AUC = 0.6959; P = 0.0156) could separate EGFR status. Patients with EGFR-amplified gliomas had a significantly shorter OS than non-amplified patients. Univariate cox regression analysis determined both R2' and rOEF significantly influence OS. No significant difference was observed in rCBV between patient cohorts nor was rCBV found to be an effective differentiator of EGFR status. CONCLUSION: Imaging of tumor oxygen characteristics revealed EGFR-amplified gliomas to be more hypoxic and contribute to shorter patient survival than EGFR non-amplified gliomas.

Diffusion MRI changes in the anterior subventricular zone following chemoradiation in glioblastoma with posterior ventricular involvement.

INTRODUCTION: There is growing evidence that the subventricular zone (SVZ) plays a key role in glioblastoma (GBM) tumorigenesis. However, little is known regarding how the SVZ, which is a harbor for adult neural stem cells, may be influenced by chemoradiation. The current diffusion-weighted imaging (DWI) study explored ipsilateral and contralateral alterations in the anterior SVZ in GBM patients with posterior enhancing lesions following chemoradiation. METHODS: Forty GBM patients with tumor involvement in the posterior SVZ (mean age = 57 ± 10; left-hemisphere N = 25; right-hemisphere N = 15) were evaluated using DWI before and after chemoradiation. Regions-of-interest were drawn on the ipsilesional and contralesional anterior SVZ on apparent diffusion coefficient (ADC) maps for both timepoints. ADC histogram analysis was performed by modeling a bimodal, double Gaussian distribution to obtain ADCL, defined as the mean of the lower Gaussian distribution. RESULTS: The ipsilesional SVZ had lower ADCL values compared to the contralesional SVZ before treatment (mean difference = 0.025 µm2/ms; P = 0.007). Following chemoradiation, these changes were no longer observed (mean difference = 0.0025 µm2/ms; P > 0.5), as ADCL values of the ipsilesional SVZ increased (mean difference = 0.026 µm2/ms; P = 0.037). An increase in ipsilesional ADCL was associated with shorter progression-free (P = 0.0119) and overall survival (P = 0.0265). CONCLUSIONS: These preliminary observations suggest baseline asymmetry as well as asymmetric changes in the SVZ proximal (ipsilesional) to the tumor with respect to contralesional SVZ regions may be present in GBM, potentially implicating this region in tumorigenesis and/or treatment resistance.

Rate of change in maximum 18F-FDOPA PET uptake and non-enhancing tumor volume predict malignant transformation and overall survival in low-grade gliomas.

PURPOSE: To examine whether the rate of change in maximum 18F-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 18F-FDOPA PET and MRI scans. METHODS: 27 LGG patients with ≥ 2 18F-FDOPA PET and MRI scans between 2003 and 2016 were included. The rate of change in FLAIR volume (uL/day) and maximum normalized 18F-FDOPA specific uptake value (nSUVmax/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 18F-FDOPA nSUVmax 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 18F-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.

Multiparametric MR-PET measurements in hypermetabolic regions reflect differences in molecular status and tumor grade in treatment-naïve diffuse gliomas.

PURPOSE: To assess whether hypermetabolically-defined regions of interest (ROIs) on 3,4-dihydroxy-6-[18F]-fluoro-L-phenylalanine (FDOPA) positron emission tomography (PET) could be used to evaluate physiological features and whether there are measurable differences between molecular subtypes and tumor grades. METHODS: Sixty-eight treatment-naïve glioma patients who underwent FDOPA PET and magnetic resonance imaging (MRI) were retrospectively included. Fluid-attenuated inversion recovery hyperintense regions (FLAIRROI) were segmented. FDOPA hypermetabolic regions (FDOPAROI, tumor-to-striatum ratios > 1) within FLAIRROI were extracted. Normalized maximum standardized uptake value (nSUVmax), volume of each ROI, and median relative cerebral blood volume (rCBV) and apparent diffusion coefficient (ADC) within FLAIRROI or FDOPAROI were calculated. Imaging metrics were compared using Students t or Mann-Whitney U tests. Area under the curve (AUC) of receiver-operating characteristic curves were used to determine whether imaging metrics within FLAIRROI or FDOPAROI can discriminate different molecular statuses or grades. RESULTS: Using either FLAIRROI or FDOPAROI, the nSUVmax and rCBV were significantly higher and the ADC was lower in isocitrate dehydrogenase (IDH) wild-type than mutant gliomas, and in higher-grade gliomas (HGGs) than lower-grade gliomas (LGGs). The FDOPAROI volume was significantly higher in 1p19q codeleted than non-codeleted gliomas, and in HGGs than LGGs. Although not significant, imaging metrics extracted by FDOPAROI discriminated molecular status and tumor grade more accurately than those extracted by FLAIRROI (AUC of IDH status, 0.87 vs. 0.82; 1p19q status, 0.78 vs. 0.73; grade, 0.87 vs. 0.76). CONCLUSION: FDOPA hypermetabolic ROI may extract useful imaging features of gliomas, which can illuminate biological differences between different molecular status or tumor grades.

pH-weighted amine chemical exchange saturation transfer echoplanar imaging (CEST-EPI) as a potential early biomarker for bevacizumab failure in recurrent glioblastoma.

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 (MTRasym) 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 MTRasym 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 (ΔMTRasym 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 MTRasym 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.

Surgery versus stereotactic radiosurgery for the treatment of multiple meningiomas in neurofibromatosis type 2: illustrative case and systematic review.

Neurofibromatosis type 2 (NF2) is a genetic neoplastic disorder that presents with hallmark bilateral vestibular schwannomas and multiple meningiomas. Though the current standard of care for meningiomas includes surgery, the multiplicity of meningiomas in NF2 patients renders complete resection of all developing lesions infeasible. Stereotactic radiosurgery (SRS) may be a viable non-invasive therapeutic alternative to surgery. We describe a particularly challenging case in a 39-year-old male with over 120 lesions who underwent more than 30 surgical procedures, and review the literature. We also searched three popular databases and compared outcomes of SRS versus surgery for the treatment of multiple meningiomas in patients with NF2. A total of 50 patients (27 radiosurgical and 23 surgical) were identified. For patients treated with SRS, local tumor control was achieved in 22 patients (81.5%) and distal control was achieved in 14 patients (51.8%). No malignant inductions were observed at an average follow-up duration of 90 months. Complications in the SRS-treated cohort were reported in 9 patients (33%). Eight patients (29.6%) died due to disease progression. Six patients experienced treatment failure and required further management. For NF2 patients treated with surgery, 11 patients (48%) showed tumor recurrence and 10 patients (43.5%) died due to neurological complications. SRS may be a safe and effective alternative for NF2-associated meningiomas. Further studies are required to identify the ideal radiosurgical candidate.

Simultaneous pH-sensitive and oxygen-sensitive MRI of human gliomas at 3 T using multi-echo amine proton chemical exchange saturation transfer spin-and-gradient echo echo-planar imaging (CEST-SAGE-EPI).

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 (MTRasym ) 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 MTRasym and R2' in normal-appearing white matter, T2 hyperintensity, contrast enhancement, and macroscopic necrosis were measured in 47 gliomas. RESULTS: Simulation and phantom results confirmed an increase in MTRasym with decreasing pH. The CEST-SAGE-EPI estimates of R2 , R2*, and R2' varied linearly with gadolinium diethylenetriamine penta-acetic acid concentration (R2 = 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 R2 (R2 = 0.9943) and multi-echo gradient-echo estimates of R2* (R2 = 0.9727) were highly correlated. T2 lesions had lower R2' and higher MTRasym compared with normal-appearing white matter, suggesting lower hypoxia and high acidity, whereas contrast-enhancement tumor regions had elevated R2' and MTRasym , 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 B0 correction, and simultaneous estimation of CEST effects, R2 , R2*, and R2' at 3 T.