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Simple Summary: Mainstay endpoints of oncological neurosurgery include preservation of function and quality of life while achieving a maximal tumor resection. Surgical resection of tumors in the Supplementary Motor Area (SMA) can cause a syndrome characterized by impaired speech and movement initiation. The pathophysiological mechanisms are not clear yet, but increasing evidence points towards white matter pathways subserving this region, particularly the Frontal Aslant Tract (FAT), which connects the SMA to the inferior frontal gyrus. In this study, we have analyzed state-of-the-art spherical deconvolution tractography data from 25 consecutive patients to determine the influence of preoperative interhemispheric differences of the FAT on the development of the SMA syndrome. Proportionally smaller FAT volumes on the dominant hemisphere compared to the nondominant side were associated with an increased postoperative risk of verbal impairment (p = 0.010), demonstrating that preoperative FAT volume asymmetry estimated according to dominance can predict the onset of a verbal SMA syndrome. Background/Objectives: The purpose of this study was to investigate preoperative interhemispheric differences of the FAT in relation to the onset of postoperative SMA syndrome. Methods: This was a single-center retrospective analysis of patients who underwent surgical resection of diffuse gliomas involving the SMA between 2018 and 2022. Inclusion criteria were availability of preoperative and postoperative Magnetic Resonance Imaging, no previous surgery, and no neurological deficits at presentation. Diffusion-weighted data were processed by spherical deconvolution (SD) and diffusion tensor imaging tractography algorithms, and TrackVis was used to dissect the FAT of both hemispheres. The FAT data were analyzed for correlation with postoperative SMA syndrome onset. Results: N = 25 cases were included in the study, among which n = 23 had preoperative bilaterally identifiable FAT by SD. N = 12 developed an SMA syndrome, 6 demonstrated a motor-only syndrome, 4 had a verbal-only syndrome, and 2 had mixed verbal and motor features. The SMA syndrome incidence was significantly more frequent in lower-grade gliomas (p = 0.005). On the tumor side, the FAT identified by SD was smaller than the contralateral (mean volume 6.53 cm3 and 13.33 cm3, respectively, p < 0.001). In the 6 cases that developed a verbal SMA syndrome, a normalized FAT volume asymmetry (FAT-VA) demonstrated an asymmetry shifted towards the non-dominant side (mean FAT-VA = −0.68), while the cases with no postoperative verbal impairment had opposite asymmetry towards the dominant side (mean FAT-VA = 0.42, p = 0.010). Conclusions: Preoperative interhemispheric FAT volume asymmetry estimated according to functional dominance can predict postoperative onset of verbal SMA syndrome, with proportionally smaller FAT on the affected dominant hemisphere. [ABSTRACT FROM AUTHOR]

Eloquent area glioma surgery is technically demanding. Identification and preservation of the functional area determines the long term outcome. Here we discuss the use of transcranial magnetic stimulation (TMS) and 2D ultrasound (2DUSG) in resection of low grade glioma (LGG) located at motor strip area. In five patients where the LGG was located close to motor area were evaluated with TMS in the preoperative period and the functional area is marked. This information is used for planning the craniotomy. A 2DUSG is used to detect the margin of resection. Complete excision was feasible in two and partial resection in three without any added deficit. TMS is an useful tool for localizing motor area in the pre operative period for patients with tumor located close to the motor area. Additionally 2DUSG provides real time imaging to safeguard the eloquent brain area. Combination of these two offers low cost, easily available method for resecting eloquent area brain tumors in resource limited areas. [ABSTRACT FROM AUTHOR]

Children with low grade glioma (LGG) may present with, or develop, elevated concentrations of insulin‐like growth factor 1 (IGF‐1). The prevalence, pathophysiology, or its possible clinical effects are poorly understood. Our aim was to evaluate the prevalence of such elevated IGF‐1 concentrations and to describe its association with linear growth, body mass index (BMI), pituitary outcome, and tumor behavior in a large retrospective national cohort. From a nationwide retrospective cohort of pediatric brain tumor survivors diagnosed between 2002 and 2012, tumor, treatment, endocrine, and auxological data of children with LGG were collected (n = 358). Prevalence and risk factors for elevated IGF‐1 concentrations, as well as the association between having elevated IGF‐1 concentrations and receiving tumor treatment, were explored. IGF‐1 concentrations had only been measured in 45.5% of cases (n = 163/358). In 18.4% of 163 children with available IGF‐1 measurements, IGF‐1 concentrations were found elevated. No association was described between having an elevated IGF‐1 concentration and tumor behavior or height SDS at last moment of follow‐up. Multivariate logistic regression identified posterior pituitary disorder (OR 6.14 95% CI: 2.21–17.09) and BMI SDS at follow‐up (OR 1.56 95% CI: 1.09–2.20) to be significantly associated with elevated IGF‐1 concentrations. In this retrospective cohort of children with LGG, IGF‐1 was found elevated in 18.4% of children with available IGF‐1 measurements. Elevated IGF‐1 seems to be related to hypothalamic dysfunction worsening over time. Larger prospective cohort studies are needed. [ABSTRACT FROM AUTHOR]

Background: Colorectal tumor differentially expressed (CRNDE) is specifically expressed in human brains and is the most highly expressed lncRNA in gliomas. Nevertheless, its implications in low grade glioma (LGG) are still indistinct. This study presented systematic analyses of CRNDE in LGG biology. Methods: We retrospectively retrieved TCGA, CGGC and GSE16011 LGG cohorts. Survival analysis was conducted for evaluating the prognostic significance of CRNDE in LGG. A CRNDE-based nomogram was established, and its predictive performance was verified. Signaling pathways underlying CRNDE were analyzed through ssGSEA and GSEA approaches. The abundance of immune cells and activity of cancer-immunity cycle were estimated with ssGSEA approach. Immune checkpoints, HLAs, chemokines, and immunotherapeutic response indicators (TIDE, and TMB) was quantified. U251 and SW1088 cells were transfected with specific shRNAs of CRNDE, and flow cytometry (apoptosis) and western blot (β-catenin and Wnt5a) assays were conducted. Results: Up-regulated CRNDE was found in LGG, and was linked to unfavorable clinical outcomes. The CRNDE-based nomogram enabled to accurately predict patients' prognosis. High CRNDE expression was linked to more genomic variations, activity of tumorigenic pathways, tumor immunity (increase in infiltration of immune cells, expression of immune checkpoints, HLAs and chemokines, and cancer-immunity cycle), and therapeutic sensitivity. CRNDE knockdown mitigated malignant phenotypes of LGG cells. Conclusions: Our study determined CRNDE as a novel predictor for patient prognosis, tumor immunity and therapeutic response in LGG. Assessment of CRNDE expression is a promising approach for predicting the therapeutic benefits of LGG patients. [ABSTRACT FROM AUTHOR]

BACKGROUND: Dynein axonemal light intermediate chain 1 (DNALI1) is a component of axonemal dyneins and its role in cancer progression is not known. OBJECTIVE: The influence of DNALI1 expression on the prognosis of low-grade gliomas (LGG) and the possible mechanisms of DNALI1 in promoting the progression of LGG was investigated by applying multiple bioinformatics analyses using datasets from TCGA, GTEx, CPTAC, and CGGA. METHODS: The expression of DNALI1 in different tumor tissues including LGG was investigated. GO functional annotation, KEGG pathway analysis, and GSEA enrichment analysis were performed. The correlation between DNALI1 and prognosis, tumor microenvironment (TME) and immune checkpoints in LGG were assessed. RESULTS: DNALI1 is mainly expressed in malignant cells in the TME of LGG and positively correlated with the development of LGG. DNALI1 expression is negatively correlated with isocitrate dehydrogenase (IDH) mutations and 1p/19q co-deletion. High DNALI1 expression is associated with poor prognosis in LGG. DNALI1 may promote LGG progression through multiple immune-related pathways. The expression of DNALI1 is positively correlated with the infiltration of certain types of immune cells and the expression of some immune checkpoints. CONCLUSIONS: DNALI1 is a potential prognostic marker for LGG, and high expression of DNALI1 may play an important role in maintaining the immunosuppressive microenvironment of LGG. [ABSTRACT FROM AUTHOR]

Simple Summary: Focal areas of signal intensity (FASI) are common neuro-imaging abnormalities in children with neurofibromatosis type 1 (NF1). They may confound tumor evaluations and have been associated with neurocognitive differences in some studies. Selumetinib is a MEK inhibitor recently studied in NF1-associated low-grade glioma by the Pediatric Brain Tumor Consortium (PBTC). The current study looked at the impact of selumetinib on FASI. Unlike its effect on NF1-associated LGG, selumetinib did not change the overall size of FASI in children with NF1. Background: Understanding the effect of selumetinib on FASI may help elucidate the biology, proliferative potential, and role in neurocognitive changes for these NF1-associated lesions. Methods: Patients with NF1-associated LGG and FASI treated with selumetinib on PBTC-029B were age-matched to untreated patients with NF1-associated FASI at Cincinnati Children's Hospital Medical Center. Paired bidirectional measurements were compared over time using nonparametric tests. Results: Sixteen age-matched pairs were assessed (age range: 2.8–16.9 years, 60% male). Initial FASI burden was not different between groups (median range 138.7 cm2 [88.4–182.0] for the treated subjects vs. 121.6 cm2 [79.6—181.9] for the untreated subjects; p = 0.98). Over a mean follow-up of 18.9 (±5.9) months, the LGG size consistently decreased with treatment while no consistent change among the treated or untreated FASI size was seen. At the paired time points, the median treated LGG decreased significantly more than the treated FASI (−41.3% (LGG) versus −10.7% (FASI), p = 0.006). However, there was no difference in the median size change in the treated versus untreated FASI (−10.7% (treated FASI) versus −17.9% (untreated FASI), p = 0.08). Among the treated subjects, there was no correlation between the change in LGG and FASI (r = −0.04, p = 0.88). Conclusions: Treatment with selumetinib did not affect the overall FASI size in children with NF1 treated for progressive low-grade glioma. [ABSTRACT FROM AUTHOR]

Detection and classification of a brain tumour in medical images is always a challenging task, as the treatment may lead to Radiosurgery depending upon the exact shape, size, and position of a tumour. To provide a complete characterization of glioma and the degree of malignancy, classification and grading are vital. In some complicated cases, localization of the tumour, comparison of tumour tissues with adjacent regions, to make it clear for detection, and finally classification without human intervention is need of the hour. Out of the available numerous imaging techniques to detect and classify brain tumours, MRI is the most suitable non-invasive technique and has superior image quality. The edge over other techniques is its superior soft-tissue resolution and the ability to acquire different images employing contrast-enhanced agents. This research work classifies Low-Grade Glioma (LGG) and High-Grade Glioma(HGG) tumours on the basis of features obtained from extracted tumor region. The results of the classification of HGG and LGG tumours using the most prominent features are validated by five-fold cross-validation. Satisfactory and encouraging classification results are obtained using large and publicly available clinical datasets. Using the extracted features, a computer-assisted algorithm is developed that uses a machine-learning algorithm along with Gradient-Based Kernel Selection Graph Cut to provide binary classification with an accuracy of 94.6% with T1ce sequence of MRI. The proposed models can be employed to assist physicians and radiologists in the early pathological detection and classification of gliomas. The proposed framework also can be a model for validating brain tumours and their initial screening for their grading classification. [ABSTRACT FROM AUTHOR]

Background: As a common primary intracranial tumor, the diagnosis and therapy of low-grade glioma (LGG) remains a pivotal barrier. Cuproptosis, a new way induces cell death, has attracted worldwide attention. However, the relationship between cuproptosis and LGG remains unknown. Our study is all about finding out if there are any genes related to coproptosis that can be used to predict the outcome of LGG. Methods: RNA data and clinical information were selected from Cancer Genome Atlas (TCGA) datasets and the Genotype-Tissue Expression (GTEx), 5 lncRNAs (GAS5.AS1, MYLK.AS1, AC142472.1, AC011346.1, AL359643.3) were identified by Cox univariate and multivariate regression, as well as LASSO Cox regression. In the training and test sets, a dual validation of the predictive signature comprised of these 5 lncRNAs was undertaken. The findings demonstrate that the risk model is able to predict the survival regression of LGG patients and has a good performance in either the KM curve approach or the ROC curve. GO, GSEA and KEGG were carried out to explore the possible molecular processes that affecting the prognosis of LGG. The characteristics of immune microenvironment were investigated by using CIBERSORT, ESTIMATE and ssGSEA. Results: We identified five lncRNAs related with cuproptosis that were closely associated with the prognosis of LGG and used these five lncRNAs to develop a risk model. Using this risk model, LGG patients were then divided into high-risk and low-risk groups. The two patient groups had significantly distinct survival characteristics. Analyses of Gene Ontology (GO) and the Kyoto Encyclopedia of Genes and Genomes (KEGG) revealed that the differential genes of the two patient groups were primarily concentrated in neural active ligand-receptor interaction and cytokine-cytokine receptor interaction. The ssGSEA score determined the information related to immune infiltration, and the two groups were differentially expressed in immune subpopulations such as T cells and B cells as well. Conclusion: Our study discovered 5 cuproptosis-related lncRNAs which contribute to predicting patients' survival of LGG and provide ideas for the exploration of new targets for LGG in the future. [ABSTRACT FROM AUTHOR]

We conducted a systematic review to evaluate outcomes and toxicities associated with proton therapy in the treatment of adult-type diffuse glioma. Following PRISMA guidelines, we searched PubMed for both prospective and retrospective studies on proton therapy for adult diffuse gliomas, including IDH-mutated gliomas WHO grade 2-3 and glioblastomas. Survival and toxicity outcomes were reported separately for these glioma types. Twelve studies from 2013 to 2023 were selected, comprising 3 prospective and 9 retrospective studies. The analysis covered 570 patients with WHO grade 2-3 gliomas and 240 patients with glioblastoma or WHO grade 4 gliomas. Proton therapy was found to be comparable to conventional radiotherapy in terms of survival outcomes. Its main advantage is the ability to minimize radiation exposure to healthy tissues. Proton therapy offers comparable survival outcomes to conventional radiotherapy for adult diffuse gliomas and may enhance treatment tolerance, especially regarding neurocognitive function. A major limitation of this review is the predominance of retrospective studies. Future research should ensure rigorous patient selection and adhere to the latest WHO 2021 classification • The main advantage of proton therapy is its ability to spare healthy tissue from low and intermediate radiation doses. • Survival outcomes are comparable between protontherapy and radiotherapy in adult diffuse glioma. • The tolerance of proton therapy in adult diffuse glioma is excellent. • Proton therapy should be considered a way to enhance tolerance. [ABSTRACT FROM AUTHOR]

Simple Summary: Around 30% of children with optic pathway glioma (OPG) require next order systemic anticancer therapy (SAT) in case of progression. Bevacizumab (BVZ) is considered an effective subsequent SAT for pediatric low grade glioma. This retrospective nationwide multicentre study evaluated the effect of treatment with BVZ of 33 children with OPG. A new finding is that visual acuity stabilised (74.4%) or improved (20.5%) after treatment in 39 analysed eyes, visual field stabilised in 15.4% and improved in 73.1% of 25 eyes. Progression free survival from start of treatment decreased from 70.9% at 18 months to 38.0% at 36 months. Reversible severe toxicity was observed in five of 33 patients (15.2%). Our results suggest that the majority of patients with OPG treated with BVZ temporarily stabilize, however most show progression at a later time point. Visual functions, especially visual field, improve in a high percentage of patients. BVZ treatment is suggested to be a useful successive SAT. Backgrounds: Bevacizumab (BVZ) is used as a subsequent line of treatment for pediatric optic pathway glioma (OPG) in the case of progression. Data on the treatment effect concerning tumor progression and visual function are scarce and nationwide studies are lacking. Methods: We performed a retrospective, nationwide, multicentre cohort study including all pediatric patients with OPG treated with BVZ in the Netherlands (2009–2021). Progression-free survival, change in visual acuity and visual field, MRI-based radiologic response, and toxicity were evaluated. Results: In total, 33 pediatric patients with OPG were treated with BVZ (median 12 months). Visual acuity improved in 20.5%, remained stable in 74.4%, and decreased in 5.1% of 39 of all analysed eyes. The monocular visual field improved in 73.1%, remained stable in 15.4%, and decreased in 7.7% of 25 analysed eyes. Radiologic response at the end of therapy showed a partial response in 7 patients (21.9%), minor response in 7 (21.9%), stable disease in 15 (46.9%), and progressive disease in 3 (9.3%). Progression-free survival at 18 and 36 months after the start of BVZ reduced from 70.9% to 38.0%. Toxicity (≥grade 3 CTCAE) during treatment was observed in five patients (15.2%). Conclusion: Treatment of BVZ in pediatric patients with OPG revealed stabilisation in the majority of patients, but was followed by progression at a later time point in more than 60% of patients. This profile seems relatively acceptable given the benefits of visual field improvement in more than 70% of analysed eyes and visual acuity improvement in more than 20% of eyes at the cessation of BVZ. [ABSTRACT FROM AUTHOR]

Cuproptosis is a newly discovered new mechanism of programmed cell death, and its unique pathway to regulate cell death is thought to have a unique role in understanding cancer progression and guiding cancer therapy. However, this regulation has not been studied in low grade glioma (LGG) at present. In this study, data on low grade glioma patients were downloaded from the TCGA database. We screened the genes related to cuproptosis from the published papers and confirmed the lncRNAs related to them. We applied univariate/ multivariate, and LASSO regression algorithms, finally identified 11 lncRNAs for constructing prognosis prediction models, and constructed a risk scoring model. The reliability and validity test of the model indicated that the model could well distinguish the prognosis and survival of LGG patients. Furthermore, the analyses of immunotherapy, immune microenvironment, as well as functional enrichment were also performed. Finally, we verified the expression of these six prognostic key lncRNAs using real-time polymerase chain reaction (RT-PCR). In conclusion, this study is the first analysis based on cuproptosis-related lncRNAs in LGG and aims to open up new directions for LGG therapy [ABSTRACT FROM AUTHOR]

Simple Summary: The use of targeted therapies is revolutionizing the prognosis of many cancers; however, there is still limited knowledge of their side effects. Dyslipidemia is often present in cancer patients due to mechanisms that are directly or indirectly related to cancer or therapies. The aim of our study is to investigate the effects of vemurafenib on lipid metabolism in a cohort of pediatric patients treated for brain tumors. For the first time, we describe dyslipidemia as a possible side effect of the BRAF inhibitors. A better understanding of the pathways that are involved in dyslipidemia could also help with a better understanding of the drug-resistance mechanisms in cancer cells. BRAF inhibitors, in recent years, have played a central role in the disease control of unresectable BRAF-mutated pediatric low-grade gliomas (LGGs). The aim of the study was to investigate the acute and long-term effects of vemurafenib on the lipid metabolism in children treated for an LGG. In our cohort, children treated with vemurafenib (n = 6) exhibited alterations in lipid metabolism a few weeks after starting, as was demonstrated after 1 month (n = 4) by the high plasma levels of the total cholesterol (TC = 221.5 ± 42.1 mg/dL), triglycerides (TG = 107.8 ± 44.4 mg/dL), and low-density lipoprotein (LDL = 139.5 ± 51.5 mg/dL). Despite dietary recommendations, the dyslipidemia persisted over time. The mean lipid levels of the TC (222.3 ± 34.7 mg/dL), TG (134.8 ± 83.6 mg/dL), and LDL (139.8 ± 46.9 mg/dL) were confirmed abnormal at the last follow-up (45 ± 27 months, n = 6). Vemurafenib could be associated with an increased risk of dyslipidemia. An accurate screening strategy in new clinical trials, and a multidisciplinary team, are required for the optimal management of unexpected adverse events, including dyslipidemia. [ABSTRACT FROM AUTHOR]

Diffusely infiltrative low-grade gliomas (LGG) are primary brain tumours that arise predominantly in the cerebral hemispheres of younger adults. LGG can display either astrocytic or oligodendroglial histology and do not express malignant histological features. Vast majority of LGG are unified by IDH mutations. Other genomic features including ATRX as well as copy number status of chromosomes 1p and 19q serve to molecularly segregate this tumor group. Despite the exponential gains in molecular profiling and understanding of LGG, survival rates and treatment options have stagnated over the past few decades with few advancements. In this study, we utilize low grade glioma RNA-seq data from the Cancer Genome Atlas (TCGA-LGG) and tandem mass-spectrometry on an in-house cohort of 54 formalin-fixed paraffin-embedded (FFPE) LGG specimens to investigate the transcriptomic and proteomic profiles across the three molecular subtypes of LGG (Type I: IDH mutant – 1p19q co-deleted, Type II: IDH mutant – 1p19q retained, Type III: IDH wildtype). Within the 3 LGG subtypes, gene expression was driven heavily by IDH mutation and 1p19q co-deletion. In concordance with RNA expression, we were able to identify decreased expressions of proteins coded in 1p19q in Type I LGG. Further proteomic analysis identified 54 subtype specific proteins that were used to classify the three subtypes using a multinomial regression model (AUC = 0.911). Type I LGG were found to have increased protein expression of several metabolic proteins while Type III LGG were found to have increased immune infiltration and inflammation related proteins. Here we present the largest proteomic cohort of LGG and show that proteomic profiles can be successfully analyzed from FFPE tissues. We uncover previously known and novel subtype specific markers that are useful for the proteomic classification of LGG subtypes. [ABSTRACT FROM AUTHOR]

Radiomics is a procedure to access quantitative features from medical images for predictive analysis. Radiomics is used extensively for malignancy and survival analysis, genomic expression analysis, cancer progression, and assessment. But radiomics does not obtain the connected components, loops, or voids information from a region of interest. Topological data analysis is a newer approach that uses persistent homology to generate multiscale features from an image. We investigated in this study whether the topological features can be as useful as the radiomics features. Glioma grading and 1p19q codeletion assessment requires surgical biopsy, which can be error prone. To reduce biopsy error, MRI‐based radiomics and topological features–based analysis were performed in our study. Topological features produced the best results for 1p19q status and tumor‐grade prediction, with 94.3% (0.93 AUC) and 97.3% (0.97 AUC), respectively, which was an improvement over radiomics. Codes and partial data are available in https://github.com/hellorp1990/TDA-analysis. [ABSTRACT FROM AUTHOR]

• Postoperative management of lower grade gliomas (grade 2 and 3) is heterogeneous. • The ARS brain panel systematically reviewed the literature to develop guidelines. • These recommendations provide an evidence-based framework for lower grade gliomas. Postoperative management of lower grade gliomas (grade 2 and 3) is heterogeneous. The American Radium Society's brain malignancies panel systematically reviewed and evaluated the literature to develop consensus guidelines addressing timing of postoperative therapy, monotherapy versus combined modality therapy, type of chemotherapy used with radiotherapy, and radiotherapy dose. Thirty-six studies were included. Using consensus methodology (modified Delphi), the panel voted upon representative case variants using a 9-point appropriateness scale to address key questions. Voting results were collated to develop summarized recommendations. Following gross-total surgical resection, close surveillance is appropriate for well-selected grade 2, IDH-mutant oligodendrogliomas or astrocytomas with low-risk features. For grade 2 gliomas with high-risk features or any grade 3 glioma, immediate adjuvant therapy is recommended. When postoperative therapy is administered, radiation and planned chemotherapy is strongly recommended over monotherapy. For grade 2 and 3 IDH-mutant oligodendrogliomas and astrocytomas, either adjunctive PCV (procarbazine, lomustine, vincristine) or temozolomide is appropriate. For grade 3 IDH-mutant astrocytomas, radiotherapy followed by temozolomide is strongly recommended. The recommended radiotherapy dose for grade 2 gliomas is 45–54 Gy/1.8–2.0 Gy, and for grade 3 gliomas is 59.4–60 Gy/1.8–2.0 Gy. While multiple appropriate treatment options exist, these consensus recommendations provide an evidence-based framework to approach postoperative management of lower grade gliomas. [ABSTRACT FROM AUTHOR]

Purpose: Ferroptosis is closely associated with tumors. The purpose of this study was to investigate the correlation between ferroptosis and prognosis of low grade glioma (LGG) via construction and verification of a risk model. Patients and Methods: The data of LGG were downloaded from public databases. Through LASSO analysis of characteristic genes, a gene signature was constructed. Patients into were divided two groups based on risk score. Subsequently, survival, clinical phenotype, functional enrichment, immune cell infiltration and somatic mutation analysis were performed. In addition, whether ferroptosis-related genes (FRGs) signature can predict the patient's response to anti-PD-1/PD-L1 immunotherapy was also investigated. Results: FRGs signature had strong prognostic assessment ability, and high risk score was associated with poor overall survival (OS) of LGG. The high risk score group had higher degree of immune cell infiltration, stronger stromal activity, higher immune score, and high expression of immune checkpoint. In low risk score group anti-PD-1/PD-L1 immunotherapy has significant therapeutic advantages and clinical response. Genes and frequency of somatic mutations and clinical phenotypes in the high and low risk score groups were significantly different. Conclusion: A prognostic model based on 7 FRGs can be used to predict the prognosis and immunotherapeutic response of LGG. [ABSTRACT FROM AUTHOR]

The median survival of patients with gliomas is relatively short. To investigate the epigenetic mechanisms associated with poor survival, we analyzed publicly available datasets from patients with glioma. This analysis revealed 12 prognosis-related m6A regulatory genes that may be responsible for poor prognosis. These genes may be involved in genomic changes inherent to oxidative phosphorylation, adipogenesis, hedgehog signaling, and Myc signaling. We reconstructed a risk model with univariate and multivariate Cox analyses and identified older age and the m6A risk score as independent risk factors for predicting the prognosis of glioma patients, which is associated with glioma immune infiltration. In conclusion, m6A regulatory genes may serve as both reliable biomarkers and potential targets to increase the chance of survival of patients with glioma. [ABSTRACT FROM AUTHOR]

Management of low-grade gliomas (LGGs) is controversial. Incidental LGGs are thought to represent an earlier stage in the disease process compared with symptomatic LGGs. With advanced imaging techniques, the discovery of these lesions is expected to increase, resulting in clinical need for further understanding of these tumors. This study aimed to identify the incidence of incidental LGGs across 2 large European neurosurgical centers and review management and survival of tumors compared with symptomatic cranial LGGs over a 5-year period. LGGs managed during 2015–2019 at the Royal Victoria Infirmary and Münster University Hospital were retrospectively reviewed. An incidental finding was strictly defined as one discovered secondary to routine clinical or research imaging, not associated with investigation for a space-occupying lesion, with no associated symptoms. All histomolecular pathology reports were reviewed. Of 150 cases of World Health Organization grade II tumors identified at both centers, 82 were symptomatic, diffuse LGGs, with 20 discovered incidentally. There were 48 nondiffuse and/or pediatric tumors, which were excluded. Incidental LGGs were mostly IDH mutated and oligodendroglial with a trend toward improved overall survival and significantly increased progression-free survival compared with symptomatic LGGs (P = 0.024). In all cases, regardless of presentation, progression-free survival and overall survival were significantly improved following gross total resection versus biopsy (hazard ratio 0.45 [95% confidence interval 0.21–0.95], P = 0.037 vs. hazard ratio 0.10 [95% confidence interval 0.02–0.44], P = 0.003). In this study, differences in characteristics and survival between incidental and symptomatic LGGs were present, yet not significant owing to the rarity, and therefore small sample size, of incidental LGGs. Further global collaboration and development of an international glioma registry with a focus on symptoms, imaging indications (if incidental), histomolecular data, and management are needed. [ABSTRACT FROM AUTHOR]

The binding of platelet-derived growth factor D (PDGF-DD) to the NKp44 receptor activates a distinct transcriptional program in primary IL-2 expanded human natural killer (NK) cells. We were interested in knowing if the PDGF-DD-NKp44 pathway of NK cell activation might play a clinically relevant role in anti-tumor immunity. In order to address this question, we determined transcriptional signatures unique to resting, IL-2 expanded, and PDGF-DD activated, NK cells, in addition to different T cell subsets, and established the abundance of these immune cell phenotypes in The Cancer Genome Atlas (TCGA) low-grade glioma (LGG) dataset using CIBERSORT. Our results show that LGG patient tumors enriched for either the PDGF-DD activated NK cell or memory CD8+ T cell phenotypes are associated with a more favorable prognosis. Combined cell phenotype analyses revealed that patients with LGG tumors enriched for the PDGF-DD activated NK cell phenotype and the CD4+ T helper cell phenotype had a more favorable prognosis. High expression of transcripts encoding members of the killer cell lectin-like receptor (KLR) family, such as KLRK1 and KLRC2, KLRC3 and KLRC4 in LGG tumors were associated with more favorable prognosis, suggesting that these NK cell family receptors may play a prominent role in LGG anti-tumor immunity. Finally, many of the TCGA findings were reciprocated in LGG patients from the Chinese Glioma Genome Atlas (CGGA) dataset. Our results provide transcriptomic evidence that PDGF-DD activated NK cells and KLR family receptors may play an important clinical role in immune surveillance of LGG. [ABSTRACT FROM AUTHOR]

The overall survival of pediatric gliomas varies over a wide spectrum depending on the tumor grade. Low-grade gliomas have an excellent long-term survival, with a possible burden of surgery, irradiation, and chemotherapy; in contrast, high-grade gliomas generally have a short-term, devastating lethal outcome. Recent advances in understanding their molecular background will transform the classification and therapeutic approaches of pediatric gliomas. Molecularly targeted treatments may acquire a leading role in the primary treatment of low-grade gliomas and may provide alternative therapeutic strategies for high-grade glioma cases in the attempt to avoid the highly unsuccessful conventional therapeutic approaches. This review aims to overview this progress. [ABSTRACT FROM AUTHOR]

Purpose: Classification and treatment of WHO grade II/III gliomas have dramatically changed. Implementing molecular markers into the WHO classification raised discussions about the significance of grading and clinical trials showed overall survival (OS) benefits for combined radiochemotherapy. As molecularly stratified treatment data outside clinical trials are scarce, we conducted this retrospective study. Methods: We identified 343 patients (1995–2015) with newly diagnosed WHO grade II/III gliomas and analyzed molecular markers, patient characteristics, symptoms, histology, treatment, time to treatment failure (TTF) and OS. Results: IDH-status was available for all patients (259 mutant, 84 IDH1-R132H-non-mutant). Molecular subclassification was possible in 173 tumors, resulting in diagnosis of 80 astrocytomas and 93 oligodendrogliomas. WHO grading remained significant for OS in astrocytomas/IDH1-R132H-non-mutant gliomas (p < 0.01) but not for oligodendroglioma (p = 0.27). Chemotherapy (and temozolomide in particular) showed inferior OS compared to radiotherapy in astrocytomas (median 6.1/12.1 years; p = 0.03) and oligodendrogliomas (median 13.2/not reached (n.r.) years; p = 0.03). While radiochemotherapy improved TTF in oligodendroglioma (median radiochemotherapy n.r./chemotherapy 3.8/radiotherapy 7.3 years; p < 0.001/ = 0.06; OS data immature) the effect, mainly in combination with temozolomide, was weaker in astrocytomas (median radiochemotherapy 6.7/chemotherapy 2.3/radiotherapy 2.0 years; p < 0.001/ = 0.11) and did not translate to improved OS (median 8.4 years). Conclusion: This is one of the largest retrospective, real-life datasets reporting treatment and outcome in low-grade gliomas incorporating molecular markers. Current histologic grading features remain prognostic in astrocytomas while being insignificant in oligodendroglioma with interfering treatment effects. Chemotherapy (temozolomide) was less effective than radiotherapy in both astrocytomas and oligodendrogliomas while radiochemotherapy showed the highest TTF in oligodendrogliomas. [ABSTRACT FROM AUTHOR]

Purpose: The present study aimed to preoperatively predict the status of 1p/19q based on radiomics analysis in patients with World Health Organization (WHO) grade II gliomas. Methods: This retrospective study enrolled 157 patients with WHO grade II gliomas (76 patients with astrocytomas with mutant IDH, 16 patients with astrocytomas with wild-type IDH, and 65 patients with oligodendrogliomas with mutant IDH and 1p/19q codeletion). Radiomic features were extracted from magnetic resonance images, including T1-weighted, T2-weighted, and contrast T1-weighted images. Elastic net and support vector machines with radial basis function kernel were applied in nested 10-fold cross-validation loops to predict the 1p/19q status. Receiver operating characteristic analysis and precision-recall analysis were used to evaluate the model performance. Student's t -tests were then used to compare the posterior probabilities of 1p/19q co-deletion prediction in the group with different 1p/19q status. Results: Six valuable radiomic features, along with age, were selected with the nested 10-fold cross-validation loops. Five features showed significant difference in patients with different 1p/19q status. The area under curve and accuracy of the predictive model were 0.8079 (95% confidence interval, 0.733–0.8755) and 0.758 (0.6879–0.8217), respectively, and the F1-score of the precision-recall curve achieved 0.6667 (0.5201–0.7705). The posterior probabilities in the 1p/19q co-deletion group were significantly different from the non-deletion group. Conclusion: Combined radiomics analysis and machine learning showed potential clinical utility in the preoperative prediction of 1p/19q status, which can aid in making customized neurosurgery plans and glioma management strategies before postoperative pathology. [ABSTRACT FROM AUTHOR]

Outcome analysis showed overall survival in patients with infratentorial IDH-mutant astrocytomas to be longer than those with diffuse midline gliomas, but shorter than patients with supratentorial IDH-mutant astrocytomas, specifically those classified as "low grade" by methylation subclass. Keywords: brain biopsy; brainstem glioma; IDH; isocitrate dehydrogenase; low grade glioma; young adult EN brain biopsy brainstem glioma IDH isocitrate dehydrogenase low grade glioma young adult 1 5 5 07/05/21 20210701 NES 210701 Isocitrate dehydrogenase (IDH) mutations are rare in pediatric and adolescent gliomas. Brainstem gliomas are very rare in adults, but approximately 10% of pediatric CNS tumors occur in this location, with diffuse midline glioma, K27M-mutant representing most cases. Brain biopsy, brainstem glioma, IDH, isocitrate dehydrogenase, low grade glioma, young adult. [Extracted from the article]

Among low-grade gliomas, representing 10–20% of all primary brain tumours, the paradigmatic entity is constituted by pilocytic astrocytoma (PA), considered a grade 1 tumour by the World Health Organization. Generally, this tumour requires surgical treatment with an infrequent progression towards malignant gliomas. The present review focuses on clinicopathological characteristics, and reports imaging, neurosurgical and molecular features using a multidisciplinary approach. Macroscopically, PA is a slow-growing soft grey tissue, characteristically presenting in association with a cyst and forming a small mural nodule, typically located in the cerebellum, but sometimes occurring in the spinal cord, basal ganglia or cerebral hemisphere. Microscopically, it may appear as densely fibrillated areas composed of elongated pilocytic cells with bipolar 'hairlike' processes or densely fibrillated areas composed of elongated pilocytic cells with Rosenthal fibres alternating with loosely fibrillated areas with a varied degree of myxoid component. A wide range of molecular alterations have been encountered in PA, mostly affecting the MAPK signalling pathway. In detail, the most frequent alteration is a rearrangement of the BRAF gene, although other alterations include neurofibromatosis type-1 mutations, BRAFV600E mutations, KRAS mutations, fibroblast growth factor receptor-1 mutations of fusions, neurotrophic receptor tyrosine kinase family receptor tyrosine kinase fusions and RAF1 gene fusions. The gold standard of PA treatment is surgical excision with complete margin resection, achieving minimal neurological damage. Conventional radiotherapy is not required; the more appropriate treatment appears to be serial follow-up. Chemotherapy should only be applied in younger children to avoid the risk of long-term growth and developmental issues associated with radiation. Finally, if PA recurs, a new surgical approach should be performed. At present, novel therapy involving agents targeting MAPK signalling pathway dysregulation is in development, defining BRAF and MEK inhibitors as target therapeutical agents. [ABSTRACT FROM AUTHOR]

Immunoreactions regulated by TAMs (Tumor-associated macrophages) play a pivotal role in tumorigenesis and metastasis. In recent decades, treatments based on immune regulation have achieved revolutionary breakthroughs in cancer targeted therapies. The phenotypes of TAMs in gliomas are more heterogeneous and inherently complex than can be simply defined by classification into the M1 and M2 polarized states. The detailed mechanisms surrounding infiltrating macrophage phenotype and glioma characteristics remain undefined. SAMD9 (Sterile Alpha Motif Domain-Containing Protein 9) was found to be highly expressed in glioma and closely related to histological and genetic features in CGGA and TCGA databases. Simultaneously, we present evidence to show that there was a positive association between SAMD9 and malignancy characters in LGG. Univariable and Multivariate proportional hazard Cox analysis showed that SAMD9 was an independent prognostic factor for LGG. Surprisingly, Gene Ontology (GO) analysis showed SAMD9 expression level was remarkably well correlated with immunological responses and the Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis supported the connection with immune responses and tumorigenesis. Immune infiltration analysis demonstrated that high SAMD9 expression resulted in an accumulation of macrophages by CIBERSORT and TIMER databases, especially positively related to macrophage total marker gene AIF1 and Macrophage M2 marker gene CD163. IHC staining further indicated a high correlation of SAMD9 with those specific macrophage markers in the immune response. Human THP-1 cells were induced into M2 macrophages, which were then co-cultured with LN229 cells. Silencing of SAMD9 by shRNA in LN229 cells attenuated the infiltration abilities of M2 macrophage. SAMD9 explored immune response via relating of M2 macrophage in vitro. Our results revealed SAMD9 acted as the malignancy characters in LGG, enrichment with M2 macrophage. [ABSTRACT FROM AUTHOR]

• Low grade glioma patients have long survival after radiotherapy treatment. • Radiation-induced neurocognitive function decline is a concern in these patients. • Proton therapy offers effective treatment with less radiation exposure to the brain. Proton therapy offers an attractive alternative to conventional photon-based radiotherapy in low grade glioma patients, delivering radiotherapy with equivalent efficacy to the tumour with less radiation exposure to the brain. In the Netherlands, patients with favourable prognosis based on tumour and patient characteristics can be offered proton therapy. Radiation-induced neurocognitive function decline is a major concern in these long surviving patients. Although level 1 evidence of superior clinical outcome with proton therapy is lacking, the Dutch National Health Care Institute concluded that there is scientific evidence to assume that proton therapy can have clinical benefit by reducing radiation-induced brain damage. Based on this decision, proton therapy is standard insured care for selected low grade glioma patients. Patients with other intracranial tumours can also qualify for proton therapy, based on the same criteria. In this paper, the evidence and considerations that led to this decision are summarised. Additionally, the eligibility criteria for proton therapy and the steps taken to obtain high-quality data on treatment outcome are discussed. [ABSTRACT FROM AUTHOR]

Background: Low grade gliomas (LGG) are most often noted with the unpredictable overall survival and progression to higher grades. Objective: In the present study, we analyze the clinicopathological features influencing the prognostic outcomes and compared the features with criteria developed by EORTC.Materials and Methods: We observed the 130 LGG clinical cases in single institute and maintained the follow-up for more than 5 years. In addition, the molecular details were confirmed with markers as IDH, 1p/19q codeletion, p53 and ATRX mutations.Results: The mean age of patients as 37.67 years and male population contributing to 70%. We observed biased incidence among the male population with dominating occurrence at frontal and parietal lobes in the brain. 40.8% patients had oligodendroglioma, 33.8% astrocytoma, 19.2% oligoastrocytoma and 2.3% gemistocytic astrocytoma pathology. Patients who were subjected to chemotherapy and radiotherapy were noted with average survival of 29 months. Oligodendroglial tumors were found with progression free survival (PFS) of 25 months, oligoastrocytoma cases with 32 months, diffuse astrocytoma cases with 23 months while the gemistocytic astrocytoma cases had 22 months. The PFS for LGG cases was 4.7 years while the overall survival was 4.9 years. Mean survival of patients with KPS score <70 and >70 was 1.5 & 4.9 years respectively. 64 patients were observed with the tumor size >5 cm. In total, 72.3% of the patients were underwent GTR, 23.3% STR and 3.8% underwent biopsy.Conclusion: Taken together, the clinical symptoms, expression of molecular markers and the prognosis details provided by our results can help for better management of LGG cases. We further propose to use following five factors to accurately describe the prognosis and tumor recurrence: 1) Age >50 years, 2) tumor size >5 cm, 3) MIB index >5%, 4) KPS score < 70 and 5) gemistocytic pathology. [ABSTRACT FROM AUTHOR]

We performed genome‐wide methylation analysis on 136 pediatric low‐grade gliomas, identifying a unique cluster consisting of three tumors with oligodendroglioma‐like histology, BRAF p.V600E mutations and recurrent whole chromosome gains of 7 and loss of 10. Morphologically, all showed similar features, including a diffusely infiltrative glioma composed of round nuclei with perinuclear halos, a chicken‐wire pattern of branching capillaries and microcalcification. None showed astrocytic features or characteristics suggestive of high‐grade tumors including necrosis or mitotic figures. All tumors harbored multiple chromosomal copy number abnormalities (>10 chromosomes altered), but none showed 1p/19q co‐deletion or IDH1 p.R132H mutation. Hierarchical clustering and t‐stochastic neighbor embedding analyses from DNA methylation data cluster them more closely to previously described pediatric‐type low‐grade gliomas and separate from adult gliomas. These tumors exhibit distinct clinical features; they are temporal lobe lesions occurring in adolescents and young adults with a prolonged history of seizures and all are alive with no recurrence (follow‐up 3.2 to 13.2 years). We encountered another young adult case with quite similar pathological appearance and molecular status except for TERT promoter mutation. Although the series is small, these may represent a new category of IDH wild‐type low‐grade gliomas which may be confused with "molecular GBM." Further, they highlight the heterogeneity of IDH wild‐type gliomas and the relatively indolent behavior of "pediatric‐type" gliomas. [ABSTRACT FROM AUTHOR]

Background:BRAF mutation analysis is important to personalize the management with low-grade gliomas (LGG) in children and adults, with therapeutic and prognostic impacts. In recurrent tumors, targeted therapies such as BRAF inhibitors had been reported to induce disease stabilization and significant radiographic responses. This highlights the potential interest of BRAF mutation to stratify patients for targeted therapy. Standard operating procedures (SOP) for BRAF V600E mutation detection can be time-consuming and consequently delay treatment choice in patients with acute deterioration. Here, we evaluated IdyllaTM fully automated PCR (FA-PCR) assay for the rapid determination of BRAF mutational status in children and adult LGG. Methods: Formalin-fixed and paraffin-embedded (FFPE) samples from three histological LGG subtypes (ganglioglioma, pleomorphic xantoastrocytoma, and dysembryoplastic neuroepithelial tumor) with previous SOP-characterized BRAF mutational status were re-analyzed using the FA-PCR. Overall concordance with the mutational status determined using SOP, as well as sensitivity and specificity of FA-PCR technique were assessed. Results: All 14 samples gave interpretable results with FA-PCR. Overall concordance of BRAF mutational status between FA-PCR and SOP was 100%. Sensitivity and specificity were 100%. Conclusion: This study confirms the reliability of FA-PCR for BRAF mutations analysis in children and adult LGG. Considering the short time to results enabled by FA-PCR, providing results in less than 90 minutes, this technique represents an interesting option for the molecular diagnosis of LGG and personalization of treatment. [ABSTRACT FROM AUTHOR]

Purpose: The majority of patients with high‐risk lower grade gliomas (LGG) are treated with single‐agent temozolomide (TMZ) and radiotherapy despite three randomized trials showing a striking overall survival benefit with adjuvant procarbazine, lomustine, and vincristine (PCV) chemotherapy and radiotherapy. This article aims to evaluate the evidence and rationale for the widespread use of TMZ instead of PCV for high‐risk LGG. Methods and Materials: We conducted a literature search utilizing PubMed for articles investigating the combination of radiotherapy and chemotherapy for high‐risk LGG and analyzed the results of these studies. Results: For patients with IDH mutant 1p/19q codeleted LGG tumors, there is limited evidence to support the use of TMZ. In medically fit patients with codeleted disease, existing data demonstrate a large survival benefit for PCV as compared to adjuvant radiation therapy alone. For patients with non‐1p/19q codeleted LGG, early data from the CATNON study supports inclusion of adjuvant TMZ for 12 months. Subset analyses of the RTOG 9402 and EORTC 26951 do not demonstrate a survival benefit for adjuvant PCV for non‐1p/19q codeleted gliomas, however secondary analyses of RTOG 9802 and RTOG 9402 demonstrated survival benefit in any IDH mutant lower grade gliomas, regardless of 1p/19q codeletion status. Conclusions: At present, we conclude that current evidence does not support the widespread use of TMZ over PCV for all patients with high‐risk LGG, and we instead recommend tailoring chemotherapy recommendation based on IDH status, favoring adjuvant PCV for patients with any IDH mutant tumors, both those that harbor 1p/19q codeletion and those non‐1p/19q codeleted. Given the critical role radiation plays in the treatment of LGG, radiation oncologists should be actively involved in discussions regarding chemotherapy choice in order to optimize treatment for their patients. [ABSTRACT FROM AUTHOR]

Abstract Purpose: Texture analysis performed on MR images can detect quantitative features that are imperceptible to human visual assessment. The purpose of this study was to evaluate the feasibility of texture analysis on preoperative conventional MRI to discriminate between histological subtypes in low-grade gliomas (LGGs), and to determine the utility of texture analysis compared to histogram analysis alone. Methods: A total of 41 patients with LGG, 21 astrocytoma and 20 1p/19q codeleted oligodendroglioma were included in this study. Patients were randomly divided into training (60%) and testing (40%) sets. Texture analysis was performed on conventional MRI sequences to obtain the most discriminant factor (MDF) values for both the training and testing data. Receiver operating characteristic (ROC) curve analyses were then performed using the MDF values and 9 histogram parameters in the training data to obtain cut-off values for determining the correct rate of discriminating between astrocytoma and oligodendroglioma in the testing data. Results: The ROC analyses using MDF values resulted in an area under the curve (AUC) of 0.91 (sensitivity 86%, specificity 87%) for T2w FLAIR, 0.94 (87%, 89%) for ADC, 0.98 (93%, 95%) for T1w, and 0.88 (78%, 86%) for T1w + Gd sequences. Using the best cut-off values, MDF correctly discriminated between the two groups in 94%, 82%, 100%, and 88% of cases in the testing data, respectively. The MDF outperformed all 9 of the histogram parameters. Conclusion: Texture analysis performed on conventional preoperative MRI images can accurately predict histological subtype of LGGs, which would have an impact on clinical management. [ABSTRACT FROM AUTHOR]

Background: Virtually all low-grade gliomas (LGGs) will progress to high-grade gliomas (HGGs), including glioblastoma, the most common malignant primary brain tumor in adults. A key regulator of immunosuppression, fibrinogen-like protein 2 (FGL2), may play an important role in the malignant transformation of LGG to HGG. We sought to determine the mechanism of FGL2 on tumor progression and to show that inhibiting FGL2 expression had a therapeutic effect.Methods: We analyzed human gliomas that had progressed from low- to high-grade for FGL2 expression. We modeled FGL2 overexpression in an immunocompetent genetically engineered mouse model to determine its effect on tumor progression. Tumors and their associated microenvironments were analyzed for their immune cell infiltration. Mice were treated with an FGL2 antibody to determine a therapeutic effect. Statistical tests were two-sided.Results: We identified increased expression of FGL2 in surgically resected tumors that progressed from low to high grade (n = 10). The Cancer Genome Atlas data showed that LGG cases with overexpression of FGL2 (n = 195) had statistically significantly shorter survival (median = 62.9 months) compared with cases with low expression (n = 325, median = 94.4 months, P < .001). In a murine glioma model, HGGs induced with FGL2 exhibited a mesenchymal phenotype and increased CD4+ forkhead box P3 (FoxP3)+ Treg cells, implicating immunosuppression as a mechanism for tumor progression. Macrophages in these tumors were skewed toward the immunosuppressive M2 phenotype. Depletion of Treg cells with anti-FGL2 statistically significantly prolonged survival in mice compared with controls (n = 11 per group, median survival = 90 days vs 62 days, P = .004), shifted the phenotype from mesenchymal HGG to proneural LGG, and decreased M2 macrophage skewing.Conclusions: FGL2 facilitates glioma progression from low to high grade. Suppressing FGL2 expression holds therapeutic promise for halting malignant transformation in glioma. [ABSTRACT FROM AUTHOR]

Gliomas are a very diverse group of brain tumors that are most commonly primary tumor and difficult to cure in central nervous system. It's necessary to distinguish low-grade tumors from high-grade tumors by understanding the molecular basis of different grades of glioma, which is an important step in defining new biomarkers and therapeutic strategies. We have chosen the gene expression profile GSE52009 from gene expression omnibus (GEO) database to detect important differential genes. GSE52009 contains 120 samples, including 60 WHO II samples and 24 WHO IV samples that were selected in our analysis. We used the GEO2R tool to pick out differently expressed genes (DEGs) between low-grade glioma and high-grade glioma, and then we used the database for annotation, visualization and integrated discovery to perform gene ontology analysis and Kyoto encyclopedia of gene and genome pathway analysis. Furthermore, we used the Cytoscape search tool for the retrieval of interacting genes with molecular complex detection plug-in applied to achieve the visualization of protein--protein interaction (PPI). We selected 15 hub genes with higher degrees of connectivity, including tissue inhibitors metalloproteinases-1 and serum amyloid A1; additionally, we used GSE53733 containing 70 glioblastoma samples to conduct Gene Set Enrichment Analysis. In conclusion, our bioinformatics analysis showed that DEGs and hub genes may be defined as new biomarkers for diagnosis and for guiding the therapeutic strategies of glioblastoma. [ABSTRACT FROM AUTHOR]

Background This study aims to evaluate the impact of preoperative functional magnetic resonance imaging (fMRI) on clinical outcomes in patients with low grade glioma (LGG). Methods In a retrospective propensity-matched cohort study, we compared patients with LGG based on whether they underwent fMRI as part of preoperative assessment. Twelve patients with LGG who underwent preoperative fMRI were selected, and a contemporaneous group of 12 control patients with LGG who did not undergo fMRI were matched to the fMRI group based on age, sex, and 1p/19q status. Results fMRI group subjects tended to have more aggressive surgeries (67% resection, 33% biopsy) than the control group (33% resection, 67% biopsy). There were no significant differences in outcomes between the 2 groups. Time between clinical assessment and surgery tended to be longer in the fMRI group (6.3 ± 4.2 weeks) than in the control group (2.7 ± 2.2 weeks). Extent of resection was similar between the 2 cohorts. fMRI group subjects had lower preoperative functional status and tended to have a greater postoperative functional status improvement than control group subjects. Mean survival was not significantly different (fMRI group 5-year survival: 88.9%, control group 5-year survival: 61.1%). Conclusions We evaluated the impact of preoperative fMRI in patients with LGG in this propensity-matched cohort study. This study has not demonstrated any significant difference in outcomes between the fMRI and control groups; however, there were nonsignificant trends for patients who underwent fMRI to undergo more aggressive surgical interventions and have a greater postoperative functional status improvement. Highlights • A propensity-matched study was performed to evaluate fMRI for low grade glioma. • fMRI patients tended to have more aggressive surgical interventions. • fMRI patients tended to have greater functional improvement. • Registries will enable a better understanding of the role of advanced imaging. [ABSTRACT FROM AUTHOR]

Through this work we propose a computational technique for the segmentation of a brain tumor, identified as low grade glioma (LGG), specifically grade II astrocytoma, which is present in magnetic resonance images (MRI). This technique consists of 3 stages developed in the three-dimensional domain. They are: pre-processing, segmentation and postprocessing. The percent relative error (PrE) is considered to compare the segmentations of the LGG, generated by a neuro- oncologist manually, with the dilated segmentations of the LGG, obtained automatically. The combination of parameters linked to the lowest PrE, allow establishing the optimal parameters of each computational algorithm that makes up the proposed computational technique. The results allow reporting a PrE of 1.43%, which indicates an excellent correlation between the manual segmentations and those produced by the computational technique developed. [ABSTRACT FROM AUTHOR]

Background: Metronomic chemotherapy (MC) is defined as the frequent administration of chemotherapy at doses below the maximal tolerated dose and with no prolonged drug-free break. MC has shown its efficacy in adult tumor types such as breast and ovarian cancer and has to some extent been studied in pediatrics. Objective: To assess the anti-tumor activity and toxicity of a four-drug metronomic regimen in relapsing/refractory pediatric brain tumors (BT) with progression-free survival (PFS) after two cycles as primary endpoint. Methods: Patients ≥4 to 25 years of age were included with progressing BT. Treatment consisted of an 8-week cycle of celecoxib, vinblastine, and cyclophosphamide alternating with methotrexate. Kepner and Chang two-steps model was used with 10 patients in the first stage. If stabilization was observed in ≥2 patients, 8 additional patients were recruited. Assessment was according WHO criteria with central radiology review. Results: Twenty-nine patients (27 evaluable) were included in two groups: ependymoma (group 1, N = 8), and miscellaneous BT (group 2): 3 medulloblastoma (MB), 5 high grade glioma (HGG), 11 low grade glioma (LGG), 2 other BT. After first stage, recruitment for ependymoma was closed [one patient had stable disease (SD) for 4 months]. Cohort 2 was opened for second stage since 1 HGG and 3 LGG patients had SD after two cycles. Recruitment was limited to LGG for the second stage and 2 partial responses (PR), 6 SD and 2 progressive disease (PD) were observed after two cycles. Of these patients with LGG, median age was 10 years, nine patients received vinblastine previously. Median number of cycles was 6.8 (range: 1-12). Treatment was interrupted in five patients for grade 3/4 toxicity. Conclusion: This regimen is active in patients with LGG, even if patients had previously received vinblastine. Toxicity is acceptable. [ABSTRACT FROM AUTHOR]

Introduction The European Organisation for Research and Treatment of Cancer (EORTC) 22033-26033 clinical trial (NCT00182819) investigated whether initial temozolomide (TMZ) chemotherapy confers survival advantage compared with radiotherapy (RT) in low-grade glioma (LGG) patients. In this study, we performed gene expression profiling on tissues from this trial to identify markers associated with progression-free survival (PFS) and treatment response. Methods Gene expression profiling, performed on 195 samples, was used to assign tumours to one of six intrinsic glioma subtypes (IGSs; molecularly similar tumours as previously defined using unsupervised expression analysis) and to determine the composition of immune infiltrate. DNA copy number changes were determined using OncoScan arrays. Results We confirm that IGSs are prognostic in the EORTC22033-26033 clinical trial. Specific genetic changes segregate in distinct IGSs: most samples assigned to IGS-9 have IDH -mutations and 1p19q codeletion, samples assigned to IGS-17 have IDH -mutations without 1p19q codeletion and samples assigned to other intrinsic subtypes often are IDH -wildtype. A trend towards benefit from RT was observed for samples assigned to IGS-9 (hazard ratio [HR] for TMZ is 1.90, P = 0.065) but not for samples assigned to IGS-17 (HR 0.87, P = 0.62). We did not identify genes significantly associated with PFS within intrinsic subtypes, although follow-up time is limited. We also show that LGGs and glioblastomas differ in their immune infiltrate, which suggests that LGGs are less amenable to checkpoint inhibitor–type immune therapies. Gene expression analysis also allows identification of relatively rare subtypes. Indeed, one patient with a pilocytic astrocytoma was identified. Conclusion IGSs are prognostic for PFS in EORTC22033-26033 clinical trial samples. [ABSTRACT FROM AUTHOR]

• In this cohort, the cumulative incidence of psPD increases from 13% in the first year to 28% at 10 years. • psPD is asymptomatic in 83% of patients. • 1p/19q codeletion and biopsy are associated with an increased risk of psPD. • When analyzed as a time-dependent covariate, psPD is not associated with overall survival. • An uniform definition and analysis method for psPD in diffuse glioma is needed for comparisons between photon - and proton beam radiotherapy. The interpretation of new enhancing lesions after radiotherapy for diffuse glioma remains a clinical challenge. We sought to characterize and classify new contrast enhancing lesions in a historical multicenter cohort of patients with IDH mutated grade 2 diffuse glioma treated with photon therapy. We reviewed all follow-up MRI's of all patients treated with radiotherapy for histologically confirmed, IDH mutated diffuse grade 2 glioma between 1–1-2007 and 31–12-2018 in two tertiary referral centers. Disease progression (PD) was defined in accordance with the RANO criteria for progressive disease in low grade glioma. Pseudoprogression (psPD) was defined as any transient contrast-enhancing lesion between the end of radiotherapy and PD, or any new contrast-enhancing lesion that remained stable over a period of 12 months in patients who did not exhibit PD. A total of 860 MRI's of 106 patients were reviewed. psPD was identified in 24 patients (23%) on 76 MRI's. The cumulative incidence of psPD was 13% at 1 year, 22% at 5 years, and 28% at 10 years. The mean of the observed maximal volume of psPD was 2.4 cc. The median Dmin in psPD lesions was 50.1 Gy. The presence of an 1p/19q codeletion was associated with an increased risk of psPD (subhazard ratio 2.34, p = 0.048). psPD was asymptomatic in 83% of patients. The cumulative incidence of psPD in grade 2 diffuse glioma increases over time. Consensus regarding event definition and statistical analysis is needed for comparisons between series investigating psPD. [ABSTRACT FROM AUTHOR]

Background The use of chemotherapy to manage newly diagnosed low grade glioma (LGG) was first introduced in the 1980s. One randomised trial has studied two- versus four-drug regimens with a duration of 12 months of treatment after resection. Methods Within the European comprehensive treatment strategy for childhood LGG, the International Society of Paediatric Oncology–Low Grade Glioma (SIOP LGG) Committee launched a randomised trial involving 118 institutions and 11 countries to investigate the addition of etoposide (100 mg/m 2 , days 1, 2 & 3) to a four-course induction of vincristine (1.5 mg/m 2 × 10 wkly) and carboplatin (550 mg/m 2 q 3 weekly) as part of 18-month continuing treatment programme. Patients were recruited after imaging diagnosis, resection or biopsy with progressive disease/symptoms. Some 497 newly diagnosed patients (M/F 231/266; median age 4.26 years (interquartile range (IQR) 2.02–7.06)) were randomised to receive vincristine carboplatin (VC) (n = 249) or VC plus etoposide (VCE) during induction (n = 248), stratified by age and tumour site. Findings No differences between the two arms were found in term of survival and radiological response. Response and non-progression rates at 24 weeks for VC and VCE, were 46% versus 41%, and 93% versus 91% respectively; 5-year Progression-Free Survival (PFS) and Overall Survival (OS) were 46% (StDev 3.5) versus 45% (StDev 3.5) and 89% (StDev 2.1) versus 89% (StDev 2.1) respectively. Age and diencephalic syndrome are adverse clinical risk factors for PFS and OS. 5-year OS for patients in early progression at week 24 were 46% (StDev 13.8) and 49% (StDev 16.5) in the two arms, respectively. Interpretation The addition of etoposide to VC did not improve PFS or OS. High non-progression rates at 24 weeks justify retaining VC as standard first-line therapy. Infants with diencephalic syndrome and early progression need new treatments to be tested. Future trials should use neurological/visual and toxicity outcomes and be designed to discriminate between the impact on disease outcomes of ‘duration of therapy’ and ‘age at stopping therapy’. [ABSTRACT FROM AUTHOR]

Background: Carboplatin based regimens have demonstrated activity in pediatric patients with low grade gliomas (LGG). However, carboplatin hypersensitivity reactions (CHRs) may be a major problem leading to premature cessation of an effective therapy. The objectives of this study were to describe the prevalence, characteristics and management of CHR. Methods: We performed a retrospective review of children with LGG treated between January 1994 and July 2015 with carboplatin and vincristine who had a documented CHR. We identified two groups: the first was treated following the schema proposed by Packer et al., and re-exposed to carboplatin using a desensitization protocol; the second was treated according to protocol SIOP LGG 2004 and re-exposed with the infusion time prolonged. Results: CHRs were observed in 16 patients (34%) out of 47. Hypersensitivity reactions occurred in 6 patients (20.7%) of the first, and 10 patients (55.5%) of the second group, respectively. The grade 2 reactions were the most common. The median number of carboplatin doses administered at the first episode of CHR was 7 (range, 3-9) for the first group, and 8.5 (range, 5-11) for the second, respectively. Six patients were re-exposed to carboplatin using a desensitization protocol; 10 with a prolonged infusion time. Overall success rate for re-exposition was 43.75% (100% and 10%, respectively) (P = 0.001). Conclusions: Our results show that re-exposure is a safe alternative to abandoning carboplatin. Desensitization showed greater effectiveness compared to a prolonged infusion time, which allowed the patients to receive effective treatment without adverse reactions. [ABSTRACT FROM AUTHOR]

Introduction. The utilization of Magnetic Resonance Spectroscopy (MRS) brings an important piece of information to an overall MR study, thus aiding the physician in making an accurate assumption regarding the histological grade of a tumor. The purpose of this study is to verify the reliability of MRS in correctly diagnosing both the nature of tumors and their grade. Material and methods. This is an observational study that was conducted from January 2011 to June 2016 on 49 patients confirmed to be low-grade gliomas (LGG) by pathological examination, who were admitted in our Neurosurgery Department in this period. Both retrospective and prospective data were collected. Inclusion criteria comprise unique tumoral lesion at the moment of diagnosis, follow-up for at least one year. Exclusion criteria included: other types of tumors with any location, patient refusal to undergo histopathological examination of the resected tissue, uncompliant and non-collaborating patients. Of all patients. 22 were subjected to an MRS study which suggested the presence of a low-grade glioma subsequently confirmed by the pathological examination. Results. MRS has been shown to provide accurate non-invasive diagnosis of LGG's by analyzing the concentration of metabolites inside the lesions which tend to be specific for these tumours: relatively elevated levels of N-acetylaspartate and creatine with reduced levels in the concentration of choline and absent lipids and lactate. It has also been observed that pre-operative MRS assists the physician in selecting the optimal place for biopsy so that the pathological examination provides conclusive results. Conclusions. With the increased availability of MRI technology, MRS comes as a milestone in the advancement of more accurate and patient-friendly methods of diagnostic for pathologies as LGG's which constitute a permanent challenge for neurosurgeons. The results of this study underlines the importance of MRS as a method for follow up patients with LGG, but cannot replace the need for obtaining bioptic tissue for pathological examination especially after the new grading system of WHO, which was published in June 2016. This new grading system takes into account the molecular biology in predicting the natural history of cerebral tumours. [ABSTRACT FROM AUTHOR]

Neurofibromatosis type 1 (NF1) is an autosomal dominant disorder, associated with a variable clinical phenotype including café-au-lait spots, intertriginous freckling, Lisch nodules, neurofibromas, optic pathway gliomas and distinctive bony lesions. NF1 is caused by a mutation in the NF1 gene, which codes for neurofibromin, a large protein involved in the MAPK- and the mTOR-pathway through RAS-RAF signalling. NF1 is a known tumour predisposition syndrome, associated with different tumours of the nervous system including low grade gliomas (LGGs) in the paediatric population. The focus of this review is on grade I pilocytic astrocytomas (PAs), the most commonly observed histologic subtype of low grade gliomas in NF1. Clinically, these PAs have a better prognosis and show different localisation patterns than their sporadic counterparts, which are most commonly associated with a KIAA1549:BRAF fusion. In this review, possible mechanisms of tumourigenesis in LGGs with and without NF1 will be discussed, including the contribution of different signalling pathways and tumour microenvironment. Furthermore we will discuss how increased understanding of tumourigenesis may lead to new potential targets for treatment. [ABSTRACT FROM AUTHOR]

We discuss the optimization of chemotherapy treatment for lowgrade gliomas using a mathematical model. We analyze the dynamics of the model and study the stability of solutions. The dynamical model is incorporated into an optimal control problem for which different objective functionals are considered. We establish the existence of optimal controls and give a detailed discussion of the necessary optimality conditions. Since the control variable appears linearly in the control problem, optimal controls are concatenations of bang-bang and singular arcs. We derive a formula of the singular control in terms of state and adjoint variables. Using discretization and optimization methods we compute optimal drug protocols in a number of scenarios. For small treatment periods, the optimal control is bang-bang, whereas for larger treatment periods we obtain both bang-bang and singular arcs. In particular, singular controls illustrate the metronomic chemotherapy. [ABSTRACT FROM AUTHOR]

Purpose: Diagnosis of childhood brain tumors is delayed more than diagnosis of other pediatric cancers. However, the contribution of the most common pediatric brain tumors, lowgrade gliomas (LGG), to this delay has never been investigated. Methods: We retrospectively reviewed cases of childhood LGG diagnosed from January 1995 through December 2005 at our institution. The pre-diagnosis symptom interval (PSI) was conservatively calculated, and its association with race, sex, age, tumor site, tumor grade, and outcome measures (survival, disease progression, shunt use, seizures, extent of resection) was analyzed. Cases of neurofibromatosis type 1 were reported separately. Results: The 258 children had a median follow-up of 11.1 years, and 226 (88 %) remained alive. Greater pre-diagnosis symptom interval (PSI) was significantly associated with grade I (vs. grade II) tumors (p = 0.03) and age >10 years at diagnosis (p = 0.03). Half of the 16 spinal tumors had a PSI > 6 months. PSI was significantly associated with progression (p = 0.02) in grade I tumors (n = 195) and in grade I tumors outside the posterior fossa (n = 134, p = 0.03). Among children with grade I tumors, median PSI was longer in those who had seizures (10.3 months) than in those who did not (2.5 months) (p = 0.09). Conclusions: Delayed diagnosis of childhood LGG allows tumor progression. To reduce time to diagnosis, medical curricula should emphasize inclusion of LGG in the differential diagnosis of CNS neoplasm. [ABSTRACT FROM AUTHOR]

Background: We compare clinical outcomes of paediatric patients with CNS tumours treated with protons or IMRT. CNS tumours form the second most common group of cancers in children. Radiotherapy plays a major role in the treatment of many of these patients but also contributes to late side effects in long term survivors. Radiation dose inevitably deposited in healthy tissues outside the clinical target has been linked to detrimental late effects such as neurocognitive, behavioural and vascular effects in addition to endocrine abnormalities and second tumours. Methods: A literature search was performed using keywords: protons, IMRT, CNS and paediatric. Of 189 papers retrieved, 10 were deemed relevant based on title and abstract screening. All papers directly compared outcomes from protons with photons, five papers included medulloblastoma, four papers each included craniopharyngioma and low grade gliomas and three papers included ependymoma. Results: This review found that while proton beam therapy offered similar clinical target coverage, there was a demonstrable reduction in integral dose to normal structures. Conclusions: This in turn suggests the potential for superior long term outcomes for paediatric patients with CNS tumours both in terms of radiogenic second cancers and out-of-field adverse effects. [ABSTRACT FROM AUTHOR]

Objective: There is a number of different methods to localize a glioma intraoperatively. Neuronavigation, intraoperative MRI, 5-aminolevulinic acid, as well as intraoperative sonography. Every method has its advantages and disadvantages. Low grade gliomas do not show a specific signal with 5-aminolevulinic acid and are difficult to distinguish macroscopically from normal tissue. In the present study we stress out the importance of intraoperative diagnostic ultrasound for localization of low grade gliomas. Methods: We retrospectively evaluated the charts and MRIs of 34 patients with low grade gliomas operated in our department from 2011 until December 2014. The efficacy of ultrasound as an intraoperative navigational tool was assessed. In 15 patients ultrasound was used and in 19 not. Only histologically proven low grades gliomas (astrocytomas grade II) were evaluated. Results: In none of the patients where ultrasound (combined with neuronavigation) was used (N =15) to find the tumors, the target was missed, whereas the exclusive use of neuronavigation missed the target in 5 of 19 cases of small subcortical low grade gliomas. Conclusions: Intraoperative ultrasound is an excellent tool in localizing low grade gliomas intraoperatively. It is an inexpensive, real time neuronavigational tool, which overcomes brain shift. Even when identifying the tumors with ultrasound is very reliable, the extend of resection and the decision to remove any residual tumor with the help of ultrasound is at the moment unreliable. [ABSTRACT FROM AUTHOR]

Objective: Low grade gliomas (LGGs) are slow-growing primary brain tumors with heterogeneous clinical behaviors. The aim of our study is to review the treatment outcome of 63 patients with LGGs focusing on surgical outcome and the current therapeutic strategy. Methods: We retrospectively enrolled 63 patients surgically treated for LGGs. The gross total resection (GTR) was performed in 35 patients (60.3%), subtotal resection (STR) was performed in 19 patients (31.7%) and partial resection (PR) or biopsy was performed in 9 patients (14.3%). We analyzed their progression-free survival (PFS), overall survival (OS), and malignant transformation with regard to age, gender, Karnofsky performance score (KPS), clinical presentation, tumor location, radiologic pattern, contrast enhancement, extent of removal, pathologic subtype, chemotherapy (CT) and radiotherapy (RT) treatment. Results: Among all LGGs, the 3-year OS rate was 80% and the 5-year OS was 76%. The 3-year PFS rate was 83.6% and the 5-year PFS was 25%. The non-eloquent area location showed a longer PFS than the eloquent area location (p = 0.05). Oligodendroglial pathology showed a longer PFS compared to oligoastrocytomas and astrocytomas (p = 0.02). Patients older than 60 years had poorer OS than younger patients (p < 0.05). Female gender had a shorter OS than male gender (p < 0.05), and a KPS of 90 or 100 had a longer OS than a KPS of 80 (p < 0.05). Oligodendroglial pathology statistically correlated with a longer OS (p < 0.05). Conclusion: The findings from our study, which were confirmed by uni- and multivariate analyses, demonstrated that radical tumor resection was associated with better long-term outcomes and tumor progression for patients with LGG. [ABSTRACT FROM AUTHOR]

BACKGROUND The objective of this study was to evaluate local control and patterns of failure in pediatric patients with low-grade glioma (LGG) who received treatment with intensity-modulated radiation therapy (IMRT). METHODS In total, 39 children received IMRT after incomplete resection or disease progression. Three methods of target delineation were used. The first was to delineate the gross tumor volume (GTV) and add a 1-cm margin to create the clinical target volume (CTV) (Method 1; n = 19). The second was to add a 0.5-cm margin around the GTV to create the CTV (Method 2; n = 6). The prescribed dose to the GTV was the same as dose to the CTV for both Methods 1 and 2 (median, 50.4 grays [Gy]). The final method was dose painting, in which a GTV was delineated with a second target volume (2TV) created by adding 1 cm to the GTV (Method 3; n = 14). Different doses were prescribed to the GTV (median, 50.4 Gy) and the 2TV (median, 41.4 Gy). RESULTS The 8-year progression-free and overall survival rates were 78.2% and 93.7%, respectively. Seven failures occurred, all of which were local in the high-dose (≥95%) region of the IMRT field. On multivariate analysis, age ≤5 years at time of IMRT had a detrimental impact on progression-free survival. CONCLUSIONS IMRT provided local control rates comparable to those provided by 2-dimensional and 3-dimensional radiotherapy. Margins ≥1 cm added to the GTV may not be necessary, because excellent local control was achieved by adding a 0.5-cm margin (Method 2) and by dose painting (Method 3). Cancer 2013;119:2654-2659. © 2013 American Cancer Society. [ABSTRACT FROM AUTHOR]