Loss of methylthioadenosine phosphorylase immunoreactivity correlates with poor prognosis and elevated uptake of 11C-methionine in IDH-mutant astrocytoma.

PURPOSE: The proximate localization of MTAP, which encodes methylthioadenosine phosphorylase, and CDKN2A/B on Chromosome 9q21 has allowed the loss of MTAP expression as a surrogate for homozygous deletion of CDKN2A/B. This study aimed to determine whether MTAP status correlates with clinical outcomes and 11C-methionine uptake in astrocytomas with IDH mutations. METHODS: We conducted immunohistochemistry for MTAP in 30 patients with astrocytoma, IDH-mutant who underwent 11C-methionine positron emission tomography scans prior to surgical resection. The tumor-to-normal (T/N) ratio of 11C-methionine uptake was calculated using the mean standardized uptake value (SUV) for tumor and normal brain tissues. Cox regression analysis was used for multivariate survival analysis. RESULTS: Among IDH-mutant astrocytomas, 26.7% (8/30) exhibited the loss of cytoplasmic MTAP expression, whereas 73.3% (22/30) tumors retained MTAP expression. The median progression-free survival (PFS) was significantly shorter in patients with MTAP loss than those with MTAP retention (1.88 years vs. 6.80 years, p = 0.003). The median overall survival (OS) was also shorter in patients with MTAP loss than in MTAP-retaining counterparts (5.23 years vs. 10.69 years, p = 0.019). Multivariate analysis identified MTAP status (hazard ratio (HR), 0.081) and extent of resection (HR, 0.104) as independent prognostic factors for PFS. Astrocytomas lacking cytoplasmic MTAP expression showed a significantly higher median T/N ratio for 11C-methionine uptake than tumors retaining MTAP (2.12 vs. 1.65, p = 0.012). CONCLUSION: Our study revealed that the loss of MTAP expression correlates with poor prognosis and an elevated T/N ratio of 11C-methionine uptake in astrocytoma, IDH-mutant.

Predictors of tumour dynamics over a 6-week course of concurrent chemoradiotherapy for glioblastoma and the impact on survival.

PURPOSE: We present the final analyses of tumour dynamics and their prognostic significance during a 6-week course of concurrent chemoradiotherapy (chemoRT) for glioblastoma (GBM) in the GLIO study. METHODS AND MATERIALS: This is a prospective serial MR imaging study in 129 patients with GBM who had MRIs obtained at RT planning (F0), fraction-10 (F10), fraction-20 (F20), and 1-month post-RT. Tumour dynamics assessed included gross tumour volume (GTV) relative to F0 (Vrel), and tumour migration distance (dmigration). Covariables evaluated included: corpus callosum involvement, extent of surgery, MGMT methylation and IDH mutation status. RESULTS: The median Vrel were 0.85 (range: 0.25-2.29) at F10, 0.79 (range: 0.09-2.22) at F20 and 0.78 (range: 0.13-4.27) at P1M. The median dmigration were 4.7mm (range: 1.1-20.4mm) at F10, 4.7mm (range: 0.8-20.7mm) at F20 and 6.1mm (range: 0.0-45.5mm) at P1M. Compared to patients who had corpus callosum involvement (n=26), those without corpus callosum involvement (n=103) had significant Vrel reduction at F20 (P=0.03) and smaller dmigration at F20 (P=0.007). Compared to patients who had biopsy alone (n=19) and subtotal resection (n=71), those who had gross total resection (n=38) had significant Vrel reduction at F10 (P=0.001) and F20 (P=0.001) and a smaller dmigration at F10 (P=0.03) and F20 (P=0.002). MGMT methylation and IDH mutation status were not significantly associated with tumour dynamics. The median progression free survival and overall survival (OS) were 8.5 months (95%CI=6.9-9.9) and 20.4 months (95%CI=17.6-25.2). In multivariable analyses, patients with Vrel≥1.33 at F10 had worse OS (HR=4.6; 95%CI=1.8-11.4; P=0.001), while patients with dmigration≥5mm at 1-month post-RT had worse PFS (HR=1.76; 95%CI=1.08-2.87) and OS (HR=2.2; 95%CI=1.2-4.0; P=0.007). CONCLUSION: Corpus callosum involvement and extent of surgery are independent predictors of tumour dynamics during RT and can enable patient selection for adaptive RT strategies. Significant tumour enlargement at F10 and tumour migration 1-month post-RT were associated with poorer OS.

Pediatric-Like Brain Tumors in Adults.

Pediatric brain tumors are different to those found in adults in pathological type, anatomical site, molecular signature, and probable tumor drivers. Although these tumors usually occur in childhood, they also rarely present in adult patients, either as a de novo diagnosis or as a delayed recurrence of a pediatric tumor in the setting of a patient that has transitioned into adult services.Due to the rarity of pediatric-like tumors in adults, the literature on these tumor types in adults is often limited to small case series, and treatment decisions are often based on the management plans taken from pediatric studies. However, the biology of these tumors is often different from the same tumors found in children. Likewise, adult patients are often unable to tolerate the side effects of the aggressive treatments used in children-for which there is little or no evidence of efficacy in adults. In this chapter, we review the literature and summarize the clinical, pathological, molecular profile, and response to treatment for the following pediatric tumor types-medulloblastoma, ependymoma, craniopharyngioma, pilocytic astrocytoma, subependymal giant cell astrocytoma, germ cell tumors, choroid plexus tumors, midline glioma, and pleomorphic xanthoastrocytoma-with emphasis on the differences to the adult population.

EGFR/CEP7 high polysomy is separate and distinct from EGFR amplification in glioblastoma as determined by fluorescence in situ hybridization.

EGFR amplification in gliomas is commonly defined by an EGFR/CEP7 ratio of ≥2. In testing performed at a major reference laboratory, a small subset of patients had ≥5 copies of both EGFR and CEP7 yet were not amplified by the EGFR/CEP7 ratio and were designated high polysomy cases. To determine whether these tumors are more closely related to traditionally defined EGFR-amplified or nonamplified gliomas, a retrospective search identified 22 out of 1143 (1.9%) gliomas with an average of ≥5 copies/cell of EGFR and CEP7 with an EGFR/CEP7 ratio of <2 displaying high polysomy. Of these cases, 4 had insufficient clinicopathologic data to include in additional analysis, 15 were glioblastomas, 2 were IDH-mutant astrocytomas, and 1 was a high-grade glial neoplasm, NOS. Next-generation sequencing available on 3 cases demonstrated one with a TERT promoter mutation, TP53 mutations in all cases, and no EGFR mutations or amplifications, which most closely matched the nonamplified cases. The median overall survival times were 42.86, 66.07, and 41.14 weeks for amplified, highly polysomic, and nonamplified, respectively, and were not significantly different (p = 0.3410). High chromosome 7 polysomic gliomas are rare but our data suggest that they may be biologically similar to nonamplified gliomas.

Status epilepticus in patients with brain tumors and metastases: A multicenter cohort study of 208 patients and literature review.

OBJECTIVE: Brain tumors and metastases account for approximately 10% of all status epilepticus (SE) cases. This study described the clinical characteristics, treatment, and short- and long-term outcomes of this population. METHODS: This retrospective, multi-center cohort study analyzed all brain tumor patients treated for SE at the university hospitals of Frankfurt and Marburg between 2011 and 2017. RESULTS: The 208 patients (mean 61.5 ± 14.7 years of age; 51% male) presented with adult-type diffuse gliomas (55.8%), metastatic entities (25.5%), intracranial extradural tumors (14.4%), or other tumors (4.3%). The radiological criteria for tumor progression were evidenced in 128 (61.5%) patients, while 57 (27.4%) were newly diagnosed with tumor at admission and 113 (54.3%) had refractory SE. The mean hospital length of stay (LOS) was 14.8 days (median 12.0, range 1-57), 171 (82.2%) patients required intensive care (mean LOS 8.9 days, median 5, range 1-46), and 44 (21.2%) were administered mechanical ventilation. All patients exhibited significant functional status decline (modified Rankin Scale) post-SE at discharge (p < 0.001). Mortality at discharge was 17.3% (n = 36), with the greatest occurring in patients with metastatic disease (26.4%, p = 0.031) and those that met the radiological criteria for tumor progression (25%, p < 0.001). Long-term mortality at one year (65.9%) was highest in those diagnosed with adult-type diffuse gliomas (68.1%) and metastatic disease (79.2%). Refractory status epilepticus cases showed lower survival rates than non-refractory SE patients (log-rank p = 0.02) and those with signs of tumor progression (log-rank p = 0.001). CONCLUSIONS: SE occurrence contributed to a decline in functional status in all cases, regardless of tumor type, tumor progression status, and SE refractoriness, while long-term mortality was increased in those with malignant tumor entities, tumor progressions, and refractory SE. SE prevention may preserve functional status and improve survival in individuals with brain tumors.

Rare dual-genotype IDH mutant glioma: Review of previously reported cases and two new cases of true "oligoastrocytoma".

In 2016, the World Health Organization (WHO) eliminated "oligoastrocytoma" from the classification of central nervous system (CNS) tumors, in favor of an integrated histologic and molecular diagnosis. Consistent with the 2016 classification, in the 2021 classification, oligodendrogliomas are defined by mutations in isocitrate dehydrogenase (IDH) with concurrent 1p19q codeletion, while astrocytomas are IDH mutant tumors, usually with ATRX loss. In 2007, a 24-year-old man presented with a brain tumor histologically described as astrocytoma, but with molecular studies consistent with an oligodendroglioma, IDH mutant and 1p19q-codeleted. Years later, at resection, pathology revealed an astrocytoma, with variable ATRX expression and mutations of IDH, ATRX, TP53, and TERT by DNA sequencing. Fluorescence in situ hybridization studies confirmed 1p19q codeletion in sections of the tumor shown to histologically retain ATRX expression. Separately, in 2017, a 36-year-old woman presented with a frontal brain tumor with pathology consistent with an oligodendroglioma, IDH mutant and 1p19q-codeleted. Two years later, pathology revealed an astrocytoma, IDH1 mutant, with ATRX loss. These two cases likely represent the rare occurrence of dual-genotype IDH mutant infiltrating glioma. Nine cases of dual-genotype IDH mutant glioma were previously reported in the literature. We present two cases in which this distinct molecular phenotype is present in a tumor in the same location with surgeries at two points in time, both with 1p19q codeletion and ATRX loss at the time of resection. Whether this represents a true "collision tumor" or genetic switching over time is not known, but the co-occurrence of these hybrid mutations supports a diagnosis of dual-genotype IDH mutant glioma.

Transmembrane Protein TMEM230, Regulator of Glial Cell Vascular Mimicry and Endothelial Cell Angiogenesis in High-Grade Heterogeneous Infiltrating Gliomas and Glioblastoma.

High-grade gliomas (HGGs) and glioblastoma multiforme (GBM) are characterized by a heterogeneous and aggressive population of tissue-infiltrating cells that promote both destructive tissue remodeling and aberrant vascularization of the brain. The formation of defective and permeable blood vessels and microchannels and destructive tissue remodeling prevent efficient vascular delivery of pharmacological agents to tumor cells and are the significant reason why therapeutic chemotherapy and immunotherapy intervention are primarily ineffective. Vessel-forming endothelial cells and microchannel-forming glial cells that recapitulate vascular mimicry have both infiltration and destructive remodeling tissue capacities. The transmembrane protein TMEM230 (C20orf30) is a master regulator of infiltration, sprouting of endothelial cells, and microchannel formation of glial and phagocytic cells. A high level of TMEM230 expression was identified in patients with HGG, GBM, and U87-MG cells. In this study, we identified candidate genes and molecular pathways that support that aberrantly elevated levels of TMEM230 play an important role in regulating genes associated with the initial stages of cell infiltration and blood vessel and microchannel (also referred to as tumor microtubule) formation in the progression from low-grade to high-grade gliomas. As TMEM230 regulates infiltration, vascularization, and tissue destruction capacities of diverse cell types in the brain, TMEM230 is a promising cancer target for heterogeneous HGG tumors.

Endoplasmic Reticulum Stress in Gliomas: Exploiting a Dual-Effect Dysfunction through Chemical Pharmaceutical Compounds and Natural Derivatives for Therapeutical Uses.

The endoplasmic reticulum maintains proteostasis, which can be disrupted by oxidative stress, nutrient deprivation, hypoxia, lack of ATP, and toxicity caused by xenobiotic compounds, all of which can result in the accumulation of misfolded proteins. These stressors activate the unfolded protein response (UPR), which aims to restore proteostasis and avoid cell death. However, endoplasmic response-associated degradation (ERAD) is sometimes triggered to degrade the misfolded and unassembled proteins instead. If stress persists, cells activate three sensors: PERK, IRE-1, and ATF6. Glioma cells can use these sensors to remain unresponsive to chemotherapeutic treatments. In such cases, the activation of ATF4 via PERK and some proteins via IRE-1 can promote several types of cell death. The search for new antitumor compounds that can successfully and directly induce an endoplasmic reticulum stress response ranges from ligands to oxygen-dependent metabolic pathways in the cell capable of activating cell death pathways. Herein, we discuss the importance of the ER stress mechanism in glioma and likely therapeutic targets within the UPR pathway, as well as chemicals, pharmaceutical compounds, and natural derivatives of potential use against gliomas.

Comparison of MRI findings of hypothalamic-optic chiasmatic gliomas and craniopharyngiomas.

BACKGROUND: Differential diagnosis of hypothalamic-optic chiasmatic gliomas (HOCGs) and craniopharyngiomas on magnetic resonance imaging (MRI) can be quite challenging. PURPOSE: To compare the MRI features of HOCGs and cranipharyngiomas. MATERIAL AND METHODS: Patients diagnosed with HOCG or craniopharyngioma in histopathological evaluation between 2012 and 2022 and who underwent preoperative contrast-enhanced brain MRI were included. Various MRI features were retrospectively evaluated for each lesion: T2-weighted imaging and fluid attenuation inversion recovery hyperintensity, calcification, cystic change, T1-weighted (T1W) imaging hyperintensity of the cystic component, hemorrhage, involvement of sellar, suprasellar or other adjacent structures, lobulated appearance, presence of hydrocephalus, and contrast enhancement pattern. Apparent diffusion coefficient (ADC) values were also evaluated and compared. RESULTS: Among 38 patients included, 13 (34%) had HOCG and 25 (66%) had craniopharyngioma. Craniopharyngiomas had a significantly higher rate of cystic changes, calcification, and T1W imaging hyperintensity of the cystic component than HOCGs (P <0.05). Of HOCGs, 92% had chiasm involvement, 23% had optic nerve involvement, and 31% had brain stem involvement. On the other hand, chiasm involvement was observed in 8% of craniopharyngiomas, but none had optic nerve and/or brain stem involvement (P <0.05). While 62% (8/13) of HOCGs had diffuse homogeneous enhancement, 80% (20/25) of craniopharyngiomas had a diffuse heterogeneous enhancement pattern. Mean ADC values were significantly higher in craniopharyngiomas compared to HOCGs (2.1 vs. 1.6 ×10-3mm2/s, P <0.05). CONCLUSION: Although some neuroimaging findings may overlap, features such as presence of cyst and calcification, brain stem and optic pathway involvement, different enhancement patterns, and ADC values may be helpful in the differential diagnosis of HOCGs and craniopharyngiomas.

Rare vermian pilocytic astrocytoma with recurrent spontaneous hemorrhage in the elderly: A case report and review of literature.

Background: Pilocytic astrocytoma (PA) is a benign glial tumor predominately seen in pediatrics and early adolescence with associated overall good outcomes. Very few cases of elderly PA have been reported in the literature, and they are known to display unique anatomic, histologic, and genetic peculiarities distinct from pediatric disease. We report a rare case of vermian PA in an octogenarian with recurrent spontaneous intratumoral hemorrhage as a presenting symptom. Furthermore, a review of the literature on the peculiarities of PA in the elderly will be discussed. Case Description: An 81-year-old woman presented with features suggestive of repeated posterior fossa hemorrhages characterized by headaches, diplopia, and alteration in sensorium occurring about 5 months apart. Brain neuroimaging showed a cerebellar vermian tumor with features suggestive of repeated intratumoral bleeding. She had an initial ventriculoperitoneal shunting for acute hydrocephalus and subsequently had a suboccipital craniotomy and subtotal tumor excision due to morbid adherence to the brainstem. The histologic diagnosis was PA with Ki-67 <1% and negative for isocitrate dehydrogenase-1. There was a slow but progressive clinical improvement, and she has remained symptom-free for 4 years on follow-up. Conclusion: PA in the elderly is a rare disease with distinct histologic and genetic peculiarities. This case review showed one of the oldest cases of cerebellar vermian PA presenting with recurrent spontaneous intratumoral hemorrhage, an extremely rare occurrence in benign glioma. Although complete surgical excision is recommended, partial resection is advocated for morbidly adherent tumors. Overall prognosis is worse in elderly PA.

SEOM-GEINO clinical guidelines for grade 2 gliomas (2023).

The 2021 World Health Organization (WHO) classification has updated the definition of grade 2 gliomas and the presence of isocitrate dehydrogenase (IDH) mutation has been deemed the cornerstone of diagnosis. Though slow-growing and having a low proliferative index, grade 2 gliomas are incurable by surgery and complementary treatments are vital to improving prognosis. This guideline provides recommendations on the multidisciplinary treatment of grade 2 astrocytomas and oligodendrogliomas based on the best evidence available.

Role of sodium fluorescein in pediatric low-grade glioma surgery: an update.

PURPOSE: Complete surgical resection is still the mainstay in the treatment of central nervous system low-grade tumors, eventually resulting curative. The complete surgical removal of these lesions, however, may be difficult in some cases because of their infiltrative nature. Intraoperative adjuncts may be a game changer. Sodium fluorescein (SF) is among the ideal candidates as intraoperative tools to favor the actual recognition of the tumor extension, since it accumulates in areas of altered blood-brain barrier, a typical characteristic of pediatric gliomas, and has a low rate of adverse events. This work proposes an update of previous works about the evaluation of the feasibility and usefulness of a systematic use of SF in a low-grade lesion group of pediatric patients. METHODS: Pediatric patients operated on for a resection or a biopsy of a low-grade glial or glioneuronal lesion (WHO grade I and II) at our Institution between September 2021 and December 2023, with the intraoperative use of sodium fluorescein (SF), were enrolled in the study. We collected pre-operative and postoperative clinical and radiological data, intraoperative findings, and post-operative pathological diagnoses. RESULTS: No adverse events were registered related to the intraoperative use of SF. SF appeared useful for the localization of boundaries of tumors, especially when characterized by a high degree of infiltration or by a deep-seated location, and for the checking of possible tumor remnants at the end of surgery. A good tumor-to-healthy tissue contrast was registered when tumor visualization was in a range between 1 to 2 h and 30 min after SF injection. Possible "false positives" due to intraoperative vascular wall injury and clearance of SF from both tumor and healthy tissue were observed in some cases and still remain open issues. CONCLUSIONS: SF is a feasible and safe intraoperative adjunct tool in the surgical removal of pediatric low-grade tumors. SF may show its usefulness especially in selected cases, such as deep-seated lesions and infiltrating tumors. Its safety profile, user-friendly management, and potential utility in both tumor resections and neuronavigated biopsies favor its wider use in the surgical treatment of pediatric low-grade tumors.

Rare Coexistence: Pilocytic Astrocytoma With Atypical Teratoid/Rhabdoid Tumor Features in an Infant.

This case report describes the presentation, diagnostic evaluation, and management challenges encountered in an eight-month-old female infant with fever, seizure, and a large cystic brain lesion initially diagnosed as pilocytic astrocytoma but later demonstrating atypical teratoid/rhabdoid tumor (AT/RT) features on histopathological examination-the infant presented with a fever and cold persisting for 10 days, followed by a seizure episode. Laboratory investigations revealed abnormalities, including anemia and leukocytosis. Imaging studies identified a large cystic lesion causing hydrocephalus. Despite initial treatment, the patient continued to experience seizures, prompting surgical intervention. Debulking surgery was performed, resulting in postoperative motor deficits. Subsequent imaging revealed persistent lesions, leading to further surgical intervention with shunt placement. Histopathological examination confirmed pilocytic astrocytoma with features suggestive of AT/RT. Despite counseling regarding poor prognosis and recommendations for chemotherapy, the parents declined further treatment, and the patient was discharged. This case underscores the diagnostic complexity and therapeutic dilemmas associated with rare histological overlaps in pediatric brain tumors, emphasizing the importance of multidisciplinary collaboration and tailored treatment strategies for optimal patient care.

Radiological characterization of pediatric intramedullary astrocytomas: Do they differ from adults?

Introduction: The incidence of intramedullary spinal cord tumors ranges from 2 to 4% of all central nervous system tumors. Only 6-8% are astrocytomas. The gold standard to diagnose a spinal cord tumor is the spinal cord MRI in toto. Specific radiological criteria orient the diagnosis of the intradural intramedullary lesion. Most of the authors studied adult populations of astrocytomas. However, pediatric astrocytomas present certain particularities. Research question: This work aims to determine if the usual radiological criteria of intramedullary astrocytomas (IMAs) are different depending on the patient's age. Material & methods: We evaluated the radiological features of IMAs in adult and pediatric groups through a retrospective study. Results: We collected 31 patients with IMAs (11 children and 20 adults). We observed some trends but we did not highlight any statistically significant difference between all the radiological criteria studied (sagittal and axial spinal cord localization, T1-and T2-weighted characteristics, contrast uptake, infiltrating character, presence of necrosis, heterogeneous lesion, necrotic, hemorrhagic, presence of edema) and the patient's age. Discussion & conclusion: Given the rarity of IMAs and the lack of large specific pediatric studies, it seems essential to routinely report all cases encountered and create multicentric pediatric databases to draw more robust conclusions.

Molecular insights and the role of 18F-FDG-PET/CT in the diagnosis of spinal gliomas.

BACKGROUND: In recent years, molecular findings on spinal gliomas have become increasingly important. This study aimed to investigate the role of 18F-fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG-PET/CT) in the diagnosis of spinal glioma. METHODS: This study included patients diagnosed with spinal cord glioma who underwent 18F-FDG-PET examination at the Department of Neurosurgery, Nagoya University Hospital between January 2016 and November 2023. The gliomas were divided into two groups, high-grade and low-grade, based on pathological and molecular studies. The maximum standardized uptake values (SUVmax) of the tumors were quantified and subsequently represented using receiver operating characteristic (ROC) curves. RESULTS: Eighteen participants were included in this study. Of the participants, seven had high-grade glioma with an SUVmax of 6.76 ± 0.72, and eleven had low-grade glioma with an SUVmax of 4.02 ± 1.78, and a statistically significant difference between the two groups. The ROC curve delineated an SUVmax cutoff value of 5.650, with an area under the curve (AUC) of approximately 0.909. Based on the cutoff value, the results of the diagnostic performance rendered a sensitivity and negative predictive value of 1.0, whereas the specificity and positive predictive value were 0.909 and 0.875, respectively. CONCLUSIONS: The present study shows that 18F-FDG-PET exhibits a markedly sensitive and negative predictive value in the assessment of spinal gliomas. Additionally, these findings have potential implications for the qualitative assessment of spinal gliomas using 18F-FDG-PET/CT. This imaging modality may be useful for making timely treatment decisions in situations where a detailed diagnosis by molecular analysis is not possible.

Unusual Extra-Axial and Extracranial Recurrence in an IDH Mutant Astrocytoma: A Case Report.

Isocitrate dehydrogenase mutant gliomas generally have a better prognosis than their wild-type counterpart. Recurrences are generally within the radiation field in the primary tumoral bed. Remote recurrence is uncommon and is usually intraparenchymal. Transformation to a higher grade has been observed with TP53 mutants. Presentation of glioma as an extra-axial lesion is extremely uncommon. No such cases of remote intracranial extra-axial recurrence have been reported in the literature. We describe the unique imaging findings in this case and attempt to formulate possible diagnoses. Intraoperative and pathological findings confirmed this unusual recurrence pattern.

Updates on management of gliomas in the molecular age.

Gliomas are primary brain tumors derived from glial cells of the central nervous system, afflicting both adults and children with distinct characteristics and therapeutic challenges. Recent developments have ushered in novel clinical and molecular prognostic factors, reshaping treatment paradigms based on classification and grading, determined by histological attributes and cellular lineage. This review article delves into the diverse treatment modalities tailored to the specific grades and molecular classifications of gliomas that are currently being discussed and used clinically in the year 2023. For adults, the therapeutic triad typically consists of surgical resection, chemotherapy, and radiotherapy. In contrast, pediatric gliomas, due to their diversity, require a more tailored approach. Although complete tumor excision can be curative based on the location and grade of the glioma, certain non-resectable cases demand a chemotherapy approach usually involving, vincristine and carboplatin. Additionally, if surgery or chemotherapy strategies are unsuccessful, Vinblastine can be used. Despite recent advancements in treatment methodologies, there remains a need of exploration in the literature, particularly concerning the efficacy of treatment regimens for isocitrate dehydrogenase type mutant astrocytomas and fine-tuned therapeutic approaches tailored for pediatric cohorts. This review article explores into the therapeutic modalities employed for both adult and pediatric gliomas in the context of their molecular classification.

Proteomic Profiling of Cerebrospinal Fluid and Its Extracellular Vesicles from Extraventricular Drainage in Pediatric Pilocytic Astrocytoma, towards Precision Oncology.

Pediatric pilocytic astrocytoma (PA) is the most common brain tumor in children. Complete resection provides a favorable prognosis, except for unresectable PA forms. There is an incomplete understanding of the molecular and cellular pathogenesis of PA. Potential biomarkers for PA patients, especially the non-BRAF-mutated ones are needed. Cerebrospinal fluid (CSF) is a valuable source of brain tumor biomarkers. Extracellular vesicles (EVs), circulating in CSF, express valuable disease targets. These can be isolated from CSF from waste extraventricular drainage (EVD). We analyzed the proteome of EVD CSF from PA, congenital hydrocephalus (CH, non-tumor control), or medulloblastoma (MB, unrelated tumoral control) patients. A total of 3072 proteins were identified, 47.1%, 65.6%, and 86.2% of which were expressed in the unprocessed total and in its large-EV (LEV), and small-EV (SEV) fractions. Bioinformatics identified 50 statistically significant proteins in the comparison between PA and HC, and PA and MB patients, in the same fractions. Kinase enrichment analysis predicted five enriched kinases involved in signaling. Among these, only Cyclin-dependent kinase 2 (CDK2) kinase was overexpressed in PA samples. PLS-DA highlighted the inactive carboxypeptidase-like protein X2 (CPXM2) and aquaporin-4 (AQP4) as statistically significant in all the comparisons, with CPXM2 being overexpressed (validated by ELISA and Western blot) and AQP4 downregulated in PA. These proteins were considered the most promising potential biomarkers for discriminating among pilocytic astrocytoma and unrelated tumoral (MB) or non-tumoral conditions in all the fractions examined, and are proposed to be prospectively validated in the plasma for translational medicine applications.