Global post­marketing safety surveillance of Tumor Treating Fields (TTFields) therapy in over 25,000 patients with CNS malignancies treated between 2011-2022.

BACKGROUND: Tumor Treating Fields (TTFields) are alternating electric fields that disrupt cancer cell processes. TTFields therapy is approved for recurrent glioblastoma (rGBM), and newly-diagnosed (nd) GBM (with concomitant temozolomide for ndGBM; US), and for grade IV glioma (EU). We present an updated global, post-marketing surveillance safety analysis of patients with CNS malignancies treated with TTFields therapy. METHODS: Safety data were collected from routine post-marketing activities for patients in North America, Europe, Israel, and Japan (October 2011-October 2022). Adverse events (AEs) were stratified by age, sex, and diagnosis. RESULTS: Overall, 25,898 patients were included (diagnoses: ndGBM [68%], rGBM [26%], anaplastic astrocytoma/oligodendroglioma [4%], other CNS malignancies [2%]). Median (range) age was 59 (3-103) years; 66% patients were male. Most (69%) patients were 18-65 years; 0.4% were < 18 years; 30% were > 65 years. All-cause and TTFields-related AEs occurred in 18,798 (73%) and 14,599 (56%) patients, respectively. Most common treatment-related AEs were beneath-array skin reactions (43%), electric sensation (tingling; 14%), and heat sensation (warmth; 12%). Treatment-related skin reactions were comparable in pediatric (39%), adult (42%), and elderly (45%) groups, and in males (41%) and females (46%); and similar across diagnostic subgroups (ndGBM, 46%; rGBM, 34%; anaplastic astrocytoma/oligodendroglioma, 42%; other, 40%). No TTFields-related systemic AEs were reported. CONCLUSIONS: This long-term, real-world analysis of > 25,000 patients demonstrated good tolerability of TTFields in patients with CNS malignancies. Most therapy-related AEs were manageable localized, non-serious skin events. The TTFields therapy safety profile remained consistent across subgroups (age, sex, and diagnosis), indicative of its broad applicability.

Exploring the mechanism of 18F-fluorodopa uptake in recurrent high-grade gliomas: A comprehensive histomolecular-positron emission tomography analysis.

BACKGROUND: Dihydroxy-6-[18F]fluoro-L-phenylalanine (18F-FDOPA) positron emission tomography (PET) is a valuable tool for managing high-grade gliomas (HGGs), but there is a lack of literature on its relationship with glioma subtypes since the 2021 reclassification of brain tumors. There is also debate surrounding the mechanism of 18F-FDOPA uptake, particularly after chemoradiation therapy. This study aimed to investigate the correlation between 18F-FDOPA uptake and histomolecular characteristics, particularly L-amino acid transporter 1 (LAT1) expression, in recurrent gliomas, and examine their impact on survival in HGGs. METHODS: Thirty-nine patients with recurrent HGGs (14 isocitrate dehydrogenase [IDH]-mutant, 25 IDH-wildtype) who underwent a brain 18F-FDOPA PET/computed tomography (CT) or PET/magnetic resonance imaging (MRI) followed by surgical resection of the 18F-FDOPA-avid lesion within 6 months, were retrospectively reviewed. PET results were compared with histological examination and for SCL7A5/LAT1 immunostaining. The study also examined the relationship between PET parameters, LAT1 expression, and survival outcomes. RESULTS: Astrocytoma IDH-mutant G4 had higher 18F-FDOPA uptake than glioblastoma IDH-wildtype G4 (maximum tumor-to-normal brain ratio [TBRmax] 5 [3.4-9] vs. 3.8 [2.8-5.9], p = 0.02). IDH-mutant gliomas had higher LAT1 expression than IDH-wildtype gliomas (100 [14-273] vs. 15.5 [0-137], p < 0.05) as well as higher TBRmax (5 [2.4-9] vs. 3.8 [2.8-6], p < 0.05). In survival analysis, LAT1 score >100 was a predictor for longer progression-free survival in IDH-mutant HGGs. CONCLUSIONS: To our knowledge, our study is the first to suggest a link between LAT1 expression and IDH mutation status. We showed that higher TBRmax was associated with higher LAT1 expression and IDH mutation status. Further studies are needed to better understand the mechanisms underlying amino acid PET tracers uptake, especially in the post-radiation and chemotherapy settings.

A Systematic Review of the Metabolism of High-Grade Gliomas: Current Targeted Therapies and Future Perspectives.

High-grade glial tumors (HGGs) exhibit aggressive growth patterns and high recurrence rates. The prevailing treatment approach comprises radiation therapy (RT), chemotherapy (CMT), and surgical resection. Despite the progress made in traditional treatments, the outlook for patients with HGGs remains bleak. Tumor metabolism is emerging as a potential target for glioma therapies, a promising approach that harnesses the metabolism to target tumor cells. However, the efficacy of therapies targeting the metabolism of HGGs remains unclear, compelling a comprehensive review. This study aimed to assess the outcome of present trials on HGG therapies targeting metabolism. A comprehensive search of PubMed, Ovid MEDLINE, and Ovid EMBASE was conducted until November 2023. The search method used pertinent Medical Subject Heading (MeSH) terminologies and keywords referring to "high-grade gliomas", "metabolism", "target therapies", "monoclonal antibodies", "overall survival", and "progression-free survival". The review analyzed studies that focused on therapies targeting the metabolism of HGGs in human subjects. These studies included both randomized controlled trials (RCTs) and non-randomized controlled trials (NRCTs). Out of 284 articles identified, 23 trials met the inclusion criteria and were thoroughly analyzed. Phase II trials were the most numerous (62%). Targeted metabolic therapies were predominantly used for recurrent HGGs (67%). The most common targeted pathways were the vascular endothelial growth factor (VEGF, 43%), the human epidermal growth factor receptor (HER, 22%), the platelet-derived growth factor (PDGF, 17%), and the mammalian target of rapamycin (mTOR, 17%). In 39% of studies, the subject treatment was combined with CMT (22%), RT (4%), or both (13%). The median OS widely ranged from 4 to 26.3 months, while the median PFS ranged from 1.5 to 13 months. This systematic literature review offers a thorough exploration of the present state of metabolic therapies for HGGs. The multitude of targeted pathways underscores the intricate nature of addressing the metabolic aspects of these tumors. Despite existing challenges, these findings provide valuable insights, guiding future research endeavors. The results serve as a foundation for refining treatment strategies and enhancing patient outcomes within the complex landscape of HGGs.

Investigating the Association between the Autophagy Markers LC3B, SQSTM1/p62, and DRAM and Autophagy-Related Genes in Glioma.

High-grade gliomas are extremely fatal tumors, marked by severe hypoxia and therapeutic resistance. Autophagy is a cellular degradative process that can be activated by hypoxia, ultimately resulting in tumor advancement and chemo-resistance. Our study aimed to examine the link between autophagy markers' expression in low-grade gliomas (LGGs) and high-grade gliomas (HGGs). In 39 glioma cases, we assessed the protein expression of autophagy markers LC3B, SQSTM1/p62, and DRAM by immunohistochemistry (IHC) and the mRNA expression of the autophagy genes PTEN, PI3K, AKT, mTOR, ULK1, ULK2, UVRAG, Beclin 1, and VPS34 using RT-qPCR. LC3B, SQSTM1/p62, and DRAM expression were positive in 64.1%, 51.3%, and 28.2% of glioma cases, respectively. The expression of LC3B and SQSTM1/p62 was notably higher in HGGs compared to LGGs. VPS34 exhibited a significant differential expression, displaying increased fold change in HGGs compared to LGGs. Additionally, it exhibited robust positive associations with Beclin1 (rs = 0.768), UVRAG (rs = 0.802), and ULK2 (rs = 0.786) in HGGs. This underscores a potential association between autophagy and the progression of gliomas. We provide preliminary data for the functional analysis of autophagy using a cell culture model and to identify potential targets for therapeutic interventions.

Added value of [18F]FDOPA PET to the management of high-grade glioma patients after their initial treatment: a prospective multicentre study.

BACKGROUND: Diagnostic value of 3,4-dihydroxy-6-[18F]fluoro-L-phenylalanine ([18F]FDOPA) PET in patients with suspected recurrent gliomas is recognised. We conducted a multicentre prospective study to assess its added value in the practical management of patients suspected of recurrence of high grade gliomas (HGG). METHODS: Patients with a proven HGG (WHO grade III and IV) were referred to the multidisciplinary neuro-oncology board (MNOB) during their follow-up after initial standard of care treatment and when MRI findings were not fully conclusive. Each case was discussed in 2 steps. For step 1, a diagnosis and a management proposal were made only based on the clinical and the MRI data. For step 2, the same process was repeated taking the [18F]FDOPA PET results into consideration. A level of confidence for the decisions was assigned to each step. Changes in diagnosis and management induced by [18F]FDOPA PET information were measured. When unchanged, the difference in the confidence of the decisions were assessed. The diagnostic performances of each step were measured. RESULTS: 107 patients underwent a total of 138 MNOB assessments. The proposed diagnosis changed between step 1 and step 2 in 37 cases (26.8%) and the proposed management changed in 31 cases (22.5%). When the management did not change, the confidence in the MNOB final decision was increased in 87 cases (81.3%). Step 1 had a sensitivity, specificity and accuracy of 83%, 58% and 66% and step 2, 86%, 64% and 71% respectively. CONCLUSION: [18F]FDOPA PET adds significant information for the follow-up of HGG patients in clinical practice. When MRI findings are not straightforward, it can change the management for more than 20% of the patients and increases the confidence level of the multidisciplinary board decisions.

Development of an integrated predictive model for postoperative glioma-related epilepsy using gene-signature and clinical data.

BACKGROUND: This study aimed to develop an integrated model for predicting the occurrence of postoperative seizures in patients with diffuse high-grade gliomas (DHGGs) using clinical and RNA-seq data. METHODS: Patients with DHGGs, who received prophylactic anti-epileptic drugs (AEDs) for three months following surgery, were enrolled into the study. The patients were assigned randomly into training (n = 166) and validation (n = 42) cohorts. Differentially expressed genes (DEGs) were identified based on preoperative glioma-related epilepsy (GRE) history. Least absolute shrinkage and selection operator (LASSO) logistic regression analysis was used to construct a predictive gene-signature for the occurrence of postoperative seizures. The final integrated prediction model was generated using the gene-signature and clinical data. Receiver operating characteristic analysis and calibration curve method were used to evaluate the accuracy of the gene-signature and prediction model using the training and validation cohorts. RESULTS: A seven-gene signature for predicting the occurrence of postoperative seizures was developed using LASSO logistic regression analysis of 623 DEGs. The gene-signature showed satisfactory predictive capacity in the training cohort [area under the curve (AUC) = 0.842] and validation cohort (AUC = 0.751). The final integrated prediction model included age, temporal lobe involvement, preoperative GRE history, and gene-signature-derived risk score. The AUCs of the integrated prediction model were 0.878 and 0.845 for the training and validation cohorts, respectively. CONCLUSION: We developed an integrated prediction model for the occurrence of postoperative seizures in patients with DHGG using clinical and RNA-Seq data. The findings of this study may contribute to the development of personalized management strategies for patients with DHGGs and improve our understanding of the mechanisms underlying GRE in these patients.

Metabolic delineation of IDH1 wild-type glioblastoma surgical anatomy: how to plan the tumor extent of resection.

PURPOSE: Magnetic resonance imaging (MRI) is the current standard for preoperative planning of glioblastoma (GBM) surgery. However, recent data on the use of 11 C-methionine positron emission tomography (11[C]-MET PET) suggest its role in providing additional information beyond MRI. The purpose of this study is to establish if there is a correlation between anatomical and metabolic data. METHODS: We retrieved all GBM cases treated from 2014 to January 2021. Preoperative MRI (Enhancing Nodule -EN-, FLAIR and Total Tumor Volume -TTV-), PET volumes and histological samples obtained from the different tumor regions were evaluated to analyze potential correlations between anatomical, metabolic and pathological data. RESULTS: 150 patients underwent surgery for GBM and 49 of these were also studied preoperatively with 11[C]-MET PET; PET volume was evaluated in 47 patients. In 33 patients (70.21%) preoperative 11[C]-MET PET volume > preoperative EN volume and in 11 (23.4%) preoperative 11[C]-MET PET volume > preoperative TTV. We found a significant correlation between preoperative TTVs and PET volumes (p = 0.016) as well as between preoperative EN volumes and PET volumes (p = < 0.001). Histologically, 109 samples were evaluated. ENs samples exhibited the conventional GBM morphology while samples from the FLAIR regions showed white matter tissue, with focal to diffuse tumor cells infiltration and areas of reactive astrogliosis. CONCLUSION: We submit that 11[C]-MET PET volume generally overcome EN. The presence of neoplastic cells confirm these metabolic data. It should be considered in the surgical planning to achieve a Supra Total Resection (SupTR).

DKI can distinguish high-grade gliomas from IDH1-mutant low-grade gliomas and correlate with their different nuclear-to-cytoplasm ratio: a localized biopsy-based study.

OBJECTIVES: To explore whether differences in diffusional kurtosis imaging (DKI) between therapy-naïve high-grade gliomas (HGGs) and low-grade gliomas (LGGs) are related to the cellularity and/or the nuclear-to-cytoplasmic (N/C) ratio. METHODS: We analyzed 44 and 40 diffuse glioma samples that were pathologically confirmed as HGGs and IDH1-mutant LGGs, respectively. The DKI parameters included kurtosis metrics (mean kurtosis [MK], axial kurtosis [K//], and radial kurtosis [K⊥]), and the diffusional metrics (fractional anisotropy [FA], mean diffusion [MD], axial diffusion [λ//], and radial diffusion [λ⊥]). The cellularity and the N/C ratio were compared within LGGs and HGGs using the Mann-Whitney U test (significant level, p < 0.007 [0.05/7]); Bonferroni correction). Spearman's correlation analysis was used to calculate the correlation coefficients among DKI metrics, cellularity, and the N/C ratio at a significant level of p = 0.05. RESULTS: Excluding FA, all DKI metrics showed significant differences between HGGs and LGGs (all p ≤ 0.001). The N/C ratio of HGGs was significantly higher than that of LGGs; however, differences in cellularity were not significant between the two glioma groups (p = 0.525). Similarly, excluding FA, all DKI metrics were significantly correlated with the N/C ratio in LGGs, with correlation coefficients of - 0.365 (MD), - 0.313 (λ//), - 0.376 (λ⊥), 0.859 (MK), 0.772 (K//), and 0.842 (K//). There was a non-significant correlation between any DKI parameters and the cellularity in LGGs. Additionally, the cellularity and N/C ratios in HGGs did not correlate with any DKI metrics. CONCLUSIONS: DKI differentiate LGGs from HGGs associated with their different N/C ratios. CLINICAL RELEVANCE STATEMENT: This study shows that DKI differentiates LGGs from HGGs may correlated with their different N/C ratios, this could provide a possible histopathological mechanism about why DKI can DKI differentiate LGGs from HGGs. KEY POINTS: • Excluding FA, all DKI metrics showed a significant difference between high-grade gliomas and IDH1-mutant low-grade gliomas. • The nuclear-to-cytoplasm ratios in high-grade gliomas were significantly more extensive than that in IDH1-mutant low-grade gliomas, but not the cellularity. • Significant associations were seen between DKI measures and the N/C ratio; a non-significant correlation was noted between any DKI metric and cellularity in glioma specimens.

Factors affecting cognitive functions of patients with high-grade gliomas: a systematic review.

BACKGROUND: Gliomas make up approximately 26.5% of all primary CNS tumors and 80.7% of malignant tumors. They are classified according to histology, location, and genetics. Grade III and IV gliomas are considered high-grade gliomas (HGGs). The cognitive signs and symptoms are attributed to mass defects depending on location, growth rapidity, and edema. Our purpose is to review the cognitive status of patients diagnosed with HGGs; the effect of treatments including surgical resection, radiotherapy, and chemotherapy; and the predictors of the cognitive status. METHODS: We utilized the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines as a template for the methodology. A comprehensive literature search was performed from three databases (PubMed, ScienceDirect, and Cochrane Library) for clinical trials and longitudinal studies on patients diagnosed with HGGs assessing their cognitive status. RESULTS: Thirteen studies were selected among which 9 assessed cognitive function before and after treatment. One assessed the consistency of cognitive complaints and objective cognitive functioning. Three reported factors affecting disease progression and cognitive status. Most HGG patients have impairment in at least one cognitive domain. Treatments including surgical resection or radio-chemotherapy did not impair cognitive status. DISCUSSION: The cognitive status could be used to assess sub-clinical tumor progression. Factors correlated to cognitive status were tumor location, edema, and grade. Patient characteristics correlated were pre-operative epilepsy, corticosteroid use, and age at the time of diagnosis. CONCLUSION: Assessment of the cognitive status of HGG patients indicates sub-clinical tumor progression and may be used to assess treatment outcomes.

Resection of the contrast-enhancing tumor in diffuse gliomas bordering eloquent areas using electrophysiology and 5-ALA fluorescence: evaluation of resection rates and neurological outcome-a systematic review and meta-analysis.

Independently, both 5-aminolevulinic acid (5-ALA) and intraoperative neuromonitoring (IONM) have been shown to improve outcomes with high-grade gliomas (HGG). The interplay and overlap of both techniques are scarcely reported in the literature. We performed a systematic review and meta-analysis focusing on the concomitant use of 5-ALA and intraoperative mapping for HGG located within eloquent cortex. Using PRISMA guidelines, we reviewed articles published between May 2006 and December 2022 for patients with HGG in eloquent cortex who underwent microsurgical resection using intraoperative mapping and 5-ALA fluorescence guidance. Extent of resection was the primary outcome. The secondary outcome was new neurological deficit at day 1 after surgery and persistent at day 90 after surgery. Overall rate of complete resection of the enhancing tumor (CRET) was 73.3% (range: 61.9-84.8%, p < .001). Complete 5-ALA resection was performed in 62.4% (range: 28.1-96.7%, p < .001). Surgery was stopped due to mapping findings in 20.5% (range: 15.6-25.4%, p < .001). Neurological decline at day 1 after surgery was 29.2% (range: 9.8-48.5%, p = 0.003). Persistent neurological decline at day 90 after surgery was 4.6% (range: 0.4-8.7%, p = 0.03). Maximal safe resection guided by IONM and 5-ALA for high-grade gliomas in eloquent areas is achievable in a high percentage of cases (73.3% CRET and 62.4% complete 5-ALA resection). Persistent neurological decline at postoperative day 90 is as low as 4.6%. A balance between 5-ALA and IONM should be maintained for a better quality of life while maximizing oncological control.

Anatomical landmarks during high-magnification microsurgery for a safe and effective resection of high-grade gliomas: how I do it.

BACKGROUND: Gross total resection, when possible, is the first crucial treatment for high-grade gliomas, as it has been demonstrated to be associated with longer survival. Different intraoperative tools, such as neuronavigation, fluorescent agents, and intra-operative ultrasound, have been developed to help neurosurgeons to extend the resection. METHODS: We describe the high-magnification microsurgery technique used during the first surgical removal for high-grade gliomas. We illustrate the key anatomical "markers" of normal brain parenchyma, which guide the surgery. CONCLUSION: High-magnification microsurgery is an anatomically based approach that allows the identification of key anatomical "markers" of normal brain parenchyma in order to resect high-grade gliomas safely and effectively.

Intracranial high-grade glioma with malignant progression of spinal intramedullary metastasis: an atypical presentation with review of literature.

PURPOSE: High-grade gliomas (grade 3 and grade 4) are known to be highly locally invasive and distant metastasis though known, rarely manifest clinically due to poor survival. Recently, due to increasing survival in view of early diagnosis at relatively young age, more cases of extra neural symptomatic metastasis are being diagnosed and treated. Among these, symptomatic spinal metastasis is even more rare. Dissemination of GBM to the spinal compartment, albeit uncommon, has an even poorer outcome, with most patients dying within 2-3 months after diagnosis of metastatic disease. MATERIALS AND METHODS: Here, we present a rare case report of a 25-year-old female with transformed/histologically progressed tumour in cranial region along with ultra-rapid progression of the spinal disease following metastasis. Proper consent of the patient relatives was taken prior to production of material as patient had expired by the time of writing of this paper. We also present an extensive review of spinal metastasis secondary to intracranial high-grade gliomas starting from 1950. We conducted a thorough and exhaustive systematic search and review of the indexed databases available in PUBMED, COCHRANE and GOOGLE SCHOLAR with key words 'spinal metastasis of glioma', 'spinal metastasis', 'glioma progression', 'secondary glioma', multicentric glioma', 'secondary spinal metastasis' and formulated a comprehensive table of the studies that met the set standards. The studies that included (a) Number of cases, (b) Age and sex of patients, (c) operated primary or non-operated primary with spinal metastasis, (d) time period from the index cranial surgery, (e) outcome after diagnosis of spine metastasis and (f) histopathology of both cranial and spinal tumour either following surgery or autopsy have been elucidated herewith. We searched the databases with no particular time period. Out of 42 case reports and series, 28 studies were selected for our publication as they met the standards set, starting from 1950 to 2020. RESULTS: In this case, the primary histopathological diagnosis post cranial tumour removal was Grade-3 anaplastic astrocytoma, whereas Spinal autopsy report done 16 months after the primary diagnosis showed Grade-4 GBM suggestive of secondary transformation (Secondary GBM), it showed same genome of IDH mutation and ATRX loss, neoplastic fibrillary and gemistocytic astrocytes with de-differentiation, foamy histiocytes as seen in primary lesion suggestive of progression and metachronicity rather than multicentricity or synchronicity. What is more peculiar and rare in our case is that the spinal disease was very malignant and it progressed in course of just two days to involve the whole spine.

Malignant ultra-rapid progression of spinal metastasis.Thorough review of literatureMetachronicity of spinal metastasis Importance of the studyThis study presents a very atypical case of malignant progression of spinal metastasis documented with successive MRI radiology scans in a span of mere two days.It is different from other studies in the sense such malignant progression in a span of few days has never been documented with radiographs.This manuscript also provides an exhaustive review of literature and draws comparisons among the same.This study compares→ Time period to diagnosis of spinal metastasis following primary diagnosis, Outcome from diagnosis of spine metastasis, age along with other variables like histopathology of spinal metastasis if available, Treatment underwent, site of metastasis among different studies.

Gene Expression Profile of 3D Spheroids in Comparison with 2D Cell Cultures and Tissue Strains of Diffuse High-Grade Gliomas.

The use of relevant, accessible, and easily reproducible preclinical models of diffuse gliomas is a prerequisite for the development of successful therapeutic approaches to their treatment. Here we studied the gene expression profile of 3D spheroids in a comparison with 2D cell cultures and tissue strains of diffuse high-grade gliomas. Using real time PCR, we evaluated the expression of Gfap, Cd44, Pten, S100b, Vegfa, Hif1a, Sox2, Melk, Gdnf, and Mgmt genes playing an important role in the progression of gliomas and regulating tumor cell proliferation, adhesion, invasion, plasticity, apoptosis, DNA repair, and recruitment of tumor-associated cells. Gene expression analysis showed that 3D spheroids are more similar to tumor tissue strains by the expression levels of Gfap, Cd44, and Pten, while the expression levels of Hif1a and Sox2 in 3D spheroids did not differ from those of 2D cell cultures, the expression levels S100b and Vegfa in 3D spheroids was higher than in other models, and the expression levels of Melk, Gdnf, and Mgmt genes changed diversely. Thus, 3D spheroid model more closely mimics the tumor tissue than 2D cell culture, but still is not the most relevant, probably due to too small size of spheroids, which does not allow reproducing hypoxia and apoptotic and necrotic processes in the tumor tissue.

MRI-based radiomics signature and clinical factor for predicting H3K27M mutation in pediatric high-grade gliomas located in the midline of the brain.

OBJECTIVE: To develop a nomogram based on MRI radiomics and clinical features for preoperatively predicting H3K27M mutation in pediatric high-grade gliomas (pHGGs) with a midline location of the brain. METHODS: The institutional database was reviewed to identify patients with pHGGs with a midline location of the brain who underwent tumor biopsy with preoperative MRI scans between June 2016 and June 2021. A total of 107 patients with pHGGs, including 79 patients with H3K27M mutation, were consecutively included and randomly divided into training and test sets. Radiomics features were extracted from fluid-attenuated inversion recovery (FLAIR), diffusion-weighted (DW) and post-contrast T1-weighted images, and apparent diffusion coefficient (ADC) maps. The minimum redundancy maximum relevance (MRMR) and least absolute shrinkage and selection operator (LASSO) logistic regression were performed for radiomics signature construction. Clinical and radiological features were analyzed to select clinical predictors. A nomogram was then developed by incorporating the radiomics signature and selected clinical predictors. RESULTS: Nine radiomics features were selected to construct the radiomics signature, which showed a favorable discriminatory ability in training and test sets with an area under the curve (AUC) of 0.95 and 0.92, respectively. Ring enhancement was identified as an independent clinical predictor (p < 0.01). The nomogram, constructed with radiomics signature and ring enhancement, showed good calibration and discrimination in training and testing sets (AUC: 0.95 and 0.90 respectively). CONCLUSIONS: The nomogram which combined radiomics signature and ring enhancement had a satisfactory ability to predict H3K27M mutation in pHGGs with a midline of the brain. KEY POINTS: • Conventional MRI features were not powerful enough to predict H3K27M mutation status in pediatric high-grade gliomas (pHGGs) with a midline location of the brain. • An MRI-based radiomics signature showed satisfactory ability to predict H3K27M mutation status of pHGGs located in the midline of the brain. • Associating the radiomics signature with clinical factors improved predictive performance.

Exploring the relationship between age and prognosis in glioma: rethinking current age stratification.

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.

Correlation analysis of tumor purity with clinicopathological, molecular, and imaging features in high-grade gliomas.

High-grade gliomas (HGG) have high malignancy, high heterogeneity, and a poor prognosis. Tumor purity is an intrinsic feature of the HGG microenvironment and an independent prognostic factor. The purpose of this study was to analyze the correlation of tumor purity with clinicopathological, molecular, and imaging features. We performed a retrospective analysis of 112 patients diagnosed with HGG (grades III and IV) in our center. Eleven regions of interest (ROI) were randomly selected on whole-slide images (WSI, 40 × magnification) based on HGG tissue paraffin sections and hematoxylin-eosin (H&E) staining. Of these 11 ROIs, five ROIs were visually estimated by pathologists and six ROIs were automatically analyzed using ImageJ software. Last, the average tumor purity (%) of the 11 ROIs was calculated. Correlation analysis of tumor purity with clinicopathological, molecular, and imaging features was conducted. Of the 112 patients included in the study, the mean tumor purity of HGG was 70.96%. There were differences in tumor purity between WHO grades III and IV; the tumor purity of grade IV patients (67.59%) was lower than that of grade III patients (76.00%) (p < 0.001). There were also differences in tumor purity between IDH1 mutant and wild type, and the tumor purity of IDH1 mutant patients was higher than that of IDH1 wild-type patients (p = 0.006). The average range of peritumoral edema was about 19.18 mm, and the diameter of edema, ADCmean, and ADCmin were negatively correlated with tumor purity(r = - 0.236, r = - 0.306, and r = - 0.242; p < 0.05). The grade of HGG, IDH1 mutant/wild type, peritumoral edema, and ADC value were correlated with tumor purity. HGG grade, IDH1 mutant/wild type, peritumoral edema, and ADC value can predict tumor purity and indirectly reflect patient prognosis.

Prognostic factors in progressive high-grade glial tumors treated with systemic approach: A single center experience.

PURPOSE: Malignant high-grade gliomas are the most common and aggressive type of primary brain tumor, and the prognosis is generally extremely poor. In this retrospective study, we analyzed the outcome of systemic treatment in recurrent high-grade glioma patients and the impact of prognostic factors on survivals. METHODS: Data from 114 patients with recurrent high-grade glioma who received systemic treatment and followed in our clinic between 2012 and 2018 were retrospectively analyzed. Eastern Cooperative Oncology Group (ECOG) performance status, age, gender, histology, type of surgical resection, side effects after systemic treatment (deep vein thrombosis, hypertension, proteinuria), IDH1 and alpha thalassemia/mental retardation syndrome X-linked (ATRX) mutation status were investigated as prognostic factors for progression-free survival and overall survival. RESULTS: At the time of diagnosis, the median age was 48 (17-77) and 68% of the patients were male. Most common pathologic subtype was glioblastoma multiforme (68%). Median follow-up duration was 9.1 months (1-68 months). Median progression-free survival and overall survival were 6.2 months and 8 months, respectively. In multivariate analysis, ECOG PS, deep venous thrombosis and the presence of ATRX and IDH1 mutation were found to be independent prognostic factors for progression-free survival (p < 0.05) and, ECOG PS, the presence of ATRX and IDH1 mutation for overall survival (p < 0.05). CONCLUSION: Our study is real life data and the median progression-free survival and overall survival rates are similar to the literature. We have found ECOG PS, presence of ATRX and IDH1 mutation to be independent prognostic factors for both progression-free survival and overall survival.

Alternative lengthening of telomeres in molecular subgroups of paediatric high-grade glioma.

PURPOSE: The maintenance of telomere length prevents cancer cell senescence and occurs via two mutually exclusive mechanisms: (a) reactivation of telomerase expression and (b) activation of alternative lengthening of telomeres (ALT). ALT is frequently related to alterations on ATRX, a chromatin-remodelling protein. Recent data have identified different molecular subgroups of paediatric high-grade glioma (pHGG) with mutations of H3F3A, TERTp and ATRX; however, differences in telomere length among these molecular subgroups were not thoroughly examined. METHODS: We investigated which genetic alterations trigger the ALT mechanism in 52 IDH-wildtype, 1p/19q-wildtype pHGG. Samples were analysed for telomere length using Tel-FISH. ATRX nuclear loss of expression was assessed by IHC, H3F3A and TERTp mutations by DNA sequencing, and TERTp methylation by MS-PCR. RESULTS: Mutant H3.3 was found in 21 cases (40.3%): 19.2% with K27M mutation and 21.1% with G34R mutation. All H3.3G34R-mutated cases showed the ALT phenotype (100%); on the opposite, only 40% of the H3.3K27M-mutated showed ALT activation. ATRX nuclear loss was seen in 16 cases (30.7%), associated sometimes with the G34R mutation, and never with the K27M mutation. ATRX nuclear loss was always related to telomere elongation. TERTp C250T mutations were rare (5.4%) and were not associated with high intensity Tel-FISH signals, as TERTp hyper-methylation detected in 21% of the cases. H3.3/ATRX/TERTp-wildtype pHGG revealed all basal levels of telomere length. CONCLUSION: Our results show a strong association between H3.3 mutations and ALT, and highlight the different telomeric profiles in histone-defined subgroups: H3.3-G34R mutants always trigger ALT to maintain telomere length, irrespective of ATRX status, whereas only some H3.3-K27M tumours activate ALT. These findings suggest that acquiring the gly34 mutation on H3.3 might suffice to trigger the ALT mechanism.

Conventional and advanced imaging throughout the cycle of care of gliomas.

Although imaging of gliomas has evolved tremendously over the last decades, published techniques and protocols are not always implemented into clinical practice. Furthermore, most of the published literature focuses on specific timepoints in glioma management. This article reviews the current literature on conventional and advanced imaging techniques and chronologically outlines their practical relevance for the clinical management of gliomas throughout the cycle of care. Relevant articles were located through the Pubmed/Medline database and included in this review. Interpretation of conventional and advanced imaging techniques is crucial along the entire process of glioma care, from diagnosis to follow-up. In addition to the described currently existing techniques, we expect deep learning or machine learning approaches to assist each step of glioma management through tumor segmentation, radiogenomics, prognostication, and characterization of pseudoprogression. Thorough knowledge of the specific performance, possibilities, and limitations of each imaging modality is key for their adequate use in glioma management.

Targeting Glucose Metabolism of Cancer Cells with Dichloroacetate to Radiosensitize High-Grade Gliomas.

As the cornerstone of high-grade glioma (HGG) treatment, radiotherapy temporarily controls tumor cells via inducing oxidative stress and subsequent DNA breaks. However, almost all HGGs recur within months. Therefore, it is important to understand the underlying mechanisms of radioresistance, so that novel strategies can be developed to improve the effectiveness of radiotherapy. While currently poorly understood, radioresistance appears to be predominantly driven by altered metabolism and hypoxia. Glucose is a central macronutrient, and its metabolism is rewired in HGG cells, increasing glycolytic flux to produce energy and essential metabolic intermediates, known as the Warburg effect. This altered metabolism in HGG cells not only supports cell proliferation and invasiveness, but it also contributes significantly to radioresistance. Several metabolic drugs have been used as a novel approach to improve the radiosensitivity of HGGs, including dichloroacetate (DCA), a small molecule used to treat children with congenital mitochondrial disorders. DCA reverses the Warburg effect by inhibiting pyruvate dehydrogenase kinases, which subsequently activates mitochondrial oxidative phosphorylation at the expense of glycolysis. This effect is thought to block the growth advantage of HGGs and improve the radiosensitivity of HGG cells. This review highlights the main features of altered glucose metabolism in HGG cells as a contributor to radioresistance and describes the mechanism of action of DCA. Furthermore, we will summarize recent advances in DCA's pre-clinical and clinical studies as a radiosensitizer and address how these scientific findings can be translated into clinical practice to improve the management of HGG patients.