Three-Dimensional Gradient-Echo-Based Amide Proton Transfer-Weighted Imaging of Brain Tumors: Comparison With Two-Dimensional Spin-Echo-Based Amide Proton Transfer-Weighted Imaging.

OBJECTIVE: Although amide proton transfer-weighted (APTw) imaging is reported by 2-dimensional (2D) spin-echo-based sequencing, 3-dimensional (3D) APTw imaging can be obtained by gradient-echo-based sequencing. The purpose of this study was to compare the efficacy of APTw imaging between 2D and 3D imaging in patients with various brain tumors. METHODS: A total of 49 patients who had undergone 53 examinations [5 low-grade gliomas (LGG), 16 high-grade gliomas (HGG), 6 malignant lymphomas, 4 metastases, and 22 meningiomas] underwent APTw imaging using 2D and 3D sequences. The magnetization transfer ratio asymmetry (MTR asym ) was assessed by means of region of interest measurements. Pearson correlation was performed to determine the relationship between MTR asym for the 2 methods, and Student's t test to compare MTR asym for LGG and HGG. The diagnostic accuracy to differentiate HGG from LGG of the 2 methods was compared by means of the McNemar test. RESULTS: Three-dimensional APTw imaging showed a significant correlation with 2D APTw imaging ( r = 0.79, P < 0.0001). The limits of agreement between the 2 methods were -0.021 ± 1.42%. The MTR asym of HGG (2D: 1.97 ± 0.96, 3D: 2.11 ± 0.95) was significantly higher than those of LGG (2D: 0.46 ± 0.89%, P < 0.01; 3D: 0.15 ± 1.09%, P < 0.001). The diagnostic performance of the 2 methods to differentiate HGG from LGG was not significantly different ( P = 1). CONCLUSIONS: The potential capability of 3D APTw imaging is equal to or greater than that of 2D APTw imaging and is considered at least as valuable in patients with brain tumors.

Carotid Plaque Diagnosis With 3-Dimensional Computed Tomography Angiography: A Comparison With Magnetic Resonance Imaging-Based Plaque Diagnosis.

OBJECTIVE: Although a qualitative diagnosis of plaque causing carotid stenosis has been attempted with carotid computed tomography angiography (CaCTA), no clear findings have been reported. We examined the correlation between the plaque CT values and plaque images obtained by magnetic resonance imaging to derive a qualitative diagnosis of the plaque using CaCTA. METHODS: Preoperative CaCTA images acquired from patients stented for carotid stenosis were retrospectively analyzed with respect to magnetization-prepared rapid acquisition with gradient echo and time-of-flight magnetic resonance angiography data. Carotid plaques in the stenosed region were quantified in terms of CT density and the plaque/muscle ratio (magnetization-prepared rapid acquisition with gradient echo), and correlations between these 2 features were determined. Plaques were classified as stable or unstable based on the plaque/muscle ratio, with the smallest plaque/muscle ratio observed among plaques positive for intraplaque hemorrhage set as the cutoff value (1.76). RESULTS: A total of 165 patients (179 plaques) were included. Perioperative complications included minor stroke (n = 3), major stroke (n = 1, fatal), and hyperperfusion (n = 2). The correlation between CT density and the plaque/muscle ratio was nonlinear ( P = 0.0139) and negative ( P < 0.0001). The cutoff point (1.76) corresponded to a CT density of 83 HU, supporting this value as a standard reference for plaque stability. CONCLUSIONS: Computed tomography density exhibits a nonlinear ( P = 0.0139) and highly negative correlation ( P < 0.0001) with the plaque/muscle ratio. Our results demonstrate that plaque characteristics can be meaningfully diagnosed based on CaCTA image data.

Applied Fence-Post Techniques Using Deep Electrodes Instead of Catheters for Resection of Glioma Complicated with Frequent Epileptic Seizures: A Case Report.

Fence-post catheter techniques are used to use tumor margins when resecting gliomas. In the present study, deep electrodes instead of catheters were used as fence-posts. The case of a 25-year-old female patient whose magnetic resonance images (MRI) revealed a tumor in the left cingulate gyrus is presented in this study. She underwent daily seizures without loss of consciousness under the administration of anti-seizure medications. Despite video electroencephalography (EEG) monitoring, the scalp inter-ictal EEG did not show obvious epileptiform discharges. We were consequently uncertain whether such frequent seizures were epileptic seizures or not. As a result, deep electrodes were used as fence-posts: three deep electrodes were inserted into the tumor's anterior, lateral, and posterior margins using a navigation-guided method. The highest epileptic discharge was detected from the anterior deep electrode. As a result, ahead of the tumor was extendedly resected, and epileptic discharges were eliminated using EEG. The postoperative MRI revealed that the tumor was resected. The patient has never experienced seizures after the surgery. In conclusion, when supratentorial gliomas complicated by frequent seizures are resected, intraoperative EEG monitoring using deep electrodes as fence-posts is useful for estimating epileptogenic areas.

Three-Dimensional Amide Proton Transfer-Weighted Imaging for Differentiating between Glioblastoma, IDH-Wildtype and Primary Central Nervous System Lymphoma.

Distinguishing primary central nervous system lymphoma (PCNSL) from glioblastoma, isocitrate dehydrogenase (IDH)-wildtype is sometimes hard. Because the role of operation on them varies, accurate preoperative diagnosis is crucial. In this study, we evaluated whether a specific kind of chemical exchange saturation transfer imaging, i.e., amide proton transfer-weighted (APTw) imaging, was useful to distinguish PCNSL from glioblastoma, IDH-wildtype. A total of 14 PCNSL and 27 glioblastoma, IDH-wildtype cases were evaluated. There was no significant difference in the mean APTw signal values between the two groups. However, the percentile values from the 1st percentile to the 20th percentile APTw signals and the width1-100 APTw signals significantly differed. The highest area under the curve was 0.796, which was obtained from the width1-100 APTw signal values. The sensitivity and specificity values were 64.3% and 88.9%, respectively. APTw imaging was useful to distinguish PCNSL from glioblastoma, IDH-wildtype. To avoid unnecessary aggressive surgical resection, APTw imaging is recommended for cases in which PCNSL is one of the differential diagnoses.

Transsylvian and trans-Heschl's gyrus approach for a left posterior insular lesion and functional analyses of the left Heschl's gyrus: illustrative case.

BACKGROUND: A common surgical approach for dominant insular lesions is to make a surgical corridor in asymptomatic cortices based on functional mapping. However, the surgical approach is difficult for posterior insular lesions in a dominant hemisphere because the posterior parts of the perisylvian cortices usually have verbal functions. OBSERVATIONS: We present the case of a 40-year-old male whose magnetic resonance images revealed the presence of contrast-enhancing lesions in the left posterior insula. Our surgical approach was to split the sylvian fissure as widely as possible, and partially resect Heschl's gyrus if the cortical mapping was negative for language tests. Because Heschl's gyrus did not have verbal functions, the gyrus was used as a surgical corridor. It was wide enough for the removal of the lesion; however, because intraoperative pathological diagnosis eliminated the possibility of brain tumors, further resection was discontinued. The tissues were histologically diagnosed as tuberculomas. Antituberculosis drugs were administered, and the residual lesions finally disappeared. According to the neurophysiological tests, the patient showed temporary impairment of auditory detection, but the low scores of these tests improved. LESSONS: The transsylvian and trans-Heschl's gyrus approach can be a novel surgical option for excising dominant posterior insular lesions.

Hydrocephalus in Neurofibromatosis Type 1 Caused by a Cyst Formation Similar to Late-Onset Aqueductal Membranous Occlusion: A Case Report and Review of Literature.

Cyst formation in the third ventricle and the histopathological findings were rarely reported. We report a similar case of late-onset aqueductal membranous occlusion (LAMO) caused by a thin gliotic cyst and a review of related literature. A 28-year-old woman with enlarged lateral ventricles was referred to our hospital with complaints of headache and dizziness. In our hospital, the obvious cause of the hydrocephalus was unknown on any examination and we decided performing endoscopic third ventriculostomy for hydrocephalus. A thin cyst covering the entrance of the aqueduct was identified and we perforated it. Histopathological finding of the cyst wall was gliosis and our case was similar to LAMO, although not typical. The postoperative symptoms and ventricle size improved for 4 years. When suspecting cases similar to definition of LAMO, neuroendoscopic surgery would be the first-choice treatment and might detect causes undetectable on preoperative imaging such as our thin membrane.

Intracranial phosphaturic mesenchymal tumors. A case report and review of literature.

Most osteomalacia-inducing tumors (OITs) are phosphaturic mesenchymal tumors (PMTs) that secrete fibroblast growth factor 23 (FGF23). These tumors usually occur in the bone and soft tissues, and intracranial OITs are rare. Therefore, intracranial OIT is difficult to diagnose and treat. This paper presents a case of intracranial OIT and shows a review of previous cases. A 45-year-old man underwent nasal cavity biopsy and treatment with active vitamin D3 and neutral phosphate for hypophosphatemia. Amplification of FGF23 mRNA level within the tumor was detected. Subsequently, the surgical specimen was diagnosed with a PMT and was considered the cause of the patient's osteomalacia. The patient was referred to a neurosurgery department for the excision of the intracranial tumor extending to the nasal cavity. After tumor removal, the serum levels of FGF23 and phosphorus were normalized as compared to preoperative those. The patient remains disease-free, without additional treatment, approximately 10 years after surgery, with no tumor recurrence. As per the literature, intracranial OITs usually occur in patients aged 8-69 years. Bone and muscle pain are major complaints. Approximately 60% of the patients reported previously had symptoms because of intracranial tumors. In some cases, it took several years to diagnose OIT after the onset of the osteomalacia symptoms. Laboratory data in such cases show hypophosphatemia and elevated FGF23 levels. Because FGF23 levels are associated with the severity of osteomalacia symptoms, total tumor resection is recommended. PMT and hemangiopericytoma (HPC) are histologically similar, but on immunochemistry, PMT is negative for signal transducer and activator of transcription 6 (STAT6), whereas HPC is positive. FGF23 amplification is seen in PMTs but not in HPCs. Therefore, the analysis of FGF23 and STAT6 was helpful in distinguishing PMTs from HPCs. In cases of hypophosphatemia and osteomalacia without a history of metabolic, renal, or malabsorptive diseases, the possibility of oncogenic osteomalacia should be considered.

PKM2 Interacts With the Cdk1-CyclinB Complex to Facilitate Cell Cycle Progression in Gliomas.

PKM2 is a phosphotyrosine-binding glycolytic enzyme upregulated in many cancers, including glioma, and contributes to tumor growth by regulating cell cycle progression. We noted, however, that in multiple glioma cell lines, PKM2 knock-down resulted in an accumulation of cells in G2-M phase. Moreover, PKM2 knock-down decreased Cdk1 activity while introducing a constitutively active Cdk1 reversed the effects of PKM2 knock-down on cell cycle progression. The means by which PKM2 increases Cdk1 activity have not been described. Transient interaction of T14/Y15-phosphorylated Cdk1 with cyclin B allows Cdk7-mediated pT161 Cdk1 phosphorylation followed by cdc25C-mediated removal of pT14/Y15 and activation of Cdk1 in cycling cells. In the present course of investigation, PKM2 modulation did not influence Cdk7 activity, but phosphotyrosine binding forms of PKM2 co-immunoprecipitated with pY15-containing Cdk1-cyclinB and enhanced formation of active pT161 Cdk1-cyclin B complexes. Moreover, exogenous expression of phosphotyrosine binding forms of PKM2 reversed the effects of PKM2 knock-down on G2-M arrest. We here show that PKM2 binds and stabilize otherwise transient pY15-containing Cdk1-cyclinB complexes that in turn facilitate Cdk1-cyclin B activation and entry of cells into mitosis. These results, therefore, establish metabolic enzyme PKM2 as a direct interactor and activator of Cdk1-cyclin B complex and thereby directly controls mitotic progression and the growth of brain tumor cells.

Contrast-Enhanced Magnetic Resonance Imaging, Perfusion Magnetic Resonance Imaging, and 1H-Magnetic Resonance Spectroscopy Distinguish Primary Central Nervous System Vasculitis from Glioblastoma.

BACKGROUND: We investigated the ability of magnetic resonance imaging (MRI) to distinguish primary central nervous system vasculitis (PCNSV) from glioblastoma to facilitate the development of an appropriate treatment for PCNSV. METHODS: We enrolled patients who were treated for PCNSV or glioblastoma at our center between January 2007 and August 2018. We compared the diagnoses of the 2 conditions by retrospectively reviewing patients' data for contrast-enhanced MRI, perfusion MRI, flow-sensitive black-blood (FSBB) imaging, and 1H-magnetic resonance spectroscopy (MRS). RESULTS: We evaluated 108 patients (6 PCNSV; 102 glioblastoma). We found a statistically significant correlation between diagnosis and the contrast pattern on MRI. Perivascular enhancement was observed in all cases of PCNSV as follows: ring-like, homogeneous, and irregular patterns were observed in 53 (60%), 18 (20%), and 17 (19%) cases of glioblastoma, respectively. We identified a statistically significant correlation between diagnosis and cerebral blood volume (CBV) in 3 patients with PCNSV who underwent perfusion MRI; and all had low CBVs. Among the 55 patients with glioblastoma who underwent perfusion MRI, low and high CBVs were detected in 3 and 52 patients, respectively. There was no significant correlation between diagnosis and FSBB findings. Evaluation of 1H-MRS data showed statistically significant differences between PCNSV and glioblastoma as functions of neuronal amino acid levels on long echo time MRS, with a slightly different amino acid profile, including glutamine + glutamate on short echo time MRS. CONCLUSIONS: Contrast-enhanced MRI, perfusion MRI, and quantitative analysis of 1H-MRS are valuable techniques for distinguishing PCNSV from glioblastoma before surgery.

Primary central nervous system lymphomas with massive intratumoral hemorrhage: Clinical, radiological, pathological, and molecular features of six cases.

Primary central nervous system lymphomas (PCNSLs) rarely exhibit intratumoral hemorrhage. The differential diagnosis of hemorrhagic neoplasms of the central nervous system (CNS) currently includes metastatic carcinomas, melanomas, choriocarcinomas, oligodendrogliomas, and glioblastomas. Here we present the clinical, radiological, pathological, and molecular genetic features of six cases of PCNSL associated with intratumoral hemorrhage. The median age of patients was 75 years, with male predominance. While conventional PCNSLs were associated with low cerebral blood volume (CBV), perfusion magnetic resonance imaging (MRI) revealed elevated CBV in three cases, consistent with vascular proliferation. All six cases were diagnosed pathologically as having diffuse large B-cell lymphoma (DLBCL) with a non-germinal center B-cell-like (non-GCB) phenotype; marked histiocytic infiltrates and abundant non-neoplastic T-cells were observed in most cases. Expression of vascular endothelial growth factor and CD105 in the lymphoma cells and the small vessels, respectively, suggested angiogenesis within the neoplasms. Neoplastic cells were immunohistochemically negative for programmed cell death ligand 1 (PD-L1), while immune cells in the microenvironment were positive for PD-L1. Mutations in the MYD88 gene (MYD88) (L265P) and the CD79B gene (CD79B) were detected in five and one case, respectively. As therapeutic modalities used for PCNSLs differ from those that target conventional hemorrhagic neoplasms, full tissue diagnoses of all hemorrhagic CNS tumors are clearly warranted.

Inhibition of DNA Repair in Combination with Temozolomide or Dianhydrogalactiol Overcomes Temozolomide-Resistant Glioma Cells.

Resistance to temozolomide and intratumoral heterogeneity contribute to the poor prognosis of glioma. The mechanisms of temozolomide resistance can vary within a heterogeneous tumor. Temozolomide adds a methyl group to DNA. The primary cytotoxic lesion, O6-methylguanine, mispairs with thymine, leading to a futile DNA mismatch repair cycle, formation of double-strand breaks, and eventual cell death when O6-methylguanine DNA methyltransferase (MGMT) is absent. N7-methylguanine and N3-methyladenine are repaired by base excision repair (BER). The study aim was to elucidate temozolomide resistance mechanisms and identify methods to overcome temozolomide resistance in glioma. Several temozolomide-resistant clones were analyzed. Increased homologous recombination and mismatch repair system deficiencies contributed to temozolomide resistance. Inhibition of homologous recombination resensitized resistant cells with high homologous recombination efficiency. For the mismatch repair-deficient cells, inhibition of BER by PARP inhibitor potentiated temozolomide-induced cytotoxicity. Dianhydrogalactiol is a bifunctional DNA-targeting agent that forms N7-alkylguanine and inter-strand DNA crosslinks. Dianhydrogalactiol reduced the proliferation of cells independent of MGMT and mismatch repair, inducing DNA double-strand breaks and apoptosis in temozolomide-resistant cells. Further, inhibition of chk1 or homologous recombination enhanced dianhydrogalactiol-induced cytotoxicity in the cells. Selecting treatments most appropriate to the types of resistance mechanisms can potentially improve the prognosis of glioma.

[Genomic and Epigenomic Abnormalities in Gliomas].

Advances in genetic and epigenetic analyses and immunohistochemical studies involving the development of mutation-specific or histone-methylated antibodies have provided many significant findings about gliomas. Based on these findings, the WHO developed and published the classification of tumors of the central nervous system in 2016. In the classification system, molecular information was combined with pathological findings. After its publication, the Consortium to Inform Molecular and Practical Approaches to CNS Tumor Taxonomy-Not Official WHO(cIMAPCT-NOW)was published to evaluate and recommend changes to future central nervous system tumor classifications. This review describes the genetic and epigenetic features of gliomas, mainly those associated with the WHO classification and cIMPACT-NOW.

Myoinositol to Total Choline Ratio in Glioblastomas as a Potential Prognostic Factor in Preoperative Magnetic Resonance Spectroscopy.

Isocitrate dehydrogenase (IDH) wild-type diffuse astrocytic tumors tend to be pathologically diagnosed as glioblastomas (GBMs). We previously reported that myoinositol to total choline (Ins/Cho) ratio in GBMs on magnetic resonance (MR) spectroscopy was significantly lower than that in IDH-mutant gliomas. We then hypothesized that a low Ins/Cho ratio is a poor prognosis factor in patients with GBMs, IDH-wild-type. In the present study, we calculated the Ins/Cho ratios of patients with GBMs and investigated their progression-free survival (PFS) and overall survival (OS) to determine their utility as prognostic marker. We classified patients with GBMs harboring wild-type IDH (n = 27) into two groups based on the Ins/Cho ratio, and compared patient backgrounds, pathological findings, PFS, OS, and copy number aberrations between the high and low Ins/Cho groups. Patients with GBMs in the low Ins/Cho ratio group indicated shorter PFS (P = 0.021) and OS (P = 0.048) than those in the high Ins/Cho group. Multivariate analysis demonstrated that the Ins/Cho ratio was significantly correlated with PFS (hazard ratio 0.24, P = 0.028). In conclusion, the preoperative Ins/Cho ratio can be used as a novel potential prognostic factor for GBM, IDH-wild-type.

RETRACTED: A subset of PARP inhibitors induces lethal telomere fusion in ALT-dependent tumor cells.

About 10% of all tumors, including most lower-grade astrocytoma, rely on the alternative lengthening of telomere (ALT) mechanism to resolve telomeric shortening and avoid limitations on their growth. Here, we found that dependence on the ALT mechanism made cells hypersensitive to a subset of poly(ADP-ribose) polymerase inhibitors (PARPi). We found that this hypersensitivity was not associated with PARPi-created genomic DNA damage as in most PARPi-sensitive populations but rather with PARPi-induced telomere fusion. Mechanistically, we determined that PARP1 was recruited to the telomeres of ALT-dependent cells as part of a DNA damage response. By recruiting MRE11 and BRCC3 to stabilize TRF2 at the ends of telomeres, PARP1 blocked chromosomal fusion. Exposure of ALT-dependent tumor cells to a subset of PARPi induced a conformational change in PARP1 that limited binding to MRE11 and BRCC3 and delayed release of the TRF2-mediated block on lethal telomeric fusion. These results therefore provide a basis for PARPi treatment of ALT-dependent tumors, as well as establish chromosome fusion as a biomarker of their activity.

Association of preoperative seizures with tumor metabolites quantified by magnetic resonance spectroscopy in gliomas.

Seizures are common in patients with gliomas; however, the mechanisms of epileptogenesis in gliomas have not been fully understood. This study hypothesized that analyzing quantified metabolites using magnetic resonance spectroscopy (MRS) might provide novel insights to better understand the epileptogenesis in gliomas, and specific metabolites might be indicators of preoperative seizures in gliomas. We retrospectively investigated patient information (gender, age at diagnosis of tumor, their survival time) and tumor information (location, histology, genetic features, and metabolites according to MRS) in patients with gliomas. The data were correlated with the incidence of seizure and analyzed statistically. Of 146 adult supratentorial gliomas, isocitrate dehydrogenase (IDH) mutant tumors significantly indicated higher incidence of preoperative seizures than IDH wild-type gliomas. However, MRS study indicated that glutamate concentration in IDH wild-type gliomas was higher than that in IDH mutant gliomas. Glutamate was not associated with high frequency of preoperative seizures in patients with gliomas. Instead, increased total N-acetyl-L-aspartate (tNAA) was significantly associated with them. Moreover, multivariable analysis indicated that increased level of tNAA was an independent predictor of preoperative seizures. According to MRS analysis, tNAA, rather than glutamate, might be a useful to detect preoperative seizures in patient with supratentorial gliomas.

Objective and quantitative evaluation of angiographic vascularity in meningioma: parameters of dynamic susceptibility contrast-perfusion-weighted imaging as clinical indicators of preoperative embolization.

Digital subtraction angiography (DSA) assesses the necessity of preoperative embolization in meningioma cases but entails complication risks. Previous studies evaluating meningiomas' angiographic vascularity using perfusion-weighted imaging (PWI) have performed subjective visual assessments, not managing to assess the need for preoperative embolization. We objectively assessed the angiographic stain of meningiomas and examined the usefulness of two parameters of dynamic susceptibility contrast (DSC)-PWI, normalized cerebral blood volume (nCBV) and cerebral blood flow (nCBF), in predicting vascularity and the necessity of preoperative embolization. We retrospectively examined 52 patients who underwent surgery for primary meningioma and preoperative DSA and DSC-PWI. We calculated the normalized luminance (nLum) of the tumor stain in DSA. In 29 meningioma cases with a single feeding artery, we determined the DSC-PWI parameter that correlated with meningioma angiographic vascularity and predicted the necessity of preoperative embolization. We also compared vascularity between meningiomas with single and multiple feeding arteries and between convexity and skull-base meningiomas. nCBF (cut off: 3.66, P = 0.03, area under the curve [AUC] = 0.80) alone could predict the necessity of preoperative embolization and was more significantly correlated with the nLum than nCBV (P = 0.08, AUC = 0.73). Vascularity did not differ between meningiomas with single and multiple feeding arteries; skull-base meningiomas were more vascularized than convexity meningiomas (P = 0.0027). Our objective, quantitative assessments revealed nCBF as the most suitable parameter for evaluating meningioma vascularity. Tumor vascularity assessment using nCBF values and CBF images may aid predicting the necessity of preoperative DSA.

Superficial Siderosis of the Central Nervous System Caused by Glioneuronal Tumor: A Case Report and Literature Review.

Superficial siderosis is a rare disease resulting from the deposited hemosiderin owing to repeated subarachnoid hemorrhage. It has been reported that hemosiderin deposits on the brain surface and brain parenchyma causes nerve disorder, resulting in progressive and irreversible hearing loss, cerebellar ataxia and pyramidal disorder. The brain tumor is one of the cause of superficial siderosis. A 16-year-old female present a nearby hospital with complaints of absence seizure. A magnetic resonance imaging (MRI) revealed a heterogeneously enhanced mass at the right temporal lobe. Susceptibility-weighted imaging revealed diffuse and extensive superficial siderosis on the brain surface. The tumor was gross totally removed and diagnosed as glioneuronal tumor. The patient had been well, although susceptibility-weighted imaging performed one year after the surgery showed superficial siderosis remained. Early diagnosis and prevention of bleeding sources are recommended to prevent symptom progression associated with superficial siderosis. Susceptibility-weighted imaging is considered useful for early detection of superficial siderosis.

Correlation between IDH, ATRX, and TERT promoter mutations in glioma.

According to the 2016 World Health Organization (WHO) classification of central nervous system tumors, diffuse astrocytic and oligodendroglial tumors are differentiated by the presence of isocitrate dehydrogenase 1 or 2 (IDH1/2) mutation and the combined loss of the short arm of chromosome 1 and the long arm of chromosome 19 (1p/19q co-deletion). IDH-mutant astrocytoma often has p53 and alpha-thalassemia/mental retardation syndrome X-linked (ATRX) mutation, showing the alternative lengthening of telomeres (ALT) phenotype, while IDH-mutant and 1p/19q-co-deleted oligodendroglioma often have wild-type p53 and telomerase reverse transcriptase (TERT) promoter mutation, showing telomerase activation. This study analyzed IDH, ATRX, and TERT promoter mutations, and the correlation between them. Immortalized cells overcome the telomere-related crisis by activating telomerase or ALT. In glioma, telomerase is mainly activated by TERT promoter mutation, while ALT is usually associated with ATRX mutation. Although the mechanism of how ATRX mutation induces ALT remains unclear, ATRX loss alone is believed to be insufficient to induce ALT. Treatments targeting telomere maintenance are promising.

Phosphoglycerate Mutase 1 Activates DNA Damage Repair via Regulation of WIP1 Activity.

The metabolic enzyme phosphoglycerate mutase 1 (PGAM1) is overexpressed in several types of cancer, suggesting an additional function beyond its established role in the glycolytic pathway. We here report that PGAM1 is overexpressed in gliomas where it increases the efficiency of the DNA damage response (DDR) pathway by cytoplasmic binding of WIP1 phosphatase, thereby preventing WIP1 nuclear translocation and subsequent dephosphorylation of the ATM signaling pathway. Silencing of PGAM1 expression in glioma cells consequently decreases formation of γ-H2AX foci, increases apoptosis, and decreases clonogenicity following irradiation (IR) and temozolomide (TMZ) treatment. Furthermore, mice intracranially implanted with PGAM1-knockdown cells have significantly improved survival after treatment with IR and TMZ. These effects are counteracted by exogenous expression of two kinase-dead PGAM1 mutants, H186R and Y92F, indicating an important non-enzymatic function of PGAM1. Our findings identify PGAM1 as a potential therapeutic target in gliomas.