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BioRxiv : the Preprint Server For... Apr 2024Oligodendroglioma is genetically defined as a tumor harboring isocitrate dehydrogenase 1 or 2 mutations (IDH1 /IDH2 ) and 1p/19q co-deletions. Previously, we reported...
Oligodendroglioma is genetically defined as a tumor harboring isocitrate dehydrogenase 1 or 2 mutations (IDH1 /IDH2 ) and 1p/19q co-deletions. Previously, we reported that in IDH1 gliomas, D-2HG, the product of IDH1 mutant enzyme produces an increase in monounsaturated fatty acid levels that are incorporated into ceramides, tilting the S1P-to-ceramide rheostat toward apoptosis. Herein, we exploited this imbalance to further induce and IDH -specific glioma cell death. We report for the first time that the inhibition of acid ceramidase (AC) induces apoptosis and provides a benefit in mice survival in IDH1 oligodendroglioma. We demonstrated an IDH1 -specific cytotoxicity of SABRAC, an irreversible inhibitor of AC, in patient-derived oligodendroglioma cells. Exploring the mechanism of action of this drug, we found that SABRAC activates both extrinsic and intrinsic apoptosis in an ER stress-independent manner, pointing to a direct action of AC-related ceramides in mitochondria permeability. The activation of apoptosis detected under SABRAC treatment was associated with up to 30-fold increase in some ceramide levels and its derivatives from the salvage pathway. We propose that this novel enzyme, AC, has the potential to increase survival in oligodendroglioma with IDH1 and should be considered in the future.
PubMed: 38903086
DOI: 10.1101/2024.04.27.591426 -
CNS Oncology 2015Oligodendroglioma is the quintessential molecularly-defined brain tumor. The characteristic whole-arm loss of the long arm of chromosome 1 and the short arm of... (Review)
Review
Oligodendroglioma is the quintessential molecularly-defined brain tumor. The characteristic whole-arm loss of the long arm of chromosome 1 and the short arm of chromosome 19 (1p/19q-codeletion) within the genome of these tumors facilitated the reproducible molecular identification of this subcategory of gliomas. More recently, recurrent molecular genetic alterations have been identified to occur concurrently with 1p/19q-codeletion, and definitively identify these tumors, including mutations in IDH1/2, CIC, FUBP1, and the TERT promoter, as well as the absence of ATRX and TP53 alterations. These findings provide a foundation for the consistent diagnosis of this tumor type, upon which a generation of clinical investigators have assembled a strong evidence base for the effective treatment of this disease with radiation and chemotherapy.
Topics: Brain Neoplasms; Chromosome Deletion; Chromosomes, Human, Pair 1; Chromosomes, Human, Pair 19; DNA Helicases; DNA-Binding Proteins; Disease Management; Epigenomics; Humans; Isocitrate Dehydrogenase; Mutation; Oligodendroglioma; RNA-Binding Proteins; Repressor Proteins; Telomerase
PubMed: 26545048
DOI: 10.2217/cns.15.32 -
Neurologia Medico-chirurgica 2015The current World Health Organization (WHO) classification of tumors of the central nervous system (CNS) is essentially a lineage-oriented classification based on a... (Review)
Review
The current World Health Organization (WHO) classification of tumors of the central nervous system (CNS) is essentially a lineage-oriented classification based on a presumable developmental tree of CNS. A four-tiered WHO grading scheme has been successfully applied to a spectrum of diffusely infiltrative astrocytomas, but it is not fully applicable to other gliomas, including oligodendrogliomas and ependymomas. Recent genetic studies have revealed that the major categories of gliomas, such as circumscribe astrocytomas, infiltrating astrocytomas/oligodendrogliomas, and glioblastoma, roughly correspond to major genetic alterations, including isocitrate dehydrogenases (IDHs) 1/2 mutations, TP53 mutations, co-deletion of chromosome arms 1p/19q, and BRAF mutation/fusion. These genetic alterations are clinically significant in terms of the response to treatment(s) and/or the prognosis. It is, thus, rational that future classification of gliomas should be based on genotypes, rather than phenotypes, although the genetic features of each tumor are not sufficiently understood at present to draw a complete map of the gliomas, and genetic testing is not yet available worldwide, particularly in Asian and African countries. This review summarizes the current concepts of the WHO classification, as well as the current understanding of the major genetic alterations in glioma and the potential use of these alterations as diagnostic criteria.
Topics: Glioma; Humans; Mutation; World Health Organization
PubMed: 25744348
DOI: 10.2176/nmc.ra.2014-0229 -
Clinical Neuroradiology Sep 2023The classification of diffuse gliomas into the adult type and the pediatric type is the new basis for the diagnosis and clinical evaluation. The knowledge for the... (Review)
Review
The classification of diffuse gliomas into the adult type and the pediatric type is the new basis for the diagnosis and clinical evaluation. The knowledge for the neuroradiologist should not remain limited to radiological aspects but should be based additionally on the current edition of the World Health Organization (WHO) classification of tumors of the central nervous system (CNS). This classification defines the 11 entities of diffuse gliomas, which are included in the 3 large groups of adult-type diffuse gliomas, pediatric-type diffuse low-grade gliomas, and pediatric-type diffuse high-grade gliomas. This article provides a detailed overview of important molecular, morphological, and clinical aspects for all 11 entities, such as typical genetic alterations, age distribution, variability of the tumor localization, variability of histopathological and radiological findings within each entity, as well as currently available statistical information on prognosis and outcome. Important differential diagnoses are also discussed.
Topics: Humans; Adult; Child; Brain Neoplasms; Glioma; Mutation; Prognosis; Diagnosis, Differential
PubMed: 36941392
DOI: 10.1007/s00062-023-01277-z -
Indian Journal of Pathology &... May 2022The fifth edition of the World Health Organization (WHO) Classification of Tumors of the Central Nervous System (WHO CNS5) features several changes in the... (Review)
Review
A review of adult-type diffuse gliomas in the WHO CNS5 classification with special reference to Astrocytoma, IDH-mutant and Oligodendroglioma, IDH-mutant and 1p/19q codeleted.
The fifth edition of the World Health Organization (WHO) Classification of Tumors of the Central Nervous System (WHO CNS5) features several changes in the classification, diagnostic criteria, nomenclature, and grading of diffuse gliomas. Adult-type diffuse gliomas are genetically defined and include astrocytoma, isocitrate dehydrogenase (IDH)-mutant, oligodendroglioma, IDH-mutant and 1p/19q codeleted, and glioblastoma, IDH-wildtype. This review briefly discusses two tumor types: astrocytoma, IDH-mutant, and oligodendroglioma, IDH-mutant and 1p/19q codeleted, with emphasis on relevant changes in their classification and defining molecular genetic alterations. A simplified approach to the diagnosis of these tumors is provided.
Topics: Adult; Astrocytoma; Brain Neoplasms; Glioma; Humans; Isocitrate Dehydrogenase; Mutation; Oligodendroglioma; World Health Organization
PubMed: 35562130
DOI: 10.4103/ijpm.ijpm_34_22 -
Journal of Family Medicine and Primary... Mar 2021Gliomas account for 45% of all intracranial tumors. Newer technologies have allowed deeper genetic and epigenetic analysis leading to the discovery of IDH (Isocitrate...
BACKGROUND
Gliomas account for 45% of all intracranial tumors. Newer technologies have allowed deeper genetic and epigenetic analysis leading to the discovery of IDH (Isocitrate dehydrogenase) mutations and their association with ATRX (alpha-thalassemia/mental retardation syndrome X-linked) and p53, for better diagnosis and prognosis. In this study, we analysed their expression and correlated with various clinicopathological parameters. A follow up to prognosticate gliomas based on the molecular findings is also attempted.
MATERIALS AND METHOD
During last 5 years both retrospective and prospective cases were included in the study. Immunohistochemistry for IDH1, ATRX, and p53 was done and reported based on intensity and percentage of tumor cells expressing the markers.
RESULTS
A total of 53 cases of gliomas were included, excluding primary glioblastomas and ependymomas. The patient's age ranged from 10 to 53 years. The male to female ratio was 1.3:1. IDH1 positivity was seen in 88% of diffuse astrocytoma, 80% of anaplastic astrocytoma, 90% of oligodendroglioma, 60% of anaplastic oligodendroglioma, and 54% of glioblastoma. A significant association was seen between positive IDH1 expression and low-grade gliomas ( = 0.028). A combined analysis of expression of IDH1 and ATRX versus IDH1, ATRX, and p53 with WHO grade showed a statistically significant association. A follow-up of 32 patients was available. Out of 24 IDH1+ (positive) cases, 22 patients had a median survival of 21.5 months (92%). Out of 8 IDH1- (negative) cases, 5 had a median survival of 15.8 months (62%).
CONCLUSION
Gliomas expressing IDH1 mutation show improved survival of patients. Combined analysis of IDH1, ATRX, and p53 has diagnostic and prognostic significance. For routine cases of gliomas, a combination of IDH1 and ATRX are sufficient; however, the use of p53 is recommended for further prognostication and for possible targeted therapy in the future.
PubMed: 34041176
DOI: 10.4103/jfmpc.jfmpc_1963_20 -
Praxis Mar 2016Gliomas are the most common primary tumors involving the central nervous system. They can manifest with diverse and non-specific general and neurological symptoms. The... (Review)
Review
Gliomas are the most common primary tumors involving the central nervous system. They can manifest with diverse and non-specific general and neurological symptoms. The diagnostic gold standard is cerebral magnetic resonance imaging and subsequent histological confirmation of the diagnosis. Steroids, especially dexamethasone, are used in case of focal symptoms and of symptoms caused by increased intracranial pressure, and antiepileptic drugs are used to manage epileptic seizures. Non-enzyme-inducing antiepileptic drugs are preferable. Glioma patients have an inherently elevated thromboembolic risk, and therapeutic anticoagulation is indicated following a thromboembolic event. Surgery, radiotherapy and systemic therapy are used as tumor-specific therapy modalities in gliomas. Molecular markers play an increasing role in the prognosis and selection of therapy in daily oncological routine.
Topics: Anticoagulants; Anticonvulsants; Brain Neoplasms; Combined Modality Therapy; Dexamethasone; Diagnosis, Differential; Glioblastoma; Glioma; Humans; Image Interpretation, Computer-Assisted; Magnetic Resonance Imaging; Oligodendroglioma; Positron-Emission Tomography; Tyrosine
PubMed: 26980684
DOI: 10.1024/1661-8157/a002303 -
Frontiers in Pharmacology 2021Theabrownin (TB), a natural compound present in the fresh leaves of green tea, is a potential antitumor agent. However, so far whether and how TB affects glioma is...
Theabrownin (TB), a natural compound present in the fresh leaves of green tea, is a potential antitumor agent. However, so far whether and how TB affects glioma is unclear. In this study, we investigated the effect of TB on astroglioma and oligodendroglioma cells. Surprisingly, TB significantly reduced the viabilities of HOG and U251 cells in a dose-dependent manner, which was accompanied by the upregulation of active-Casp-3, Bax, and PTEN; meanwhile, the antiapoptotic gene Bcl-2 was downregulated. In addition, TB treatment induced cell cycle arrest at the G1 and G2/M phases in HOG and U251 cells, respectively. TB treatment caused the downregulating of c-myc, cyclin D, CDK2, and CDK4 and upregulating of p21 and p27 in the HOG cell, while TB increased P53, p21, and p27 levels and decreased the levels of cell cycle regulator proteins such as CDK and cyclin A/B in the U251 cells. Therefore, the c-myc- and P53-related mechanisms were proposed for cell cycle arrest in these two glioma cell lines, respectively. Overall, our findings indicated that TB could be a novel candidate drug for the treatment of gliomas.
PubMed: 33995088
DOI: 10.3389/fphar.2021.664003 -
Journal of Cancer Research and... 2023Gliomas are the most common primary intracranial tumors. The current World Health Organization (WHO) classification of central nervous system tumors recommends...
INTRODUCTION
Gliomas are the most common primary intracranial tumors. The current World Health Organization (WHO) classification of central nervous system tumors recommends integrated histo-molecular diagnosis of gliomas. However, molecular testing is not available in even most of the advanced centers of our country, and histopathology aided with immunohistochemistry (IHC) is still widely used for diagnosis. Immunohistochemical markers such as iso-citrate dehydrogenase1 (IDH1) and Alpha Thalassemia/Mental Retardation Syndrome X-linked (ATRX) can be reliably used for the correct diagnosis, prognosis, and treatment of gliomas.
AIM
We aimed to develop a diagnostic algorithm by integrating morphology, IDH1, and ATRX status of gliomas seen in our institute for 1 year.
SETTINGS AND DESIGN
Analytical cross-sectional study.
MATERIALS AND METHODS
This study included 60 histopathologically confirmed cases of astrocytic (n = 51) and oligodendroglial tumors (n = 9). Clinical, radiological, and histopathological features were noted and tumor grades assigned according to the WHO recommendations. IDH1 and ATRX mutation status was evaluated using IHC. The tumors were divided into three molecular groups on the basis of their IDH1 and ATRX mutation status: (1) Group 1: IDH1 negative and ATRX positive, (2) Group 2: IDH1 positive and ATRX positive, (3) Group 3: IDH1 positive and ATRX negative.
RESULTS
The mean age of presentation was 45.0 ± 15.8 years with a male-to-female ratio of 2:1. Seizures, headache, and hemiparesis were the most common modes of presentation. The tumor subtypes studied were glioblastoma (n = 32), anaplastic astrocytoma (n = 7), diffuse astrocytoma (n = 6), oligodendroglioma (n = 6), pilocytic astrocytoma (n = 6), and anaplastic oligodendroglioma (n = 3). IDH1 mutation was present in 26 cases including anaplastic astrocytoma (n = 7), diffuse astrocytoma (n = 6), oligodendroglioma (n = 5), secondary glioblastoma (n = 5), and anaplastic oligodendroglioma (n = 3). ATRX mutation, i. e., loss of ATRX was observed in 17 cases including diffuse astrocytoma (n = 5), anaplastic astocytoma (n = 5), anaplastic oligodendroglioma (n = 3), oligodendroglioma (n = 3), and secondary glioblastoma (n = 1). All six cases of pilocytic astrocytoma were negative for IDH1 and ATRX mutation. There were 34 patients in Group 1 (IDH1- and ATRX +), nine cases in Group 2 (IDH1 + and ATRX +), and 17 patients in Group 3 (IDH1 + and ATRX-).
CONCLUSION
Diagnosis of gliomas should be based on a detailed clinicoradiological and histopathological assessment, followed by genotypic characterization. Evaluation for IDH1and ATRX status has both diagnostic and prognostic value as it helps in differentiating gliomas from reactive gliosis, primary glioblastoma from secondary glioblastoma, and pilocytic astrocytoma (WHO grade I) from diffuse astrocytoma (WHO grade II). Tumors with IDH1 mutations have a better outcome than those with wild-type IDH. IHC can serve as a useful surrogate to conventional molecular tests in resource-constrained settings. By devising an algorithm based on morphological and IHC features, we were able to stratify gliomas into three prognostic subgroups.
Topics: Humans; Male; Female; Adult; Middle Aged; Oligodendroglioma; Glioblastoma; Cross-Sectional Studies; X-linked Nuclear Protein; Glioma; Astrocytoma; Brain Neoplasms; Mutation; Prognosis; Citrates; Citric Acid; Isocitrate Dehydrogenase; Algorithms
PubMed: 37470575
DOI: 10.4103/jcrt.jcrt_102_21 -
Clinical and Translational Radiation... Jul 2023Oligodendrogliomas (ODG) are rare, diffusely infiltrating brain tumors, defined by their 1p/19q-codeletion and isocitrate dehydrogenase (IDH) mutation. Herein, we...
BACKGROUND
Oligodendrogliomas (ODG) are rare, diffusely infiltrating brain tumors, defined by their 1p/19q-codeletion and isocitrate dehydrogenase (IDH) mutation. Herein, we analyze the influence of various tumor and patient characteristics on progression-free survival (PFS) and overall survival (OS) in a homogeneous patient cohort.
MATERIAL AND METHODS
Patients treated for a 1p/19q-codeleted and IDH-mutant ODG were evaluated. The patient and tumor characteristics were analyzed for their influence on PFS and OS.
RESULTS
One-hundred-fourteen patients met the inclusion criteria. The median clinical and radiographic follow-up periods were 68.6 and 69.8 months. The median PFS and OS were 66.9 and 236.0 months, respectively. The 2-, 4- and 6-year PFS rates were 89.5%, 76.3%, and 46.0%. The 2-, 4- and 6-year OS rates were 99.0%, 97.9%, and 96.2%. For WHO grade 2 ODG, extent of resection ( 0.01, 0.01; 0.02, 0.02), radiotherapy ( 0.01, < 0.01) and chemotherapy ( 0.01, 0.01) were associated with a prolonged PFS. For WHO grade 3 ODG, only a combined radiochemotherapy (RCT) lowered the risk of progression in the multivariable analysis ( = 0.02, 0.09). Most RCT patients received temozolomide (TMZ) instead of procarbazine, lomustine, and vincristine.
CONCLUSION
Whereas previous studies often comprise tumors with IDH wild type status and without 1p/19q-codeletion, this homogeneous ODG cohort, as defined by the current WHO classification, demonstrated PFS benefits for various therapies, especially concerning RCT. While this is generally in accordance with comparable studies, more prospective work on homogeneous patient cohorts is required to refine treatment guidelines and to determine the role of TMZ in ODG.
PubMed: 37216045
DOI: 10.1016/j.ctro.2023.100626