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Cancer Control : Journal of the Moffitt... Apr 2015Progress in molecular oncology during the last decade has enabled investigators to more precisely define and group gliomas. The impacts of isocitrate dehydrogenase (IDH)... (Review)
Review
BACKGROUND
Progress in molecular oncology during the last decade has enabled investigators to more precisely define and group gliomas. The impacts of isocitrate dehydrogenase (IDH) mutation (mut) status and other molecular markers on the classification, prognostication, and management of diffuse gliomas are likely to be far-reaching.
METHODS
Clinical experience and the medical literature were used to assess the current status of glioma categorization and the likely impact of the pending revision of the classification scheme of the World Health Organization (WHO).
RESULTS
IDH-mut is a defining event in most adult fibrillary astrocytomas (FAs) and nearly all oligodendrogliomas (ODs). The IDH-mut status of most gliomas can be established by immunohistochemistry for the most common mutant of IDH1 (R132H). IDH wild-type (wt) diffuse gliomas include several familiar entities -- in particular, glioblastoma (GBM) and most pediatric gliomas -- as well as an assortment of less well-defined entities. The codeletion of 1p/19q distinguishes OD from FA, which, by contrast, shows frequent loss of the α thalassemia/mental retardation syndrome X-linked protein. Mixed oligoastrocytomas are typically classifiable as either OD or FA using molecular testing.
CONCLUSIONS
The current practice of designating IDH-mut WHO grade 4 astrocytoma as secondary GBM will likely be discouraged, and primary or de novo GBM, which is always IDH-wt, may lose this qualification. Histologically, low- or intermediate-grade IDH-wt gliomas with molecular changes characteristic of GBM might justify the designation of GBM WHO grade 3. Mixed oligoastrocytoma is losing popularity as a diagnostic term because most cases will fall into either the FA or OD category. Distinguishing IDH-mut from IDH-wt tumors in clinical trials is likely to clarify sensitivity rates or tumor resistance among subgroups, thus suggesting opportunities for targeted therapy.
Topics: Astrocytoma; Biomarkers, Tumor; Brain Neoplasms; DNA Helicases; Genes, p53; Glioma; Glutarates; Humans; Immunohistochemistry; Isocitrate Dehydrogenase; Mutation; Nuclear Proteins; Oligodendroglioma; Prognosis; X-linked Nuclear Protein
PubMed: 26068765
DOI: 10.1177/107327481502200211 -
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 -
Neurologia Medico-chirurgica 2015The committee of Brain Tumor Registry of Japan (BTRJ) was founded in 1973 and conducts surveys and analyses of incidence, therapeutic methods, and treatment outcomes of... (Review)
Review
The committee of Brain Tumor Registry of Japan (BTRJ) was founded in 1973 and conducts surveys and analyses of incidence, therapeutic methods, and treatment outcomes of primary and metastatic brain tumors with the cooperation of the Japan Neurosurgical Society members. Newly diagnosed 3,000-4,000 primary brain tumors and 600-1,000 brain metastases patients were enrolled in each year. This report describes the trends and treatment outcomes of gliomas from BTRJ volume 13, including 13,431 patients with primary brain tumors who newly started treatment from 2001 to 2004. Data from 382 diffuse astrocytomas (DAs), 121 oligodendrogliomas (OLs), 90 oligoastrocytomas (OAs), 513 anaplastic astrocytomas (AAs), 126 anaplastic oligodendrogliomas (AOs), 106 anaplastic oligoastrocytomas (AOAs), and 1,489 glioblastomas (GBMs) were analyzed for overall survival (OS) and progression free survival (PFS) depending on age, symptoms, Karnofsky performance status, location of the tumor, extent of resection (EOR), initial radiotherapy and chemotherapy. The 5-year PFS rates of the patients with DA, OL+OA, AA, AO+AOA, and GBM were 57.0%, 74.6%, 28.7%, 54.0%, and 9.2%, and the 5-year OS rates were 75.0%, 90.0%, 41.1%, 68.2%, and 10.1%, respectively. Higher EOR≥75% in DA and OL+OA and that ≥50% in AA, AO+AOA, and GBM significantly prolonged OS. Complications and cause of death were also reported. BTRJ had been edited for all the patients, researchers, and especially for clinicians at bedside to give useful information about brain tumors and to contribute to the advances in brain tumor treatment. This report revealed various clinical problematic issues pertaining to the diagnosis and treatment of gliomas.
Topics: Brain Neoplasms; Glioma; Humans; Japan; Registries
PubMed: 25797780
DOI: 10.2176/nmc.ra.2014-0348 -
Frontiers in Neurology 2018We present a case of a 43-year-old woman with a history of headaches and blurry vision. Ophthalmologic examination identified papilledema. MR imaging demonstrated a...
We present a case of a 43-year-old woman with a history of headaches and blurry vision. Ophthalmologic examination identified papilledema. MR imaging demonstrated a right parietal region mass with patchy areas of contrast enhancement and focal calcifications. Intraoperative examination and exploration revealed an extra-axial mass with no apparent parenchymal involvement. Microscopic examination revealed solid sheets of tumor cells with clear cell cytologic features and no discernable intra-parenchymal tumor component. Molecular studies demonstrated the presence of c.395G>A p.R132H and c.601C>T p.R281W mutations and 1p/19q codeletion. The radiographic features, gross appearance, and microscopic and molecular characteristics of the mass support the diagnosis of primary leptomeningeal oligodendroglioma, IDH-mutant, 1p/19-codeleted. This case represents one of a very few reported instances of molecularly-defined solitary, primary, intracranial oligodendroglioma, without definitive involvement of the brain parenchyma.
PubMed: 30210430
DOI: 10.3389/fneur.2018.00700 -
Clinical Cancer Research : An Official... Apr 2019The integrated histopathologic and molecular diagnoses of the 2016 WHO classification of central nervous system tumors have revolutionized patient care by improving...
PURPOSE
The integrated histopathologic and molecular diagnoses of the 2016 WHO classification of central nervous system tumors have revolutionized patient care by improving diagnostic accuracy and reproducibility; however, the frequency and consequences of misclassification of histologically diagnosed diffuse gliomas are unknown.
EXPERIMENTAL DESIGN
Patients with newly diagnosed ICD-O-3 (International Classification of Diseases) histologically encoded diffuse gliomas from 2010-2015 were identified from the National Cancer Database, the misclassification rates and overall survival (OS) of which were assessed by WHO grade and 1p/19q status. In addition, misclassification rates by isocitrate dehydrogenase (IDH), ATRX, and p53 statuses were examined in an analogous multi-institutional cohort of registry-encoded diffuse gliomas.
RESULTS
Of 74,718 patients with diffuse glioma, only 74.4% and 78.8% of molecularly characterized WHO grade II and III oligodendrogliomas were in fact 1p/19q-codeleted. In addition, 28.9% and 36.8% of histologically encoded grade II and III "oligoastrocytomas", and 6.3% and 8.8% of grade II and III astrocytomas had 1p/19q-codeletion, thus molecularly representing oligodendrogliomas if also IDH mutant. OS significantly depended on accurate WHO grading and 1p/19q status.
CONCLUSIONS
On the basis of 1p/19q, IDH, ATRX, and p53, the misclassification rates of histologically encoded oligodendrogliomas, astrocytomas, and glioblastomas are approximately 21%-35%, 6%-9%, and 9%, respectively; with significant clinical implications. Our findings suggest that when compared with historical histology-only classified data, in national registry, as well as, institutional databases, there is the potential for false-positive results in contemporary trials of molecularly classified diffuse gliomas, which could contribute to a seemingly positive phase II trial (based on historical comparison) failing at the phase III stage. Critically, findings from diffuse glioma clinical trials and historical cohorts using prior histology-only WHO schemes must be cautiously reinterpreted.
Topics: Biomarkers, Tumor; Brain Neoplasms; Chromosome Aberrations; Diagnostic Errors; Female; Glioma; Humans; Male; Neoplasm Grading; Neoplasm Staging; World Health Organization
PubMed: 30635340
DOI: 10.1158/1078-0432.CCR-18-3101 -
Frontiers in Cell and Developmental... 2021Diffuse glioma is the most common primary tumor of the central nervous system. The prognosis of the individual tumor is heavily dependent on its grade and subtype....
Diffuse glioma is the most common primary tumor of the central nervous system. The prognosis of the individual tumor is heavily dependent on its grade and subtype. Homeobox B7 (HOXB7), a member of the homeobox family, is abnormally overexpressed in a variety of tumors. However, its function in glioma is unclear. In this study, HOXB7 mRNA and protein expression levels were analyzed in 401 gliomas from the CGGA RNA-seq database (325 cases) and our hospital (76 cases). HOXB7 expression, at both mRNA and protein levels, were upregulated in glioblastoma (GBM) and isocitrate dehydrogenase 1 () wild-type glioma tissues. Kaplan-Meier with log-rank test showed that patients with high HOXB7 expression had a poor prognosis ( < 0.0001). Moreover, HOXB7 protein was deleted in 90.9% (20/22) of oligodendrogliomas and 13.0% (3/23) of astrocytomas. The sensitivity and specificity of HOXB7 protein deletion in oligodendroglioma were 90.9% (20/22) and 87.0% (20/23), respectively. To verify the reliability of using HOXB7 in differentiating oligodendroglioma, we used 1p/19q fluorescence hybridization (FISH) testing as a positive control. The Cohen's kappa coefficient of HOXB7 immunohistochemistry staining and 1p/19q FISH testing was 0.778 (95% CI: 0.594-0.962, < 0.001). In conclusion, HOXB7 is an independent predictor of poor prognosis in all grade gliomas. Additionally, HOXB7 is also a highly sensitive and specific indicator to differentiate oligodendroglioma from astrocytoma.
PubMed: 34458259
DOI: 10.3389/fcell.2021.697086 -
Pathology Jun 2023Homozygous deletion (HD) of the CDKN2A/B locus has emerged as an unfavourable prognostic marker in diffuse gliomas, both IDH-mutant and IDH-wild-type. Testing for...
Homozygous deletion (HD) of the CDKN2A/B locus has emerged as an unfavourable prognostic marker in diffuse gliomas, both IDH-mutant and IDH-wild-type. Testing for CDKN2A/B deletions can be performed by a variety of approaches, including copy number variation (CNV) analysis based on gene array analysis, next generation sequencing (NGS) or fluorescence in situ hybridisation (FISH), but questions remain regarding the accuracy of testing modalities. In this study, we assessed: (1) the utility of S-methyl-5'-thioadenosine phosphorylase (MTAP) and cellular tumour suppressor protein pl61NK4a (p16) immunostainings as surrogate markers for CDKN2A/B HD in gliomas, and (2) the prognostic value of MTAP, across different histological tumour grades and IDH mutation status. One hundred consecutive cases of diffuse and circumscribed gliomas (Cohort 1) were collected, in order to correlate MTAP and p16 expression with the CDKN2A/B status in the CNV plot of each tumour. IDH1 R132H, ATRX and MTAP immunohistochemistry was performed on next generation tissue microarrays (ngTMAs) of 251 diffuse gliomas (Cohort 2) for implementing survival analysis. Complete loss of MTAP and p16 by immunohistochemistry was 100% and 90% sensitive as well as 97% and 89% specific for CDKN2A/B HD, respectively, as identified on CNV plot. Only two cases (2/100) with MTAP and p16 loss of expression did not demonstrate CDKN2A/B HD in CNV plot; however, FISH analysis confirmed the HD for CDKN2A/B. Moreover, MTAP deficiency was associated with shortened survival in IDH-mutant astrocytomas (n=75; median survival 61 vs 137 months; p<0.0001), IDH-mutant oligodendrogliomas (n=59; median survival 41 vs 147 months; p<0.0001) and IDH-wild-type gliomas (n=117; median survival 13 vs 16 months; p=0.011). In conclusion, MTAP immunostaining is an important complement for diagnostic work-up of gliomas, because of its excellent correlation with CDKN2A/B status, robustness, rapid turnaround time and low costs, and provides significant prognostic value in IDH-mutant astrocytomas and oligodendrogliomas, while p16 should be used cautiously.
Topics: Humans; Cyclin-Dependent Kinase Inhibitor p16; Oligodendroglioma; Homozygote; DNA Copy Number Variations; Sequence Deletion; Gene Deletion; Glioma; Biomarkers; Phosphorylases; Astrocytoma; Brain Neoplasms; Isocitrate Dehydrogenase; Mutation
PubMed: 37032198
DOI: 10.1016/j.pathol.2023.01.005 -
Molecular and Clinical Oncology Aug 2021The present study aimed to evaluate the impact caused by the 2016 World Health Organization (WHO) diagnostic classification of gliomas in 139 patients studied in...
The present study aimed to evaluate the impact caused by the 2016 World Health Organization (WHO) diagnostic classification of gliomas in 139 patients studied in Argentina. Formalin-fixed paraffin-embedded tissues were used for histological and immunohistochemical analysis [glial fibrillary acidic protein, KI67, synaptophysin and isocitrate dehydrogenase (IDH)1-R132H]. DNA from formalin-fixed paraffin-embedded tissues was used for molecular analysis: 1p/19q co-deletion and mutation status of the IDH gene. These experiments were performed by direct Sanger sequencing and multiplex ligation-dependent probe amplification. According to the new classification, diagnoses included oligodendroglioma IDH-mutant and 1p/19q co-deletion (4.20%), anaplastic oligodendroglioma IDH-mutant and 1p/19q co-deletion (2.52%), diffuse astrocytoma IDH-mutant (6.72%), diffuse astrocytoma IDH-wild type (1.68%), anaplastic astrocytoma IDH-mutant (5.04%), anaplastic astrocytoma IDH-wild type (8.40%), glioblastoma IDH-mutant (5.88%) and glioblastoma IDH-wild type (65.56%). Regarding tumor histology, 60% of oligodendrogliomas, 35% of astrocytoma and 100% of unclassified gliomas were re-classified, while glioblastomas maintained their initial classification. Additionally, the present study evaluated the prognostic value of the histological grade for the 2007 and 2016 WHO classifications of gliomas. The histological subgroup associated with longer overall survival (OS) was grade II glioma (OS-2007WHO, 35.6 months; and OS-2016WHO, 47.7 months). Glioblastoma was the subgroup associated with a poor outcome (OS-2007WHO, 10.4 months; and OS-2016WHO, 11.1 months). The present study evaluated the OS of tumor grade subgroups with respect to their IDH status. For all subgroups, IDH-mutant tumors were associated with an improved prognosis compared with IDH-wild type tumors. The results suggested that the incorporation of molecular biomarkers in the new WHO classification improves tumor characterization and prognostic value of the subgroups.
PubMed: 34141429
DOI: 10.3892/mco.2021.2312 -
Neurosurgery May 2022Reports suggest that phosphatidylinositol 3-kinase pathway alterations confer increased risk of progression and poor prognosis in oligodendroglioma, IDH-mutant, and...
BACKGROUND
Reports suggest that phosphatidylinositol 3-kinase pathway alterations confer increased risk of progression and poor prognosis in oligodendroglioma, IDH-mutant, and 1p/19q-codeleted molecular oligodendrogliomas (mODG). However, factors that affect prognosis in mODG have not been thoroughly studied. In addition, the benefits of adjuvant radiation and temozolomide (TMZ) in mODGs remain to be determined.
OBJECTIVE
To evaluate the role of PIK3CA mutations in mODGs.
METHODS
One hundred seven mODGs (2008-2019) diagnosed at 2 institutions were included. A retrospective review of clinical characteristics, molecular alterations, treatments, and outcomes was performed.
RESULTS
The median age was 37 years, and 61 patients (57%) were male. There were 64 (60%) World Health Organization (WHO) grade 2 and 43 (40%) WHO grade 3 tumors. Eighty-two patients (77%) were stratified as high risk (age 40 years or older and/or subtotal resection per Radiation Treatment Oncology Group-9802). Gross-total resection was achieved in 47 patients (45%). Treatment strategies included observation (n = 15), TMZ (n = 11), radiation (n = 13), radiation/TMZ (n = 62), and others (n = 6). Our results show a benefit of TMZ vs observation in progression-free survival (PFS). No difference in PFS or overall survival (OS) was observed between radiation and radiation/TMZ. PIK3CA mutations were detected in 15 (14%) mODG, and shorter OS was observed in PIK3CA-mutant compared with PIK3CA wild-type mODGs (10.7 years vs 15.1 years, P = .009). WHO grade 3 tumors showed a shorter PFS, but no significant difference in OS was observed between WHO grades.
CONCLUSION
Our findings suggest that mODGs harboring PIK3CA mutations have worse OS. Except for an advantage in PFS with TMZ treatment, adjuvant TMZ, radiation, or a combination of the two showed no significant improvement in OS.
Topics: Adult; Brain Neoplasms; Class I Phosphatidylinositol 3-Kinases; Female; Humans; Male; Oligodendroglioma; Retrospective Studies; Temozolomide
PubMed: 35179134
DOI: 10.1227/neu.0000000000001875 -
Neurosurgical Focus Dec 2019Resting-state functional MRI (rs-fMRI) is a well-established method for studying intrinsic connectivity and mapping the topography of functional networks in the human... (Review)
Review
Resting-state functional MRI (rs-fMRI) is a well-established method for studying intrinsic connectivity and mapping the topography of functional networks in the human brain. In the clinical setting, rs-fMRI has been used to define functional topography, typically language and motor systems, in the context of preoperative planning for neurosurgery. Intraoperative mapping of critical speech and motor areas with electrocortical stimulation (ECS) remains standard practice, but preoperative noninvasive mapping has the potential to reduce operative time and provide functional localization when awake mapping is not feasible. Task-based fMRI has historically been used for this purpose, but it can be limited by the young age of the patient, cognitive impairment, poor cooperation, and need for sedation. Resting-state fMRI allows reliable analysis of all functional networks with a single study and is inherently independent of factors affecting task performance. In this review, the authors provide a summary of the theory and methods for resting-state network mapping. They provide case examples illustrating clinical implementation and discuss limitations of rs-fMRI and review available data regarding performance in comparison to ECS. Finally, they discuss novel opportunities for future clinical applications and prospects for rs-fMRI beyond mapping of regions to avoid during surgery but, instead, as a tool to guide novel network-based therapies.
Topics: Adult; Brain Mapping; Brain Neoplasms; Connectome; Electric Stimulation; False Negative Reactions; False Positive Reactions; Forecasting; Frontal Lobe; Glioblastoma; Humans; Incidental Findings; Magnetic Resonance Imaging; Male; Nerve Net; Oligodendroglioma; Temporal Lobe; Young Adult
PubMed: 31786561
DOI: 10.3171/2019.9.FOCUS19656