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OBJECTIVE Meningioma prognostication and treatment continues to evolve with an increasing understanding of tumor biology. In this study, the authors aimed to test conventional predictors of meningioma recurrence, histopathology variables for which there exists some controversy (brain invasion), as well as a novel molecular-based location paradigm. METHODS This is a retrospective study of a consecutive series of patients with WHO grade I–III meningioma resected at The University of Texas Southwestern Medical Center between 1994 and 2015. Time to meningioma recurrence (i.e., recurrence-free survival [RFS]) was the primary endpoint measured. Kaplan-Meier curves were constructed and compared using log-rank tests. Cox univariate and multivariate analyses were performed to identify predictors of RFS. RESULTS A total of 703 consecutive patients with meningioma underwent resection at The University of Texas Southwestern Medical Center between the years 1994 and 2015. A total of 158 patients were excluded for insufficient follow-up (< 3 months). The median age of the cohort was 55 years (range 16–88 years) and 69.5% (n = 379) were female. The median follow-up was 48 months (range 3–289 months). There was not a significantly increased risk of recurrence in patients with evidence of brain invasion, in patients with otherwise WHO grade I meningioma (Cox univariate HR 0.92, 95% CI 0.44–1.91, p = 0.82, power 4.4%). Adjuvant radiosurgery to subtotally resected WHO grade I meningiomas did not prolong the time to recurrence (n = 52, Cox univariate HR 0.21, 95% CI 0.03–1.61, p = 0.13, power 71.6%). Location (midline skull base, lateral skull base, and paravenous) was significantly associated with RFS (p < 0.01, log-rank test). In patients with high-grade meningiomas (WHO grade II or III), location was predictive of RFS (p = 0.03, log-rank test), with paravenous meningiomas exhibiting the highest rates of recurrence. Location was not significant on multivariate analysis. CONCLUSIONS The data suggest that brain invasion does not increase the risk of recurrence in otherwise WHO grade I meningioma. Adjuvant radiosurgery to subtotally resected WHO grade I meningiomas did not prolong the time to recurrence. Location categorized by distinct molecular signatures did not predict RFS in a multivariate model. Larger studies are needed to confirm these findings.

Supplementary Data from The Telomerase Antagonist, Imetelstat, Efficiently Targets Glioblastoma Tumor-Initiating Cells Leading to Decreased Proliferation and Tumor Growth

Purpose: Telomerase activity is one of the hallmarks of cancer and is a highly relevant therapeutic target. The effects of a novel human telomerase antagonist, imetelstat, on primary human glioblastoma (GBM) tumor-initiating cells were investigated in vitro and in vivo.Experimental Design: Tumor-initiating cells were isolated from primary GBM tumors and expanded as neurospheres in vitro. The GBM tumor-initiating cells were treated with imetelstat and examined for the effects on telomerase activity levels, telomere length, proliferation, clonogenicity, and differentiation. Subsequently, mouse orthotopic and subcutaneous xenografts were used to assess the in vivo efficacy of imetelstat.Results: Imetelstat treatment produced a dose-dependent inhibition of telomerase (IC50 0.45 μmol/L). Long-term imetelstat treatment led to progressive telomere shortening, reduced rates of proliferation, and eventually cell death in GBM tumor-initiating cells. Imetelstat in combination with radiation and temozolomide had a dramatic effect on cell survival and activated the DNA damage response pathway. Imetelstat is able to cross the blood-brain barrier in orthotopic GBM xenograft tumors. Fluorescently labeled GBM tumor cells isolated from orthotopic tumors, following systemic administration of imetelstat (30 mg/kg every day for three days), showed ∼70% inhibition of telomerase activity. Chronic systemic treatment produced a marked decrease in the rate of xenograft subcutaneous tumor growth.Conclusion: This preclinical study supports the feasibility of testing imetelstat in the treatment of GBM patients, alone or in combination with standard therapies. Clin Cancer Res; 16(1); 154–63

Nuclear factor-κB (NF-κB) activation may play an important role in the pathogenesis of cancer and also in resistance to treatment. Inactivation of the p53 tumor suppressor is a key component of the multistep evolution of most cancers. Links between the NF-κB and p53 pathways are under intense investigation. In this study, we show that the receptor interacting protein 1 (RIP1), a central component of the NF-κB signaling network, negatively regulates p53 tumor suppressor signaling. Loss of RIP1 from cells results in augmented induction of p53 in response to DNA damage, whereas increased RIP1 level leads to a complete shutdown of DNA damage–induced p53 induction by enhancing levels of cellular mdm2. The key signal generated by RIP1 to up-regulate mdm2 and inhibit p53 is activation of NF-κB. The clinical implication of this finding is shown in glioblastoma, the most common primary malignant brain tumor in adults. We show that RIP1 is commonly overexpressed in glioblastoma, but not in grades II and III glioma, and increased expression of RIP1 confers a worse prognosis in glioblastoma. Importantly, RIP1 levels correlate strongly with mdm2 levels in glioblastoma. Our results show a key interaction between the NF-κB and p53 pathways that may have implications for the targeted treatment of glioblastoma. [Cancer Res 2009;69(7):2809–16]

Therapeutic inhibition of mammalian target of rapamycin (mTOR) in cancer is complicated by the existence of a negative feedback loop linking mTOR to the phosphatidylinositol 3-kinase (PI3K)-Akt pathway. Thus, mTOR inhibition by rapamycin or TSC1/2 results in increased PI3K-Akt activation. The death domain kinase receptor interacting protein 1 (RIP1) plays a key role in nuclear factor-κB (NF-κB) activation and also activates the PI3K-Akt pathway through unknown mechanisms. RIP1 has recently been found to be overexpressed in glioblastoma multiforme, the most common adult primary malignant brain tumor, but not in grade II to III glioma. Our data suggest that RIP1 activates PI3K-Akt using dual mechanisms by removing the two major brakes on PI3K-Akt activity. First, increased expression of RIP1 activates PI3K-Akt by interrupting the mTOR negative feedback loop. However, unlike other signals that regulate mTOR activity without affecting its level, RIP1 negatively regulates mTOR transcription via a NF-κB–dependent mechanism. The second mechanism used by RIP1 to activate PI3K-Akt is down-regulation of cellular PTEN levels, which appears to be independent of NF-κB activation. The clinical relevance of these findings is highlighted by the demonstration that RIP1 levels correlate with activation of Akt in glioblastoma multiforme. Thus, our study shows that RIP1 regulates key components of the PTEN-PI3K-Akt-mTOR pathway and elucidates a novel negative regulation of mTOR signaling at the transcriptional level by the NF-κB pathway. Our data suggest that the RIP1-NF-κB status of tumors may influence response to treatments targeting the PTEN-PI3K-mTOR signaling axis. [Cancer Res 2009;69(10):4107–11]

Supplementary Figures 1-5 from RIP1 Activates PI3K-Akt via a Dual Mechanism Involving NF-κB–Mediated Inhibition of the mTOR-S6K-IRS1 Negative Feedback Loop and Down-regulation of PTEN

Purpose Subependymomas located within the 4th ventricle are rare, and the literature describing imaging characteristics is sparse. Here, we describe the clinical and radiological characteristics of 29 patients with 4th ventricle subependymoma. Methods This is a retrospective multi-center study performed after Institutional Review Board (IRB) approval. Patients diagnosed with suspected 4th ventricle subependymoma were identified. A review of clinical, radiology, and pathology reports along with magnetic resonance imaging (MRI) images was performed. Results Twenty-nine patients, including 6 females, were identified. Eighteen patients underwent surgery with histopathological confirmation of subependymoma. The median age at diagnosis was 52 years. Median tumor volume for the operative cohort was 9.87 cm3, while for the non-operative cohort, it was 0.96 cm3. Thirteen patients in the operative group exhibited symptoms at diagnosis. For the total cohort, the majority of subependymomas (n = 22) were isointense on T1, hyperintense (n = 22) on T2, and enhanced (n = 24). All tumors were located just below the body of the 4th ventricle, terminating near the level of the obex. Fourteen cases demonstrated extension of tumor into foramen of Magendie or Luschka. Conclusion To the best of our knowledge, this is the largest collection of 4th ventricular subependymomas with imaging findings reported to date. All patients in this cohort had tumors originating between the bottom of the body of the 4th ventricle and the obex. This uniform and specific site of origin aids with imaging diagnosis and may infer possible theories of origin.

Purpose 1 H MRS provides a noninvasive tool for identifying mutations in isocitrate dehydrogenase (IDH). Quantification of the prominent 2-hydroxyglutarate (2HG) resonance at 2.25 ppm is often confounded by the lipid resonance at the same frequency in tumors with elevated lipids. We propose a new spectral fitting approach to separate these overlapped signals, therefore, improving 2HG evaluation. Methods TE 97 ms PRESS was acquired at 3T from 42 glioma patients. New lipid basis sets were created, in which the small lipid 2.25-ppm signal strength was preset with reference to the lipid signal at 0.9 ppm, incorporating published fat relaxation data. LCModel fitting using the new lipid bases (Fitting method 2) was conducted along with fitting using the LCModel built-in lipid basis set (Fitting method 1), in which the lipid 2.25-ppm signal is assessed with reference to the lipid 1.3-ppm signal. In-house basis spectra of low-molecular-weight metabolites were used in both fitting methods. Results Fitting method 2 showed marked improvement in identifying IDH mutational status compared with Fitting method 1. 2HG estimates from Fitting method 2 were overall smaller than those from Fitting method 1, which was because of differential assignment of the signal at 2.25 ppm to lipids. In receiver operating characteristic analysis, Fitting method 2 provided a complete distinction between IDH mutation and wild-type whereas Fitting method 1 did not. Conclusion The data suggest that 1 H MR spectral fitting using the new lipid basis set provides a robust fitting strategy that improves 2HG evaluation in brain tumors with elevated lipids.

Glioblastoma (GBM) multiforme is the most aggressive type of brain cancer. These lethal brain tumors are characterized by the inter- and intra-tumor molecular heterogeneity and diverse cell plasticity. We sought to interrogate the immune landscape of GBM, tease out the distinct biological and therapeutic niches in GBM and to understand how the tumor microenvironments mediated the heterogeneity of GBM. We have collected six human GBM samples for spatial profiling and single-nucleus RNA sequencing. Multiple sets of spatial gene panels were designed to capture the cell identities (cancer stem cells, astrocytes, oligodendrocytes, microglia, macrophages, endothelial cells, etc.) and the spatially-resolved expression patterns of genes indicative of different functional states. We also aim to find altered neurovascular units by examining the spatial correlation between cells that highly express angiogenesis markers such as VEGFA with tumor-associated macrophages, which could be recruited to the angiogenic niche by GBM tumor cells. From the spatial RNA dataset of the first two samples, we observed close proximity of tumor-associated macrophages and endothelial cells that form the microvasculature. Our preliminary results from the single-nucleus RNA sequencing and spatial transcriptomics of two samples shed light on the complex cell landscape and the dynamic interaction between tumor cells and infiltrating or resident immune cells in the GBM tumor tissue. Citation Format: Yue Hao, Angela Baker, Brian Hilbush, Marcos Otero, Chris Streck, Karen L. Fink, George J. Snipes, Bruce E. Mickey, Michael Berens. Spatial and single-nucleus transcriptomics of human glioblastoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6779.

Background One of the most important recent discoveries in brain glioma biology has been the identification of the isocitrate dehydrogenase (IDH) mutation and 1p/19q co-deletion status as markers for therapy and prognosis. 1p/19q co-deletion is the defining genomic marker for oligodendrogliomas and confers a better prognosis and treatment response than gliomas without it. Our group has previously developed a highly accurate deep-learning network for determining IDH mutation status using T2-weighted (T2w) MRI only. The purpose of this study was to develop a similar 1p/19q deep-learning classification network. Methods Multiparametric brain MRI and corresponding genomic information were obtained for 368 subjects from The Cancer Imaging Archive and The Cancer Genome Atlas. 1p/19 co-deletions were present in 130 subjects. Two-hundred and thirty-eight subjects were non-co-deleted. A T2w image-only network (1p/19q-net) was developed to perform 1p/19q co-deletion status classification and simultaneous single-label tumor segmentation using 3D-Dense-UNets. Three-fold cross-validation was performed to generalize the network performance. Receiver operating characteristic analysis was also performed. Dice scores were computed to determine tumor segmentation accuracy. Results 1p/19q-net demonstrated a mean cross-validation accuracy of 93.46% across the 3 folds (93.4%, 94.35%, and 92.62%, SD = 0.8) in predicting 1p/19q co-deletion status with a sensitivity and specificity of 0.90 ± 0.003 and 0.95 ± 0.01, respectively and a mean area under the curve of 0.95 ± 0.01. The whole tumor segmentation mean Dice score was 0.80 ± 0.007. Conclusion We demonstrate high 1p/19q co-deletion classification accuracy using only T2w MR images. This represents an important milestone toward using MRI to predict glioma histology, prognosis, and response to treatment.

Enhanced understanding of the molecular features of glioma has led to an expansion of murine glioma models and successful preclinical studies. However, clinical trials continue to have a high cost, extended production time, and low proportion of success. Studies in large-animal models of various cancer types have emerged to bridge the translational gap between in vitro and in vivo animal studies and human clinical trials. The anatomy and physiology of large animals are of more direct relevance to human disease, allowing for more rigorous testing of treatments such as surgical resection and adjuvant therapy in glioma. The recent generation of multiple porcine glioma models supports their use in high-throughput preclinical studies. The demonstration of spontaneous glioblastoma formation in canines further provides a unique avenue for the study of de novo glioma. The aim of this review was to outline the current status of large animal models of glioma and their value as a transitional step between rodent models and human clinical trials.

Background Rathke cleft cysts (RCCs) are known sellar/suprasellar lesions that can grow and become symptomatic. For most asymptomatic lesions, stability is a typical outcome of surveillance; however, random relapse or cyst size fluctuation may also be observed. The conventional treatment for growing cysts is transsphenoidal removal. Methods A literature review was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guidelines. For significance, all journals were screened. Only records of tissue diagnosed RCCs with changes in size were included. Age and sex at diagnosis, size of the lesion, symptoms (if any), pituitary dysfunction, follow-up period, and size reduction were included in the data items. Results A total of 4 articles where selected after the second exclusion method. Three articles where case series and one was a case report. Eight total patients where histologically proven to have Rathke cleft cysts which fluctuated in size without intervention. Conclusion This review shows that RCCs can decrease or fluctuate in size following a dynamic process that is not fully understood. In the absence of symptoms, a larger cyst or an absolute increase in a cyst size, which may traditionally provoke an early surgical intervention, should be assessed and managed carefully to avoid potentially unneeded surgical morbidity.

Isolated central nervous system lymphomatoid granulomatosis (CNS‐LYG) can mimic aggressive glioblastomas. We describe a complex presentation of CNS‐LYG coexisting with immune thrombocytopenia successfully managed with rituximab and ultra‐low‐dose radiation therapy.

Distant spread of pituitary adenoma outside the sellar/suprasellar region is classified as pituitary carcinoma. Cerebrospinal fluid (CSF)-born spread of pituitary adenoma can occur after tumor cell spillage into the CSF space after surgery, irradiation, or apoplexy and is not necessarily related to intrinsic tumor biology.To systematically review the literature and describe the clinical characteristics and treatment strategies of patients with pituitary carcinomas. We further present 2 cases from our institution.A single-center retrospective review of patients with pituitary adenoma spread to distant intracranial locations between 2000 and 2020 was performed. Electronic databases were searched from their inception to May 25, 2021, and studies describing patients with pituitary spread to distant locations were included.Of 1210 pituitary adenoma cases reviewed, 2 (0.16%) showed tumor spread to distant locations. We found 134 additional cases (from 108 published articles) resulting in a total of 136 cases (61.9% were male). The time to tumor spread ranged between 0 and 516 months (median: 96 months). The follow-up duration ranged between 0 and 240 months (median: 11.5 months). All but 2 patients (98.5%) underwent surgical resection before adenoma spread. The 2 exceptions included a patient with evidence of an apoplectic event on autopsy and another patient with leptomeningeal pituitary spread but an unclear history of apoplexy. Elevated tumor markers were not linked to poor outcomes.Distant spread of pituitary adenoma may occur after surgery, irradiation, or apoplexy. It is not necessarily associated with a malignant clinical course.

Objective Stereotactic radiosurgery (SRS) has redefined the treatment paradigm for cerebral metastases. The benefits of SRS after surgical resection of a metastatic brain tumor have been well-defined. However, it is unclear whether preoperative SRS can improve the outcomes in select patients. The present study examined the safety and efficacy of preoperative neoadjuvant SRS (NaSRS) for the treatment of cerebral metastases. Methods We performed a retrospective review of 12 patients treated at The University of Texas Southwestern Medical Center. All patients underwent NaSRS, followed by surgical resection of a cerebral metastasis, from 2011 to 2015. Recurrence and overall survival were characterized using Kaplan-Meier and log-rank analyses. Results The mean age was 57.5 years (range, 39–69). The median follow-up period was 13 months (range, 1–22.6). The median maximum tumor diameter was 3.66 cm (range, 2.19–4.85). The 6- and 12-month local control rates were 81.8% and 49.1%, respectively. The distant disease control rates were 72.7% and 14.5% at 6 and 12 months, respectively. Overall survival was 83.3% and 74.1% at 6 and 12 months, respectively. Two patients developed leptomeningeal disease at a mean of 11.3 months. A trend toward increased local failure was seen with larger tumor volumes and diameters (P = 0.06). Conclusions NaSRS is a promising new approach for the treatment of select cerebral metastases that require surgical intervention. The approach is safe and effective at achieving local control. Further randomized studies with larger patient cohorts are necessary to determine whether the long-term outcomes are improved.

We describe a case of isolated primary CNS lymphomatoid granulomatosis and a discordant low-grade B-cell lymphoma involving the bone marrow causing chronic immune thrombocytopenia. Clinical course was complicated with disseminated zoster and sub-massive pulmonary embolism. Our patient was successfully managed with a combination radioimmunotherapy strategy with rituximab and radiation therapy.

Background Glioblastoma remains incurable despite treatment with surgery, radiation therapy, and cytotoxic chemotherapy, prompting the search for a metabolic pathway unique to glioblastoma cells.13C MR spectroscopic imaging with hyperpolarized pyruvate can demonstrate alterations in pyruvate metabolism in these tumors. Methods Three patients with diagnostic MRI suggestive of a glioblastoma were scanned at 3 T 1–2 days prior to tumor resection using a 13C/1H dual-frequency RF coil and a 13C/1H-integrated MR protocol, which consists of a series of 1H MR sequences (T2 FLAIR, arterial spin labeling and contrast-enhanced [CE] T1) and 13C spectroscopic imaging with hyperpolarized [1-13C]pyruvate. Dynamic spiral chemical shift imaging was used for 13C data acquisition. Surgical navigation was used to correlate the locations of tissue samples submitted for histology with the changes seen on the diagnostic MR scans and the 13C spectroscopic images. Results Each tumor was histologically confirmed to be a WHO grade IV glioblastoma with isocitrate dehydrogenase wild type. Total hyperpolarized 13C signals detected near the tumor mass reflected altered tissue perfusion near the tumor. For each tumor, a hyperintense [1-13C]lactate signal was detected both within CE and T2-FLAIR regions on the 1H diagnostic images (P = .008). [13C]bicarbonate signal was maintained or decreased in the lesion but the observation was not significant (P = .3). Conclusions Prior to surgical resection, 13C MR spectroscopic imaging with hyperpolarized pyruvate reveals increased lactate production in regions of histologically confirmed glioblastoma.

The aim of this study is to investigate facial nerve outcomes after microsurgical resection in neurofibromatosis type 2 (NF2) compared to sporadic tumors.Single institutional retrospective chart review.Tertiary referral center.All adult patients with NF2 vestibular schwannoma (VS) or sporadic VS who underwent microsurgical resection from 2008 to 2019 with preoperative magnetic resonance imaging (MRI) and 1 year of postsurgical follow-up were included. The primary outcome measure was postoperative House-Brackmann (HB) facial nerve score measured at first postoperative visit and after at least 10 months.In total, 161 sporadic VSs and 14 NF2 VSs met inclusion criteria. Both median tumor diameter (NF2, 33.5 mm vs sporadic, 24 mm,Tumor volume3 cm

BackgroundHigh-grade gliomas likely remodel the metabolic machinery to meet the increased demands for amino acids and nucleotides during rapid cell proliferation. Glycine, a non-essential amino acid and intermediate of nucleotide biosynthesis, may increase with proliferation. Non-invasive measurement of glycine by magnetic resonance spectroscopy (MRS) was evaluated as an imaging biomarker for assessment of tumor aggressiveness.MethodsWe measured glycine, 2-hydroxyglutarate (2HG), and other tumor-related metabolites in 35 glioma patients using an MRS sequence tailored for co-detection of glycine and 2HG in gadolinium-enhancing and non-enhancing tumor regions on 3T MRI. Glycine and 2HG concentrations as measured by MRS were correlated with tumor cell proliferation (MIB-1 labeling index), expression of mitochondrial serine hydroxymethyltransferase (SHMT2), and glycine decarboxylase (GLDC) enzymes, and patient overall survival.ResultsElevated glycine was strongly associated with presence of gadolinium enhancement, indicating more rapidly proliferative disease. Glycine concentration was positively correlated with MIB-1, and levels higher than 2.5 mM showed significant association with shorter patient survival, irrespective of isocitrate dehydrogenase status. Concentration of 2HG did not correlate with MIB-1 index. A high glycine/2HG concentration ratio, >2.5, was strongly associated with shorter survival (P ConclusionsThe data suggest that aggressive gliomas reprogram glycine-mediated one-carbon metabolism to meet the biosynthetic demands for rapid cell proliferation. MRS evaluation of glycine provides a non-invasive metabolic imaging biomarker that is predictive of tumor progression and clinical outcome.Key Points1. Glycine and 2-hydroxyglutarate in glioma patients are precisely co-detected using MRS at 3T.2. Tumors with elevated glycine proliferate and progress rapidly.3. A high glycine/2HG ratio is predictive of shortened patient survival.

BACKGROUND AND PURPOSE: O6-Methylguanine-DNA methyltransferase (MGMT) promoter methylation confers an improved prognosis and treatment response in gliomas. We developed a deep learning network for determining MGMT promoter methylation status using T2 weighted Images (T2WI) only. MATERIALS AND METHODS: Brain MR imaging and corresponding genomic information were obtained for 247 subjects from The Cancer Imaging Archive and The Cancer Genome Atlas. One hundred sixty-three subjects had a methylated MGMT promoter. A T2WI-only network (MGMT-net) was developed to determine MGMT promoter methylation status and simultaneous single-label tumor segmentation. The network was trained using 3D-dense-UNets. Three-fold cross-validation was performed to generalize the performance of the networks. Dice scores were computed to determine tumor-segmentation accuracy. RESULTS: The MGMT-net demonstrated a mean cross-validation accuracy of 94.73% across the 3 folds (95.12%, 93.98%, and 95.12%, [SD, 0.66%]) in predicting MGMT methylation status with a sensitivity and specificity of 96.31% [SD, 0.04%] and 91.66% [SD, 2.06%], respectively, and a mean area under the curve of 0.93 [SD, 0.01]. The whole tumor-segmentation mean Dice score was 0.82 [SD, 0.008]. CONCLUSIONS: We demonstrate high classification accuracy in predicting MGMT promoter methylation status using only T2WI. Our network surpasses the sensitivity, specificity, and accuracy of histologic and molecular methods. This result represents an important milestone toward using MR imaging to predict prognosis and treatment response.

OBJECTIVE To explore the relationship between tumor size and facial nerve outcomes following vestibular schwannoma (VS) resection. STUDY DESIGN Single institutional retrospective chart review of all adult patients with untreated sporadic VS who underwent surgical resection from 2008 to 2018 with preoperative magnetic resonance imaging (MRI) and 1 year of follow-up. The primary outcome measure was facial nerve outcome as assessed by the House-Brackmann facial nerve grading system. RESULTS One hundred sixty-seven patients, 54.5% female, with a median age of 49 years (20-76 years), were identified who underwent VS resection. Surgical resection was performed by translabyrinthine (76.7%), middle cranial fossa (14.4%), retrosigmoid (7.2%), and transpromontorial (1.8%) approaches. The median tumor diameter and volume were 25.3 mm (range: 4.1-47.1 mm) and 3.17 cm3 (range: 0.01-30.6 cm3 ), respectively. The median follow-up was 24.2 months (range: 12-114.2 months). Gross total resection was performed in 79% of cases, with residual tumor identified on MRI in 17% of cases. For patients with tumors 3 cm3 (univariate logistic regression OR = 2.9, P = .03). Tumor volume >3 cm3 was predictive of facial weakness on multivariate regression analysis (OR = 7.4, P = .02) when controlling for surgical approach, internal auditory canal extension, anterior extension, age, gender, and extent of resection. CONCLUSIONS Tumor volume >3 cm3 is associated with worse facial nerve outcomes 12 months following surgical resection. LEVEL OF EVIDENCE IV Laryngoscope, 131:E1328-E1334, 2021.

PURPOSEMethylation of the O6-Methylguanine-DNA Methyltransferase (MGMT) promoter results in epigenetic silencing of the MGMT enzyme and confers an improved prognosis and treatment response in gliomas. The purpose of this study was to develop a deep-learning network for determining the methylation status of the MGMT Promoter in gliomas using T2-w magnetic resonance images only.METHODSBrain MRI and corresponding genomic information were obtained for 247 subjects from The Cancer Imaging Archive (TCIA) and The Cancer Genome Atlas (TCGA). 163 subjects had a methylated MGMT promoter. A T2-w image only network (MGMT-net) was developed to determine MGMT promoter methylation status and simultaneous single label tumor segmentation. The network was trained using 3D-Dense-UNets. Three-fold cross-validation was performed to generalize the networks’ performance. Dice-scores were computed to determine tumor segmentation accuracy.RESULTSMGMT-net demonstrated a mean cross validation accuracy of 94.73% across the 3 folds (95.12%, 93.98%, and 95.12%, standard dev=0.66) in predicting MGMT methylation status with a sensitivity and specificity of 96.31% ±0.04 and 91.66% ±2.06, respectively and a mean AUC of 0.93 ±0.01. The whole tumor segmentation mean Dice-score was 0.82 ± 0.008.CONCLUSIONWe demonstrate high classification accuracy in predicting the methylation status of the MGMT promoter using only T2-w MR images that surpasses the sensitivity, specificity, and accuracy of invasive histological methods such as pyrosequencing, methylation-specific PCR, and immunofluorescence methods. This represents an important milestone toward using MRI to predict glioma histology, prognosis, and response to treatment.

Purpose To generate a preclinical model of isocitrate dehydrogenase (IDH) mutant gliomas from glioma patients and design a MRS method to test the compatibility of 2-hydroxyglutarate (2HG) production between the preclinical model and patients. Methods Five patient-derived xenograft (PDX) mice were generated from two glioma patients with IDH1 R132H mutation. A PRESS sequence was tailored at 9.4 T, with computer simulation and phantom analyses, for improving 2HG detection in mice. 2HG and other metabolites in the PDX mice were measured using the optimized MRS at 9.4 T and compared with 3 T MRS measurements of the metabolites in the parental-tumor patients. Spectral fitting was performed with LCModel using in-house basis spectra. Metabolite levels were quantified with reference to water. Results The PRESS TE was optimized to be 96 ms, at which the 2HG 2.25 ppm signal was narrow and inverted, thereby leading to unequivocal separation of the 2HG resonance from adjacent signals from other metabolites. The optimized MRS provided precise detection of 2HG in mice compared to short-TE MRS at 9.4 T. The 2HG estimates in PDX mice were in excellent agreement with the 2HG measurements in the patients. Conclusion The similarity of 2HG production between PDX models and parental-tumor patients indicates that PDX tumors retain the parental IDH metabolic fingerprint and can serve as a preclinical model for improving our understanding of the IDH-mutation associated metabolic reprogramming.

Cancers reprogram their metabolism and the resulting alterations in metabolite abundance can be monitored in patients noninvasively using proton magnetic resonance spectroscopy (MRS). We evaluated glutamine, glycine and 2-hydroxyglutarate (2HG) in 27 adult subjects with gliomas (17 male and 10 female; age 22 - 69, median 39 years) using optimized MRS at 3T (PRESS TE 97ms) and examined their association with post-gadolinium enhancement, cell proliferation rate (MIB-1 labeling index), and overall survival of patients. The tumors included 9 glioblastomas (3 IDH mutated and 6 IDH wildtype), 10 astrocytomas (7 IDH mutated and 3 IDH wildtype), and 8 oligodendrogliomas (IDH mutated). The concentrations of glutamine and glycine were both significantly higher in enhancing tumors than in non-enhancing tumors (p=0.001 and 0.0001, respectively). The concentrations of glutamine and glycine were both positively correlated with MIB-1 (p=4E-5 and 1E-7, respectively). The sum of glutamine and glycine levels showed stronger association with MIB-1 (p=5E-10, r=0.89). In the Kaplan-Meier overall survival analysis, the survival was significantly shorter in patients with glutamine levels higher than 4.1 mM than those with concentrations less than 4.1 mM (p=0.02). For glycine, the patients with higher than 2.4 mM showed association with poor survival (p=0.03). The sum of glutamine and glycine levels showed stronger association with overall survival (p=0.008, cutoff 8.5mM). 2HG level greater than 0.5 mM was associated with long survival (p=0.01). We tested metabolic ratios to 2HG, in which 2HG estimates less than 1 mM were put as 1 mM (avoiding infinite ratios arising from null 2HG cases). The glutamine/2HG, glycine/2HG, and (glutamine+glycine)/2HG showed strong association with overall survival (p=2E-4, 2E-5 and 4.5E-7, respectively). Our data suggest that increased metabolism of glutamine and glycine is closely associated with rapid cell proliferation and poor survival, suggesting the metabolites are imaging biomarkers of glioma aggressiveness.

Background Intracranial hemangiopericytomas (HPCs) are characterized by high recurrence rates and extracranial metastases. Radiotherapy provides an adjunct to surgery, but the timing of therapy and the patients most likely to benefit remain unclear. Methods A retrospective review of 20 patients with HPC treated at the University of Texas Southwestern Medical Center between 1985 and 2014 was conducted. Recurrence and metastasis rates along with overall survival (OS) were characterized based on therapeutic approach and tumor pathology using Kaplan-Meier and Cox regression analyses. Results The mean age was 45.6 years (range: 19–77). Gross total resection (GTR) was achieved in 13 patients, whereas 5 patients underwent subtotal resection. Median follow-up was 91.5 months (range: 8–357). The 5-, 10-, and 15-year recurrence-free survival (RFS) rates were 61, 41, and 20%, respectively. Six patients developed metastases at an average of 113 months (range: 42–231). OS at last follow-up was 80%. Importantly, immediate postoperative adjuvant radiotherapy (IRT) did not influence RFS compared with surgery alone or OS compared with delayed radiotherapy at the time of recurrence. Conclusion HPCs have high recurrence rates necessitating close follow-up. Surgery remains an important first step, but the timing of radiotherapy for optimal control and OS remains uncertain.

Efforts to identify and target glioblastoma (GBM) drivers have primarily focused on receptor tyrosine kinases (RTKs). Clinical benefits, however, have been elusive. Here, we identify a SRY-related box 2 (SOX2) transcriptional regulatory network that is independent of upstream RTKs and is capable of driving glioma initiating cells. We identified oligodendrocyte lineage transcription factor 2 (OLIG2) and zinc finger E-box binding homeobox 1 (ZEB1) as potential SOX2 targets, which are frequently co-expressed irrespective of driver mutations. In murine glioma models, we show that different combinations of tumor suppressor and oncogene mutations can activate Sox2, Olig2, and Zeb1 expression. We demonstrate that ectopic co-expression of the three transcription factors can transform tumor suppressor deficient astrocytes into glioma initiating cells in the absence of an upstream RTK oncogene. Finally, we demonstrate that the transcriptional inhibitor mithramycin downregulates SOX2 and its target genes, resulting in markedly reduced proliferation of GBM cells in vivo.

Background Anaplastic ependymoma with extraneural metastases is associated with a poor clinical outcome. Metastatic spread to the parotid gland is a rare clinical entity that requires multidisciplinary intervention. Herein, we present a systematic review of anaplastic ependymoma with extraneural metastases and report on a case with metastases to both parotid glands. Methods Electronic databases were searched from their inception to February 2019. Inclusion criteria included reports of anaplastic ependymoma with extraneural metastasis. Studies were excluded if the tumor grade was not reported. A case illustration is provided. Results The search yielded 15 cases of anaplastic ependymoma with extraneural metastases, including the present case. Mean age at diagnosis was 15 years. The initial tumor location was predominantly supratentorial (93.3%). All cases demonstrated leptomeningeal seeding before extraneural metastasis. Mean survival from initial diagnosis was 4.5 years. Metastasis to the parotid gland occurred in 2 cases, including the present case. We present a 17-year-old female patient who underwent gross total resection of a supratentorial, paraventricular anaplastic ependymoma followed by adjuvant external beam radiation therapy. The patient developed recurrent leptomeningeal seeding, treated with Gamma Knife radiosurgery over a 5-year period. She returned with a parotid mass and cervical lymphadenopathy and underwent parotidectomy and modified radical neck dissection. She continued to experience recurrences, including the left parotid gland, and was ultimately placed in hospice care. Conclusions Anaplastic ependymoma with extraneural metastasis is rare. A combination of repeated surgical resection, radiation therapy, and chemotherapy can be used to manage recurrent and metastatic disease, but outcomes remain poor.

Background Isocitrate dehydrogenase (IDH) mutation status has emerged as an important prognostic marker in gliomas. Currently, reliable IDH mutation determination requires invasive surgical procedures. The purpose of this study was to develop a highly-accurate, MRI-based, voxel-wise deep-learning IDH-classification network using T2-weighted (T2w) MR images and compare its performance to a multi-contrast network. Methods Multi-parametric brain MRI data and corresponding genomic information were obtained for 214 subjects (94 IDH-mutated, 120 IDH wild-type) from The Cancer Imaging Archive (TCIA) and The Cancer Genome Atlas (TCGA). Two separate networks were developed including a T2w image only network (T2-net) and a multi-contrast (T2w, FLAIR, and T1 post-contrast), network (TS-net) to perform IDH classification and simultaneous single label tumor segmentation. The networks were trained using 3D-Dense-UNets. A three-fold cross-validation was performed to generalize the networks’ performance. ROC analysis was also performed. Dice-scores were computed to determine tumor segmentation accuracy. Results T2-net demonstrated a mean cross-validation accuracy of 97.14% +/-0.04 in predicting IDH mutation status, with a sensitivity of 0.97 +/-0.03, specificity of 0.98 +/-0.01, and an AUC of 0.98 +/-0.01. TS-net achieved a mean cross-validation accuracy of 97.12% +/-0.09, with a sensitivity of 0.98 +/-0.02, specificity of 0.97 +/-0.001, and an AUC of 0.99 +/-0.01. The mean whole tumor segmentation Dice-scores were 0.85 +/-0.009 for T2-net and 0.89 +/-0.006 for TS-net. Conclusion We demonstrate high IDH classification accuracy using only T2-weighted MRI. This represents an important milestone towards clinical translation. Keypoints – 1 IDH status is an important prognostic marker for gliomas. 2. We developed a non-invasive, MRI based, highly accurate deep-learning method for the determination of IDH status 3. The deep-learning networks utilizes only T2 weighted MR images to predict IDH status thereby facilitating clinical translation. IMPORTANCE OF THE STUDY One of the most important recent discoveries in brain glioma biology has been the identification of the isocitrate dehydrogenase (IDH) mutation status as a marker for therapy and prognosis. The mutated form of the gene confers a better prognosis and treatment response than gliomas with the non-mutated or wild-type form. Currently, the only reliable way to determine IDH mutation status is to obtain glioma tissue either via an invasive brain biopsy or following open surgical resection. The ability to non-invasively determine IDH mutation status has significant implications in determining therapy and predicting prognosis. We developed a highly accurate, deep learning network that utilizes only T2-weighted MR images and outperforms previously published methods. The high IDH classification accuracy of our T2w image only network (T2-net) marks an important milestone towards clinical translation. Imminent clinical translation is feasible because T2-weighted MR imaging is widely available and routinely performed in the assessment of gliomas.

Isocitrate dehydrogenase (IDH) mutation status is an important marker in glioma diagnosis and therapy. We propose a novel automated pipeline for predicting IDH status noninvasively using deep learning and T2-weighted (T2w) MR images with minimal preprocessing (N4 bias correction and normalization to zero mean and unit variance). T2w MRI and genomic data were obtained from The Cancer Imaging Archive dataset (TCIA) for 260 subjects (120 High grade and 140 Low grade gliomas). A fully automated 2D densely connected model was trained to classify IDH mutation status on 208 subjects and tested on another held-out set of 52 subjects, using 5-fold cross validation. Data leakage was avoided by ensuring subject separation during the slice-wise randomization. Mean classification accuracy of 90.5% was achieved for each axial slice in predicting the three classes of no tumor, IDH mutated and IDH wild-type. Test accuracy of 83.8% was achieved in predicting IDH mutation status for individual subjects on the test dataset of 52 subjects. We demonstrate a deep learning method to predict IDH mutation status using T2w MRI alone. Radiologic imaging studies using deep learning methods must address data leakage (subject duplication) in the randomization process to avoid upward bias in the reported classification accuracy.

Background Glioblastoma (GBM) is the most common primary malignant adult brain tumor. Temozolomide (TMZ) is the standard of care and is most effective in GBMs that lack the DNA repair protein O6-methylguanine-DNA methyltransferase (MGMT). Moreover, even initially responsive tumors develop a secondary resistance to TMZ and become untreatable. Since aberrant epidermal growth factor receptor (EGFR) signaling is widespread in GBM, EGFR inhibition has been tried in multiple clinical trials without success. We recently reported that inhibiting EGFR leads to increased secretion of tumor necrosis factor (TNF) and activation of a survival pathway in GBM. Here, we compare the efficacy of TMZ versus EGFR plus TNF inhibition in an orthotopic mouse model of GBM. Methods We use an orthotopic model to examine the efficacy of TMZ versus EGFR plus TNF inhibition in multiple subsets of GBMs, including MGMT methylated and unmethylated primary GBMs, recurrent GBMs, and GBMs rendered experimentally resistant to TMZ. Results The efficacy of the 2 treatments was similar in MGMT methylated GBMs. However, in MGMT unmethylated GBMs, a combination of EGFR plus TNF inhibition was more effective. We demonstrate that the 2 treatment approaches target distinct and non-overlapping pathways. Thus, importantly, EGFR plus TNF inhibition remains effective in TMZ-resistant recurrent GBMs and in GBMs rendered experimentally resistant to TMZ. Conclusion EGFR inhibition combined with a blunting of the accompanying TNF-driven adaptive response could be a viable therapeutic approach in MGMT unmethylated and recurrent EGFR-expressing GBMs.

This report portrays an unusual presentation of a dysembryoplastic neuroepithelial tumor characterized by a chronic, enlarging, heterogeneously enhancing organizing hematoma. Differential diagnoses included the malignant transformation of a low-grade glioma, radiation necrosis, and radiation-induced cavernoma. A dysembryoplastic neuroepithelial tumor may have atypical characteristics and behavior, so continued follow-up with serial imaging is recommended.

BACKGROUND: Brain metastases (BM) occur frequently in patients with metastatic kidney cancer and are a significant source of morbidity and mortality. While historically associated with a poor prognosis, survival outcomes for patients in the modern era are incompletely characterized. In particular, outcomes after adjusting for systemic therapy administration and International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) risk factors are not well known. METHODS: A retrospective database of metastatic RCC patients treated at UT Southwestern Medical Center between 2006 and 2015 was created. Data relevant to their diagnosis, treatment course and outcomes was systematically collected. Survival was analyzed by the Kaplan-Meier method. BM patients were compared to non-BM patients after adjusting for the timing of BM diagnosis, either prior to or after first-line systemic therapy. The impact of stratification according to IMDC risk group was assessed. RESULTS: 56 of 268 patients (28.4%) with metastatic RCC were diagnosed with brain metastases (BM) prior to or during first-line systemic therapy. Median OS for systemic therapy-naïve BM patients compared with matched non-BM patients was 19.5 vs. 28.7 months (p=0.0117). When analyzed according to IMDC risk group, median OS for patients with BM was similar for favorable and intermediate-risk patients (NR vs NR; and 29.0 vs. 36.7 months, p=0.5254), and inferior for poor-risk patients (3.5 vs 9.4 months, p=0.0462). For patients developing BM while on first-line systemic therapy, survival from the time of progression did not significantly differ by presence or absence of BM (11.8 vs. 17.8 months, p=0.6658). CONCLUSIONS: Survival rates for patients with BM are significantly better than historical reports. After adjusting for systemic therapy, survival rates of patients with BM in good and intermediate-risk groups were remarkably better than expected and not statistically different from patients without BM, though this represents a single institution experience and numbers are modest. MICRO-ABSTRACT: In this study, we analyze survival for metastatic renal cell carcinoma patients with brain metastases compared with disease-matched patients without brain metastases, adjusting for line of systemic therapy and IMDC risk group. We observed that the development of brain metastases did not significant impact survival for favorable and intermediate-risk patients, while poor-risk patients with brain metastases fared worse.

Purpose To test the efficacy of triple-refocusing MR spectroscopy (MRS) for improved detection of 2-hydroxyglutarate (2HG) in brain tumors at 3T in vivo. Methods The triple-refocusing sequence parameters were tailored at 3T, with density-matrix simulations and phantom validation, for enhancing the 2HG 2.25-ppm signal selectivity with respect to the adjacent resonances of glutamate (Glu), glutamine (Gln), and gamma-aminobutyric acid (GABA). In vivo MRS data were acquired from 15 glioma patients and analyzed with LCModel using calculated basis spectra. Metabolites were quantified with reference to water. Results A triple-refocusing sequence (echo time = 137 ms) was obtained for 2HG detection. The 2HG 2.25-ppm signal was large and narrow while the Glu and Gln signals between 2.2 and 2.3 ppm were minimal. The optimized triple refocusing offered improved separation of 2HG from Glu, Gln and GABA when compared with published MRS methods. 2HG was detected in all 15 patients, the estimated 2HG concentrations ranging from 2.4 to 15.0 mM, with Cramer-Rao lower bounds of 2%–11%. The 2HG estimates did not show significant correlation with total choline. Conclusion The optimized triple refocusing provides excellent 2HG signal discrimination from adjacent resonances and may confer reliable in vivo measurement of 2HG at relatively low concentrations. Magn Reson Med 78:40–48, 2017. © 2016 International Society for Magnetic Resonance in Medicine

(13)C-enriched compounds are readily metabolized in human malignancies. Fragments of the tumor, acquired by biopsy or surgical resection, may be acid-extracted and (13)C NMR spectroscopy of metabolites such as glutamate, glutamine, 2-hydroxyglutarate, lactate and others provide a rich source of information about tumor metabolism in situ. Recently we observed (13)C-(13)C spin-spin coupling in (13)C NMR spectra of lactate in brain tumors removed from patients who were infused with [1,2-(13)C]acetate prior to the surgery. We found, in four patients, that infusion of (13)C-enriched acetate was associated with synthesis of (13)C-enriched glucose, detectable in plasma. (13)C labeled glucose derived from [1,2-(13)C]acetate metabolism in the liver and the brain pyruvate recycling in the tumor together lead to the production of the (13)C labeled lactate pool in the brain tumor. Their combined contribution to acetate metabolism in the brain tumors was less than 4.0%, significantly lower than the direct oxidation of acetate in the citric acid cycle in tumors.

PURPOSE To test the efficacy of 7T MRS for in vivo detection of 2-hydroxyglutarate (2HG) in brain tumors. METHODS The subecho times of point-resolved spectroscopy (PRESS) were optimized at 7T with density-matrix simulations and phantom validation to improve the 2HG signal selectivity with respect to the neighboring resonances of γ-aminobutyric acid (GABA), glutamate (Glu), and glutamine (Gln). MRS data were acquired from 12 subjects with gliomas in vivo and analyzed with LCModel using calculated basis spectra. Metabolite levels were quantified using unsuppressed short echo time (TE) water as a reference. RESULTS The PRESS TE was optimized as TE = 78 ms (TE1 = 58 ms and TE2 = 20 ms), at which the 2HG 2.25 ppm resonance appeared as a temporally maximum inverted narrow peak and the GABA, Glu, and Gln resonances between 2.2 and 2.5 ppm were all positive peaks. The PRESS TE = 78 ms method offered improved discrimination of 2HG from Glu, Gln, and GABA when compared with short-TE MRS. 2HG was detected in all patients enrolled in the study, the estimated 2HG concentrations ranging from 1.0 to 6.2 mM, with percentage standard deviation of 2%-7%. CONCLUSION Data indicate that the optimized MRS provides good selectivity of 2HG from other metabolite signals and may confer reliable in vivo detection of 2HG at relatively low concentrations. Magn Reson Med 77:936-944, 2017. © 2016 International Society for Magnetic Resonance in Medicine.

The number of brain metastases identified on diagnostic magnetic resonance imaging (MRI) is a key factor in consideration of stereotactic radiosurgery (SRS). However, additional lesions are often detected on high-resolution SRS-planning MRI. We investigated pre-treatment clinical characteristics that are associated with finding additional metastases at SRS. Patients treated with SRS for brain metastases between the years of 2009-2014 comprised the study cohort. All patients underwent frame-fixed, 1 mm thick MRI on the day of SRS. Patient, tumor, and treatment characteristics were analyzed for an association with increase in number of metastases identified on SRS-planning MRI. 289 consecutive SRS cases were analyzed. 725 metastases were identified on pre-treatment MRI and 1062 metastases were identified on SRS-planning MRI. An increase in the number of metastases occurred in 34 % of the cases. On univariate analysis, more than four metastases and the diameter of the largest lesion were significantly associated with an increase in number of metastases on SRS-planning MRI. When stratified by the diameter of the largest lesion into

Reconstructive surgeons may encounter patients presenting after intracranial facial nerve resection and grafting in the setting of skull base tumors, who inquire regarding progression, final facial function, and need for future operations. Study goals were to analyze global and regional facial function using established grading systems and videography, while examine variables possibly affecting outcomes.Between 1997 and 2012, 28 patients underwent intracranial nerve grafting. Fifteen were prospectively evaluated by three facial nerve physical therapists with the Facial Nerve Grading System 2.0 and the Sunnybrook Facial Grading Score for function and the Facial Disability Index for quality of life. Still photographs and videography were used to assess quality of motion and tone, while demographic and medical variables were analyzed regarding their effect on end results.Average patient age was 41.9 years (range, 22 to 66 years), and there were 10 women and five men. Average time interval between nerve grafting and evaluations was 42.9 months (range, 12 to 146 months). Both grading scores demonstrated best outcomes in the periorbita and worst outcomes in the brow. Buccinator muscle tone also improved. The average total Facial Disability Index was 67.5 percent. Although not statistically significant, the data suggest that nerve gap length affected total resting symmetry and voluntary movement, whereas preoperative palsy and age may affect total resting symmetry. Perioperative radiation therapy, tumor type, donor nerve, and coaptation technique were not found to affect outcomes.Intracranial facial nerve grafting largely provides better resting tone and facial symmetry, potentially improving end results of future intervention; however, overall voluntary facial motion is poor.Therapeutic, IV.

Background Hemangiopericytomas (HPCs) are rare vascular tumors that resemble meningiomas on imaging and have a high rate of local recurrence and metastases. There remains a paucity of data to guide management decisions of intraspinal dissemination of HPCs in the literature, and none specifically related to anaplastic HPCs. Case Description We report a case of a 34-year-old woman with locally and distantly recurrent anaplastic HPC (World Health Organization grade III). She initially presented with tinnitus in her right ear. A well-circumscribed, contrast-enhancing lesion was identified in the right cerebellopontine angle. Treatment consisted of subtotal resection and postoperative radiation therapy (RT) to a dose of 60 Gy in 30 fractions. After a 3-year disease-free interval, 7 lesions recurred intra- and extracranially. The extracranial lesions were drop metastases of the original HPC through the cerebrospinal fluid into the spinal canal. Of note, fluorodeoxyglucose positron emission tomography (PET)/computed tomography scan was not sensitive enough to detect these new lesions. The intracranial recurrence was on the edge of the prior radiotherapy field, representing a marginal failure having received less than 50 Gy. The intracranial recurrences were treated with salvage gamma knife stereotactic radiosurgery (SRS) with local control. She underwent intradural extramedullary hemilaminectomy of a thoracic spine metastasis followed by fractionated proton beam therapy (PBT) with a boost to unresected lesions. Within a few months of PBT, she became pregnant. Pregnancy did not affect recurrence or ameliorate tumor growth. Conclusions This case report discusses the role genetics, adjuvant RT, SRS, magnetic resonance imaging, and PET scan played in this unique clinical scenario of anaplastic HPC.

PURPOSE: To develop 3D high-resolution imaging of 2-hydroxyglutarate (2HG) at 3T in vivo. METHODS: Echo-planar spectroscopic imaging with dual-readout alternated-gradients (DRAG-EPSI), which was recently reported for 2D imaging of 2HG at 7T, was tested for 3D imaging of 2HG at 3T. The frequency drifts and acoustic noise induced by DRAG-EPSI were investigated in comparison with conventional EPSI. Four patients with IDH-mutant gliomas were enrolled for 3D imaging of 2HG and other metabolites. A previously-reported 2HG-tailored TE 97ms PRESS sequence preceded the DRAG-EPSI readout gradients. Unsuppressed water, acquired with EPSI, was used as reference for multi-channel combination, eddy-current compensation, and metabolite quantification. Spectral fitting was conducted with the LCModel using in-house basis sets. RESULTS: With gradient strength of 4 mT/m and slew rate of 20 mT/m/ms, DRAG-EPSI produced frequency drifts smaller by 5.5 fold and acoustic noise lower by 25 dB compared to conventional EPSI. In a 19-min scan, 3D DRAG-EPSI provided images of 2HG with precision (CRLB

Adult brainstem gliomas are difficult to classify based on radiologic and histologic features. A K27M mutation in histone 3 has been described to identify high-grade midline gliomas associated with a particularly unfavorable prognosis. While initially considered a pediatric entity, it is now known that H3K27M-mutant brainstem gliomas occur in all age groups, but they are less well understood in adults. We studied clinical, radiologic, and pathologic features of 25 brainstem gliomas diagnosed at our institution between 1994 and 2017 in subjects at least 18 years old. Seven tumors (28%) were positive for the H3K27M mutation, and their median overall survival was significantly shorter than in the H3-wildtype group (p = 0.004). Although the mutation was invariably associated with a poor prognosis, our study also illustrates the radiologic and pathologic heterogeneity in this molecular tumor subtype. The results showed that H3K27M-mutant status and clinically aggressive course cannot be ruled out based on low-grade histology on the initial biopsy, exophytic growth, only focal or minimal enhancement or an extrapontine location, such as midbrain or medulla. These results favor an integrated approach employing a combination of clinical, radiologic, histologic features as well as H3K27M immunohistochemistry for the diagnostic subclassification of adult brainstem gliomas.

OBJECTIVEMutations in the isocitrate dehydrogenase (IDH) genes are of proven diagnostic and prognostic significance for cerebral gliomas. The objective of this study was to evaluate the clinical feasibility of using a recently described method for determining IDH mutation status by using magnetic resonance spectroscopy (MRS) to detect the presence of 2-hydroxyglutarate (2HG), the metabolic product of the mutant IDH enzyme.METHODSBy extending imaging time by 6 minutes, the authors were able to include a point-resolved spectroscopy (PRESS) MRS sequence in their routine glioma imaging protocol. In 30 of 35 patients for whom this revised protocol was used the lesions were subsequently diagnosed histologically as gliomas. Of the remaining 5 patients, 1 had a gangliocytoma, 1 had a primary CNS lymphoma, and 3 had nonneoplastic lesions. Immunohistochemistry and/or polymerase chain reaction were used to detect the presence of IDH mutations in the glioma tissue resected.RESULTSIn vivo MRS for 2HG correctly identified the IDH mutational status in 88.6% of patients. The sensitivity and specificity was 89.5% and 81.3%, respectively, when using 2 mM 2HG as threshold to discriminate IDH-mutated from wildtype tumors. Two glioblastomas that had elevated 2HG levels did not have detectable IDH mutations, and in 2 IDH-mutated gliomas 2HG was not reliably detectable.CONCLUSIONSThe noninvasive determination of the IDH mutation status of a presumed glioma by means of MRS may be incorporated into a routine diagnostic imaging protocol and can be used to obtain additional information for patient care.

BACKGROUND AND PURPOSE: Meningiomas are very commonly diagnosed intracranial primary neoplasms, of which the chordoid subtype is seldom encountered. Our aim was to retrospectively review preoperative MR imaging of intracranial chordoid meningiomas, a rare WHO grade II variant, in an effort to determine if there exist distinguishing MR imaging characteristics that can aid in differentiating this atypical variety from other meningioma subtypes. MATERIALS AND METHODS: Ten cases of WHO grade II chordoid meningioma were diagnosed at our institution over an 11-year span, 8 of which had preoperative MR imaging available for review and were included in our analysis. Chordoid meningioma MR imaging characteristics, including ADC values and normalized ADC ratios, were compared with those of 80 consecutive cases of WHO grade I meningioma, 21 consecutive cases of nonchordoid WHO grade II meningioma, and 1 case of WHO grade III meningioma. RESULTS: Preoperative MR imaging revealed no significant differences in size, location, signal characteristics, or contrast enhancement between chordoid meningiomas and other meningiomas. There were, however, clear differences in the ADC values and normalized ADC ratios, with a mean absolute ADC value of 1.62 ± 0.33 × 10(−3) mm(2)/s and a mean normalized ADC ratio of 2.22 ± 0.47 × 10(−3) mm(2)/s in chordoid meningiomas compared with mean ADC and normalized ADC values, respectively, of 0.88 ± 0.13 × 10(−3) mm(2)/s and 1.17 ± 0.16 × 10(−3) mm(2)/s in benign WHO grade I meningiomas, 0.84 ± 0.11 × 10(−3) mm(2)/s and 1.11 ± 0.15 × 10(−3) mm(2)/s in nonchordoid WHO grade II meningiomas, and 0.57 × 10(−3) mm(2)/s and 0.75 × 10(−3) mm(2)/s in the 1 WHO grade III meningioma. CONCLUSIONS: Chordoid meningiomas have statistically significant elevations of ADC and normalized ADC values when compared with all other WHO grade I, II, and III subtypes, which enables reliable preoperative prediction of this atypical histopathologic diagnosis.

Glioblastoma (GBM) is the most common and aggressive adult brain malignancy for which conventional surgery, radiation treatment and chemotherapy based on alkylating agent Temozolomide (TMZ) have limited benefit. Overall survival is variable but less than 10% of GBM patients survive 5 years, making it one of the most aggressive and clinically intractable cancers. The main cause of poor prognosis is the rapid emergence of recurrent disease, despite extensive removal of cancer cells from the primary site. Here, by using patient-derived xenografts we demonstrate that GBM is fueled by a mixture of fast- and slow-cycling cells. In vivo, treatment based on TMZ triggers a transient cell arrest in G2/M and DNA damage but does not promote cell death. In particular, by causing DNA double strand breaks, TMZ induces the autophosphorylation of ataxia telangiectasia mutated (ATM S1981) and the downstream phosphorylation of histone H2AX (YH2AX). In response to TMZ, GBM cells undergo a transient switch to a p53-driven mesenchymal phenotype with significant up-regulation of CD44, Vimentin and Gfap expression. The transient phenotype switch is followed by down-regulation of p53 and the emergence of treatment-resistant GBM. Illumina-based gene expression profiling and marker analysis reveal striking similarities between matched control and treatment-resistant tumors. ChIP-seq experiments are currently ongoing to identify critical nodes of phenotype switch. We are also using genetically-engineered mouse models of gliomas to understand if wild-type p53 drives a mesenchymal phenotype in Nestin-, Gfap-, Glast-, ApoE- and Pla2-derived tumors. Altogether, these results contribute to increase our knowledge of the biology of GBM growth and treatment resistance and identify p53 as a driver of phenotypic plasticity.

PURPOSE To develop echo-planar spectroscopic imaging (EPSI) with large spectral width and accomplish high-resolution imaging of 2-hydroxyglutarate (2HG) at 7 T. METHODS We designed a new EPSI readout scheme at 7 T. Data were recorded with dual-readout alternated gradients and combined according to the gradient polarity. Following validation of its performance in phantoms, the new readout scheme, together with previously reported 2HG-optimized magnetic resonance spectroscopy (point-resolved spectroscopy echo time of 78 ms), was used for time-efficient and high-resolution imaging of 2HG and other metabolites in five glioma patients before treatment. Unsuppressed water, acquired with EPSI, was used as reference for multichannel combination, eddy-current compensation, and metabolite quantification. Spectral fitting was conducted with the LCModel using in-house calculated basis sets. RESULTS Using a readout gradient strength of 9.5 mT/m and slew rate of 90 mT/m/ms, dual-readout alternated gradients EPSI permitted 1638-Hz spectral width with 6 × 6 mm2 in-plane resolution at 7 T. Phantom data indicated that dual-readout alternated gradients EPSI provides proper metabolite signals and induces much less frequency drifts than conventional EPSI. For a spatial resolution of 0.5 mL, 2HG was detected in tumors with precision (Cramer-Rao lower bound