de Biase D.

Franceschi E.

Marucci G.

English

Archivio istituzionale della ricerca - Alma Mater Studiorum Università di Bologna

TYPE EditorialPUBLISHED 04 May 2023DOI 10.3389/fmed.2023.1152547OPEN ACCESSEDITED BYNavid Razmjooy,Islamic Azad University, Ardabil, IranREVIEWED BYVeena Rajaram,University of Texas Southwestern MedicalCenter, United StatesCheng-Ying Ho,Johns Hopkins Medicine, United StatesDavid Meredith,Brigham and Women’s Hospital and HarvardMedical School, United States*CORRESPONDENCEDario de Biasedario.debiase@unibo.it†These authors have contributed equally to thisworkRECEIVED 27 January 2023ACCEPTED 19 April 2023PUBLISHED 04 May 2023CITATIONde Biase D, Franceschi E and Marucci G (2023)Editorial: Advances in brain tumors diagnosisand treatment. Front. Med. 10:1152547.doi: 10.3389/fmed.2023.1152547COPYRIGHT© 2023 de Biase, Franceschi and Marucci. Thisis an open-access article distributed under theterms of the Creative Commons AttributionLicense (CC BY). The use, distribution orreproduction in other forums is permitted,provided the original author(s) and thecopyright owner(s) are credited and that theoriginal publication in this journal is cited, inaccordance with accepted academic practice.No use, distribution or reproduction ispermitted which does not comply with theseterms.Editorial: Advances in braintumors diagnosis and treatmentDario de Biase1,2*†, Enrico Franceschi3† and Gianluca Marucci4†1Department of Pharmacy and Biotechnology (FaBiT), University of Bologna, Bologna, Italy, 2Solid TumorMolecular Pathology Laboratory, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy,3Nervous System Medical Oncology Department, IRCCS Istituto Delle Scienze Neurologiche di Bologna,Bologna, Italy, 4Neuropathology Unit, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan, ItalyKEYWORDSbrain tumors, gliomas, brain tumors diagnosis, molecular pathology of brain tumors,microRNA, target therapy, therapeutic approach in brain tumorsEditorial on the Research TopicAdvances in brain tumors diagnosis and treatmentThe 2021 WHO (World Health Organization) classification of Central Nervous System(CNS) tumors has integrated the histological findings with molecular characterization (1).The characterization of brain tumors to predict survival outcomes and treatment responsehas been significantly improved (2, 3). This Research Topic focused on the applicationof novel discovery in characterizing brain tumors for diagnostic, prognostic, or predictivepurposes and draws together a series of reports focusing on different aspects of thisimportant item.New tumor types and rare entitiesThe 2021 WHO classification of CNS tumors recognized various new tumor types.PLNTY (Polymorphous low-grade neuroepithelial tumor of the young) is a novelepileptogenic neoplasm, included in the 2021 WHO classification (1). Fei et al. reported8 new cases of PLNTY describing its clinical, histopathological, imaging, and molecularprofile. The authors observed that all cases exhibited intense labeling of CD34 and theabsence of IDH1/IDH2 mutations and 1p/19q codeletion. The BRAF p.V600E mutationwas detected in 66.7% of cases. In this paper, the authors demonstrated that the post-operative seizure-free rate is improved by early surgical intervention and enlarged resectionof epilepsy-associated PLNTY.The skull-base meningiomas with extracranial extensions are a rare type ofmeningiomas. He et al. summarized the prognostic and clinical features of skull-basemeningiomas with extracranial extensions. About 50 cases of skull-based meningiomas wereinvestigated to review clinical symptoms, treatment strategies, radiological characteristics,and prognosis. Patients with communicative meningiomas were younger when comparedwith those with intracranial meningiomas. Moreover, these patients showed a highertendency to develop low-grade tumors. Imaging allowed the detection of high boneinvasion rate, heterogeneous enhancement, high dural tail sign rate, and high incidence ofperitumoral edema.Internò et al. overviewed the role of molecular aberrations in astrocytomas togetherwith the most effective post-surgical strategies. According to their data, the subgroup ofIDH1/IDH2 mutant astrocytomas showed a demonstrable survival benefit with adjuvantchemoradiotherapy, if compared to the IDH-WT group.Frontiers inMedicine 01 frontiersin.orgde Biase et al. 10.3389/fmed.2023.1152547Prediction of post-operative mortalityThe relationship between post-operative mortality in patientsundergoing craniotomy and pre-operative blood urea nitrogen(BUN) was investigated by Liu Y. et al.. The study showed thatpost-operative mortality was associated with pre-operative BUN.Data demonstrated that the risk of post-operative mortality maybe reduced by proper pre-operative management of BUN.Radiotherapy in patients withglioblastomaChemoradiation followed by maintenance temozolomide(TMZ) with tumor-treating fields (TTFields) is a treatment forpatients with newly diagnosed glioblastoma (GBM) (4). Miller et al.evaluated the safety of chemoradiation used concurrently withTTFields. The Authors evidenced that concurrent scalp-sparingchemoradiation with TTFields is a well-tolerated and feasibletreatment option, with only limited toxicity.Huang Y. et al. proposed an approach to delineate the clinicaltarget volume in GBM, based on the relationship between theneural pathways and the growth patterns, enrolling a total of 69patients. The clinical target volume (CTV) was delineated using anew approach. The used regimen showed a trend of lower rates ofmarginal recurrence, and the brain volume of high-dose radiationfields was similar to that of the European Organization for Researchand Treatment of Cancer (EORTC).Kaina et al. discussed the synergistic effect of temozolomideand radiation, proposing an optimal timing of TMZ treatmentconcurrent with radiotherapy. The authors assert that it could beconcluded that the TMZ treatment should initially be carried outfor 3 days without radiotherapy.Immunotherapies in high-gradegliomasThe development of immunotherapies in the treatment ofHigh-Grade Gliomas (HGG), has been limited by several elements,such as the anti-inflammatory tumor microenvironment (TME)(5). Franson et al. reviewed in depth the TME in HGG(adult and pediatric type), the various drivers of the TMEin HGG, and different immunotherapeutic approaches. Namely,they focused on myeloid-derived suppressor cells (MDSCs),glioma-associated macrophages and microglia (GAMs), T cellinfiltration and dysfunction, cytokines as a putative driver of tumorimmune escape, IDH mutations, and effects on the TME, theactual immunotherapies and the challenges in immunotherapydevelopment for HGG.Immunotherapy may become a promising approach also forGBM treatment (6), even if the role of PD-1/PD-L1 expression inGBM is still controversial. Guo et al. performed a meta-analysisto verify the possible link between high/positive PD-L1 expressionand overall survival (OS) in GBM. According to this study, in GBMthere is a positive correlation between PD-L1 and low OS.Inflammation is a crucial marker to promote tumorigenesisand tumor progression. However, the role of immune-related genesin GBM remains still unclear. Yu et al. looked for a relationshipbetween the immune microenvironment and GBM. The Authorsexamined GBM-related RNA sequencing (RNA-seq), clinical data,and survival, acquiring data from four databases. According to theirstudy, three immune-related genes (PTX3, TNFSF9, and BMP2)may be prognostic factors for patients with GBM.Brain metastasesCNS metastases are the most common brain tumor type inadults. The extent of resection and the impact of post-operativeresidual tumor burden (RTB) in brain metastases are still notdefined enough. In the study by Aftahy et al. the authorsdemonstrated that RTB is a predictor for survival.Barakeh et al. performed NGS (Next-Generation Sequencing)on brain metastases from the following primary tumors: breastcarcinomas, colorectal cancers, renal, and thyroid tumors. TheAuthors identified clinically relevant mutations in brain metastasesthat were not detected in the corresponding primary tumors, asalterations in the MAPK, PI3K, and CDK pathways. These datahighlighted the possibility of having differences between brainmetastases and primary cancers regards molecular profile, and thusthe importance of performing the molecular analysis on brainmetastatic samples for further clinical management.Leptomeningeal metastases (LM) of lung cancer have beenusually associated with poor prognosis. Osimertinib has shownpromising efficacy in NSCLC–LM patients, however resistanceto osimertinib develops over time. Yang et al. evaluated theclinical effects of EGFR amplification by targeted next-generationsequencing in Cerebrospinal fluid (CSF) samples in patientsdiagnosed with NSCLC–LM and who had received previous EGFR-TKI treatment. EGFR amplification had been evaluated by targetednext-generation sequencing in Cerebrospinal fluid (CSF) samples.Data suggested that the amplification of the EGFR gene may induceresistance of NSCLC–LM patients to EGFR-TKIs.Tumor cell infiltration at the macro-metastasis/brainparenchyma interface (MMPI) is usually correlated with pooroutcomes. Blazquez et al. identified specific magnetic resonanceimaging (MRI) patterns in patients with brain metastasis, andcorrelated patient outcomes with these MRI patterns. The authorsanalyzed the preoperative magnetic resonance images of about 260patients with brain metastasis. Their results indicated that the MRIbreakout pattern is an imaging biomarker for particularly pooroutcomes in patients with brain metastasis.New diagnostic technologiesNew approaches are increasingly leveraged to betterunderstand complex biological systems. The tricarboxylicacid (TCA) cycle is related to the occurrence and developmentof glioma, and cuproptosis is closely related to the inhibition ofthe TCA cycle (7). Ye et al. developed and validated cuproptosis-associated prognostic signatures in WHO 2/3 gliomas. In theirstudy, the authors found that eight cuproptosis-related genes(CRGs) were differentially expressed between glioma and normalFrontiers inMedicine 02 frontiersin.orgde Biase et al. 10.3389/fmed.2023.1152547tissues. The Authors constructed a cuproptosis-associated risksignature, able to predict the prognosis of glioma patients.Ferroptosis, caused by excessive lipid peroxidation, is anotherform of form cell death (8). Huang Q. R. et al. have explored theprognostic value of ferroptosis-related lncRNAs (long non-codingRNAs) in low-grade glioma (LGG). Three databases (The CancerGenome Atlas—TCGA, Chinese Glioma Genome Atlas—CGGA,and Gravendeel) were used to obtain the expression profiles. Theanalysis led to build a risk signature consisting of 8 lncRNAs, witha good performance in predicting the prognosis of LGG.Necroptosis is a programmed inflammatory cell death or lysiscell death, playing a fundamental role in killing damaged cellsand/or pathogen-infected (8). Xia et al. analyzed the differentiallyexpressed necroptosis-related lncRNAs and their possible impacton the overall survival of glioma patients. The risk score modeldeveloped by the authors according to nine necroptosis-relatedlncRNAs allowed the prediction of the prognosis of glioma patients.The detection of circulating tumor cells (CTCs) is a promisingtechnology in tumor management (9). A karyoplasmic ratio (KR)-based identification method was developed by Zhu X. et al.. Anautomatic recognition algorithm was constructed, to determinethe correlation between patients’ clinical characteristics and high-KR circulating tumor cells. This study revealed a correlationbetween CTCs and patients’ clinical characteristics and increasedthe efficiency of detecting glioma CTCs.Liquid biopsy is a minimally invasive method of analysisof molecular biomarkers (e.g., circulating tumor cells, cell-freeDNA) starting from any type of patient’s body fluid (e.g., plasma,urine, bile, pleural effusion, and cerebrospinal fluid). The lackof permeability of the blood-brain barrier (BBB) may limit therelease of ctDNA into the blood. However, it has been shown thatexosomes microvesicles and apoptotic vesicles can all cross theintact BBB, and then peripheral blood may be sometimes usedfor analysis of circulating markers in glioma (10). Balana et al.reviewed several studies using radiogenomics and liquid biopsyin the characterization of gliomas. The authors demonstrated thatliquid biopsies and radiogenomics will likely be used initially foradditional diagnostic information that could be incorporated intoroutine clinical practice in the future.Micro-RNAs are one of the circulating markers that can beanalyzed in peripheral blood in patients with gliomas (11). Xuet al. have studied the potential clinical role of miR-4297 inglioma. The authors observed that miR-4297 levels were higher infemales with high-grade glioma, but not in male patients, and ahigher level of miR-4297 had been associated with a higher risk ofglioma recurrence.In the study by Liu X. et al. specific urine metabolitesof Medulloblastoma (MB) were identified using liquid-chromatography–mass spectrometry (LC–MS)-basedmetabolomics. MB was distinguished with high diagnosticaccuracy from non-MB by the combination of cortolone andtetrahydrocortisone, demonstrating that urine metabolomicsmight be also used for MB monitoring.Based on the recent tumor classification, a comprehensiveapproach to molecular testing in the adolescents and young adults(AYA; aged 15–39) was proposed by Lim-Fat et al.. This reviewwill help in improving the classification and identification of braintumors in the AYA population.Liu D. et al. explored tumor habitat characteristicsin the peritumoral and intratumoral regions, to help indistinguishing primary central nervous system lymphoma(LMPA), common malignant brain tumors, and brain metastases.Quantitative radiomics features provide a useful tool for thenon-invasive assessment of a CNS tumor. The model classifiercan preoperatively differentiate GBM from brain metastasesand LMPA by incorporating peritumoral information intothe model.High-grade glioma (HGG) and primary central nervoussystem lymphoma look similar under imaging. Zhang et al.performed a systematic metanalysis to determine the efficacyof 18F-fluorodeoxyglucose positron emission tomography-computed tomography (18F-FDG-PET/CT) in distinguishingPCNSL and HGG. According to their data, 18F-FDG-PET/CThad high accuracy for the differential diagnosis of HGGand PNCSL.Artificial intelligence technologies, such as machine learning(ML), have improved radiomics predictive performance. Baharet al. have systematically reviewed studies describing ML modelsfor glioma grade prediction and evaluated the possibility ofbringing ML from bench to clinic. The review highlightedthat studies using ML applied to glioma had reported a highpredictive accuracy. However, the authors have also demonstratedthat to increase the standardization and the reproducibilityof this technique in the glioma field, it is crucial to trainand test on large, multi-institutional datasets, and adhere toreporting guidelines.Anti-silencing function-1-B (ASF1B) belongs to thehistone chaperone H3/H4 family. This protein is mainlyinvolved in the regulation of cell proliferation and may be apotential prognostic marker in several tumors. Zhu H. et al.evaluated the role of ASF1B expression levels in gliomas.Transcriptomic clinical data were downloaded from threedatabases (genotypic tissue expression—GTEx, The CancerGenome Atlas database—TCGA, and the Chinese GliomasGenome Atlas database) and ASF1B levels were investigatedin association with clinical variables. Authors found thathigh levels of ASF1B were associated with poor outcomes forglioma patients.ConclusionsRecently we have observed the advent of new advancedmethodologies, bioinformatics, and genomic investigations; weare now witnessing the impact of these advances in thestudy of brain tumors. The collection of articles on thisResearch Topic encompasses the extent of attempts beingdone to advance scientific research, clinical diagnosis, andtherapeutic development; these efforts are needed to obtainthe aim of improving and lengthening the life of braintumor patients.Frontiers inMedicine 03 frontiersin.orgde Biase et al. 10.3389/fmed.2023.1152547Author contributionsAll authors listed have made a substantial, direct, andintellectual contribution to the work and approved itfor publication.Conflict of interestThe authors declare that the research was conductedin the absence of any commercial or financial relationshipsthat could be construed as a potential conflictof interest.Publisher’s noteAll claims expressed in this article are solely those of theauthors and do not necessarily represent those of their affiliatedorganizations, or those of the publisher, the editors and thereviewers. Any product that may be evaluated in this article, orclaim that may be made by its manufacturer, is not guaranteed orendorsed by the publisher.References1. Brat DJ, Ellison DW, Figarella-Brangen D, eds. WHO Classification of Tumours.Central Nervous System Tumours. 5th ed. Lyon: International Agency for Research onCancer (2021).2. Bale TA, Rosenblum MK. The 2021 WHO classification of tumors of the centralnervous system: an update on pediatric lowgrade gliomas and glioneuronal tumors.Brain Pathol. (2022) 32:e13060. doi: 10.1111/bpa.130603. Capper D, Stichel D, Sahm F, Jones DTW, Schrimpf D, Sill M, et al.Practical implementation of DNA methylation and copy-number-based CNStumor diagnostics: the Heidelberg experience. Acta Neuropathol. (2018) 136:181–210. doi: 10.1007/s00401-018-1879-y4. Network NCC “Central Nervous System Cancers (Version: 2.2021). Available onlineat: https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1425 (accessedJanuary 26, 2023).5. Giraldo NA, Sanchez-Salas R, Peske JD, Vano Y, Becht E, Petitprez F,et al. The clinical role of the tme in solid cancer. Br J Cancer. (2019) 120:45–53. doi: 10.1038/s41416-018-0327-z6. Bausart M, Préat V, Malfanti A. Immunotherapy for glioblastoma:the promise of combination strategies. J Exp Clin Cancer Res. (2022)41:35. doi: 10.1186/s13046-022-02251-27. Ding L, Li W, Tu J, Cao Z, Li J, Cao H, et al. Identification of cuproptosis-related subtypes, cuproptosis-related geneprognostic index in hepatocellularcarcinoma. Front Immunol. (2022) 13:989156. doi: 10.3389/fimmu.2022.9891568. Galluzzi L, Vitale I, Aaronson SA, Abrams JM, AdamD, Agostinis P, et al. Molecular mechanisms of cell death:recommendations of the Nomenclature Committee on Cell Death.Cell Death Differ. (2018) 25:486–541. doi: 10.1038/s41418-017-0012-49. Deng Z, Wu S, Wang Y, Shi D. Circulating tumor cell isolation for cancerdiagnosis and prognosis. EBioMedicine. (2022) 83:104237. doi: 10.1016/j.ebiom.2022.10423710. Banks WA, Sharma P, Bullock KM, Hansen KM, Ludwig N, WhitesideTL. Transport of extracellular vesicles across the blood-brain barrier:brain pharmacokinetics and effects of inflammation. Int J Mol Sci. (2020)21:4407. doi: 10.3390/ijms2112440711. Sufianov A, Begliarzade S, Ilyasova T, Liang Y, Beylerli O.MicroRNAs asprognostic markers and therapeutic targets in gliomas.Noncoding RNA Res. (2022) 7:171–7. doi: 10.1016/j.ncrna.2022.07.001Frontiers inMedicine 04 frontiersin.org

Editorial: Advances in brain tumors diagnosis and treatment

Dario de Biase

Enrico Franceschi

Gianluca Marucci

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Editorial: Advances in brain tumors diagnosis and treatment

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Archivio istituzionale della ricerca - Alma Mater Studiorum Università di Bologna

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