Search

Objectives: This study aimed to assess the diagnostic management and follow-up imaging for glioma patients across Belgian hospitals by calculating process indicators., Methods: Patients with newly diagnosed glioma in Belgium (2016-2019) were selected from the Belgian Cancer Registry. The National Social Security Number served as unique patient identifier, linking the Registry to vital status and reimbursement data. Nine measurable process related to diagnosis and follow-up imaging were identified, with reformulations for 7 due to data limitations. For each indicator, technical documentation sheets, containing all required details (rationale, numerator and denominator, target, limitations, benchmarking, subgroup analyses) were developed, reviewed by a multidisciplinary expert panel, and validated in six pilot hospitals. Per indicator, patients were assigned to the most relevant hospital per indicator using allocation algorithms., Results: Results for process indicators assessing MRI use in glioma diagnosis and follow-up aligned with predefined targets (90%), except for early postoperative MRI (48.5% vs. target 90%). Mandatory reporting of the WHO performance status (89.3% vs. target 100%) and performance of full-spine (43.6% vs. target 90%) and follow-up MRI (73.5% vs. target 90%) in ependymoma were suboptimal. The largest variability across centers was noted for the indicator on early postoperative MRI., Conclusion: This calculation of process indicators identified opportunities for improvement in diagnosis and follow-up imaging for glioma patients in Belgium. Monitoring indicator results and providing individual feedback reports to the Belgian hospitals invites neuro-oncology care teams and hospital managements to reflect on their results and to take measures to continuously improve care for glioma., (© 2024 The Author(s). Cancer Medicine published by John Wiley & Sons Ltd.)

Brain tumors are a threat to life for every other human being, be it adults or children. Gliomas are one of the deadliest brain tumors with an extremely difficult diagnosis. The reason is their complex and heterogenous structure which gives rise to subjective as well as objective errors. Their manual segmentation is a laborious task due to their complex structure and irregular appearance. To cater to all these issues, a lot of research has been done and is going on to develop AI-based solutions that can help doctors and radiologists in the effective diagnosis of gliomas with the least subjective and objective errors, but an end-to-end system is still missing. An all-in-one framework has been proposed in this research. The developed end-to-end multi-task learning (MTL) architecture with a feature attention module can classify, segment, and predict the overall survival of gliomas by leveraging task relationships between similar tasks. Uncertainty estimation has also been incorporated into the framework to enhance the confidence level of healthcare practitioners. Extensive experimentation was performed by using combinations of MRI sequences. Brain tumor segmentation (BraTS) challenge datasets of 2019 and 2020 were used for experimental purposes. Results of the best model with four sequences show 95.1% accuracy for classification, 86.3% dice score for segmentation, and a mean absolute error (MAE) of 456.59 for survival prediction on the test data. It is evident from the results that deep learning-based MTL models have the potential to automate the whole brain tumor analysis process and give efficient results with least inference time without human intervention. Uncertainty quantification confirms the idea that more data can improve the generalization ability and in turn can produce more accurate results with less uncertainty. The proposed model has the potential to be utilized in a clinical setup for the initial screening of glioma patients., (© 2024. The Author(s) under exclusive licence to Society for Imaging Informatics in Medicine.)

Purpose: High-grade gliomas in infants and very young children (less than 3 to 5 years old) pose significant challenges due to the limited scientific literature available and high risks associated with treatments. This study aims to investigate their characteristics, treatment, and outcomes., Methods: A cohort study was conducted at Children's Cancer Hospital, Egypt. Cases included children aged < 5 years old with confirmed CNS high-grade glioma. Baseline clinical and radiological characteristics, besides potential prognostic factors were assessed., Results: In total, 76 cases were identified, 7 of them were < 1 year old. Gross- or near-total resection (GTR/NTR) was achieved in 32.9% of all cases. Of the tested cases, H3K27M-alteration was present in 5 subjects only. The 3-year OS and EFS for all cases were 26.9% and 15.4%, respectively. Extent of resection was the most important prognostic factor, as those achieving GTR/NTR experienced more than double the survival compared to those who do not (p = 0.05). Age had a "bimodal" effect on EFS, with those aged 1 to 3 years old faring better than younger and older age groups. Subjects with midline tumors had worse survival compared to non-midline tumors (1-year EFS = 18.5% vs 35%, respectively, p = 0.02)., Conclusion: This study in a large cohort of HGG in infants and very young children offers insights into the characteristics and treatment challenges. Extent of resection, age group, and tumor localization are important prognostic factors. Further research with larger sample size is warranted to refine treatment approaches and improve outcomes., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Background: Alopecia causes significant distress for patients and negatively impacts quality of life for low-grade glioma (LGG) patients. We aimed to compare and evaluate variations in dose distribution for scalp-sparing in LGG patients with proton therapy and photon therapy, namely intensity-modulated proton therapy (IMPT), intensity-modulated radiotherapy (IMRT), volumetric modulated arc therapy (VMAT), and helical tomotherapy (HT)., Methods: This retrospective study utilized a dataset comprising imaging data from 22 patients with LGG who underwent postoperative radiotherapy. Treatment plans were generated for each patient with scalp-optimized (SO) approaches and scalp-non-optimized (SNO) approaches using proton techniques and photons techniques; all plans adhered to the same dose constraint of delivering a total radiation dose of 54.04 Gy to the target volume. All treatment plans were subsequently analyzed., Results: All the plans generated in this study met the dose constraints for the target volume and OARs. The SO plans resulted in reduced maximum scalp dose (D max ), mean scalp dose (D mean ), and volume of the scalp receiving 30 Gy (V 30 ) and 40 Gy (V 40 ) compared with SNO plans in all radiation techniques. Among all radiation techniques, the IMPT plans exhibited superior performance compared to other plans for dose homogeneity as for SO plans. Also, IMPT showed lower values for D mean and D max than all photon radiation techniques., Conclusion: Our study provides evidence that the SO approach is a feasible technique for reducing scalp radiation dose. However, it is imperative to conduct prospective trials to assess the benefits associated with this approach., (© 2024. Springer-Verlag GmbH Germany, part of Springer Nature.)

The preoperative diagnosis of brain tumors is important for therapeutic planning as it contributes to the tumors' prognosis. In the last few years, the development in the field of artificial intelligence and machine learning has contributed greatly to the medical area, especially the diagnosis of the grades of brain tumors through radiological images and magnetic resonance images. Due to the complexity of tumor descriptors in medical images, assessing the accurate grade of glioma is a major challenge for physicians. We have proposed a new classification system for glioma grading by integrating novel MRI features with an ensemble learning method, called Ensemble Learning based on Adaptive Power Mean Combiner (EL-APMC). We evaluate and compare the performance of the EL-APMC algorithm with twenty-one classifier models that represent state-of-the-art machine learning algorithms. Results show that the EL-APMC algorithm achieved the best performance in terms of classification accuracy (88.73%) and F1-score (93.12%) over the MRI Brain Tumor dataset called BRATS2015. In addition, we showed that the differences in classification results among twenty-two classifier models have statistical significance. We believe that the EL-APMC algorithm is an effective method for the classification in case of small-size datasets, which are common cases in medical fields. The proposed method provides an effective system for the classification of glioma with high reliability and accurate clinical findings., (© 2024. The Author(s).)

SorLA, encoded by the gene SORL1, is an intracellular sorting receptor of the VPS10P domain receptor gene family. Although SorLA is best recognized for its ability to shuttle target proteins between intracellular compartments in neurons, recent data suggest that also its microglial expression can be of high relevance for the pathogenesis of brain diseases, including glioblastoma (GBM). Here, we interrogated the impact of SorLA on the functional properties of glioma-associated microglia and macrophages (GAMs). In the GBM microenvironment, GAMs are re-programmed and lose the ability to elicit anti-tumor responses. Instead, they acquire a glioma-supporting phenotype, which is a key mechanism promoting glioma progression. Our re-analysis of published scRNA-seq data from GBM patients revealed that functional phenotypes of GAMs are linked to the level of SORL1 expression, which was further confirmed using in vitro models. Moreover, we demonstrate that SorLA restrains secretion of TNFα from microglia to restrict the inflammatory potential of these cells. Finally, we show that loss of SorLA exacerbates the pro-inflammatory response of microglia in the murine model of glioma and suppresses tumor growth., (© 2024. The Author(s).)

Background: This study aimed to examine the association between risk of brain tumors and radiofrequency (RF) exposure from mobile phones among young people in Korea and Japan., Methods: This case-control study of brain tumors in young people was conducted in Korea and Japan under the framework of the international MOBI-Kids study. We included 118 patients diagnosed with brain tumors between 2011 and 2015 and 236 matched appendicitis controls aged 10-24 years. Information on mobile phone use was collected through face-to-face interviews. A detailed RF exposure algorithm, based on the MOBI-Kids algorithm and modified to account for the specificities of Japanese and Korean phones and networks, was used to calculate the odds ratios (ORs) for total cumulative specific energy using conditional logistic regression., Results: The adjusted ORs in the highest tertile of cumulative call time at 1 year before the reference date were 1.61 (95% confidence interval [CI], 0.72-3.60) for all brain tumors and 0.70 (95% CI, 0.16-3.03) for gliomas, with no indication of a trend with exposure. The ORs for glioma specifically, were below 1 in the lowest exposure category., Conclusion: This study provided no evidence of a causal association between mobile phone use and risk of brain tumors as a whole or of glioma specifically. Further research will be required to evaluate the impact of newer technologies of communication in the future.

The increasing global incidence of glioma tumors has raised significant healthcare concerns due to their high mortality rates. Traditionally, tumor diagnosis relies on visual analysis of medical imaging and invasive biopsies for precise grading. As an alternative, computer-assisted methods, particularly deep convolutional neural networks (DCNNs), have gained traction. This research paper explores the recent advancements in DCNNs for glioma grading using brain magnetic resonance images (MRIs) from 2015 to 2023. The study evaluated various DCNN architectures and their performance, revealing remarkable results with models such as hybrid and ensemble based DCNNs achieving accuracy levels of up to 98.91%. However, challenges persisted in the form of limited datasets, lack of external validation, and variations in grading formulations across diverse literature sources. Addressing these challenges through expanding datasets, conducting external validation, and standardizing grading formulations can enhance the performance and reliability of DCNNs in glioma grading, thereby advancing brain tumor classification and extending its applications to other neurological disorders.

Purpose: The aim of this study is to reduce treatment planning time by predicting the intensity-modulated radiotherapy 3D dose distribution using deep learning for brain cancer patients. "For this purpose, two different approaches in dose prediction, i.e., first only planning target volume (PTV) and second PTV with organs at risk (OARs) as input of the U-net model, are employed and their results are compared.", Methods and Materials: The data of 99 patients with glioma tumors referred for IMRT treatment were used so that the images of 90 patients were regarded as training datasets and the others were for the test. All patients were manually planned and treated with sixth-field IMRT; the photon energy was 6MV. The treatment plans were done with the Collapsed Cone Convolution algorithm to deliver 60 Gy in 30 fractions., Results: The obtained accuracy and similarity for the proposed methods in dose prediction when compared to the clinical dose distributions on test patients according to MSE, dice metric and SSIM for the Only-PTV and PTV-OARs methods are on average (0.05, 0.851, 0.83) and (0.056, 0.842, 0.82) respectively. Also, dose prediction is done in an extremely short time., Conclusion: The same results of the two proposed methods prove that the presence of OARs in addition to PTV does not provide new knowledge to the network and only by defining the PTV and its location in the imaging slices, does the dose distribution become predictable. Therefore, the Only-PTV method by eliminating the process of introducing OARs can reduce the overall designing time of treatment by IMRT in patients with glioma tumors., (© 2023 The Authors. Journal of Applied Clinical Medical Physics published by Wiley Periodicals, LLC on behalf of The American Association of Physicists in Medicine.)

Objective: Surgery is the mainstay of treatment for low-grade glioma (LGG)-related epilepsy. However, the goal of achieving both oncological radical resection and seizure freedom can be challenging. PET with [11C]methionine (MET) has been recently introduced in clinical practice for the management of patients with LGGs, not only to monitor the response to treatments, but also as a preoperative tool to define the metabolic tumor extent and to predict tumor grading, type, and prognosis. Still, its role in defining tumor-related epilepsy and postoperative seizure outcomes is limited. The aim of this preliminary study was to investigate the role of MET PET in defining preoperative seizure characteristics and short-term postoperative seizure control in a cohort of patients with newly diagnosed temporal lobe low-grade gliomas (tLGGs)., Methods: Patients with newly diagnosed and histologically proven temporal lobe grade 2/3 gliomas (2021 WHO CNS tumor classification) who underwent resection at the authors' institution between July 2011 and March 2021 were included in this retrospective study. MET PET images were acquired, fused with MRI scans, and qualitatively and semiquantitatively analyzed. Any eventual PET/MRI involvement of the temporomesial area, seizure characteristics, and 1-year seizure outcomes were reported., Results: A total of 52 patients with tLGGs met the inclusion criteria. MET PET was positive in 41 (79%) patients, with a median metabolic tumor volume of 14.56 cm3 (interquartile range [IQR] 6.5-28.2 cm3). The median maximum and mean tumor-to-background ratio (TBRmax, TBRmean) were 2.24 (IQR 1.58-2.86) and 1.53 (IQR 1.37-1.70), respectively. The metabolic tumor volume was found to be related to the presence of seizures at disease onset, but only in noncodeleted tumors (p = 0.014). Regarding patients with uncontrolled seizures at surgery, only the temporomesial area PET involvement showed a statistical correlation both in the univariate (p = 0.058) and in the multivariate analysis (p = 0.030). At 1-year follow-up, seizure control was correlated with MET PET-derived semiquantitative data. Particularly, higher TBRmax (p = 0.0192) and TBRmean (p = 0.0128) values were statistically related to uncontrolled seizures 1 year after surgery., Conclusions: This preliminary study suggests that MET PET may be used as a preoperative tool to define seizure characteristics and outcomes in patients with tLGGs. These findings need to be further validated in larger series with longer epileptological follow-ups.

Objective. Current radiotherapy guidelines for glioma target volume definition recommend a uniform margin expansion from the gross tumor volume (GTV) to the clinical target volume (CTV), assuming uniform infiltration in the invaded brain tissue. However, glioma cells migrate preferentially along white matter tracts, suggesting that white matter directionality should be considered in an anisotropic CTV expansion. We investigate two models of anisotropic CTV expansion and evaluate their clinical feasibility. Approach. To incorporate white matter directionality into the CTV, a diffusion tensor imaging (DTI) atlas is used. The DTI atlas consists of water diffusion tensors that are first spatially transformed into local tumor resistance tensors, also known as metric tensors, and secondly fed to a CTV expansion algorithm to generate anisotropic CTVs. Two models of spatial transformation are considered in the first step. The first model assumes that tumor cells experience reduced resistance parallel to the white matter fibers. The second model assumes that the anisotropy of tumor cell resistance is proportional to the anisotropy observed in DTI, with an 'anisotropy weighting parameter' controlling the proportionality. The models are evaluated in a cohort of ten brain tumor patients. Main results. To evaluate the sensitivity of the model, a library of model-generated CTVs was computed by varying the resistance and anisotropy parameters. Our results indicate that the resistance coefficient had the most significant effect on the global shape of the CTV expansion by redistributing the target volume from potentially less involved gray matter to white matter tissue. In addition, the anisotropy weighting parameter proved useful in locally increasing CTV expansion in regions characterized by strong tissue directionality, such as near the corpus callosum. Significance. By incorporating anisotropy into the CTV expansion, this study is a step toward an interactive CTV definition that can assist physicians in incorporating neuroanatomy into a clinically optimized CTV., (© 2024 Institute of Physics and Engineering in Medicine.)

Contrast-enhanced MRI is the method of choice for brain tumor diagnostics, despite its low specificity for tumor tissue. This study compared the contribution of MR spectroscopic imaging (MRSI) and amino acid PET to improve the detection of tumor tissue. Methods: In 30 untreated patients with suspected glioma, O -(2-[ 18 F]fluoroethyl)-l-tyrosine ( 18 F-FET) PET; 3-T MRSI with a short echo time; and fluid-attenuated inversion recovery, T2-weighted, and contrast-enhanced T1-weighted MRI were performed for stereotactic biopsy planning. Serial samples were taken along the needle trajectory, and their masks were projected to the preoperative imaging data. Each sample was individually evaluated neuropathologically. 18 F-FET uptake and the MRSI signals choline (Cho), N -acetyl-aspartate (NAA), creatine, myoinositol, and derived ratios were evaluated for each sample and classified using logistic regression. The diagnostic accuracy was evaluated by receiver operating characteristic analysis. Results: On the basis of the neuropathologic evaluation of tissue from 88 stereotactic biopsies, supplemented with 18 F-FET PET and MRSI metrics from 20 areas on the healthy-appearing contralateral hemisphere to balance the glioma/nonglioma groups, 18 F-FET PET identified glioma with the highest accuracy (area under the receiver operating characteristic curve, 0.89; 95% CI, 0.81-0.93; threshold, 1.4 × background uptake). Among the MR spectroscopic metabolites, Cho/NAA normalized to normal brain tissue showed the highest diagnostic accuracy (area under the receiver operating characteristic curve, 0.81; 95% CI, 0.71-0.88; threshold, 2.2). The combination of 18 F-FET PET and normalized Cho/NAA did not improve the diagnostic performance. Conclusion: MRI-based delineation of gliomas should preferably be supplemented by 18 F-FET PET., (© 2024 by the Society of Nuclear Medicine and Molecular Imaging.)

Susceptibility-weighted imaging (SWI) is a magnetic resonance imaging (MRI) technique able to depict the magnetic susceptibility produced by different substances, such as deoxyhemoglobin, calcium, and iron. The main application of SWI in clinical neuroimaging is detecting microbleedings and venous vasculature. Quantitative analyses of SWI have been developed over the last few years, aimed to offer new parameters, which could be used as neuroimaging biomarkers. Each technique has shown pros and cons, but no gold standard exists yet. The fractal dimension (FD) has been investigated as a novel potential objective parameter for monitoring intratumoral space-filling properties of SWI patterns. We showed that SWI patterns found in different tumors or different glioma grades can be represented by a gradient in the fractal dimension, thereby enabling each tumor to be assigned a specific SWI fingerprint. Such results were especially relevant in the differentiation of low-grade versus high-grade gliomas, as well as from high-grade gliomas versus lymphomas.Therefore, FD has been suggested as a potential image biomarker to analyze intrinsic neoplastic architecture in order to improve the differential diagnosis within clinical neuroimaging, determine appropriate therapy, and improve outcome in patients.These promising preliminary findings could be extended into the field of neurotraumatology, by means of the application of computational fractal-based analysis for the qualitative and quantitative imaging of microbleedings in traumatic brain injury patients. In consideration of some evidences showing that SWI signals are correlated with trauma clinical severity, FD might offer some objective prognostic biomarkers.In conclusion, fractal-based morphometrics of SWI could be further investigated to be used in a complementary way with other techniques, in order to form a holistic understanding of the temporal evolution of brain tumors and follow-up response to treatment, with several further applications in other fields, such as neurotraumatology and cerebrovascular neurosurgery as well., (© 2024. The Author(s), under exclusive license to Springer Nature Switzerland AG.)

Objective: To study 11C-methionine (MET) metabolism in gliomas using CNS tumor biobank imaging data., Material and Methods: MRI and 11C-MET PET/CT were performed in 225 patients (49±14 years, M/F=84/101) according to standard protocols with analysis of 11C-MET accumulation index and volumetric parameters (V&#95;FLAIR, V&#95;PET and V&#95;PET/FLAIR). These results were compared with molecular genetic testing and 2-year overall survival., Results: We examined 225 patients with gliomas (97 glioblastomas, 70 astrocytomas, 58 oligodendrogliomas). Accumulation index and volume of 11C-MET in glioblastomas were significantly higher in the general group (AI=2.90, Se 69%, Sp 76%, AUC 0.76; V&#95;PET=24.3 cm 3 , Se 67%, Sp 60%, AUC 0.65; V&#95;PET/FLAIR 0.46, Se 60%, Sp 69%, AUC 0.67) and within the group of astrocytomas (AI=2.93, Se 68%, Sp 89%, AUC 0.84; V&#95;PET=8.06 cm 3 , Se 91%, Sp 35%, AUC 0.66; V&#95;PET/FLAIR 0.27, Se 77%, Sp 60%, AUC 0.71). The median 2-year overall survival in patients with glioblastomas was 13 months that was significantly lower compared to IDH «+» gliomas ( p <0.0001). There was a relationship between high accumulation index of 11C-MET and shorter overall survival in patients with glioblastomas. Significantly higher AI >3.59 (Se 89%, Sp 67%, AUC 0.79) was additionally obtained in subgroup of patients with glioblastomas >50 years ( n =34) for EGFR «+» tumors., Conclusion: We found variable 11C-MET metabolism in WHO 2021 gliomas and confirmed significant difference in metabolic activity and volume of 11C-MET accumulation in glioblastomas compared to IDH «+» gliomas. Moreover, we revealed the relationship between high accumulation index and shorter survival. Analysis of 11C-MET metabolism in patients over 50 years old revealed higher accumulation index in the EGFR «+» group. Further comparison of these imaging methods and assessment of other significant mutations are necessary to identify the anatomical and metabolic patterns of IDH «+» gliomas.

Background: Drug-resistant epilepsy is a common condition in patients with brain neoplasms. The pathogenesis of tumor-associated seizures is poorly understood. Among the possible pathogenetic mechanisms, the increase in glutamate concentration has been proposed. Glutamate transporters, glutamine synthetase and pyruvate carboxylase are involved in maintaining the physiological concentration of glutamate in the intersynaptic spaces. In our previous research on angiocentric gliomas, we demonstrated that all tumors lacked the expression of the main glutamate transporter EAAT2, while the expression of glutamine synthetase and pyruvate carboxylase was mostly preserved., Methods: In the present study, we evaluated the immunohistochemical expression of EAAT2, glutamine synthetase and pyruvate carboxylase in a heterogeneous series of 25 long-term epilepsy-associated tumors (10 dysembryoplastic neuroepithelial tumors, 7 gangliogliomas, 3 subependymal giant cell astrocytomas, 3 rosette forming glioneuronal tumors, 1 diffuse astrocytoma MYB- or MYBL1-altered and 1 angiocentric glioma). In order to evaluate the incidence of variants in the SLC1A2 gene, encoding EAAT2, in a large number of central nervous system tumors we also queried the PedcBioPortal., Results: EAAT2 protein expression was lost in 9 tumors (36 %: 3 dysembryoplastic neuroepithelial tumors, 1 ganglioglioma, 3 subependymal giant cell astrocytomas, 1 diffuse astrocytoma MYB- or MYBL1-altered and 1 angiocentric glioma). Glutamine synthetase protein expression was completely lost in 2 tumors (8 %; 1 ganglioglioma and 1 diffuse astrocytoma MYB- or MYBL1-altered). All tumors of our series but rosette forming glioneuronal tumors (in which neurocytic cells were negative) were diffusely positive for pyruvate carboxylase. Consultation of the PedcBioPortal revealed that of 2307 pediatric brain tumors of different histotype and grade, 20 (< 1%) had variants in the SLC1A2 gene. Among the SLC1A2-mutated tumors, there were no angiocentric gliomas or other LEATs CONCLUSIONS: In conclusion, unlike angiocentric gliomas where the EAAT2 loss is typical and constant, the current study shows the loss of EAAT2 expression only in a fraction of the LEATs. In these cases, we may hypothesize some possible epileptogenic role of the EAAT2 loss. The retained expression of pyruvate carboxylase may contribute to determining a pathological glutamate excess unopposed by glutamine synthetase that resulted expressed to a variable extent in the majority of the tumors. Furthermore, we can assume that the EAAT2 loss in brain tumors in general and in LEATs in particular is more conceivably epigenetic., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Background: The significant progress of immune therapy in non-central nervous system tumors has sparked interest in employing the same strategy for adult brain tumors. However, the advancement of immunotherapy in pediatric central nervous system (CNS) tumors is not yet on par. Currently, there is a lack of comprehensive comparative studies investigating the immune ecosystem in pediatric and adult CNS tumors at a high-resolution single-cell level., Methods: In this study, we comprehensively analyzed over 0.3 million cells from 171 samples, encompassing adult gliomas (IDH wild type and IDH mutation) as well as four major types of pediatric brain tumors (medulloblastoma (MB), ependymoma (EPN), H3K27M-mutation (DIPG), and pediatric IDH-mutation glioma (P-IDH-M)). Our approach involved integrating publicly available and newly generated single-cell datasets. We compared the immune landscapes in different brain tumors, as well as the detailed functional phenotypes of T-cell and myeloid subpopulations. Through single-cell analysis, we identified gene sets associated with major cell types in the tumor microenvironment (gene features from single-cell data, scFes) and compared them with existing gene sets such as GSEA and xCell. The CBTTC and external GEO cohort was used to analyze and validate the immune-stromal-tumor patterns in pediatric brain tumors which might potentially respond to the immunotherapy., Results: From the perspective of single-cell analysis, it was observed that major pediatric brain tumors (MB, EPN, P-IDH-M, DIPG) exhibited lower immune contents compared with adult gliomas. Additionally, these pediatric brain tumors displayed diverse immunophenotypes, particularly in regard to myeloid cells. Notably, the presence of HLA-enriched myeloid cells in MB was found to be independently associated with prognosis. Moreover, the scFes, when compared with commonly used gene features, demonstrated superior performance in independent single-cell datasets across various tumor types. Furthermore, our study revealed the existence of heterogeneous immune ecosystems at the bulk-RNA sequencing level among different brain tumor types. In addition, we identified several immune-stromal-tumor patterns that could potentially exhibit significant responses to conventional immune checkpoint inhibitors., Conclusion: The single-cell technique provides a rational path to deeply understand the unique immune ecosystem of pediatric brain tumors. In spite of the traditional attitudes of "cold" tumor towards pediatric brain tumor, the immune-stroma-tumor patterns identified in this study suggest the feasibility of immune checkpoint inhibitors and pave the way for the upcoming tide of immunotherapy in pediatric brain tumors., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The reviewer XD declared a past co-authorship with the author JM to the handling editor., (Copyright © 2023 Cao, Xie, Ma, Zhao, Wang, Liang, Tian, Wang and Ma.)

The median survival time has been reported to vary between 5 and 8 years in low-grade (WHO grade 2) astrocytoma, and between 10 and 15 years for grade 2 oligodendroglioma. Targeted alpha therapy (TAT), using the modified peptide vector [ 213 Bi]Bi/[ 225 Ac]Ac-DOTA-substance P, has been developed to treat glioblastoma (GBM), a prevalent malignant brain tumor. In order to assess the risk of late neurotoxicity, assuming that reduced tumor cell proliferation and invasion should directly translate into good responses in low-grade gliomas (LGGs), a limited number of patients with diffuse invasive astrocytoma (n = 8) and oligodendroglioma (n = 3) were offered TAT. In two oligodendroglioma patients, TAT was applied as a second-line treatment for tumor progression, 10 years after targeted beta therapy using [ 90 Y]Y-DOTA-substance P. The radiopharmaceutical was locally injected directly into the tumor via a stereotactic insertion of a capsule-catheter system. The activity used for radiolabeling was 2-2.5 GBq of Bismuth-213 and 17 to 35 MBq of Actinium-225, mostly applied in a single fraction. The recurrence-free survival times were in the range of 2 to 16 years (median 11 years) in low-grade astrocytoma (n = 8), in which TAT was administered following a biopsy or tumor debulking. Regarding oligodendroglioma, the recurrence-free survival time was 24 years in the first case treated, and 4 and 5 years in the two second-line cases. In conclusion, TAT leads to long-term tumor control in the majority of patients with LGG, and recurrence has so far not manifested in patients with low-grade (grade 2) astrocytomas who received TAT as a first-line therapy. We conclude that targeted alpha therapy has the potential to become a new treatment paradigm in LGG.

Objective: Intravenous sodium fluorescein (SF) is increasingly used during surgery of gliomas and brain metastases to improve tumor resection. Currently, SF is believed to permeate the brain regions where the blood-brain barrier (BBB) is damaged and to accumulate in the extracellular space but not in tumor or healthy cells, making it possible to demarcate tumor margins to guide resection. By evaluating the immune contexture of a number of freshly resected gliomas and brain metastases from patients undergoing SF-guided surgery, the authors recurrently observed fluorescence-positive cells. Therefore, the aim of this study was to determine if SF accumulates inside the cells of the tumor microenvironment (TME), and if so, in which type of cells, and whether incorporation can also be observed in the leukocytes of peripheral blood., Methods: Freshly resected tumor specimens were dissociated to single cells and analyzed by multiparametric flow cytometry. Peripheral blood leukocytes, macrophages, and a glioma cell line were treated with SF in vitro, and their cell uptake was assessed by multiparametric and imaging flow cytometry and by confocal microscopy., Results: The ex vivo and in vitro analyses revealed that SF accumulates intracellularly in leukocytes as well as in tumor cells, but with a high variability of incorporation in the different cell subsets analyzed. Myeloid cells showed the highest level of fluorescence. In vitro uptake experiments showed that SF accumulation increases over time. The imaging analyses confirmed the internalization of the compound inside the cells., Conclusions: SF is not just a marker of BBB damage, but its intracellular detection suggests that it selectively accumulates intracellularly. Future efforts should target the mechanisms of its differential uptake by the different TME cell types in depth.

Extensive research efforts in the field of brain tumor studies have led to the reclassification of tumors by the World Health Organization (WHO) and the identification of various molecular subtypes, aimed at enhancing diagnosis and treatment strategies. However, the quest for biomarkers that can provide a deeper understanding of tumor development mechanisms, particularly in the case of gliomas, remains imperative due to their persistently incurable nature. Oxidative stress has been widely recognized as a key mechanism contributing to the formation and progression of malignant tumors, with imbalances in antioxidant defense systems being one of the underlying causes for the excess production of reactive oxygen species (ROS) implicated in tumor initiation. In this study, we investigated the gene expression patterns of the eight known isoforms of glutathione peroxidase (GPx) in brain tissue obtained from male and female control rats, as well as rats with transplacental ethyl nitrosourea (ENU)-induced brain tumors. Employing the delta-delta Ct method for RT-PCR, we observed minimal expression levels of gpx2 , gpx5 , gpx6 , and gpx7 in the brain tissue from the healthy control animals, while gpx3 and gpx8 exhibited moderate expression levels. Notably, gpx1 and gpx4 displayed the highest expression levels. Gender differences were not observed in the expression profiles of these isoforms in the control animals. Conversely, the tumor tissue exhibited elevated relative expression levels in all isoforms, except for gpx4 , which remained unchanged, and gpx5 , which exhibited alterations solely in female animals. Moreover, except for gpx1 , which displayed no gender differences, the relative expression values of gpx2 , gpx3 , gpx6 , gpx7 , and gpx8 were significantly higher in the male animals compared to their female counterparts. Hence, the analysis of glutathione peroxidase isoforms may serve as a valuable approach for discerning the behavior of brain tumors in clinical settings.

Brain tumors have been proved challenging to treat. Here we established a Multi-Target Neural Differentiation (MTND) therapeutic cocktail to achieve effective and safe treatment of brain malignancies by targeting the important hallmarks in brain cancers: poor cell differentiation and compromised cell cycle. In-vitro and in-vivo experiments confirmed the significant therapeutic effect of our MTND therapy. Significantly improved therapeutic effects over current first-line chemo-drugs have been identified in clinical cells, with great inhibition of the growth and migration of tumor cells. Further in-vivo experiments confirmed that sustained MTND treatment showed a 73% reduction of the tumor area. MTND also induced strong expression of phenotypes associated with cell cycle exit/arrest and rapid neural reprograming from clinical glioma cells to glutamatergic and GABAergic expressing cells, which are two key neuronal types involved in many human brain functions, including learning and memory. Collectively, MTND induced multi-targeted genotypic expression changes to achieve direct neural conversion of glioma cells and controlled the cell cycle/tumorigenesis development, helping control tumor cells' malignant proliferation and making it possible to treat brain malignant tumors effectively and safely. These encouraging results open avenues to developing new therapies for brain malignancies beyond cytotoxic agents, providing more effective medication recommendations with reduced toxicity.

In recent years, research on brain cancers has turned towards the study of the interplay between the tumor and its host, the normal brain. Starting from the establishment of a parallelism between neurogenesis and gliomagenesis, the influence of neuronal activity on the development of brain tumors, particularly gliomas, has been partially unveiled. Notably, direct electrochemical synapses between neurons and glioma cells have been identified, paving the way for new approaches for the cure of brain cancers. Since this novel field of study has been defined "cancer neuroscience", anticancer therapeutic approaches exploiting these discoveries can be referred to as "cancer neuromodulation". In the present review, we provide an up-to-date description of the novel findings and of the therapeutic neuromodulation perspectives in cancer neuroscience. We focus both on more traditional oncologic approaches, aimed at modulating the major pathways involved in cancer neuroscience through drugs or genetic engineering techniques, and on electric stimulation proposals; the latter is at the cutting-edge of neuro-oncology.

Background: In 2017, the European Association for Neuro-Oncology (EANO) published the guideline for palliative care (PC) in adults with glioma. The Italian Society of Neurology (SIN), the Italian Association for Neuro-Oncology (AINO), and the Italian Society for Palliative Care (SICP) joined forces to update and adapt this guideline to the Italian context and aimed to involve patients and carers in the formulation of the clinical questions., Methods: During semi-structured interviews with glioma patients and focus group meetings (FGMs) with family carers of deceased patients, participants rated the importance of a set of pre-specified intervention topics, shared their experience, and suggested additional topics. Interviews and FGMs were audio-recorded, transcribed, coded, and analyzed (framework and content analysis)., Results: We held 20 interviews and five FGMs (28 carers). Both parties considered the pre-specified topics as important, chiefly information/communication, psychological support, symptoms management, and rehabilitation. Patients aired the impact of focal neurological and cognitive deficits. Carers reported difficulties in dealing with patient's behavior and personality changes and appreciated the preservation of patient's functioning via rehabilitation. Both affirmed the importance of a dedicated healthcare path and patient's involvement in the decision-making process. Carers expressed the need to be educated and supported in their caregiving role., Conclusions: Interviews and FGMs were well informative and emotionally challenging. Both parties confirmed the importance of the pre-specified topics, and carers suggested one additional topic: education/support to caregivers. Our findings strengthen the importance of a comprehensive care approach and of addressing the needs of both patients and their family carers., (© 2023. Fondazione Società Italiana di Neurologia.)

Purpose of Review: The article gives an overview of the current knowledge in the management of tumor related epilepsy, including systematic reviews and consensus statements as well as recent insight into a potentially more individualized treatment approach., Recent Findings: Tumor molecular markers as IDH1 mutation and MGMT methylation status may provide future treatment targets. Seizure control should be included as a metric in assessing efficacy of tumor treatment. Prophylactic treatment is recommended in all brain tumor patients after the first seizure. Epilepsy has a profound effect on the quality of life in this patient group. The clinician should tailor the choice of seizure prophylactic treatment to the individual patient, with the goal of limiting adverse effects, avoiding interactions and obtaining a high degree of seizure freedom. Status epilepticus is associated with inferior survival and must be treated promptly. A multidisciplinary team should treat patients with brain tumors and epilepsy., (© 2023. The Author(s).)

Exosomes constitute small extracellular vesicles that contain lipids, proteins, nucleic acids, and glycoconjugates from the secreted cells and are capable of transmitting signals between cells and coordinating cellular communication. By this means, they are ultimately involved in physiology and disease, including development, homeostasis, and immune system regulation, as well as contributing to tumor progression and neurodegenerative diseases pathology. Recent studies have shown that gliomas secrete a panel of exosomes which have been associated with cell invasion and migration, tumor immune tolerance, potential for malignant transformation, neovascularization, and resistance to treatment. Exosomes have therefore emerged as intercellular communicators, which mediate the tumor-microenvironment interactions and exosome-regulated glioma cell stemness and angiogenesis. They may induce tumor proliferation and malignancy in normal cells by carrying pro-migratory modulators from cancer cells as well as many different molecular cancer modifiers, such as oncogenic transcripts, miRNAs, mutant oncoproteins, etc., which promote the communication of cancer cells with the surrounding stromal cells and provide valuable information on the molecular profile of the existing tumor. Moreover, engineered exosomes can provide an alternative system for drug delivery and enable efficient treatment. In the present review, we discuss the latest findings regarding the role of exosomes in glioma pathogenesis, their utility in non-invasive diagnosis, and potential applications to treatment.

Solute carriers (SLCs) are essential for brain physiology and homeostasis due to their role in transporting necessary substances across cell membranes. There is an increasing need to further unravel their pathophysiological implications since they have been proposed to play a pivotal role in brain tumor development, progression, and the formation of the tumor microenvironment (TME) through the upregulation and downregulation of various amino acid transporters. Due to their implication in malignancy and tumor progression, SLCs are currently positioned at the center of novel pharmacological targeting strategies and drug development. In this review, we discuss the key structural and functional characteristics of the main SLC family members involved in glioma pathogenesis, along with their potential targeting options to provide new opportunities for CNS drug design and more effective glioma management.

Type I interferons have long been appreciated as a cytokine family that regulates antiviral immunity. Recently, their role in eliciting antitumor immune responses has gained increasing attention. Within the immunosuppressive tumor microenvironment (TME), interferons stimulate tumor-infiltrating lymphocytes to promote immune clearance and essentially reshape a "cold" TME into an immune-activating "hot" TME. In this review, we focus on gliomas, with an emphasis on malignant glioblastoma, as these brain tumors possess a highly invasive and heterogenous brain TME. We address how type I interferons regulate antitumor immune responses against malignant gliomas and reshape the overall immune landscape of the brain TME. Furthermore, we discuss how these findings can translate into future immunotherapies targeting brain tumors in general., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Lim, Kang, La, Ku, Kang, Kim, Park and Lee.)

Phospholipases are essential intermediaries that work as hydrolyzing enzymes of phospholipids (PLs), which represent the most abundant species contributing to the biological membranes of nervous cells of the healthy human brain. They generate different lipid mediators, such as diacylglycerol, phosphatidic acid, lysophosphatidic acid, and arachidonic acid, representing key elements of intra- and inter-cellular signaling and being involved in the regulation of several cellular mechanisms that can promote tumor progression and aggressiveness. In this review, it is summarized the current knowledge about the role of phospholipases in brain tumor progression, focusing on low- and high-grade gliomas, representing promising prognostic or therapeutic targets in cancer therapies due to their influential roles in cell proliferation, migration, growth, and survival. A deeper understanding of the phospholipases-related signaling pathways could be necessary to pave the way for new targeted therapeutic strategies.

Background: In 2017, the European Association of Neuro-Oncology (EANO) published the guideline for palliative care in adults with glioma. The Italian Society of Neurology (SIN), the Italian Society for Palliative Care (SICP), and the Italian Association for Neuro-Oncology (AINO) joined forces to update the guideline, and adapt it to the Italian context., Aim: We involved patients, caregivers, and (herein presented) healthcare professionals (HPs) in the formulation of the guideline clinical questions., Design and Participants: Online survey of Italian HPs experienced in the care of patients with glioma. Participants rated the importance of 14 pre-specified intervention topics on a 0/10 scale and gave their free comments., Results: Of 244 participants, 149 (61%) were palliative medicine (PM) HPs and 95 Neuro HPs. Their mean age was 48.9 years, 63% were women, and 48% had over 12 years of experience in the care of glioma patients. Physicians were 68%, followed by nurses (28%), psychologists (7%), therapists (3%), and social workers (2%). Most HPs rated the pre-specified topics as important (score ≥ 7) or critical (score ≥ 9), with some differences between PM and Neuro HP groups. There were 58 free comments: 46 (78%) on nine pre-specified topics, and 13 on four new topics, three of which were guideline-pertinent ("caregiver's support and education"; "family physician's training in neuro-oncology"; and "PM HPs' training in neuro-oncology")., Conclusions: Participation in the survey was high and information-rich, between-group rating differences reflecting HP background. Participants endorsed the 14 intervention topics devised by the guideline panel and identified three additional topics., (© 2023. Fondazione Società Italiana di Neurologia.)

Background: Two fundamental challenges in the current therapeutic approach for central nervous system tumors are the tumor heterogeneity and the absence of specific treatments and biomarkers that selectively target the tumor tissue. Therefore, we aimed to investigate the potential relationship between discoidin domain receptor 1 (DDR1) expression and the prognosis and characteristics of glioma patients., Materials and Methods: Tissue and serum samples from 34 brain tumor patients were evaluated for DDR1 messenger ribonucleic acid levels in comparison to 10 samples from the control group, and Kaplan-Meier survival analysis has performed., Results: DDR1 expression was observed in both tissue and serum samples of the patient and control groups. DDR1 expression levels in tissue and serum samples from patients were higher in comparison to the control group, although not statistically significant (P > 0.05). A significant correlation between tumor size and DDR1 serum measurements at the level of 0.370 was reported (r = 0.370; P = 0.034). The levels of DDR1 in serum showed a positive correlation with the increasing size of tumor. The results of the 5-year survival analysis depending on the DDR1 tissue levels showed a significantly higher survival rate (P = 0.041) for patients who have DDR1 tissue levels above cutoff value., Conclusions: DDR1 expression was significantly higher among brain tumor tissues and serum samples and its levels showed a positive correlation with the increased size of tumor. This study can be a starting point, since it investigated and indicated, for the first time, that DDR1 can be a novel therapeutic and prognostic target for aggressive high-grade gliomas., Competing Interests: None

Purpose: Primary malignant brain and other central nervous system tumors are rare cancers that have shown rising mortality rates in recent years. To elucidate potential factors involved in this rising death rate, we examined mortality trends for primary malignant BT in the United States stratified by histopathology groupings, age, race, and sex., Methods: Mortality rates for demographic factors within primary malignant BT were generated using the National Center for Health Statistics' National Vital Statistics Systems data from 2004 to 2018. Additionally, histopathology-specific incidence-based mortality rates were calculated using the National Cancer Institute's Surveillance, Epidemiology, and End-Results (SEER) 18 data from 2004 to 2018. Joinpoint modeling was used to estimate mortality trends and annual percent changes with corresponding 95% confidence intervals., Results: Overall, there was a very small increase in mortality from 2004 to 2018. Individuals > 65 years saw a small increase in mortality, while changes in individuals of other ages were non-significant. Asian/Pacific Islander or American Indian/Alaskan Native had the largest increase in mortality. Among histopathology groupings, there was a small mortality increase in adults ages > 65 years with glioblastoma, while the mortality rate of other malignant gliomas declined in the same age group. CNS lymphoma mortality rates in patients ages 15-39 and 40-64 years declined significantly while rising significantly in the > 65 age group. In pediatric patients, embryonal tumor mortality had a non-significant increase between 2004 and 2007 but declined significantly between 2007 and 2018., Conclusion: Examining age, race, sex, and histopathology-specific mortality trends at the population level can provide important information for clinicians, researchers, and aid in public health planning., (© 2023. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)

In 2021, the World Health Organization (WHO) Classification of Tumors of the Central Nervous System (CNS) underwent significant restructuring to incorporate additional molecular diagnostics, several newly recognized tumor types, and new grading schemes for existing tumor types. The 2021 CNS WHO classification further elaborates and integrates histopathologic and molecular diagnostic criteria to improve diagnostic classification. Furthermore, it is the hope that identification of molecular alterations in pediatric and adult tumors facilitates improved prognostic information and development of novel targeted therapies for adults and children with CNS tumors. In one of the largest changes in the new WHO classification, diffuse gliomas are divided into pediatric-type and adult-type gliomas to highlight our expanding knowledge of their different molecular drivers and prognostic associations. Several new pediatric-type diffuse low-grade gliomas are defined including (I) diffuse astrocytoma, MYB- or MYBL1-altered, (II) polymorphous low-grade neuroepithelial tumor of the young (PLNTY), and (III) diffuse low-grade glioma, MAPK-pathway altered. In addition, several new pediatric-type diffuse high-grade gliomas are recognized including (I) diffuse hemispheric glioma, H3 G34R-mutant (II) diffuse pediatric-type high-grade glioma, H3-wildtype and IDH-wildtype, and (III) infant-type hemispheric glioma. These new tumor types have associated clinical, genetic and epigenetic features that are distinct from adult-type diffuse gliomas. This review provides an overview of updates in the 2021 CNS WHO classification specific to diffuse gliomas, with a particular focus on the histopathology and molecular findings of the newly described pediatric-type low-grade and high-grade gliomas.

Background: Gliomas are the most aggressive form of brain tumors responsible for the majority of brain cancer related deaths. Interleukin (IL)-6, 10 and tumor necrosis factor (TNF)- α are tumor specific proteins that are expressed in gliomas. This study aims to estimate the pre- and postoperative levels of serum markers of these cytokines to evaluate any bearing with its grade and volume., Methods: Prospective analysis of 80 patients of newly-diagnosed gliomas of any grade was carried out. Pre- and postoperative blood samples day one, one month and at 3rd month of surgery was taken and levels of IL-6, 10 and TNF- α measured and matched with 20 healthy controls., Results: Of the 80 patients, 3 patients had pilocytic astrocytoma, 4 had ganglioglioma, 9 had oligodendroglioma, 17 had diffuse astrocytoma, 5 had anaplastic astrocytoma while 43 had glioblastoma. Preoperative levels of IL-6 and TNF- α was found to be markedly raised in high grade gliomas. Positive correlation was seen between IL-6 with the grade of tumor and high-grade tumors were seen to be more significantly correlated with IL-6. However, preoperative IL-10 in both low and high grade of gliomas did not show any correlation with the volume and grade of tumor., Conclusion: High level of IL-6 and TNF-α in peripheral blood in patients of high-grade gliomas provides clue to the invasiveness of the disease which can be useful for understanding the premorbid development of tumor and perhaps extrapolating to ongoing tumor response to treatment.

Brain tumors are among the 10 leading causes of cancer-related death and present unique treatment challenges due to their critical location, genetic heterogeneity, and the blood-brain barrier. Recent advances in targeted immunotherapy and immune checkpoint blocking therapy provide alternative therapeutic strategies for brain tumors. Fibrinogen-like protein 2 (FGL2), which induces transformation from low-grade glioma to high-grade glioblastoma, is a type II membrane protein that is highly expressed in both host immune cells and tumor cells. Studies have uncovered multiple forms of FGL2 proteins with a broad range of roles in inducing immune tolerance and avoiding immune surveillance in tumor cells. Of note, presence of FGL2 transforms low grade to high grade brain tumors via promoting Treg, macrophages, and perhaps stemness. Absence (knockout) of FGL2 in tumor cells (not in host cells) induces CD103 DC cells, which triggers tumor specific CD8 +T cell activity to reject brain tumor progression. Immunotherapies targeting FGL2 have shown great promise in improving survival time in murine models. In this article, we will summarize the biological function of FGL2 in immune and tumor cells., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Background: Awake brain mapping in multilingual patients with brain tumors presents unique challenges to the neurosurgeon. Knowledge of potential eloquent sites is vital to preserve language function., Methods: We present two cases of pars opercularis glioma and perform a systematic review in accordance with PRISMA guidelines., Results: Our review yielded 7 studies, with a total of 25 multilingual brain tumor patients who underwent awake brain mapping. The age ranged from 25 to 62 years. Majority were female (56.5%). Most (52%) were trilingual, while 20% were quadrilingual and 28% were pentalingual. All tumors were left-sided, mostly in the frontal lobe. These were predominantly gliomas. Extent of resection was gross total in 61%. The brain mapping findings were heterogeneous. Some authors reported a greater number of cortical sites for the first language compared to others. Others found that the first and second languages shared cortical sites whereas the third and subsequent languages were located in distant sites. The peri-Sylvian area was also found to be involved in language that was learned at an earlier age. Subsequent languages thus involved more distant sites. A larger number of cortical areas were also activated for languages that were learned later in life. In terms of language disturbance and recovery, there were mixed results., Conclusion: Cortical mapping in multilingual brain tumor patients showed heterogeneity in terms of the location and number of language areas in the face of pathology. These findings may influence neurosurgical and oncological management of tumors in the speech area but emphasize the need to tailor surgical approaches and intraoperative testing to the patient., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Introduction: Adult-type diffuse gliomas are malignant primary brain tumors characterized by very poor prognosis. Dendritic cells (DCs) are key in priming antitumor effector functions in cancer, but their role in gliomas remains poorly understood., Methods: In this study, we characterized tumor-infiltrating DCs (TIDCs) in adult patients with newly diagnosed diffuse gliomas by using multi-parametric flow cytometry and single-cell RNA sequencing., Results: We demonstrated that different subsets of DCs are present in the glioma microenvironment, whereas they are absent in cancer-free brain parenchyma. The largest cluster of TIDCs was characterized by a transcriptomic profile suggestive of severe functional impairment. Patients undergoing perioperative corticosteroid treatment showed a significant reduction of conventional DC1s, the DC subset with key functions in antitumor immunity. They also showed phenotypic and transcriptional evidence of a more severe functional impairment of TIDCs., Discussion: Overall, the results of this study indicate that functionally impaired DCs are recruited in the glioma microenvironment. They are severely affected by dexamethasone administration, suggesting that the detrimental effects of corticosteroids on DCs may represent one of the mechanisms contributing to the already reported negative prognostic impact of steroids on glioma patient survival., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Carenza, Franzese, Castagna, Terzoli, Simonelli, Persico, Bello, Nibali, Pessina, Kunderfranco, Peano, Balin, Mikulak, Calcaterra, Bonecchi, Savino, Locati, Della Bella and Mavilio.)

High-grade gliomas (HGGs) are the most common and aggressive primary brain tumors in both adult and pediatric populations. Despite the multimodal treatment modality currently available for HGG, the prognosis is dismal, with a low overall survival rate at two years after diagnosis. In the last decade, oncolytic virotherapy has emerged as a promising and feasible therapeutic tool in management of these tumors due to its oncolytic and immunostimulatory properties. Various oncolytic viruses, such as herpes simplex virus, adenovirus, poliovirus, reovirus, parvovirus and others, have been evaluated in the early stages of the clinical setting with regard to improving the outcome of patients with HGG. In this review, we summarize completed and ongoing clinical trials of oncolytic virotherapy for adult and pediatric malignant gliomas in terms of safety and efficacy, followed by a brief discussion about the current status and future directions of this therapy in the brain tumor field., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Background: Myocardial infarction-associated transcript (MIAT) is a long non-coding RNA (lncRNA) with altered expression in different diseases and malignancies. In this study, the potential expression and function of lncRNA MIAT in intuition and progression of brain cancer was investigated., Methods and Results: At first, TCGA data analysis demonstrated that lncRNA MIAT is significantly upregulated in various malignancies, especially its expression is dramatically elevated in brain tumors. In line with the data, we further evaluated the expression of MIAT in a series of brain tumor tissue, and our results revealed that the expression of MIAT was noticeably overexpressed in glioblastoma (p = < 0.0001). We further found that the expression of MIAT was markedly upregulated in low-grade brain tumors rather than high-grade ones. To further investigate the biological function of MIAT in brain cancer cells, its expression was suppressed by si-RNA-mediated knocking down. Inhibition of MIAT resulted in reduced proliferation of brain tumor cells followed by cell cycle arrest at the G1 phase, and significant induction of apoptosis, and senescence, but limited the migration ability and epithelial-mesenchymal-transition (EMT). Moreover, knocking-down of MIAT reduced the expression of stemness factors, followed by upregulation of their downstream miRNAs (micro RNAs), let-7a-5p, and miR-29b-3p., Conclusions: Altogether, our data demonstrated that lncRNA MIAT could control proliferation, migration, and metastasis of brain cancer cells via regulating the Nanog/ Sox2 / let-7a-5p / miR-29b-3p axis. This data could introduce lncRNA MIAT as a novel oncogene in brain cancer pathogenesis., (© 2022. The Author(s), under exclusive licence to Springer Nature B.V.)

The antithesis between childhood cancer survival rates in low- and middle-income countries (LMIC) and high-income countries (HIC) represents one of healthcare's most significant disparities. In HICs, the 5-year survival rate for children with cancer, including most brain tumors, exceeds 80%. Unfortunately, children in LMICs experience far worse outcomes with 5-year survival rates as low as 20%. To address inequities in the treatment of childhood cancer and disease burden globally, the World Health Organization (WHO) launched the Global Initiative for Childhood Cancer. Within this initiative, pediatric low-grade glioma (LGG) represents a unique opportunity for the neurosurgical community to directly contribute to a paradigm shift in the survival outcomes of children in LMICs, as many of these tumors can be managed with surgical resection alone. In this chapter, we discuss the burden of pediatric LGG and outline actions the neurosurgical community might consider to improve survival for children with LGG in LMICs., (© 2023. The Author(s), under exclusive license to Springer Nature Switzerland AG.)

Purpose: This review article discusses the studies concerning advances in radiotherapy of high-grade gliomas published in the second half of 2021., Methods: A literature search was performed in PubMed using the terms ("gliom* and radio*") and time limits 1 July 2021-31 December 2021. The articles were then manually selected for relevance to the analyzed topics., Results: Considerable progress has been made in the preclinical field on the mechanisms of radioresistance and radiosensitization of high-grade gliomas (HGG). However, fewer early-phase (I/II) clinical trials have been performed and, of the latter, even fewer have produced results that justify moving to phase III. In the 6‑month period under consideration, no studies were published that would lead to a change in clinical practice and the overall survival (OS) of patients remained similar to that of 2005, the year in which it increased significantly for the last time thanks to introduction of the alkylating agent temozolomide., Conclusion: After 17 years of stalemate in improving the OS of patients with HGG, an in-depth analysis of the causes should be carried out in order to identify whether the research efforts conducted so far, including in the radiotherapeutic field, have been the most effective or require improvement. In our opinion, in addition to the therapeutic difficulties related to the biology of HGG tumors (e.g., high infiltrating capacity, multiple resistance mechanisms, blood-brain barrier), some public research policy choices may also play a role, especially in consideration of the limited interest of the pharmaceutical industry in the field of rare cancers., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany.)

Background: To date, this is the only report showing with close and consecutive magnetic resonance images the extremely rapid response of two types of pediatric low-grade gliomas (PLGG) to vemurafenib and its impact on the surgical approach., Cases Presentation: We report two cases of symptomatic PLGG treated with vemurafenib, a BRAF inhibitor: in a 12-year-old girl it was used as first-line medical treatment, reducing the tumor by 45% within a month and stabilizing to 76% after a year; in a 3-year-old boy with no improvement after SIOP LGG 2004 Protocol, vemurafenib induced in only one week a 34% shrinkage and solved the hydrocephalus, avoiding surgical operation. DISCUSSION AND CONCLUSIONS: Our cases demonstrate how an early molecular diagnosis of BRAF mutations through the neurosurgical biopsy is essential to promptly start targeted therapies., whose effect can influence both therapeutic and surgical decisions, hopefully reducing the occurrence of second neurosurgery with associated risks of neurological sequelae., (© 2022. The Author(s).)

In 2016, the World Health Organization (WHO) updated the glioma classification by incorporating molecular biology parameters, including low-grade glioma (LGG). In the new scheme, LGGs have three molecular subtypes: isocitrate dehydrogenase (IDH)-mutated 1p/19q-codeleted, IDH-mutated 1p/19q-noncodeleted, and IDH-wild type 1p/19q-noncodeleted entities. This work proposes a model prediction of LGG molecular subtypes using magnetic resonance imaging (MRI). MR images were segmented and converted into radiomics features, thereby providing predictive information about the brain tumor classification. With 726 raw features obtained from the feature extraction procedure, we developed a hybrid machine learning-based radiomics by incorporating a genetic algorithm and eXtreme Gradient Boosting (XGBoost) classifier, to ascertain 12 optimal features for tumor classification. To resolve imbalanced data, the synthetic minority oversampling technique (SMOTE) was applied in our study. The XGBoost algorithm outperformed the other algorithms on the training dataset by an accuracy value of 0.885. We continued evaluating the XGBoost model, then achieved an overall accuracy of 0.6905 for the three-subtype classification of LGGs on an external validation dataset. Our model is among just a few to have resolved the three-subtype LGG classification challenge with high accuracy compared with previous studies performing similar work., (© 2022 John Wiley & Sons Ltd.)

There is an urgent need for drug development in brain tumors. While current radiographic response assessment provides instructions for identifying large treatment effects in simple high- and low-grade gliomas, there remains a void of strategies to evaluate complex or difficult to measure tumors or tumors of mixed grade with enhancing and non-enhancing components. Furthermore, most patients exhibit some period of alteration in tumor growth after starting a new therapy, but simple response categorization (e.g., stable disease, progressive disease) fails to provide any meaningful insight into the depth or degree of potential "subclinical" therapeutic response. We propose a creative solution to these issues based on a tiered strategy meant to increase confidence in identifying therapeutic effects even in the most challenging tumor types, while also providing a framework for complex evaluation of combination and sequential treatment schemes. Specifically, we demonstrate the utility of digital "flipbooks" to quickly identify subtle changes in complex tumors. We show how a modified Levin criteria can be used to quantify the degree of visual changes, while establishing estimates of the association between tumor volume and visual inspection. Lastly, we introduce the concept of quantifying therapeutic response using control systems theory. We propose measuring changes in volume (proportional), the area under the volume vs. time curve (integral) and changes in growth rates (derivative) to utilize a "PID" controller model of single or combination therapeutic activity., (© 2022. The Author(s).)

The nervous system integrates and processes information to act as master regulator of various vital, biological processes. However, increasing data suggest that the nervous system is also a key player in the initiation of cancer and cancer progression. Following the tenet that oncology follows ontogeny, it has been shown that brain tumors follow neural developmental processes. Incurable gliomas form neurite-like membrane tubes called tumor microtubes and are controlled by neurodevelopmental pathways. Tumor microtubes are used for invasion, proliferation and interconnection with other tumor cells, forming a tumor network that is therapeutically resistant. Additionally, neurons can activate tumor cells via glutamatergic synapses to drive tumor invasion and growth. The most recent knowledge of brain cancer neuroscience presented here with a focus on brain tumours has already led to new approaches for antitumour treatment., (© 2022. The Author(s), under exclusive licence to Springer Medizin Verlag GmbH, ein Teil von Springer Nature.)

Background: The age of glioma plays a unique role in prognosis. We hypothesized that age is not positively correlated with survival prognosis and explored its exact relationship., Methods: Glioma was identified from the SEER database (between 2000 and 2018). A multivariate Cox proportional regression model and restricted cubic spline (RCS) plot were used to assess the relationship between age and prognosis., Results: A total of 66465 patients with glioma were included. Hazard ratios (HR) for ten-year by age: 0-9 years, HR 1.06 (0.93-1.20); 10-19 years: reference; 20-29 years, HR 0.90 (0.82-1.00); 30-39 years, HR 1.14 (1.04-1.25); 40-49 years, HR 2.09 (1.91-2.28); 50-59 years, HR 3.48 (3.19-3.79); 60-69 years, HR 4.91 (4.51-5.35);70-79 years, HR 7.95 (7.29-8.66); 80-84 years, HR 12.85 (11.74-14.06). After adjusting for covariates, the prognosis was not positively correlated with age. The smooth curve of RCS revealed this non-linear relationship: HR increased to 10 years first, decreased to 23 years, reached its lowest point, and became J-shaped., Conclusion: The relationship between age and glioma prognosis is non-linear. These results challenge the applicability of current age groupings for gliomas and advocate the consideration of individualized treatment guided by precise age., (© 2022. The Author(s).)

Background: PET with radiolabeled amino acids is used in the preoperative evaluation of patients with glial neoplasms. This study aimed to assess the role of [11C]methionine (MET) PET in assessing molecular features, tumor extent, and prognosis in newly diagnosed lower-grade gliomas (LGGs) surgically treated., Methods: One hundred and fifty-three patients with a new diagnosis of grade 2/3 glioma who underwent surgery at our Institution and were imaged preoperatively using [11C]MET PET/CT were retrospectively included. [11C]MET PET images were qualitatively and semi-quantitatively analyzed using tumor-to-background ratio (TBR). Progression-free survival (PFS) rates were estimated using the Kaplan-Meier method and Cox proportional-hazards regression was used to test the association of clinicopathological and imaging data to PFS., Results: Overall, 111 lesions (73%) were positive, while thirty-two (21%) and ten (6%) were isometabolic and hypometabolic at [11C]MET PET, respectively. [11C]MET uptake was more common in oligodendrogliomas than IDH-mutant astrocytomas (87% vs 50% of cases, respectively). Among [11C]MET-positive gliomas, grade 3 oligodendrogliomas had the highest median TBRmax (3.22). In 25% of patients, PET helped to better delineate tumor margins compared to MRI only. In IDH-mutant astrocytomas, higher TBRmax values at [11C]MET PET were independent predictors of shorter PFS., Conclusions: This work highlights the role of preoperative [11C]MET PET in estimating the type of suspected LGGs, assessing tumor extent, and predicting biological behavior and prognosis of histologically confirmed LGGs. Our findings support the implementation of [11C]MET PET in routine clinical practice to better manage these neoplasms., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Society for Neuro-Oncology.)

Purpose: To investigate the potential of radiomics applied to static clinical PET data using the tracer O-(2-[ 18 F]fluoroethyl)-L-tyrosine (FET) to differentiate treatment-related changes (TRC) from tumor progression (TP) in patients with gliomas., Patients and Methods: One hundred fifty-one (151) patients with histologically confirmed gliomas and post-therapeutic progressive MRI findings according to the response assessment in neuro-oncology criteria underwent a dynamic amino acid PET scan using the tracer O-(2-[ 18 F]fluoroethyl)-L-tyrosine (FET). Thereof, 124 patients were investigated on a stand-alone PET scanner (data used for model development and validation), and 27 patients on a hybrid PET/MRI scanner (data used for model testing). Mean and maximum tumor to brain ratios (TBR mean , TBR max ) were calculated using the PET data from 20 to 40 min after tracer injection. Logistic regression models were evaluated for the FET PET parameters TBR mean , TBR max , and for radiomics features of the tumor areas as well as combinations thereof to differentiate between TP and TRC. The best performing models in the validation dataset were finally applied to the test dataset. The diagnostic performance was assessed by receiver operating characteristic analysis., Results: Thirty-seven patients (25%) were diagnosed with TRC, and 114 (75%) with TP. The logistic regression model comprising the conventional FET PET parameters TBR mean and TBR max resulted in an AUC of 0.78 in both the validation (sensitivity, 64%; specificity, 80%) and the test dataset (sensitivity, 64%; specificity, 80%). The model combining the conventional FET PET parameters and two radiomics features yielded the best diagnostic performance in the validation dataset (AUC, 0.92; sensitivity, 91%; specificity, 80%) and demonstrated its generalizability in the independent test dataset (AUC, 0.85; sensitivity, 81%; specificity, 70%)., Conclusion: The developed radiomics classifier allows the differentiation between TRC and TP in pretreated gliomas based on routinely acquired static FET PET scans with a high diagnostic accuracy., (© 2022. The Author(s).)

Pioneer transcription factors (TFs) present an important subtype of transcription factors which are vital for cell programming during embryonic development and cellular memory during mitotic growth, as well as cell fate reprogramming. Pioneer TFs can engage specific target binding sites on nucleosomal DNA to attract chromatin remodeling complexes, cofactors, and other transcription factors, ultimately controlling gene expression by shaping locally the epigenome. The priority of binding that they exhibit in contrast to other transcription factors and their involvement in crucial events regarding cell fate, has implicated their aberrant function in the pathogenesis of several disorders including carcinogenesis. Emerging experimental data indicate that certain Pioneer TFs are highly implicated in gliomas development, in neoplastic cell proliferation, angiogenic processes, resistance to therapy, and patient survival. Herein, we describe the main structural characteristics and functional mechanisms of pioneer TFs, focusing on their central role in the pathogenesis and progression of gliomas. We further highlight the current treatment options ranging from natural agents (oleanolic acid) to a variety of chemical compounds (APR-246, COTI-2) and discuss potential delivery systems, including nanoparticles, viral vectors, and intracellular protein delivery techniques., Competing Interests: Declaration of Competing Interest The authors declare that they have no conflict of interest., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Objective: The objective of the study was to summarize the clinical characteristics, histo-genomic profiles, management strategies, and survival outcomes of H3K27M-altered adult diffuse midline gliomas (aDMGs)., Methods: PubMed, Scopus, and Cochrane databases were used to identify relevant articles. Papers including H3K27M-altered aDMGs with sufficient clinical outcome data were included. Descriptive clinical characteristics and survival analysis were also conducted., Results: Twenty studies describing 135 patients were included. The median age at diagnosis was 42 years, and there was a slight male predominance (N = 60, 54%). In our cohort, 15 (11%) patients experienced headache, 10 had nausea and vomiting (7%), and 10 had ataxia (7%). Within this cohort, histopathologic diagnoses included glioblastoma (N = 22, 40%) and anaplastic astrocytoma (N = 21, 38%), while genetic alterations included ATRX mutation (N = 22, 16%), PTPN11 mutation (N = 9, 7%), and MGMT promoter methylation (N = 9, 7%). Among histo-genetic alterations, only ATRX mutation was associated with survival and correlated with worse prognosis (log-rank test, P = 0.04). Neither surgical resection versus biopsy nor greater extent of resection demonstrated survival benefit in our cohort. Chemotherapy was administered in 98 (73%) cases with radiotherapy administered in 71 (53%) cases. Unlike chemotherapy, radiotherapy demonstrated a significant survival benefit (log-rank test, P = 0.019). The median overall survival and progression-free survival within our patient cohort were 10 and 7 months, respectively., Conclusions: H3K27M-altered aDMGs were associated with relatively poor survival. ATRX gene mutation was significantly associated with survival disadvantage, while radiotherapy was associated with survival benefit. Large, prospective studies are needed to establish a standard management strategy and provide reliable prognostic conclusions., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Gliomas are highly aggressive cancer types that are in urgent need of novel drugs and targeted therapies. Treatment protocols have not improved in over a decade, and glioma patient survival remains among the worst of all cancer types. As a result, cancer metabolism research has served as an innovative approach to identifying novel glioma targets and improving our understanding of brain tumors. Recent research has uncovered a unique metabolic vulnerability in the sphingolipid pathways of gliomas that possess the IDH1 mutation. Sphingolipids are a family of lipid signaling molecules that play a variety of second messenger functions in cellular regulation. The two primary metabolites, sphingosine-1-phosphate (S1P) and ceramide, maintain a rheostat balance and play opposing roles in cell survival and proliferation. Altering the rheostat such that the pro-apoptotic signaling of the ceramides outweighs the pro-survival S1P signaling in glioma cells diminishes the hallmarks of cancer and enhances tumor cell death. Throughout this review, we discuss the sphingolipid pathway and identify the enzymes that can be most effectively targeted to alter the sphingolipid rheostat and enhance apoptosis in gliomas. We discuss each pathway's steps based on their site of occurrence in the organelles and postulate novel targets that can effectively exploit this vulnerability.