Elevated Fras1-related extracellular matrix 3 in isocitrate dehydrogenase 1-mutant astrocytoma World Health Organization grade 4 predicts favorable prognosis in glioma: A bioinformatic and experimental analysis

Anaplastic spheno-orbital meningioma: rapid growth after extensive exenteration

Secondary Glioblastoma: Molecular and Clinical Factors That Affect Outcome After Malignant Progression of a Lower Grade Tumor

Hypofractionated stereotactic radiotherapy combined with topotecan in recurrent malignant glioma

Accurately distinguishing the different molecular subtypes of 2021 World Health Organization (WHO) grade 4 Central Nervous System (CNS) gliomas is highly relevant for prognostic stratification and personalized treatment. To develop and validate a machine learning (ML) model using multiparametric MRI for the preoperative differentiation of astrocytoma, CNS WHO grade 4, and glioblastoma (GBM), isocitrate dehydrogenase-wild-type (IDH-wt) (WHO 2021) (Task 1:grade 4 vs. GBM); and to stratify astrocytoma, CNS WHO grade 4, by distinguish astrocytoma, IDH-mutant (IDH-mut), CNS WHO grade 4 from astrocytoma, IDH-wild-type (IDH-wt), CNS WHO grade 4 (Task 2:IDH-mut grade 4 vs. IDH-wt grade 4). Additionally, to evaluate the model's prognostic value. We retrospectively analyzed 320 glioma patients from three hospitals (training/testing, 7:3 ratio) and 99 patients from ‌The Cancer Genome Atlas (TCGA) database for external validation‌. Radiomic features were extracted from tumor and edema on contrast-enhanced T1-weighted imaging (CE-T1WI) and T2 fluid-attenuated inversion recovery (T2-FLAIR). Extreme gradient boosting (XGBoost) was utilized for constructing the ML, clinical, and combined models. Model performance was evaluated with receiver operating characteristic (ROC) curves, decision curves, and calibration curves. Stability was evaluated using six additional classifiers. Kaplan-Meier (KM) survival analysis and the log-rank test assessed the model's prognostic value. In Task 1 and Task 2, the combined model (AUC = 0.907, 0.852 and 0.830 for Task 1; AUC = 0.899, 0.895 and 0.792 for Task 2) and the optimal ML model (AUC = 0.902, 0.854 and 0.832 for Task 1; AUC = 0.904, 0.899 and 0.783 for Task 2) significantly outperformed the clinical model (AUC = 0.671, 0.656, and 0.543 for Task 1; AUC = 0.619, 0.605 and 0.400 for Task 2) in both the training, testing and validation sets. Survival analysis showed the combined model performed similarly to molecular subtype in both tasks (p = 0.964 and p = 0.746). The multiparametric MRI ML model effectively distinguished astrocytoma, CNS WHO grade 4 from GBM, IDH-wt (WHO 2021) and differentiated astrocytoma, IDH-mut from astrocytoma, IDH-wt, CNS WHO grade 4. Additionally, the model provided reliable survival stratification for glioma patients across different molecular subtypes.

Alterations in the epidermal growth factor receptor (EGFR) and its main ligand, transforming growth factor-alpha (TGF alpha), were investigated for a possible prognostic relevance in 125 astrocytic gliomas (44 World Health Organization (WHO) Grade II, 19 WHO Grade III, and 62 WHO Grade IV tumors). The TGF alpha and EGFR proteins were detected immunohistochemically using monoclonal antibodies. A positive immunoreaction to TGF alpha was detected in 33 (75%) of 44 WHO Grade II astrocytomas, 18 (95%) of 19 WHO Grade III astrocytoma, and 50 (81%) of 62 WHO Grade IV glioblastomas. No correlation between TGF alpha immunoreaction and duration of survival could be found. A positive EGFR immunoreaction was detected in seven (16%) of 44 WHO Grade II astrocytomas, five (26%) of 19 WHO Grade III astrocytomas, and 32 (52%) of 62 WHO Grade IV glioblastomas. Of these gliomas, 97 (26 WHO Grade II, 17 WHO Grade III, and 54 WHO Grade IV gliomas) were examined for EGFR gene amplification using a differential polymerase chain reaction assay. Amplification of the EGFR gene was detected in none of the WHO Grade II astrocytomas, one (6%) of 17 WHO Grade III astrocytomas, and 18 (33%) of 54 WHO Grade IV glioblastomas. Twenty-two of the tumors investigated showed a positive EGFR immunoreaction without detectable gene amplification (five WHO Grade II, four WHO Grade III, and 13 WHO Grade IV tumors). Gene amplification was invariably associated with a positive EGFR immunoreaction. For the entire study group, a strong correlation between EGFR alterations (gene amplification and positive immunoreaction) and survival could be found. However, this correlation only reflected the higher percentages of cases with EGFR alterations in malignant gliomas and was not an independent prognostic factor as determined by multifactorial analysis. These data demonstrate that EGFR alterations are frequent events in astrocytic gliomas and are largely restricted to glioblastomas. However, within one tumor grade they do not provide prognostic information.

Gliomas are the most frequent primary brain tumors. In a minority of cases, the differentiation between astrocytomas and oligodendrogliomas based on morphologic characteristics alone can be difficult; though it is important, as patients with oligodendrogliomas follow a more favorable clinical course. Here we report on the immunohistochemical expression pattern of the oligodendrocytic marker Nogo-A in 113 central nervous system tumors including 28 oligodendrogliomas [15, World Health Organization (WHO) grade II; 13, grade WHO III], 50 astrocytomas [10, grade WHO II; 11, grade WHO III; 29 glioblastoma multiforme (GBM)], 11 ependymomas WHO grade II, 7 central neurocytomas, 2 dysembryoplastic neuroepithelial tumors (DNTs), 5 clear cell meningiomas, and 10 metastases to the brain. The oligodendrocytic marker Nogo-A was found to be strongly expressed in 71% of oligodendrogliomas, but in 0% of ependymomas WHO grade II, astrocytomas WHO grade II or III, DNTs, central neurocytomas, or clear cell meningiomas. In GBM, a subgroup of tumors (24%) showed strong expression of Nogo-A coincidently with Ki67 positivity but glial fibrillary acidic protein-negativity. However, neither in oligodendrogliomas nor GBM was a correlation between the loss of 1p19q and the extent of Nogo-A expression observed. Our findings indicate that Nogo-A is strongly expressed in the majority of oligodendrogliomas and might be a helpful marker to distinguish oligodendrogliomas from astrocytomas WHO grades II and III as well as ependymomas. They also support the hypothesis that GBM may be a heterogeneous group of tumors derived from different progenitor cells.

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. We aimed to develop a diagnostic algorithm by integrating morphology, IDH1, and ATRX status of gliomas seen in our institute for 1 year. Analytical cross-sectional study. 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. 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-). 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.

There has been no research investigating susceptibility-weighted imaging (SWI) radiomics features in evaluating molecular makers in gliomas. The aim of this study was to assess the predictive value of radiomics features extracted from structural magnetic resonance imaging (MRI), apparent diffusion coefficient (ADC), and SWI in determining World Health Organization (WHO) Grade, isocitrate dehydrogenase (IDH) mutation, and oxygen 6-methylguanine-DNA methyltransferase (MGMT) promoter methylation in patients with diffuse gliomas. Retrospective MRI data of 539 patients from University of California San Francisco and Nanjing Drum Tower Hospital between January 2010 and December 2022 were analyzed in this study. The training, internal validation, and external test cohorts included 426 (median age 60 years, 168 female), 67 (median age 56 years, 31 female), and 46 (median age 55 years, 22 female) patients, respectively. A total of 7,896 radiomics features were extracted from structural MRI, ADC, and SWI within two regions of interest (ROIs). Feature selection was conducted using analysis of variance (ANOVA) F-test, and random forest was employed to establish predictive models. Chi-square test and Mann-Whitney U test were used for assessing the statistical differences in patients' clinical characteristics. Delong test was performed to compare the areas under the curve (AUCs) of different radiomics models. For WHO Grade task, the combined model of structural MRI, ADC, and SWI achieved the highest AUC of 0.951 [95% confidence interval (CI): 0.886-1.000] on the external test cohort. For IDH mutation task, the structural MRI model achieved the highest AUC of 0.917 (95% CI: 0.801-1.000) on the external test cohort. For MGMT task, the combined model of structural MRI and ADC achieved the highest AUC of 0.650 (95% CI: 0.485-0.814) on the internal validation cohort. The combined structural MRI, ADC, and SWI models achieved promising performance in assessing WHO Grade and IDH mutation status but showed no efficacy in predicting MGMT methylation status. Adding SWI and ADC features cannot provide extra information to structural MRI in predicting WHO grade and IDH mutation.

An analysis of 170 glioma patients and systematic review to investigate the association between IDH-1 mutations and preoperative glioma-related epilepsy

Simple SummaryApproximately 75–80% of according to the classification of world health organization (WHO) grade II and III gliomas are characterized by a mutation of the isocitrate dehydrogenase (IDH) enzymes, which are very important in glioma cell metabolism. Patients with IDH mutated glioma have a significantly better prognosis than patients with IDH wildtype status, typically seen in glioblastoma WHO grade IV. Here we used a prospective O-(2-18F-fluoroethyl)-L-tyrosine (18F-FET) positron emission tomography guided single-voxel 1H-magnetic resonance spectroscopy approach to predict the IDH status before surgery. Finally, 34 patients were included in this neuroimaging study, of whom eight had additionally tissue analysis. Using a machine learning technique, we predicted IDH status with an accuracy of 88.2%, a sensitivity of 95.5% and a specificity of 75.0%. It was newly recognized, that two metabolites (myo-inositol and glycine) have a particularly important role in the determination of the IDH status.Isocitrate dehydrogenase (IDH)-1 mutation is an important prognostic factor and a potential therapeutic target in glioma. Immunohistological and molecular diagnosis of IDH mutation status is invasive. To avoid tumor biopsy, dedicated spectroscopic techniques have been proposed to detect D-2-hydroxyglutarate (2-HG), the main metabolite of IDH, directly in vivo. However, these methods are technically challenging and not broadly available. Therefore, we explored the use of machine learning for the non-invasive, inexpensive and fast diagnosis of IDH status in standard 1H-magnetic resonance spectroscopy (1H-MRS). To this end, 30 of 34 consecutive patients with known or suspected glioma WHO grade II-IV were subjected to metabolic positron emission tomography (PET) imaging with O-(2-18F-fluoroethyl)-L-tyrosine (18F-FET) for optimized voxel placement in 1H-MRS. Routine 1H-magnetic resonance (1H-MR) spectra of tumor and contralateral healthy brain regions were acquired on a 3 Tesla magnetic resonance (3T-MR) scanner, prior to surgical tumor resection and molecular analysis of IDH status. Since 2-HG spectral signals were too overlapped for reliable discrimination of IDH mutated (IDHmut) and IDH wild-type (IDHwt) glioma, we used a nested cross-validation approach, whereby we trained a linear support vector machine (SVM) on the complete spectral information of the 1H-MRS data to predict IDH status. Using this approach, we predicted IDH status with an accuracy of 88.2%, a sensitivity of 95.5% (95% CI, 77.2–99.9%) and a specificity of 75.0% (95% CI, 42.9–94.5%), respectively. The area under the curve (AUC) amounted to 0.83. Subsequent ex vivo 1H-nuclear magnetic resonance (1H-NMR) measurements performed on metabolite extracts of resected tumor material (eight specimens) revealed myo-inositol (M-ins) and glycine (Gly) to be the major discriminators of IDH status. We conclude that our approach allows a reliable, non-invasive, fast and cost-effective prediction of IDH status in a standard clinical setting.

Impact of Grade on Survival in Pleomorphic Xanthoastrocytoma and Low Prevalence of BRAF V600E Mutation

In most cases, theallelic losses involve loci along the entire chromosome, afinding in line with monosomy 10. LOH on chromosome 10may also be detected in anaplastic astrocytomas (WHO GradeIII) and diffuse astrocytomas (WHO Grade II), but is lesscommon than in glioblastomas and more frequently restrictedto partial losses.

Isocitrate dehydrogenase (IDH)-mutant astrocytomas show a peak incidence in young and middle-aged adults and have relatively favorable outcomes. In patients with these tumors ≥55 years at diagnosis, clinical, histopathologic, and prognostic characteristics are less clear. Here, we compared histopathological, immunohistochemical, molecular, and overall survival of 34 patients aged ≥55 years with a group of 84 patients aged 19-54 years; all had IDH mutant astrocytomas. The older cohort had 14 World Health Organization (WHO) grade 2, 7 WHO grade 3, and 13 WHO grade 4 tumors versus 24, 32, and 28 WHO grade 2, 3, and 4 tumors in the younger group. Comparing equal-grade tumors in both cohorts, Kaplan-Meyer survival analysis revealed that patients ≥55 years of age showed worse prognosis despite receiving comparable treatment regimens (Stupp protocol). Roughly equal numbers of noncanonical IDH mutations were seen in both groups (11.76% in ≥55 vs 19.04% in <55). Older patients were more likely to show retention of nuclear protein alpha-thalassemia and mental retardation X-linked syndrome (ATRX) and/or absence of strong P53 staining by immunohistochemistry. Although patients ≥55 years of age with astrocytomas, IDH-mutant, had worse overall survival, many, particularly those with low-grade tumors, had 5 years or greater survival. Employing parallel treatment regimens with chemotherapy, radiation, and maximum safe resection may improve survival of older patients with IDH mutant gliomas.

R132H-mutation of isocitrate dehydrogenase-1 is not sufficient for HIF-1α upregulation in adult glioma

Despite its significant overexpression in several malignant neoplasms, the expression of RPS27 in the central nervous system (CNS) is widely unknown. We identified the cell types expressing RPS27 in the CNS under normal and disease conditions. We acquired specimens of healthy brain (NB), adult pilocytic astrocytoma (PA) World Health Organization (WHO) grade I, anaplastic PA WHO grade III, gliomas WHO grade II/III with or without isocitrate dehydrogenase (IDH) mutation, and glioblastoma multiforme (GBM). RPS27 protein expression was examined by immunohistochemistry and double-fluorescence staining and its mRNA expression quantified by RT-PCR. Patients’ clinical and tumor characteristics were collected retrospectively. RPS27 protein was specifically expressed in tumor cells and neurons, but not in healthy astrocytes. In tumor tissue, most macrophages were positive, while this was rarely the case in inflamed tissue. Compared to NB, RPS27 mRNA was in mean 6.2- and 8.8-fold enhanced in gliomas WHO grade II/III with (p < 0.01) and without IDH mutation (p = 0.01), respectively. GBM displayed a 4.6-fold increased mean expression (p = 0.02). Although RPS27 expression levels did not affect the patients’ survival, their association with tumor cells and tumor-associated macrophages provides a rationale for a future investigation of a potential function during gliomagenesis and tumor immune response.