Transaminase Inhibition by 2-Hydroxyglutarate Impairs Glutamate Biosynthesis and Redox Homeostasis in Glioma.

IDH1 mutations are common in low-grade gliomas and secondary glioblastomas and cause overproduction of (R)-2HG. (R)-2HG modulates the activity of many enzymes, including some that are linked to transformation and some that are probably bystanders. Although prior work on (R)-2HG targets focused on 2OG-dependent dioxygenases, we found that (R)-2HG potently inhibits the 2OG-dependent transaminases BCAT1 and BCAT2, likely as a bystander effect, thereby decreasing glutamate levels and increasing dependence on glutaminase for the biosynthesis of glutamate and one of its products, glutathione. Inhibiting glutaminase specifically sensitized IDH mutant glioma cells to oxidative stress in vitro and to radiation in vitro and in vivo. These findings highlight the complementary roles for BCATs and glutaminase in glutamate biosynthesis, explain the sensitivity of IDH mutant cells to glutaminase inhibitors, and suggest a strategy for maximizing the effectiveness of such inhibitors against IDH mutant gliomas.

Rapid tumor DNA analysis of cerebrospinal fluid accelerates treatment of central nervous system lymphoma.

ABSTRACT: Delays and risks associated with neurosurgical biopsies preclude timely diagnosis and treatment of central nervous system (CNS) lymphoma and other CNS neoplasms. We prospectively integrated targeted rapid genotyping of cerebrospinal fluid (CSF) into the evaluation of 70 patients with CNS lesions of unknown cause. Participants underwent genotyping of CSF-derived DNA using a quantitative polymerase chain reaction-based approach for parallel detection of single-nucleotide variants in the MYD88, TERT promoter, IDH1, IDH2, BRAF, and H3F3A genes within 80 minutes of sample acquisition. Canonical mutations were detected in 42% of patients with neoplasms, including cases of primary and secondary CNS lymphoma, glioblastoma, IDH-mutant brainstem glioma, and H3K27M-mutant diffuse midline glioma. Genotyping results eliminated the need for surgical biopsies in 7 of 33 cases (21.2%) of newly diagnosed neoplasms, resulting in significantly accelerated initiation of disease-directed treatment (median, 3 vs 12 days; P = .027). This assay was then implemented in a Clinical Laboratory Improvement Amendments environment, with 2-day median turnaround for diagnosis of CNS lymphoma from 66 patients across 4 clinical sites. Our study prospectively demonstrates that targeted rapid CSF genotyping influences oncologic management for suspected CNS tumors.

Understanding the molecular pathogenesis of primary central nervous system lymphoma by experimental animal models.

Primary central nervous system lymphoma (PCNSL) is a rare and invasive diffuse large B cell lymphoma confined in central nervous system (CNS). The effort to press forward the translational progress has been frustrated by the insufficient understanding of immunophenotype of CNS and tumor genetic alterations of PCNSL, and the lack of validated diagnostic biomarkers. Researchers now have a variety of PCNSL animal models at their disposal that resemble the morphology and immunophenotype of PCNSL, however, a careful and detailed re-examination of these animal models is needed to clarify the differences in genetic alterations, migration capability, and immune status. In this review, we present the knowledge about the phenotypic and genotypic features of PCNSL tumor cells, and compile the preclinical animal models of PCNSL with regard to various injection sites, cell origins, recipient animals, and immune status, and elaborate on the tropism and migration of tumor cells and novel therapeutic strategies for PCNSL. We envisage that the selection of suitable animal models will serve as a well-defined preclinical system to understand the molecular pathogenesis of PCNSL, thereby galvanizing the development of novel and potent therapeutic approaches.

A rapid genotyping panel for detection of primary central nervous system lymphoma.

Diagnosing primary central nervous system lymphoma (PCNSL) frequently requires neurosurgical biopsy due to nonspecific radiologic features and the low yield of cerebrospinal fluid (CSF) studies. We characterized the clinical evaluation of suspected PCNSL (N = 1007 patients) and designed a rapid multiplexed genotyping assay for MYD88, TERT promoter, IDH1/2, H3F3A, and BRAF mutations to facilitate the diagnosis of PCNSL from CSF and detect other neoplasms in the differential diagnosis. Among 159 patients with confirmed PCNSL, the median time to secure a diagnosis of PCNSL was 10 days, with a range of 0 to 617 days. Permanent histopathology confirmed PCNSL in 142 of 152 biopsies (93.4%), whereas CSF analyses were diagnostic in only 15/113 samplings (13.3%). Among 86 archived clinical specimens, our targeted genotyping assay accurately detected hematologic malignancies with 57.6% sensitivity and 100% specificity (95% confidence interval [CI]: 44.1% to 70.4% and 87.2% to 100%, respectively). MYD88 and TERT promoter mutations were prospectively identified in DNA extracts of CSF obtained from patients with PCNSL and glioblastoma, respectively, within 80 minutes. Across 132 specimens, hallmark mutations indicating the presence of malignancy were detected with 65.8% sensitivity and 100% specificity (95% CI: 56.2%-74.5% and 83.9%-100%, respectively). This targeted genotyping approach offers a rapid, scalable adjunct to reduce diagnostic and treatment delays in PCNSL.

[Circumscribed Astrocytic Gliomas].

In the fifth edition central nervous system tumours volume of the WHO Classification of Tumours series, gliomas, glioneuronal tumors, and neuronal tumors are divided into six groups. The term "circumscribed" is used to refer to a relatively contained growth pattern, as compared to other inherently "diffuse" tumors. Circumscribed astrocytic gliomas include six types: pilocytic astrocytoma, high-grade astrocytoma with piloid features, pleomorphic xanthoastrocytoma, subependymal giant cell astrocytoma, chordoid glioma, and astroblastoma, MN1-altered. The vast majority of circumscribed astrocytic gliomas harbor genetic alterations in the mitogen-activated protein kinase pathway. Here, we review the circumscribed astrocytic gliomas, including etiology, clinical and imaging features, pathology and molecular genetics, treatment, and prognosis. This study will lead to better understanding of these newly classified tumors.

Genotype-targeted local therapy of glioma.

Aggressive neurosurgical resection to achieve sustained local control is essential for prolonging survival in patients with lower-grade glioma. However, progression in many of these patients is characterized by local regrowth. Most lower-grade gliomas harbor isocitrate dehydrogenase 1 (IDH1) or IDH2 mutations, which sensitize to metabolism-altering agents. To improve local control of IDH mutant gliomas while avoiding systemic toxicity associated with metabolic therapies, we developed a precision intraoperative treatment that couples a rapid multiplexed genotyping tool with a sustained release microparticle (MP) drug delivery system containing an IDH-directed nicotinamide phosphoribosyltransferase (NAMPT) inhibitor (GMX-1778). We validated our genetic diagnostic tool on clinically annotated tumor specimens. GMX-1778 MPs showed mutant IDH genotype-specific toxicity in vitro and in vivo, inducing regression of orthotopic IDH mutant glioma murine models. Our strategy enables immediate intraoperative genotyping and local application of a genotype-specific treatment in surgical scenarios where local tumor control is paramount and systemic toxicity is therapeutically limiting.

[Glioma Cell Biology].

In this review, I summarized the biology of gliomas. Through past clinical and basic studies, I reviewed the evidence of the cell of origin of gliomas and the presence of brain tumor-initiating cells in gliomas, which are driven by multiple genomic alterations. In addition, the complicated tumor heterogeneity and neuronal-glioma network were studied. These mechanisms may underlie the treatment resistance and poor prognosis and support the identification of novel therapeutic targets for gliomas.

Genome-wide DNA methylation profiling shows molecular heterogeneity of anaplastic pleomorphic xanthoastrocytoma.

In the revised World Health Organization classification 2016, anaplastic pleomorphic xanthoastrocytoma (PXA) has been newly defined as a variant of the PXA entity. Furthermore, some anaplastic PXA were reported to have extremely poor prognosis which showed a type of pediatric glioblastoma (GBM) molecular profile. Recent integrated molecular classification for primary central nervous system tumors proposed some differences between histological and molecular features. Herein, in a genome-wide molecular analysis, we show an extreme aggressive anaplastic PXA that resulted in a pediatric GBM molecular profile. A full implementation of the molecular approach is the key to predict prognosis and decide the treatment strategy for anaplastic PXA.

Three-dimensional multimodality fusion imaging as an educational and planning tool for deep-seated meningiomas.

INTRODUCTION: The utility of surgical simulation with three-dimensional multimodality fusion imaging (3D-MFI) has been demonstrated. However, its potential in deep-seated brain lesions remains unknown. The aim of this study was to investigate the impact of 3D-MFI in deep-seated meningioma operations. MATERIAL AND METHODS: Fourteen patients with deeply located meningiomas were included in this study. We constructed 3D-MFIs by fusing high-resolution magnetic resonance (MR) and computed tomography (CT) images with a rotational digital subtraction angiogram (DSA) in all patients. The surgical procedure was simulated by 3D-MFI prior to operation. To assess the impact on neurosurgical education, the objective values of surgical simulation by 3D-MFIs/virtual reality (VR) video were evaluated. To validate the quality of 3D-MFIs, intraoperative findings were compared. The identification rate (IR) and positive predictive value (PPV) for the tumor feeding arteries and involved perforating arteries and veins were also assessed for quality assessment of 3D-MFI. RESULTS: After surgical simulation by 3D-MFIs, near-total resection was achieved in 13 of 14 (92.9%) patients without neurological complications. 3D-MFIs significantly contributed to the understanding of surgical anatomy and optimal surgical view (p < .0001) and learning how to preserve critical vessels (p < .0001) and resect tumors safety and extensively (p < .0001) by neurosurgical residents/fellows. The IR of 3D-MFI for tumor-feeding arteries and perforating arteries and veins was 100% and 92.9%, respectively. The PPV of 3D-MFI for tumor-feeding arteries and perforating arteries and veins was 98.8% and 76.5%, respectively. CONCLUSIONS: 3D-MFI contributed to learn skull base meningioma surgery. Also, 3D-MFI provided high quality to identify critical anatomical structures within or adjacent to deep-seated meningiomas. Thus, 3D-MFI is promising educational and surgical planning tool for meningiomas in deep-seated regions.

[Efficacy and Safety of Salvage ESHAP Chemotherapy for Recurrent/Refractory PCNSLs].

BACKGROUND: Primary central nervous system lymphoma(PCNSL)is a primary brain tumor, which appears commonly and occupies around 4.6% of all primary brain tumors. The standard therapy for this tumor is high-dose methotrexate chemotherapy(HD-MTX)and whole-brain irradiation. No salvage therapies for HD-MTX therapy-refractory or recurrent PCNSLs have been standardized. In our institution, ESHAP therapy(high-dose cytarabine:2,000mg, cisplatin:25mg/m2, etoposide:40mg/m2, methylprednisolone:500mg)was administered as a secondary chemotherapy, and the efficiency was examined. METHODS: We administered ESHAP therapy as secondary chemotherapy for patients with refractory/recurrent PCNSL after HD-MTX therapy. Patients with PCNSL who were diagnosed and treated at our institute since 1996 were retrospectively studied. Clinical evaluations were performed based on Karnofsky Performance Status and overall survival, and the effect of ESHAP therapy was evaluated using the Response Assessment in Neuro-Oncology criteria. RESULTS: The number of patients with refractory/recurrent PCNSLs were 18(28-77 years of age, median age of 58.5 years). The response rate(RR)after the first course of salvage ESHAP therapy was 77.8%(14 cases), and complete response(CR)was achieved in 6 cases. The RR after the final course of ESHAP therapy was as high as 61.1%(11 cases), and 4 patients retained CR status. In patients with refractory PCNSL who were treated with HD-MTX, the RR in the final course of salvage ESHAP therapy was as high as 77.8%(7 cases), and 3 patients retained CR status during the periods. The occurrence rate of Grade 3 or higher adverse events, according to the Common Terminology Criteria for Adverse Events version 4.0, was 66.7%(12 cases);all events that were associated with blood and lymphatic system disorders were quickly alleviated, and no fatal adverse events occurred. CONCLUSION: In this study, we retrospectively examined the efficacy of ESHAP therapy as a secondary chemotherapy for patients with refractory/recurrent PCNSL after receiving HD-MTX therapy. Based on our findings, we suggest that ESHAP therapy should be considered as an encouraging secondary chemotherapy for patients with refractory/recurrent PCNSL.

Characteristics and surgical strategies for posterior clinoid process meningioma: two case reports and review of the literature.

Clinical and radiological features or characteristics of posterior clinoid process (PCP) meningiomas have rarely been described because of their extreme scarcity and terminological confusion. Therefore, the strategies in the surgical intervention for PCP meningiomas have not been well established. Moreover, the presence of deep and critical neuroanatomical structures and relatively high morbidity, which can be difficult to predict preoperatively, make their surgical excision more challenging. We report two surgical cases of PCP meningioma and discuss the appropriate assessment of preoperative features and surgical strategies with review of the literature. Our study suggests that PCP meningioma may be characterized by the anterior displacement of internal carotid artery, and infero-laterally shifted posterior communicating arteries, and homonymous hemianopsia, a distinctive clinical feature. One of the key issues in PCP meningioma surgery is preservation of the optic nerve. Unlocking the optic nerve by anterior clinoidectomy and dissection, the falciform ligament is the important step to preserve vision for larger tumors. Complication with the perforators is also hazardous of these challenging surgeries than anterior clinoid meningiomas for their specific neuroanatomical structures and might not be feasible to avoid even with additional techniques and critical monitoring. A combination and multi-staged-surgical approach can be options of tailor-made surgical strategy in cases with tumor adhesion to the perforators.

[Intraoperative Artery Wall Stimulating Electromyography during Microvascular Decompression Surgery to Treat Hemifacial Spasm:A Case Report].

OBJECTIVE: Microvascular decompression(MVD)surgery has been established as a standard treatment for hemifacial spasm. However, because decompression surgery results in unfavorable outcomes in some cases, a more critical monitoring strategy is required. To improve surgical outcome for hemifacial spasms, abnormal muscle response(AMR)has been proposed as a tool for intraoperative electrophysiological monitoring during MVD surgery. Here, we report a single case of surgical MVD monitoring using artery wall stimulating electromyography(AWS-EMG). AWS-EMG was developed as a new monitoring method in addition to AMR. CASE DESCRIPTION: A 60-year-old woman was diagnosed with hemifacial spasm using magnetic resonance imaging and magnetic resonance angiography fusion imaging. We performed MVD surgery using AWS-EMG and AMR. We successfully identified AWS-EMG before decompression and confirmed immediate AWS-EMG loss after decompression. This behavior was consistent with AMR. After surgery, the patient showed no further symptoms of hemifacial spasm. CONCLUSIONS: In addition to AMR, AWS-EMG might be a promising candidate for intraoperative monitoring for patients with hemifacial spasm.

Multimodal approach to detect osseous involvement in meningioma: additional value of (18)F-fluoride PET/CT for conventional imaging.

PURPOSE: To compare the diagnostic performance of fluorine 18 ((18)F) fluoride positron emission tomography (PET)/computed tomography (CT) with that of conventional imaging (CT and magnetic resonance [MR] imaging) in evaluating the osseous involvement in meningioma. MATERIALS AND METHODS: The study was approved by the ethics committee and institutional review board and was conducted according to the Declarations of Helsinki and Tokyo. Written informed consent was obtained from all patients. A retrospective comparative study between (18)F-fluoride PET/CT and conventional imaging was conducted to detect osseous involvement in patients with a verified diagnosis of meningioma. Osseous involvement was verified by using definitive surgery (including drilling or careful sampling of the skull in all patients). The diagnostic performance, determined by calculating the sensitivity, specificity, positive predictive value ( PPV positive predictive value ), negative predictive value ( NPV negative predictive value ), and accuracy, was assessed. RESULTS: Data sets from a total of 78 patients with proven meningioma were compared. Osseous involvement was histopathologically confirmed in 25 patients (32%). The sensitivity, specificity, PPV positive predictive value , NPV negative predictive value , and accuracy were 92.0%, 86.8%, 76.7%, 95.8%, and 88.5% for (18)F-fluoride PET/CT and 64.0%, 83.0%, 64.0%, 83.0%, and 76.9% for conventional imaging, respectively. The receiver operating characteristic ( ROC receiver operating characteristic ) analysis revealed that the area under the ROC receiver operating characteristic curve ( Az area under the ROC curve ) value of (18)F-fluoride PET/CT was significantly greater than that of conventional imaging (0.965 ± 0.02 [standard error] vs 0.703 ± 0.066 [standard error], P < .0001). CONCLUSION: An approach using (18)F-fluoride PET/CT improves preoperative detection of osseous involvement. In those without abnormal (18)F-fluoride uptake within the skull, the patient may proceed directly to conventional surgery. However, a positive finding of osseous involvement at (18)F-fluoride PET/CT should prompt confirmation by drilling or sampling of bone.

Tumor hypoxia and microscopic diffusion capacity in brain tumors: a comparison of (62)Cu-Diacetyl-Bis (N4-Methylthiosemicarbazone) PET/CT and diffusion-weighted MR imaging.

OBJECTIVES: The aim of this study was to clarify the relationship between tumor hypoxia and microscopic diffusion capacity in primary brain tumors using (62)Cu-Diacetyl-Bis (N4-Methylthiosemicarbazone) ((62)Cu-ATSM) PET/CT and diffusion-weighted MR imaging (DWI). METHODS: This study was approved by the institutional human research committee and was HIPAA compliant, and informed consent was obtained from all patients. (62)Cu-ATSM PET/CT and DWI were performed in a total of 40 primary brain tumors of 34 patients with low grade glioma (LGG, n = 13), glioblastoma (GBM, n = 20), and primary central nervous system lymphoma (PCNSL, n = 7). (62)Cu-ATSM PET/CT parameters and apparent diffusion coefficient (ADC) obtained by DWI were compared. RESULTS: High intensity signals by (62)Cu-ATSM PET/CT and DWI in patients with GBM and PCNSL, and low intensity signals in LGG patients were observed. An inverse correlation was found between maximum SUV (SUVmax) and minimum ADC (ADCmin) (r = -0.583, p < 0.0001), and between tumor/brain ratio (T/Bratio) and ADCmin for all tumors (r = -0.532, p < 0.0001). Both SUVmax and T/Bratio in GBM were higher than LGG (p < 0.0001 and p < 0.0001), and those in PCNSL were also higher than GBM (p = 0.033 and p = 0.044). The ADCmin was lower in GBM (p = 0.011) and PCNSL (p = 0.01) than in LGG, while no significant difference was found between GBM and PCNSL (p = 0.90). CONCLUSION: Tumor hypoxia assessed by (62)Cu-ATSM PET/CT correlated with microscopic diffusion capacity obtained by DWI in brain tumors. Both (62)Cu-ATSM PET/CT and DWI were considered feasible imaging methods for grading glioma. However, (62)Cu-ATSM PET/CT provided additional diagnostic information to differentiate between GBM and PCNSL.

Occipitocervical fusion with relief of odontoid invagination: atlantoaxial distraction method using cylindrical titanium cage for basilar invagination--case report.

A 65-year-old woman presented with basilar invagination manifesting as neck pain, dysesthesia around the lips, and truncal ataxia. The radiological findings demonstrated invagination of the odontoid process into the medulla oblongata and vertical atlantoaxial subluxation with C1 assimilation. The clivo-axial angle was 88° and the cervicomedullary angle was 115°, indicating severe basilar invagination. We planned occipitocervical fusion with atlantoaxial distraction using a cylindrical titanium cage. C2 pedicle screws were inserted, and the atlantoaxial joint was opened to translocate the odontoid process downward. A cylindrical titanium cage packed with local bone graft was inserted into the opened facet joint space. Occipital-C2 fusion was completed by fastening the occipital bone plates with pedicle screws using titanium rods. Postoperatively, the apex of the odontoid process descended by 7 mm, and the clivo-axial and cervicomedullary angles opened to 112° and 125°, respectively. Invagination of the odontoid process into the medulla oblongata was relieved. The preoperative symptoms improved, and she remained symptom-free without requiring anterior decompression over 2 years. Bone fusion of the atlantoaxial joints was completed with sustained facet distraction 12 months after the surgery, and adequate relief of the basilar invagination was maintained. The atlantoaxial distraction method using a cylindrical titanium cage can be a useful option in posterior fusion surgery for basilar invagination.

Translational Research Platform for Malignant Central Nervous System Tumors.

Some central nervous system (CNS) malignancies are highly aggressive and urgently need innovative treatment strategies to improve prognosis. A significant concern for therapeutic development is the time-consuming nature of developing treatments for CNS tumors. Therefore, a rapid and efficient translational approach is needed to address this problem. Translational and reverse translational research aims to bridge the gap between laboratory data and clinical applications and has been developed in the field of neuro-oncology. This study presents our translational platform systems for malignant CNS tumors, which combine an intraoperative integrated diagnostic system and comprehensive in vitro and in vivo assay systems. These laboratory systems may contribute to a better understanding of tumor biology and the development of novel therapeutic strategies for the poor prognosis of CNS tumors.

Anti-epileptic drug use and subsequent degenerative dementia occurrence.

INTRODUCTION: The use of anti-epileptic drugs (AEDs) in degenerative dementia (DD) remains uncertain. We aimed to evaluate the association of early AED administration with subsequent DD occurrence. METHODS: Using a large nationwide database, we enrolled patients newly diagnosed with epilepsy from 2014 to 2019 (n = 104,225), and using propensity score matching, we divided them into treatment (those prescribed AEDs in 2014) and control groups. The primary outcome was subsequent DD occurrence in 2019. RESULTS: Overall, 4489 pairs of patients (2156 women) were matched. The odds ratio (treatment/control) for DD occurrence was 0.533 (95% confidence interval: 0.459-0.617). The DD proportions significantly differed between the treatment (340/4489 = 0.076) and control (577/4489 = 0.129) groups. DISCUSSION: Among patients newly diagnosed with epilepsy, compared to non-use, early AED use was associated with a lower occurrence of subsequent DD. Further investigations into and optimization of early intervention for epilepsy in DD are warranted. Highlights: Anti-epileptic drug (AED) use before epilepsy diagnosis was linked with a lower subsequent degenerative dementia (DD) occurrence.Identifying the epileptic phenotype was crucial for justifying early AED use in DD.AED use with an epilepsy diagnosis did not pose an additional risk of DD.The potential contribution of combination drug therapy to the strategy was noted.

Intraoperative Integrated Diagnostic System for Malignant Central Nervous System Tumors.

PURPOSE: The 2021 World Health Organization (WHO) classification of central nervous system (CNS) tumors uses an integrated approach involving histopathology and molecular profiling. Because majority of adult malignant brain tumors are gliomas and primary CNS lymphomas (PCNSL), rapid differentiation of these diseases is required for therapeutic decisions. In addition, diffuse gliomas require molecular information on single-nucleotide variants (SNV), such as IDH1/2. Here, we report an intraoperative integrated diagnostic (i-ID) system to classify CNS malignant tumors, which updates legacy frozen-section (FS) diagnosis through incorporation of a qPCR-based genotyping assay. EXPERIMENTAL DESIGN: FS evaluation, including GFAP and CD20 rapid IHC, was performed on adult malignant CNS tumors. PCNSL was diagnosed through positive CD20 and negative GFAP immunostaining. For suspected glioma, genotyping for IDH1/2, TERT SNV, and CDKN2A copy-number alteration was routinely performed, whereas H3F3A and BRAF SNV were assessed for selected cases. i-ID was determined on the basis of the 2021 WHO classification and compared with the permanent integrated diagnosis (p-ID) to assess its reliability. RESULTS: After retrospectively analyzing 153 cases, 101 cases were prospectively examined using the i-ID system. Assessment of IDH1/2, TERT, H3F3AK27M, BRAFV600E, and CDKN2A alterations with i-ID and permanent genomic analysis was concordant in 100%, 100%, 100%, 100%, and 96.4%, respectively. Combination with FS and intraoperative genotyping assay improved diagnostic accuracy in gliomas. Overall, i-ID matched with p-ID in 80/82 (97.6%) patients with glioma and 18/19 (94.7%) with PCNSL. CONCLUSIONS: The i-ID system provides reliable integrated diagnosis of adult malignant CNS tumors.

Upregulating mutations in the TERT promoter commonly occur in adult malignant gliomas and are strongly associated with total 1p19q loss.

Telomere lengthening is one of the key events in most cancers, and depends largely on telomerase activation. Telomerase activation is a well-known phenomenon in gliomas; however, its mechanism remains obscure. In this study, we investigated the presence of mutations in the promoter of the telomerase reverse transcriptase (TERT) gene in a series of 546 gliomas. We found a high incidence of mutually exclusive mutations located at two hot spots, C228T and C250T, in all subtypes of gliomas (55 %). The frequency of mutation was particularly high among primary glioblastomas (70 %) and pure oligodendroglial tumors (74 %), while relatively low in diffuse astrocytomas and anaplastic astrocytomas (19 and 25 %, respectively). The expression level of TERT in tumors carrying those mutations was on average 6.1 times higher than that of wild-type tumors, indicating that the mutated promoter leads to upregulation of TERT. TERT promoter mutations were observed in almost all tumors harboring concurrent total 1p19q loss and IDH1/2 mutations (98 %). Otherwise TERT promoter mutations were mostly observed among IDH wild-type tumors. Most EGFR amplifications (92 %) were also associated with TERT promoter mutations. Our data indicate that mutation of the TERT promoter is one of the major mechanisms of telomerase activation in gliomas. The unique pattern of TERT promoter mutations in relation to other genetic alterations suggests that they play distinct roles in the pathogenesis of oligodendroglial and astrocytic tumors. Our results shed a new light on the role of telomerase activation in the development of adult gliomas.