Diffuse Low-grade Gliomas Research Articles

The Evolving Classification of Diffuse Gliomas: World Health Organization Updates for 2021.

The upcoming 2021 World Health Organization (WHO) Classification of Tumours of the Central Nervous System will feature numerous changes in classification, diagnostic criteria, nomenclature, and grading of diffuse gliomas. This article reviews these changes and the clinical and molecular findings underlying them. Since the publication of the 2016 World Health Organization (WHO) Classification of Tumours of the Central Nervous System, research has led to new insights into how molecular changes impact both the classification and grading of CNS tumors. The continued integration of molecular and histopathological features has led to changes in diagnostic criteria and grading for various tumors. In the new 2021 WHO CNS tumor classification scheme, diffuse gliomas will be classified as either adult-type diffuse gliomas, pediatric-type diffuse high-grade gliomas, or pediatric-type diffuse low-grade gliomas. The upcoming changes in the classification of adult-type and pediatric-type diffuse gliomas allow for more effective communication of both diagnostic and prognostic information, and-particularly in the case of pediatric-type diffuse gliomas-may suggest possible targeted strategies for therapeutic intervention.

Pediatric and Adult Low-Grade Gliomas: Where Do the Differences Lie?

Two thirds of pediatric gliomas are classified as low-grade (LGG), while in adults only around 20% of gliomas are low-grade. However, these tumors do not only differ in their incidence but also in their location, behavior and, subsequently, treatment. Pediatric LGG constitute 65% of pilocytic astrocytomas, while in adults the most commonly found histology is diffuse low-grade glioma (WHO II), which mostly occurs in eloquent regions of the brain, while its pediatric counterpart is frequently found in the infratentorial compartment. The different tumor locations require different skillsets from neurosurgeons. In adult LGG, a common practice is awake surgery, which is rarely performed on children. On the other hand, pediatric neurosurgeons are more commonly confronted with infratentorial tumors causing hydrocephalus, which more often require endoscopic or shunt procedures to restore the cerebrospinal fluid flow. In adult and pediatric LGG surgery, gross total excision is the primary treatment strategy. Only tumor recurrences or progression warrant adjuvant therapy with either chemo- or radiotherapy. In pediatric LGG, MEK inhibitors have shown promising initial results in treating recurrent LGG and several ongoing trials are investigating their role and safety. Moreover, predisposition syndromes, such as neurofibromatosis or tuberous sclerosis complex, can increase the risk of developing LGG in children, while in adults, usually no tumor growth in these syndromes is observed. In this review, we discuss and compare the differences between pediatric and adult LGG, emphasizing that pediatric LGG should not be approached and managed in the same way as adult LCG.

Low‐grade epilepsy‐associated neuroepithelial tumours with a prominent oligodendroglioma‐like component: The diagnostic challenges

We searched for recurrent pathological features and molecular alterations in a retrospective series of 72 low-grade epilepsy-associated neuroepithelial tumours (LEATs) with a prominent oligodendroglioma-like component, in order to classify them according to the 2021 World Health Organization (WHO) classification of central nervous system (CNS) tumours. Centralised pathological examination was performed as well as targeted molecular analysis of v-Raf murine sarcoma viral oncogene homologue B (BRAF) and fibroblast growth factor receptor 1 (FGFR1) by multiplexed digital polymerase chain reaction (mdPCR). DNA methylation profiling was performed in cases with sufficient DNA. In cases with no genetic alteration by mdPCR and sufficient material, RNA sequencing was done. We first reclassified our cohort into three groups: ganglioglioma (GG, n = 14), dysembryoplastic neuroepithelial tumours (DNTs, n = 19) and glioneuronal tumours/paediatric-type low-grade glioma (LGG) not otherwise specified (GNT/PLGG NOS, n = 39). mdPCR found an alteration in 38/72 cases. Subsequent RNA sequencing revealed a fusion transcript involving BRAF, FGFR1/2/3 or neurotrophic tyrosine kinase receptor type 2 [NTRK2] in 9/25 cases. DNA methylation profiling found 12/46 cases with a calibrated score ≥0.9. Unsupervised hierarchical clustering revealed two clusters: Cluster 1 was enriched with cases classified as DNT at histology, belonging to the LGG-DNT methylation class (MC), with haematopoietic progenitor cell antigen (CD34) negativity and FGRF1 alterations; Cluster 2 was enriched with cases classified at histology as GG, belonging to the LGG-GG MC MC, with BRAF V600E mutation and CD34 positivity. The tumours reclassified as GNT/PLGG NOS were equally distributed across both clusters. Interestingly, all polymorphous low-grade neuroepithelial tumour of the young belonged to Cluster 2, whereas diffuse LGG mitogen-activated protein kinase (MAPK) pathway-altered were equally distributed among the two clusters. This led us to build an algorithm to classify LEATs with a prominent oligodendroglioma-like component. Integrated histomolecular diagnosis of LEATs with a prominent oligodendroglioma-like component remains challenging. Because these tumours can be split into two major clusters of biological significance, the clinicopathological relevance of the four types recognised by the WHO CNS5 within this spectrum of tumours is questionable.

History of atopy confers improved outcomes in IDH mutant and wildtype lower grade gliomas.

A history of atopy or allergy has been shown to be protective against the development of glioma, however the effect of atopy on patient outcomes, especially in conjunction with the survival benefit associated with IDH mutation, has not yet been investigated, and is the focus of the study we present here. Low grade glioma (LGG) data from the TCGA was downloaded, along with IDH, TERT, 1p/19q and ATRX mutational status and genetic alterations. History of asthma, eczema, hay fever, animal, or food allergies, as documented in TCGA, was used to determine patient atopy status. Patients with missing variables were excluded from the study. 374 LGG studies were included. Patients with a history of atopy demonstrated longer overall survival (OS) compared to those without (145.3 vs. 81.5months, p = 00.0195). IDH mutant patients with atopy had longer OS compared those without atopy (158.8 vs. 85months, p = 0.035). Multivariate cox regression analysis demonstrated that the effects of atopy on survival were independent of IDH and histological grade, (p = 0.002, HR 0.257, 95% 0.109-0.604), (p = < 0.001, HR 0.217, 95% 0.107-0.444), and (p = 0.004, HR 2.72, 95% 1.373-5.397), respectively. In terms of treatment outcomes, patients with atopy did not differ in treatment response compared to their counterpart. Pathway analysis demonstrated an upstream activation of the BDNF pathway (p = 0.00027). A history of atopy confers a survival benefit in patients with diffuse low-grade glioma. Activation of the BDNF pathway may drive the observed differences.

Lower-Grade Gliomas: An Epidemiological Voxel-Based Analysis of Location and Proximity to Eloquent Regions.

BackgroundGlioma is the most common intra-axial tumor, and its location relative to critical areas of the brain is important for treatment decision-making. Studies often report tumor location based on anatomical taxonomy alone since the estimation of eloquent regions requires considerable knowledge of functional neuroanatomy and is, to some degree, a subjective measure. An unbiased and reproducible method to determine tumor location and eloquence is desirable, both for clinical use and for research purposes.ObjectiveTo report on a voxel-based method for assessing anatomical distribution and proximity to eloquent regions in diffuse lower-grade gliomas (World Health Organization grades 2 and 3).MethodsA multi-institutional population-based dataset of adult patients (≥18 years) histologically diagnosed with lower-grade glioma was analyzed. Tumor segmentations were registered to a standardized space where two anatomical atlases were used to perform a voxel-based comparison of the proximity of segmentations to brain regions of traditional clinical interest.ResultsExploring the differences between patients with oligodendrogliomas, isocitrate dehydrogenase (IDH) mutated astrocytomas, and patients with IDH wild-type astrocytomas, we found that the latter were older, more often had lower Karnofsky performance status, and that these tumors were more often found in the proximity of eloquent regions. Eloquent regions are found slightly more frequently in the proximity of IDH-mutated astrocytomas compared to oligodendrogliomas. The regions included in our voxel-based definition of eloquence showed a high degree of association with performing biopsy compared to resection.ConclusionWe present a simple, robust, unbiased, and clinically relevant method for assessing tumor location and eloquence in lower-grade gliomas.

PL02.4.A Chromosome 1p19q codeletion frequency, but not survival, varies according to the IDH mutation subtypes: analysis of 1050 IDH-mutated diffuse gliomas

Abstract BACKGROUND recurring hotspot mutations in isocitrate dehydrogenase (IDH) 1 enzymes, and to a lesser extent IDH2, are the main oncogenic alteration in most of lower-grade diffuse gliomas and a subset of grade 4 gliomas. Although most commonly represented by the IDH1R132H mutation, non-canonical IDH1/2-nonR132H mutations are present in about 10% of cases. As the neomorphic enzymatic activity can vary depending on the type of the hotspot mutation, a different biological behaviour may be inferred. Nevertheless, the prognostic significance of the different IDH1/2 mutations remains a matter of debate. MATERIAL AND METHODS we queried the OncoNeuroTek tumor bank (Pitié-Salpêtrière Hospital, Paris) to identify all registered cases of IDH-mutated diffuse gliomas. Most relevant clinical and molecular data were collected. RESULTS We identified 1050 IDH mutated diffuse gliomas (481 grade 2 [46%], 459 grade 3 [44%], and 110 grade 4 [10%]), of which 1007 (96%) were IDH1 mutated (934 IDH1R132H [89%] and 73 IDH-nonR132H [7%]) and 43 (4%) were IDH2 mutated (24 IDH2R172K [2%] and 19 IDH2-nonR172K [2%]). The chromosomes 1p/19q codeletion was more frequent in IDH2-mutated tumors (25/42 [60%] versus 350/918 [38%] in IDH1-mutated cases, p=0.005). Nevertheless, only IDH2R172K mutation was associated with the codeletion (18/24 [75%], versus 7/18 [39%] in IDH2-nonR172K-mutated tumors, p=0.02). IDH1-nonR132H tumors showed the lowest rate of 1p/19q codeletion (9/69 [13%], versus 341/849 [40%] in IDH1R132H-mutated cases, p&amp;lt;0.001). At the time of observation, 536 patients were deceased (51%), with a median overall survival (OS) of 115 months (mo., 95% CI 108–125 mo.). Median follow up for censored patients was 77 mo. Codeleted patients had a significantly longer OS compared to non-codeleted ones (179 vs. 96 mo., p&amp;lt;0.001). No significant differences in survival were seen when stratifying according to IDH mutation type (115 mo. for IDH1R132H vs. 136 mo. for IDH1-nonR132H vs. 112 mo. for IDH2R172K vs. 150 mo. for IDH2-nonR172K, p=0.8). No differences were seen when restricting the analysis to codeleted or not-codeleted patients only, respectively. In a multivariate analysis including the main prognostic factors (age, sex, preoperative performance status, tumor grade, surgical resection, midline location, 1p/19q codeletion, and p16 homozygous deletion), no survival difference was associated with any of the IDH mutation subtype. CONCLUSION although significantly different rates of 1p/19q codeletion were seen according to the four main IDH mutation subgroups, these groups does not associate with different survival profiles in our cohort.

The benefit of early surgery on overall survival in incidental low-grade glioma patients: A multicenter study.

The role of surgery for incidentally discovered diffuse incidental low-grade gliomas (iLGGs) is debatable and poorly documented in current literature. The aim was to identify factors that influence survival for patients that underwent surgical resection of iLGGs in a large multicenter population. Clinical, radiological, and surgical data were retrospectively analyzed in 267 patients operated for iLGG from 4 neurosurgical Centers. Univariate and multivariate analyses were performed to identify predictors of overall survival (OS) and tumor recurrence (TR). The OS rate was 92.41%. The 5- and 10-year estimated OS rates were 98.09% and 93.2%, respectively. OS was significantly longer for patients with a lower preoperative tumor volume (P = .001) and higher extent of resection (EOR) (P = .037), regardless the WHO-defined molecular class (P = .2). In the final model, OS was influenced only by the preoperative tumor volume (P = .006), while TR by early surgery (P = .028). A negative association was found between preoperative tumor volumes and EOR (rs = -0.44, P < .001). The median preoperative tumor volume was 15 cm3. The median EOR was 95%. Total or supratotal resection of T2-FLAIR abnormality was achieved in 61.62% of cases. Second surgery was performed in 26.22%. The median time between surgeries was 5.5 years. Histological evolution to high-grade glioma was detected in 22.85% of cases (16/70). Permanent mild deficits were observed in 3.08% of cases. This multicenter study confirms the results of previous studies investigating surgical management of iLGGs and thereby strengthens the evidence in favor of early surgery for these lesions.

Variations in the management of diffuse low-grade gliomas-A Scandinavian multicenter study.

BackgroundEarly extensive surgery is a cornerstone in treatment of diffuse low-grade gliomas (DLGGs), and an additional survival benefit has been demonstrated from early radiochemotherapy in selected “high-risk” patients. Still, there are a number of controversies related to DLGG management. The objective of this multicenter population-based cohort study was to explore potential variations in diagnostic work-up and treatment between treating centers in 2 Scandinavian countries with similar public health care systems.MethodsPatients screened for inclusion underwent primary surgery of a histopathologically verified diffuse WHO grade II glioma in the time period 2012 through 2017. Clinical and radiological data were collected from medical records and locally conducted research projects, whereupon differences between countries and inter-hospital variations were explored.ResultsA total of 642 patients were included (male:female ratio 1:4), and annual age-standardized incidence rates were 0.9 and 0.8 per 100 000 in Norway and Sweden, respectively. Considerable inter-hospital variations were observed in preoperative work-up, tumor diagnostics, surgical strategies, techniques for intraoperative guidance, as well as choice and timing of adjuvant therapy.ConclusionsDespite geographical population-based case selection, similar health care organizations, and existing guidelines, there were considerable variations in DLGG management. While some can be attributed to differences in clinical implementation of current scientific knowledge, some of the observed inter-hospital variations reflect controversies related to diagnostics and treatment. Quantification of these disparities renders possible identification of treatment patterns associated with better or worse outcomes and may thus represent a step toward more uniform evidence-based care.

The Effect of Radiotherapy on Diffuse Low-Grade Gliomas Evolution: Confronting Theory with Clinical Data.

Diffuse low-grade gliomas are slowly growing tumors that always recur after treatment. In this paper, we revisit the modeling of the evolution of the tumor radius before and after the radiotherapy process and propose a novel model that is simple yet biologically motivated and that remedies some shortcomings of previously proposed ones. We confront this with clinical data consisting of time series of tumor radii from 43 patient records by using a stochastic optimization technique and obtain very good fits in all cases. Since our model describes the evolution of a tumor from the very first glioma cell, it gives access to the possible age of the tumor. Using the technique of profile likelihood to extract all of the information from the data, we build confidence intervals for the tumor birth age and confirm the fact that low-grade gliomas seem to appear in the late teenage years. Moreover, an approximate analytical expression of the temporal evolution of the tumor radius allows us to explain the correlations observed in the data.

Selected Articles from This Issue

Current treatments for diffuse lower-grade gliomas are noncurative, and patients with long-term disease control often experience disease- or treatment-related symptoms. Vorasidenib, a first-in-class, brain-penetrant dual inhibitor of mutant IDH1/2 (mIDH1/2), reduced tumor growth and levels of the oncometabolite D-2-hydroxyglutarate in an orthotopic mIDH glioma mouse model. In a phase I, first-in-human study, Mellinghoff and colleagues reported a favorable safety profile and preliminary clinical activity for vorasidenib at doses &lt;100 mg once daily in recurrent or progressive mIDH1/2 glioma. Introducing mIDH-targeted therap. during what is now the “watch-and-wait” period could potentially delay the need for more toxic treatments.Biomarkers are needed to identify patients with metastatic melanoma who will benefit from targeted therapy. Brase and colleagues analyzed biomarkers in pretreatment melanoma samples from the dabrafenib plus trametinib arm of the randomized, phase III COMBI-v trial using a large-scale digital pathology approach. High T-cell/low B-cell signatures were associated with improved overall survival compared to high T-cell/high B-cell signatures. Patients with high B-cell signatures had high tumor B-cell infiltration, decreased MAPK activity, and evidence of immunosuppression. These results suggest that B cells may serve as a prognostic marker for patients with melanoma to determine the utility of dabrafenib plus trametinib, although further validation of this work is needed.The standard of care for patients with locoregionally advanced, resectable cutaneous squamous cell carcinoma of the head and neck (CSCC-HN), is surgery followed by radiotherapy. However, this regimen is problematic for cosmetic and functional reasons, and due to recurrence. Ferrarotto and colleagues conducted a clinical trial of neoadjuvant PD-1 inhibition in patients with stage III-IVA CSCC-HN. This treatment strategy was, generally, well tolerated. Of 20 patients enrolled, the RECIST response rate was (30%), while the pathologic response rate (pCR and MPR) was 70%. Patients with pCR and MCR showed enhanced inflammation of the tumor microenvironment. These results are encouraging for the treatment of this disease, but further clinical trials are warranted.Androgen receptor (AR) inhibitors are a core treatment modality in metastatic prostate cancer, but cross-resistance between agents hinders sequential use. To explore genomic contributors to cross-resistance, Annala and colleagues analyzed 458 plasma cell-free DNA samples from 202 clinical trial patients receiving sequential AR inhibitors. Targeted and exome sequencing revealed frequent shifts in the somatic populations present in circulating tumor DNA after treatment. Acquired genomic alterations converged upon the AR gene. Recurrent acquisition of aggressive AR genotypes after multiple lines of AR inhibition treatment suggests that the AR remains a driver of resistance and a key therapeutic target.

Simulation of surgery for supratentorial gliomas in virtual reality using a 3D volume rendering technique: a poor man's neuronavigation.

Different techniques of performing image-guided neurosurgery exist, namely, neuronavigation systems, intraoperative ultrasound, and intraoperative MRI, each with its limitations. Except for ultrasound, other methods are expensive. Three-dimensional virtual reconstruction and surgical simulation using 3D volume rendering (VR) is an economical and excellent technique for preoperative surgical planning and image-guided neurosurgery. In this article, the authors discuss several nuances of the 3D VR technique that have not yet been described. The authors included 6 patients with supratentorial gliomas who underwent surgery between January 2019 and March 2021. Preoperative clinical data, including patient demographics, preoperative planning details (done using the VR technique), and intraoperative details, including relevant photos and videos, were collected. RadiAnt software was used for generating virtual 3D images using the VR technique on a computer running Microsoft Windows. The 3D VR technique assists in glioma surgery with a preoperative simulation of the skin incision and craniotomy, virtual cortical surface marking and navigation for deep-seated gliomas, preoperative visualization of morbid cortical surface and venous anatomy in surfacing gliomas, identifying the intervenous surgical corridor in both surfacing and deep-seated gliomas, and pre- and postoperative virtual 3D images highlighting the exact spatial geometric residual tumor location and extent of resection for low-grade gliomas (LGGs). Image-guided neurosurgery with the 3D VR technique using RadiAnt software is an economical, easy-to-learn, and user-friendly method of simulating glioma surgery, especially in resource-constrained countries where expensive neuronavigation systems are not readily available. Apart from cortical sulci/gyri anatomy, FLAIR sequences are ideal for the 3D visualization of nonenhancing diffuse LGGs using the VR technique. In addition to cortical vessels (especially veins), contrast MRI sequences are perfect for the 3D visualization of contrast-enhancing high-grade gliomas.

Development of a Prognostic Five-Gene Signature for Diffuse Lower-Grade Glioma Patients

Background: Diffuse lower-grade gliomas (LGGs) are infiltrative and heterogeneous neoplasms. Gene signature including multiple protein-coding genes (PCGs) is widely used as a tumor marker. This study aimed to construct a multi-PCG signature to predict survival for LGG patients.Methods: LGG data including PCG expression profiles and clinical information were downloaded from The Cancer Genome Atlas (TCGA) and the Chinese Glioma Genome Atlas (CGGA). Survival analysis, receiver operating characteristic (ROC) analysis, and random survival forest algorithm (RSFVH) were used to identify the prognostic PCG signature.Results: From the training (n = 524) and test (n = 431) datasets, a five-PCG signature which can classify LGG patients into low- or high-risk group with a significantly different overall survival (log rank P < 0.001) was screened out and validated. In terms of prognosis predictive performance, the five-PCG signature is stronger than other clinical variables and IDH mutation status. Moreover, the five-PCG signature could further divide radiotherapy patients into two different risk groups. GO and KEGG analysis found that PCGs in the prognostic five-PCG signature were mainly enriched in cell cycle, apoptosis, DNA replication pathways.Conclusions: The new five-PCG signature is a reliable prognostic marker for LGG patients and has a good prospect in clinical application.

MOMC-3. Hypermethylation and overexpression of HOX genes are poor prognosticators in Lower-Grade Glioma

Abstract Diffuse gliomas represent over 80% of malignant brain tumors ranging from low-grade to aggressive high-grade lesions. Molecular characterization of these tumors led to the development of new classification system comprising specific glioma subtypes. While this provides novel molecular insight into gliomas it does not fully explain the variability in patient outcome. To identify and characterize a predictive signature of outcome in diffuse gliomas, we utilized an integrative molecular analysis (methylation, mRNA, copy number variation (CNV) and mutation data) using multiple molecular platforms, including a total of 310 IDH mutant glioma samples from University Health Network (UHN) and German Cancer Research Center (DKFZ) together with 419 samples from The Cancer Genome Atlas (TCGA). Cox regression analysis of methylation data from the UHN cohort identified CpG-based signatures that split the glioma cohort into two prognostic groups strongly predicting survival (p-value &amp;lt; 0.0001). The CpG-based signatures were reliably validated using two independent datasets from TCGA and DKFZ cohorts (both p-values &amp;lt; 0.0001). The results show that the methylation signatures that predict poor outcome also correlated with G-CIMP low status, elevated CNV instability and hypermethylation of a set of HOX gene probes. Further study in diffuse lower-grade glioma (LGG) using integrated mRNA and methylation (iRM) analyses showed that parallel HOX gene overexpression and hypermethylation in the same direction were significantly associated with increased mutational load, high aneuploidy and worse survival (p-value &amp;lt; 0.0001). Furthermore, this iRM high group was characterized by a 7-HOX gene signature showed significant survival differences not only in IDH mutant LGG but also in IDH wildtype LGG. These results demonstrate the importance of HOX genes in predicting the outcome of diffuse gliomas to identify relevant molecular subtyping independent of histology.

IDH Inhibitors and Beyond: The Cornerstone of Targeted Glioma Treatment.

Diffuse low-grade gliomas account for approximately 20% of all primary brain tumors, they arise from glial cells and show infiltrative growth without histological features of malignancy. Mutations of the IDH1 and IDH2 genes constitute a reliable molecular signature of low-grade gliomas and are the earliest driver mutations occurring during gliomagenesis, representing a relevant biomarker with diagnostic, prognostic, and predictive value. IDH mutations induce a neomorphic enzyme that converts α-ketoglutarate to the oncometabolite D-2-hydroxyglutarate, which leads to widespread effects on cellular epigenetics and metabolism. Currently, there are no approved molecularly targeted therapies and the standard treatment for low-grade gliomas consists of radiation therapy and chemotherapy, with rising concern about treatment-related toxicities. Targeting D-2-hydroxyglutarate is considered a novel attractive therapeutic approach for low-grade gliomas and the insights from clinical trials suggest that mutant-selective IDH inhibitors are the ideal candidates, with a favorable benefit/risk ratio. A pivotal question is whether blocking IDH neomorphic activity may activate alternative oncogenetic pathways, inducing acquired resistance to IDH inhibitors. Based on this rationale, combination therapies to enhance the antitumor activity of IDH inhibitors and approaches aimed at exploiting, rather than inhibiting, the metabolism of IDH-mutant cancer cells, such as poly (adenosine 5'-diphosphate-ribose) polymerase inhibitors, are emerging from preclinical research and clinical trials. In this review, we discuss the pivotal role of IDH mutations in gliomagenesis and the complex interactions between the genomic and epigenetic landscapes, providing an overview of how, in the last decade, therapeutic approaches for low-grade gliomas have evolved.

LGG-15. COMPREHENSIVE ANALYSIS OF MYB/MYB1-ALTERED GLIOMAS: A MULTI-INSTITUTIONAL EXPERIENCE OF 33 GLIOMAS

BackgroundPediatric diffuse gliomas harbor recurrent genetic alterations, including those in MYB and MYBL1. Regardless of histopathologic classification, low-grade diffuse gliomas with MYB/MYBL1 alterations represent a single disease entity. Additional insight is needed to define optimal therapeutic strategies for these tumors. MethodsWe retrospectively reviewed gliomas with MYB or MYB1L alterations treated or referred for pathologic review at St. Jude Children’s Research Hospital (St. Jude). Tumor specimens were centrally reviewed. Molecular characterization and clinical data were collated from St. Jude and referring institutions. ResultsThirty-three patients were identified. Two tumors had MYBL1 alterations, while 31 had MYB alterations. MYB-QKI fusion was the most common alteration. Eighteen (55%) were male. The median age at diagnosis was 5 years (range, 0–40 years). Most tumors were in the cerebral cortex (22/33), and the most common presentation was seizures (16/33). Three patients (9%) presented with hydrocephalus and required cerebrospinal fluid diversion. Two patients (6%) presented with metastatic disease. Gross-total resection was achieved in 15 patients (45%). Of the 7 patients receiving cytotoxic chemotherapy, no substantial response was observed. Of the 6 patients who received RT, one had disease progression. The median follow-up was 5.9 years. The 5-year event-free survival was 88.1%, while the 5-year overall survival was 96.3%. Two patients died, one of unclear cause and one of treatment-related acute myelogenous leukemia. Using log-rank tests, no difference in outcomes was observed based on molecular characteristics, degree of resection, metastatic status, or treatment modality. ConclusionsAlthough tumors with MYB and MYBL1 alterations present with varying molecular and clinical features, they represent a group of tumors with favorable outcomes. Further characterization is required to identify the subgroup of tumors with a higher propensity for progression.

Immune-Related Gene SERPINE1 Is a Novel Biomarker for Diffuse Lower-Grade Gliomas via Large-Scale Analysis.

BackgroundGlioma is one of the highly fatal primary tumors in the central nervous system. As a major component of tumor microenvironment (TME), immune cell has been proved to play a critical role in the progression and prognosis of the diffuse lower-grade gliomas (LGGs). This study aims to screen the key immune-related factors of LGGs by investigating the TCGA database.MethodsThe RNA-sequencing data of 508 LGG patients were downloaded in the TCGA database. ESTIMATE algorithm was utilized to calculate the stromal, immune, and ESTIMATE scores, based on which, the differentially expressed genes (DEGs) were analyzed by using “limma” package. Cox regression analysis and the cytoHubba plugin of Cytoscape software were subsequently applied to screen the survival-related genes and hub genes, the intersection of which led to the identification of SERPINE1 that played key roles in the LGGs. The expression patterns, clinical features, and regulatory mechanisms of SERPINE1 in the LGGs were further analyzed by data mining of the TCGA database. What’s more, the above analyses of SERPINE1 were further validated in the LGG cohort from the CGGA database.ResultWe found that stromal and immune cell infiltrations were strongly related to the prognosis and malignancy of the LGGs. A total of 54 survival-related genes and 46 hub genes were screened out in the DEGs, within which SERPINE1 was identified to be significantly overexpressed in the LGG samples compared with the normal tissues. Moreover, the upregulation of SERPINE1 was more pronounced in the gliomas of WHO grade III and IDH wild type, and its expression was correlated with poor prognosis in the LGG patients. The independent prognostic value of SERPINE1 in the LGG patients was also confirmed by Cox regression analysis. In terms of the functions of SERPINE1, the results of enrichment analysis indicated that SERPINE1 was mainly enriched in the immune‐related biological processes and signaling pathways. Furthermore, it was closely associated with infiltrations of immune cells in the LGG microenvironment and acted synergistically with PD1, PD-L1, PD-L2.ConclusionThese findings proved that SERPINE1 could serve as a prognostic biomarker and potential immunotherapy target of LGGs.

Metabolic expression profiling stratifies diffuse lower-grade glioma into three distinct tumour subtypes.

Lower-grade gliomas (LGGs) show highly metabolic heterogeneity and adaptability. To develop effective therapeutic strategies targeting metabolic processes, it is necessary to identify metabolic differences and define metabolic subtypes. Here, we aimed to develop a classification system based on metabolic gene expression profile in LGGs. The metabolic gene profile of 402 diffuse LGGs from the Cancer Genome Atlas (TCGA) was used for consensus clustering to determine robust clusters of patients, and the reproducibility of the classification system was evaluated in three Chinese Glioma Genome Atlas (CGGA) cohorts. Then, the metadata set for clinical characteristics, immune infiltration, metabolic signatures and somatic alterations was integrated to characterise the features of each subtype. We successfully identified and validated three highly distinct metabolic subtypes in LGGs. M2 subtype with upregulated carbohydrate, nucleotide and vitamin metabolism correlated with worse prognosis, whereas M1 subtype with upregulated lipid metabolism and immune infiltration showed better outcome. M3 subtype was associated with low metabolic activities and displayed good prognosis. Three metabolic subtypes correlated with diverse somatic alterations. Finally, we developed and validated a metabolic signature with better performance of prognosis prediction. Our study provides a new classification based on metabolic gene profile and highlights the metabolic heterogeneity within LGGs.

Multimodal integrated approaches in low grade glioma surgery

Surgical management of Diffuse Low-Grade Gliomas (DLGGs) has radically changed in the last 20 years. Awake surgery (AS) in combination with Direct Electrical Stimulation (DES) and real-time neuropsychological testing (RTNT) permits continuous intraoperative feedback, thus allowing to increase the extent of resection (EOR). The aim of this study was to evaluate the impact of the technological advancements and integration of multidisciplinary techniques on EOR. Two hundred and eighty-eight patients affected by DLGG were enrolled. Cases were stratified according to the surgical protocol that changed over time: 1. DES; 2. DES plus functional MRI/DTI images fused on a NeuroNavigation system; 3. Protocol 2 plus RTNT. Patients belonging to Protocol 1 had a median EOR of 83% (28–100), while those belonging to Protocol 2 and 3 had a median EOR of 88% (34–100) and 98% (50–100) respectively (p = 0.0001). New transient deficits with Protocol 1, 2 and 3 were noted in 38.96%, 34.31% and 31,08% of cases, and permanent deficits in 6.49%, 3.65% and 2.7% respectively. The average follow-up period was 6.8 years. OS was influenced by molecular class (p = 0.028), EOR (p = 0.018) and preoperative tumor growing pattern (p = 0.004). Multimodal surgical approach can provide a safer and wider removal of DLGG with potential subsequent benefits on OS. Further studies are necessary to corroborate our findings.

What is the current clinico-radiological diagnostic accuracy for intracranial tumours?

To determine the diagnostic accuracy of routine clinico-radiological workup for a population-based selection of intracranial tumours. In this prospective cohort study, we included consecutive adult patients who underwent a primary surgical intervention for a suspected intracranial tumour between 2015 and 2019 at a single-neurosurgical centre. The treating team estimated the expected diagnosis prior to surgery using predefined groups. The expected diagnosis was compared to final histopathology and the accuracy of preoperative clinico-radiological diagnosis (sensitivity, specificity, positive and negative predictive values) was calculated. 392 patients were included in the data analysis, of whom 319 underwent a primary surgical resection and 73 were operated with a diagnostic biopsy only. The diagnostic accuracy varied between different tumour types. The overall sensitivity, specificity and diagnostic mismatch rate of clinico-radiological diagnosis was 85.8%, 97.7% and 4.0%, respectively. For gliomas (including differentiation between low-grade and high-grade gliomas), the same diagnostic accuracy measures were found to be 82.2%, 97.2% and 5.6%, respectively. The most common diagnostic mismatch was between low-grade gliomas, high-grade gliomas and metastases. Accuracy of 90.2% was achieved for differentiation between diffuse low-grade gliomas and high-grade gliomas. The current accuracy of a preoperative clinico-radiological diagnosis of brain tumours is high. Future non-invasive diagnostic methods need to outperform our results in order to add much value in a routine clinical setting in unselected patients.

DNA methylation profiling for molecular classification of adult diffuse lower-grade gliomas

BackgroundDNA methylation profiling has facilitated and improved the classification of a wide variety of tumors of the central nervous system. In this study, we investigated the potential utility of DNA methylation profiling to achieve molecular diagnosis in adult primary diffuse lower-grade glioma (dLGG) according to WHO 2016 classification system. We also evaluated whether methylation profiling could provide improved molecular characterization and identify prognostic differences beyond the classical histological WHO grade together with IDH mutation status and 1p/19q codeletion status. All patients diagnosed with dLGG in the period 2007–2016 from the Västra Götaland region in Sweden were assessed for inclusion in the study.ResultsA total of 166 dLGG cases were subjected for genome-wide DNA methylation analysis. Of these, 126 (76%) were assigned a defined diagnostic methylation class with a class prediction score ≥ 0.84 and subclass score ≥ 0.50. The assigned methylation classes were highly associated with their IDH mutation status and 1p/19q codeletion status. IDH-wildtype gliomas were further divided into subgroups with distinct molecular features.ConclusionThe stratification of the patients by methylation profiling was as effective as the integrated WHO 2016 molecular reclassification at predicting the clinical outcome of the patients. Our study shows that DNA methylation profiling is a reliable and robust approach for the classification of dLGG into molecular defined subgroups, providing accurate detection of molecular markers according to WHO 2016 classification.