Impact of upfront adjuvant chemoradiation on survival in patients with molecularly defined oligodendroglioma: the benefits of PCV over TMZ.

PURPOSE: Oligodendroglioma is an adult-type diffuse glioma defined by 1p/19q codeletion and IDH1/2 mutation. Treatment includes surgery followed by observation alone in select low-grade tumors, or combination radiation and chemotherapy with procarbazine, lomustine, and vincristine (PCV) or temozolomide (TMZ). While prospective studies investigating treatments for molecularly defined oligodendrogliomas are ongoing, this retrospective study analyzes the relationship between adjuvant regimens and progression-free survival (PFS). METHODS: Adults with IDH-mutant, 1p/19q codeleted oligodendroglioma (WHO grade 2 or 3) who underwent surgery between 2005 and 2021 were identified. Clinical data, disease characteristics, treatment, and outcomes were collected. RESULTS: A total of 207 patients with grade 2 and 70 with grade 3 oligodendrogliomas were identified. Median (IQR) follow-up was 57 (87) months. Patients with grade 3 tumors who received adjuvant radiation and PCV had longer median PFS (> 110 months) than patients who received radiation and TMZ (52 months, p = 0.008) or no adjuvant chemoradiation (83 months, p = 0.03), which was not seen in grade 2 tumors (p = 0.8). In multivariate analysis, patients who received PCV chemotherapy (Relative Risk [95% CI] = 0.24[0.05-1.08] and radiotherapy (0.46[0.21-1.02]) trended towards longer PFS, independently of grade. CONCLUSION: Adjuvant radiation and PCV are associated with improved PFS over radiation with TMZ in patients with grade 3 molecularly defined oligodendrogliomas, and all-grade patients treated with PCV trended towards decreased risk of recurrence and progression. These results highlight the importance of ongoing clinical trials investigating these treatments.

Amide proton transfer weighted and diffusion weighted imaging based radiomics classification algorithm for predicting 1p/19q co-deletion status in low grade gliomas.

BACKGROUND: 1p/19q co-deletion in low-grade gliomas (LGG, World Health Organization grade II and III) is of great significance in clinical decision making. We aim to use radiomics analysis to predict 1p/19q co-deletion in LGG based on amide proton transfer weighted (APTw), diffusion weighted imaging (DWI), and conventional MRI. METHODS: This retrospective study included 90 patients histopathologically diagnosed with LGG. We performed a radiomics analysis by extracting 8454 MRI-based features form APTw, DWI and conventional MR images and applied a least absolute shrinkage and selection operator (LASSO) algorithm to select radiomics signature. A radiomics score (Rad-score) was generated using a linear combination of the values of the selected features weighted for each of the patients. Three neuroradiologists, including one experienced neuroradiologist and two resident physicians, independently evaluated the MR features of LGG and provided predictions on whether the tumor had 1p/19q co-deletion or 1p/19q intact status. A clinical model was then constructed based on the significant variables identified in this analysis. A combined model incorporating both the Rad-score and clinical factors was also constructed. The predictive performance was validated by receiver operating characteristic curve analysis, DeLong analysis and decision curve analysis. P < 0.05 was statistically significant. RESULTS: The radiomics model and the combined model both exhibited excellent performance on both the training and test sets, achieving areas under the curve (AUCs) of 0.948 and 0.966, as well as 0.909 and 0.896, respectively. These results surpassed the performance of the clinical model, which achieved AUCs of 0.760 and 0.766 on the training and test sets, respectively. After performing Delong analysis, the clinical model did not significantly differ in predictive performance from three neuroradiologists. In the training set, both the radiomic and combined models performed better than all neuroradiologists. In the test set, the models exhibited higher AUCs than the neuroradiologists, with the radiomics model significantly outperforming resident physicians B and C, but not differing significantly from experienced neuroradiologist. CONCLUSIONS: Our results suggest that our algorithm can noninvasively predict the 1p/19q co-deletion status of LGG. The predictive performance of radiomics model was comparable to that of experienced neuroradiologist, significantly outperforming the diagnostic accuracy of resident physicians, thereby offering the potential to facilitate non-invasive 1p/19q co-deletion prediction of LGG.

Artificial Intelligence Applications in Glioma With 1p/19q Co-Deletion: A Systematic Review.

As an important genomic marker for oligodendrogliomas, early determination of 1p/19q co-deletion status is critical for guiding therapy and predicting prognosis in patients with glioma. The purpose of this study is to systematically review the literature concerning the magnetic resonance imaging (MRI) with artificial intelligence (AI) methods for predicting 1p/19q co-deletion status in glioma. PubMed, Scopus, Embase, and IEEE Xplore were searched in accordance with the Preferred Reporting Items for systematic reviews and meta-analyses guidelines. Methodological quality of studies was assessed according to the Quality Assessment of Diagnostic Accuracy Studies-2. Finally, 28 studies were included in the quantitative analysis. Diagnostic test accuracy reached an area under the ROC curve of 0.71-0.98 were reported in 24 studies. The remaining four studies with no available AUC provided an accuracy of 0.75-0. 89. The included studies varied widely in terms of imaging sequences, input features, and modeling methods. The current review highlighted that integrating MRI with AI technology is a potential tool for determination 1p/19q status pre-operatively and noninvasively, which can possibly help clinical decision-making. However, the reliability and feasibility of this approach still need to be further validated and improved in a real clinical setting. EVIDENCE LEVEL: 2. TECHNICAL EFFICACY: 2.

Long-term follow up of patients with WHO grade 2 oligodendroglioma.

PURPOSE: Since the introduction of the molecular definition of oligodendrogliomas based on isocitrate dehydrogenase (IDH)-status and the 1p19q-codeletion, it has become increasingly evident how this glioma entity differs much from other diffuse lower grade gliomas and stands out with longer survival and often better responsiveness to adjuvant therapy. Therefore, apart from using a molecular oligodendroglioma definition, an extended follow-up time is necessary to understand the nature of this slow growing, yet malignant condition. The aim of this study was to describe the long-term course of the oligodendroglioma disease in a population-based setting and to determine which factors affect outcome in terms of survival. METHODS: All adults with WHO-grade 2 oligodendrogliomas with known 1p19q-codeletion from five Scandinavian neurosurgical centers and with a follow-up time exceeding 5 years, were analyzed regarding survival and factors potentially affecting survival. RESULTS: 126 patients diagnosed between 1998 and 2016 were identified. The median follow-up was 12.0 years, and the median survival was 17.8 years (95% CI 16.0-19.6). Factors associated with shorter survival in multivariable analysis were age (HR 1.05 per year; CI 1.02-1.08, p < 0.001), tumor diameter (HR 1.05 per millimeter; CI 1.02-1.08, p < 0.001) and poor preoperative functional status (KPS < 80) (HR 4.47; CI 1.70-11.78, p = 0.002). In our material, surgical strategy was not associated with survival. CONCLUSION: Individuals with molecularly defined oligodendrogliomas demonstrate long survival, also in a population-based setting. This is important to consider for optimal timing of therapies that may cause long-term side effects. Advanced age, large tumors and poor function before surgery are predictors of shorter survival.

The role of DSC MR perfusion in predicting IDH mutation and 1p19q codeletion status in gliomas: meta-analysis and technical considerations.

PURPOSE: Isocitrate dehydrogenase (IDH) mutation and 1p19q codeletion status are important for managing glioma patients. However, current practice dictates invasive tissue sampling for histomolecular classification. We investigated the current value of dynamic susceptibility contrast (DSC) MR perfusion imaging as a tool for the non-invasive identification of these biomarkers. METHODS: A systematic search of PubMed, Medline, and Embase up to 2023 was performed, and meta-analyses were conducted. We removed studies employing machine learning models or using multiparametric imaging. We used random-effects standardized mean difference (SMD) and bivariate sensitivity-specificity meta-analyses, calculated the area under the hierarchical summary receiver operating characteristic curve (AUC) and performed meta-regressions using technical acquisition parameters (e.g., time to echo [TE], repetition time [TR]) as moderators to explore sources of heterogeneity. For all estimates, 95% confidence intervals (CIs) are provided. RESULTS: Sixteen eligible manuscripts comprising 1819 patients were included in the quantitative analyses. IDH mutant (IDHm) gliomas had lower rCBV values compared to their wild-type (IDHwt) counterparts. The highest SMD was observed for rCBVmean, rCBVmax, and rCBV 75th percentile (SMD≈ - 0.8, 95% CI ≈ [- 1.2, - 0.5]). In meta-regression, shorter TEs, shorter TRs, and smaller slice thicknesses were linked to higher absolute SMDs. When discriminating IDHm from IDHwt, the highest pooled specificity was observed for rCBVmean (82% [72, 89]), and the highest pooled sensitivity (i.e., 92% [86, 93]) and AUC (i.e., 0.91) for rCBV 10th percentile. In the bivariate meta-regression, shorter TEs and smaller slice gaps were linked to higher pooled sensitivities. In IDHm, 1p19q codeletion was associated with higher rCBVmean (SMD = 0.9 [0.2, 1.5]) and rCBV 90th percentile (SMD = 0.9 [0.1, 1.7]) values. CONCLUSIONS: Identification of vascular signatures predictive of IDH and 1p19q status is a novel promising application of DSC perfusion. Standardization of acquisition protocols and post-processing of DSC perfusion maps are warranted before widespread use in clinical practice.

Impact of IDH Mutations, the 1p/19q Co-Deletion and the G-CIMP Status on Alternative Splicing in Diffuse Gliomas.

By generating protein diversity, alternative splicing provides an important oncogenic pathway. Isocitrate dehydrogenase (IDH) 1 and 2 mutations and 1p/19q co-deletion have become crucial for the novel molecular classification of diffuse gliomas, which also incorporates DNA methylation profiling. In this study, we have carried out a bioinformatics analysis to examine the impact of the IDH mutation, as well as the 1p/19q co-deletion and the glioma CpG island methylator phenotype (G-CIMP) status on alternative splicing in a cohort of 662 diffuse gliomas from The Cancer Genome Atlas (TCGA). We identify the biological processes and molecular functions affected by alternative splicing in the various glioma subgroups and provide evidence supporting the important contribution of alternative splicing in modulating epigenetic regulation in diffuse gliomas. Targeting the genes and pathways affected by alternative splicing might provide novel therapeutic opportunities against gliomas.

[Astrocytoma with 1p19q codeletion]. / Astrotsitoma s kodeletsiei 1p19q.

Using the example of a recurrent tumor with a 10-year follow-up, the authors show that mutation of the IDH1/2 genes in astrocytomas is not always an early event in the pathogenesis of glioma, that in rare cases a 1p19q codeletion can be found in astrocytomas, and that IDH-mutant tumors can occur in childhood.

Diagnostic accuracy of 1p/19q codeletion tests in oligodendroglioma: A comprehensive meta-analysis based on a Cochrane systematic review.

Codeletion of chromosomal arms 1p and 19q, in conjunction with a mutation in the isocitrate dehydrogenase 1 or 2 gene, is the molecular diagnostic criterion for oligodendroglioma, IDH mutant and 1p/19q codeleted. 1p/19q codeletion is a diagnostic marker and allows prognostication and prediction of the best drug response within IDH-mutant tumours. We performed a Cochrane review and simple economic analysis to establish the most sensitive, specific and cost-effective techniques for determining 1p/19q codeletion status. Fluorescent in situ hybridisation (FISH) and polymerase chain reaction (PCR)-based loss of heterozygosity (LOH) test methods were considered as reference standard. Most techniques (FISH, chromogenic in situ hybridisation [CISH], PCR, real-time PCR, multiplex ligation-dependent probe amplification [MLPA], single nucleotide polymorphism [SNP] array, comparative genomic hybridisation [CGH], array CGH, next-generation sequencing [NGS], mass spectrometry and NanoString) showed good sensitivity (few false negatives) for detection of 1p/19q codeletions in glioma, irrespective of whether FISH or PCR-based LOH was used as the reference standard. Both NGS and SNP array had a high specificity (fewer false positives) for 1p/19q codeletion when considered against FISH as the reference standard. Our findings suggest that G banding is not a suitable test for 1p/19q analysis. Within these limits, considering cost per diagnosis and using FISH as a reference, MLPA was marginally more cost-effective than other tests, although these economic analyses were limited by the range of available parameters, time horizon and data from multiple healthcare organisations.

CEST MRI provides amide/amine surrogate biomarkers for treatment-naïve glioma sub-typing.

PURPOSE: Accurate glioma classification affects patient management and is challenging on non- or low-enhancing gliomas. This study investigated the clinical value of different chemical exchange saturation transfer (CEST) metrics for glioma classification and assessed the diagnostic effect of the presence of abundant fluid in glioma subpopulations. METHODS: Forty-five treatment-naïve glioma patients with known isocitrate dehydrogenase (IDH) mutation and 1p/19q codeletion status received CEST MRI (B1rms = 2µT, Tsat = 3.5 s) at 3 T. Magnetization transfer ratio asymmetry and CEST metrics (amides: offset range 3-4 ppm, amines: 1.5-2.5 ppm, amide/amine ratio) were calculated with two models: 'asymmetry-based' (AB) and 'fluid-suppressed' (FS). The presence of T2/FLAIR mismatch was noted. RESULTS: IDH-wild type had higher amide/amine ratio than IDH-mutant_1p/19qcodel (p < 0.022). Amide/amine ratio and amine levels differentiated IDH-wild type from IDH-mutant (p < 0.0045) and from IDH-mutant_1p/19qret (p < 0.021). IDH-mutant_1p/19qret had higher amides and amines than IDH-mutant_1p/19qcodel (p < 0.035). IDH-mutant_1p/19qret with AB/FS mismatch had higher amines than IDH-mutant_1p/19qret without AB/FS mismatch ( < 0.016). In IDH-mutant_1p/19qret, the presence of AB/FS mismatch was closely related to the presence of T2/FLAIR mismatch (p = 0.014). CONCLUSIONS: CEST-derived biomarkers for amides, amines, and their ratio can help with histomolecular staging in gliomas without intense contrast enhancement. T2/FLAIR mismatch is reflected in the presence of AB/FS CEST mismatch. The AB/FS CEST mismatch identifies glioma subgroups that may have prognostic and clinical relevance.

Current Considerations in the Treatment of Grade 3 Gliomas.

OPINION STATEMENT: Treatment recommendations for grade 3 gliomas are guided by their histopathologic and molecular phenotype. In the 2021 WHO classification, these tumors are categorized into two types, grade 3 IDH mutant (IDHmt), 1p/19q codeleted oligodendroglioma and IDH mutant astrocytoma. Treatment consists of maximal safe surgery, followed by radiation therapy (RT) and alkylating agent-based chemotherapy. Based on the updated CATNON result, RT followed by temozolomide improves outcome in patients with non-codeleted grade 3 IDHmt astrocytoma. In patients with IDHmt, codeleted oligodendroglioma, the addition of procarbazine, CCNU, and vincristine regimen is the recommended treatment, based on large randomized controlled trials. These current treatments prolong the overall survival to up to 10 years in patients with grade 3 IDHmt astrocytoma and 14 years in grade 3 IDHmt codeleted oligodendroglioma. Treatment options at recurrence include re-resection, re-irradiation, and other cytotoxic chemotherapy; however, these are of limited benefit. Novel agents targeting IDH mutation and its metabolic effects are currently under investigation to improve the outcome of these patients.

Histopathological investigation of the 1p/19q-codeleted gliomas resected following alkylating agent chemotherapy.

PURPOSE: Lower grade gliomas with 1p/19q codeletion are often responsive to chemotherapy, and several of these have been treated using upfront chemotherapy and subsequent resection following tumor volume decrease. This study aimed to elucidate the histological changes and the mechanism of recurrence after alkylating agent chemotherapy in 1p/19-codeleted gliomas. METHODS: Fourteen 1p/19q-codeleted gliomas resected following tumor volume decrease after alkylating agent chemotherapy were included and compared with their pre-chemotherapy specimens. Histological changes were investigated using hematoxylin-eosin staining, and changes in proliferative activity, status of glioma stem cells (GSCs), and tumor-infiltrating macrophages were assessed using immunohistochemistry for Ki-67/MIB-1, CD68 as a pan-macrophage/monocyte marker, CD163 as a presumed marker of M2 polarity, and nestin and CD133 as markers of GSCs. RESULTS: The most frequent histological findings following chemotherapy included a sparse glial background and abundant foamy cell infiltration. The Ki-67/MIB-1 index decreased and the number of CD68 + cells increased after chemotherapy. The increasing rate of CD68 + cells in the post-/pre-chemotherapy specimens was inversely correlated with patient prognosis but not tumor response. The number of CD163 + cells, M2/M1 + M2 ratio, and the ratio of GSCs to total tumor cells increased after chemotherapy, and those in the post-chemotherapy specimens were negatively correlated with patient prognosis. There was a correlation between the M2/M1 + M2 ratio and the ratio of GSCs in both pre- and post-chemotherapy specimens. CONCLUSION: GSCs in conjunction with M2 macrophages constitute the mechanism of resistance to and recurrence after alkylating agent chemotherapy in 1p/19q-codeleted gliomas.

Histogram-based analysis of cerebral blood flow using arterial spin labeling MRI in de novo brain gliomas: relationship to histopathologic grade and molecular markers.

PURPOSE: We developed multiple histogram-based CBF indices and evaluated their association with histopathologic grade in de novo brain tumor patients. Furthermore, the associations between these advanced CBF indices and molecular markers, including IDH1 mutation, ATRX loss, and 1p/19q co-deletion were also investigated. METHODS: Thirteen de novo brain tumor patients (age 21-68 years, 9 M/4F) who were enrolled in our prospective study were scanned on 3 T MRI using a pCASL perfusion sequence following IRB-approved written informed consent. All patients have since undergone surgical intervention with tissue sampling for histopathologic tumor grading and molecular marker assessment. Tumor region of interest (ROI) were manually delineated on FLAIR images including the full extent of the tumor and peritumoral edema. Fourteen rCBF indices were derived from the histogram of the voxels with the ROI. Multi-linear regression was then used to compare rCBF indices with histopathologic tumor grade and molecular markers. RESULTS: Averaged rCBF in top 10 and top 20 voxels (p < 0.004), but not the entire tumor ROI, was positively associated with WHO tumor grade. After accounting for tumor grade, the presence of 1p/19q co-deletion was associated with higher rCBF in top voxels, as well as with standard deviation of rCBF in the tumor ROI (p < 0.001). ATRX retention was related to higher rCBF, and this effect appears to be present in both higher-perfusion (p < 0.004) and low-perfusion (p < 0.05) voxels. IDH mutation was not significantly associated with any of the CBF indices investigated. CONCLUSION: ASL MRI may provide useful supplemental noninvasive imaging assessment of brain tumor grade and molecular marker status.

Predicting 1p/19q codeletion status using diffusion-, susceptibility-, perfusion-weighted, and conventional MRI in IDH-mutant lower-grade gliomas.

BACKGROUND: Isocitrate dehydrogenase (IDH)-mutant lower-grade gliomas (LGGs) are further classified into two classes: with and without 1p/19q codeletion. IDH-mutant and 1p/19q codeleted LGGs have better prognosis compared with IDH-mutant and 1p/19q non-codeleted LGGs. PURPOSE: To evaluate conventional magnetic resonance imaging (cMRI), diffusion-weighted imaging (DWI), susceptibility-weighted imaging (SWI), and dynamic susceptibility contrast perfusion-weighted imaging (DSC-PWI) for predicting 1p/19q codeletion status of IDH-mutant LGGs. MATERIAL AND METHODS: We retrospectively reviewed cMRI, DWI, SWI, and DSC-PWI in 142 cases of IDH mutant LGGs with known 1p/19q codeletion status. Features of cMRI, relative ADC (rADC), intratumoral susceptibility signals (ITSSs), and the value of relative cerebral blood volume (rCBV) were compared between IDH-mutant LGGs with and without 1p/19q codeletion. Receiver operating characteristic curve and logistic regression were used to determine diagnostic performances. RESULTS: IDH-mutant and 1p/19q non-codeleted LGGs tended to present with the T2/FLAIR mismatch sign and distinct borders (P < 0.001 and P = 0.038, respectively). Parameters of rADC, ITSSs, and rCBVmax were significantly different between the 1p/19q codeleted and 1p/19q non-codeleted groups (P < 0.001, P = 0.017, and P < 0.001, respectively). A combination of cMRI, SWI, DWI, and DSC-PWI for predicting 1p/19q codeletion status in IDH-mutant LGGs resulted in a sensitivity, specificity, positive predictive value, negative predictive value, and an AUC of 80.36%, 78.57%, 83.30%, 75.00%, and 0.88, respectively. CONCLUSION: 1p/19q codeletion status of IDH-mutant LGGs can be stratified using cMRI and advanced MRI techniques, including DWI, SWI, and DSC-PWI. A combination of cMRI, rADC, ITSSs, and rCBVmax may improve the diagnostic performance for predicting 1p/19q codeletion status.

[Histomolecular diagnosis of glial and glioneuronal tumours]. / Le diagnostic histo-moléculaire des tumeurs gliales et glioneuronales.

While rare compared to extra-cranial neoplasms, glial and glioneuronal tumors are responsible of high morbidity and mortality. In 2016, the World Health Organization introduced histo-molecular ("integrated") diagnostics for central nervous system tumors based on morphology, immunohistochemistry and the presence of key genetic alterations. This combined phenotypic-genotypic classification allows for a more objective diagnostic of brain tumors. The implementation of such a classification in daily practice requires immunohistochemical surrogates to detect common genetic alterations and sometimes expensive and not widely available molecular biology techniques. The first step in brain tumor diagnostics is to inquire about the clinical picture and the imaging findings. When dealing with a glial tumor, the pathologist needs to assess its nature, infiltrative or circumscribed. If the tumor is infiltrative, IDH1/2 genes (prognostic marker) and chromosomes 1p/19q (diagnosis of oligodendroglioma) need to be assessed. If the tumor appears circumscribed, the pathologist should look for a neuronal component associated with the glial component (glioneuronal tumor). A limited immunohistochemistry panel will help distinguish between diffuse glioma (IDH1-R132H, ATRX, p53) and circumscribed glial/glioneuronal tumor (CD34, neuronal markers, BRAF-V600E), and some antibodies may reliably detect genetic alterations (IDH1-R132H, BRAF-V600E and H3-K27M mutations). Chromosomal imbalances (1p/19q codeletion in oligodendroglioma; chromosome 7 gain/chromosome 10 loss and EGFR amplification in glioblastoma) and gene rearrangements (BRAF fusion, FGFR1 fusion) will be identified by molecular biology techniques. The up-coming edition of the WHO classification of the central nervous system tumors will rely more heavily on molecular alterations to accurately diagnose and treat brain tumors.

A tailored next-generation sequencing panel identified distinct subtypes of wildtype IDH and TERT promoter glioblastomas.

Central nervous system tumors are classified based on an integrated diagnosis combining histology and molecular characteristics, including IDH1/2 and H3-K27M mutations, as well as 1p/19q codeletion. Here, we aimed to develop and assess the feasibility of a glioma-tailored 48-gene next-generation sequencing (NGS) panel for integrated glioma diagnosis. We designed a glioma-tailored 48-gene NGS panel for detecting 1p/19q codeletion and mutations in IDH1/2, TP53, PTEN, PDGFRA, NF1, RB1, CDKN2A/B, CDK4, and the TERT promoter (TERTp). We analyzed 106 glioma patients (grade II: 19 cases, grade III: 23 cases, grade IV: 64 cases) using this system. The 1p/19q codeletion was detected precisely in oligodendroglial tumors using our NGS panel. In a cohort of 64 grade Ⅳ gliomas, we identified 56 IDH-wildtype glioblastomas. Within these IDH-wildtype glioblastomas, 33 samples (58.9%) showed a mutation in TERTp. Notably, PDGFRA mutations and their amplification were more commonly seen in TERTp-wildtype glioblastomas (43%) than in TERTp-mutant glioblastomas (6%) (P = .001). Hierarchical molecular classification of IDH-wildtype glioblastomas revealed 3 distinct groups of IDH-wildtype glioblastomas. One major cluster was characterized by mutations in PDGFRA, amplification of CDK4 and PDGFRA, homozygous deletion of CDKN2A/B, and absence of TERTp mutations. This cluster was significantly associated with older age (P = .021), higher Ki-67 score (P = .007), poor prognosis (P = .012), and a periventricular tumor location. We report the development of a glioma-tailored NGS panel for detecting 1p/19q codeletion and driver gene mutations on a single platform. Our panel identified distinct subtypes of IDH- and TERTp-wildtype glioblastomas with frequent PDGFRA alterations.

Is the anatomical distribution of low-grade gliomas linked to regions of gliogenesis?

INTRODUCTION: According to the stem cell theory, two neurogenic niches in the adult human brain may harbor cells that initiate the formation of gliomas: The larger subventricular zone (SVZ) and the subgranular zone (SGZ) in the hippocampus. We wanted to explore whether defining molecular markers in low-grade gliomas (LGG; WHO grade II) are related to distance to the neurogenic niches. METHODS: Patients treated at two Norwegian university hospitals with population-based referral were included. Eligible patients had histopathological verified supratentorial low-grade glioma. IDH mutational status and 1p19q co-deletion status was retrospectively assessed. 159 patients were included, and semi-automatic tumor segmentation was done from pre-treatment T2-weighted (T2W) or Fluid-Attenuated Inversion Recovery (FLAIR) images. 3D maps showing the anatomical distribution of the tumors were then created for each of the three molecular subtypes (IDH mutated/1p19q co-deleted, IDH mutated and IDH wild-type). Both distance from tumor center and tumor border to the neurogenic niches were recorded. RESULTS: In this population-based cohort of previously untreated low-grade gliomas, we found that low-grade gliomas are more often found closer to the SVZ than the SGZ, but IDH wild-type tumors are more often found near SGZ. CONCLUSION: Our study suggests that the stem cell origin of IDH wild-type and IDH mutated low-grade gliomas may be different.

A multi-institutional analysis of clinical outcomes and patterns of care of 1p/19q codeleted oligodendrogliomas treated with adjuvant or salvage radiation therapy.

PURPOSE: Practice patterns vary for adjuvant treatment of 1p/19q-codeleted oligodendroglioma patients. This study evaluates the outcomes of adjuvant (aRT) versus salvage radiation therapy (sRT) in a multi-institutional cohort. METHODS: Oligodendroglioma patients with confirmed 1p/19q codeletion who were treated with RT with or without chemotherapy from 2000 to 2017 at four tertiary centers were retrospectively reviewed. Overall survival (OS), post-RT progression-free survival (PFS), freedom-from-RT (FFRT), and radiation necrosis (RN) rates were determined using Kaplan-Meier analyses. OS1/PFS1 were defined from the initial surgery. OS2/PFS2 were defined from the RT start-date. Multivariable analyses (MVAs) of prognostic factors for OS and PFS were performed with Cox regression. RESULTS: One hundred eighty-six patients were identified: 124(67%) received aRT and 62(33%) received sRT; of sRT patients, 58% were observed after surgery while 42% received chemotherapy without aRT. The median time from initial diagnosis to sRT was 61 months, and 74% had reoperations before sRT. sRT had longer OS1 than aRT (94% vs. 69% at 10 years, p = 0.03) and PFS1 (10-year PFS of 80% vs. 68%, p = 0.03), though sRT was not associated with significantly different OS1/PFS1 on MVAs. Chemotherapy did not delay sRT compared to observation and had worse PFS2 (42% vs. 79% at 5 years, p = 0.08). Higher RT dose was not associated with improved clinical outcomes but was associated with higher symptomatic RN rate (15% vs. 0% at 2 years, p = 0.003). CONCLUSIONS: Delaying RT for selected oligodendroglioma patients appears safe. Adjuvant chemotherapy does not delay sRT longer than observation and may be associated with worse PFS after RT.

Oligodendroglioma showing pleomorphic xanthoastrocytoma-like perivascular microlesion: With IDH1, TERT promoter mutation and 1p/19q codeletion detected in both components.

We report a histological and genetic study of concurrent oligodendroglioma and a microscopic pleomorphic xanthoastrocytoma (PXA)-like lesion in a 48-year-old male. He presented with generalized seizure, and magnetic resonance imaging revealed a nonenhanced left frontal lobe mass suggesting low-grade glioma. The patient underwent craniotomy and tumor resection. Histopathological examination of the surgical specimen showed an oligodendroglioma with a PXA-like element; the latter measured 0.9 mm and occupied a Virchow-Robin space of the superficial cortex. The whole tumor had no elevated mitotic activity, microvascular proliferation or necrosis. Each component was immunohistochemically isocitrate dehydrogenase (IDH1)-R132H positive, p53 negative and ATRX positive. Genetic analyses clarified identical IDH1 G395A mutation, promoter C228T mutation and 1p/19q codeletion in both elements. Careful integration of histology and telomerase reverse transcriptase (TERT) molecular parameters revealed that this case was an oligodendroglioma showing PXA-like features, rather than a collision tumor. This case provides further insights into the gliomagenesis.

Clinical impact of revisions to the WHO classification of diffuse gliomas and associated future problems.

The publication of the 2016 World Health Organization Classification of Tumors of the Central Nervous System (2016 WHO CNS) represented a major change in the classification of brain tumors. It is essential to determine the IDH and 1p/19q statuses of diffuse gliomas to ensure that the final diagnosis is accurate. The integrated diagnostic method outlined in the 2016 WHO CNS has enabled more precise prediction of the prognoses of diffuse gliomas. However, there are further two points that need to be addressed when planning future clinical trials. The first is the problems with the WHO grading system for diffuse gliomas. The second is that examinations for IDH mutations and 1p/19q co-deletion are not sufficient on their own to accurately predict the prognosis of diffuse glioma patients. Risk of an IDH-mut diffuse glioma should be evaluated based on a combination of clinical factors (age and the resection rate), molecular factors (the presence/absence of CDKN2A deletion), and histological factors (morphology and the mitotic index). Glioblastoma (GBM) have also been classified according to their IDH status; however, the frequency of IDH gene mutations is only 5-10% in GBM. Other molecular markers such as MGMT methylation, pTERT mutations and EGFR amplification could be more important to predict clinical outcome. Therefore, the next revision of the classification of diffuse gliomas will propose a detailed classification based on additional markers. In the near future, treatments for diffuse gliomas will be chosen according to the molecular profile of each tumor.

High-grade gliomas with isocitrate dehydrogenase wild-type and 1p/19q codeleted: Atypical molecular phenotype and current challenges in molecular diagnosis.

Glioma is the most common intracranial malignant tumor, with poor prognosis. The new World Health Organization (WHO) integrated classification (2016) for diffuse glioma is mainly based on the status of the isocitrate dehydrogenase (IDH) gene (IDH) mutation and 1p/19q codeletion, with diffuse glioma separated into three distinct molecular categories: chromosome 1p/19q codeletion/IDH mutant, 1p/19q intact /IDH mutant, and IDH wild-type. Gliomas harboring 1p/19q codeletion but without IDH mutation are rare and cannot be classified according to the new revision of the WHO classification. Here we report three high-grade gliomas with this atypical molecular phenotype, and describe their histological and immunohistochemical features, the status of mutations in TERT promopter, H3F3A, HIST1H3B, and BRAF, as well as MGMT promoter methylation, and prognosis. Considering morphology, molecular parameters, and patients prognosis, we found that high-grade gliomas harboring 1p/19q codeletion but without IDH mutation were not typical glioblastoma multiforme (GBM) but were more likely to be GBM than anaplastic oligodendroglioma.