The neurotrophic tropomyosin receptor kinase (NTRK) genes (NTRK1, NTRK2, and NTRK3) code for three transmembrane high-affinity tyrosine-kinase receptors for nerve growth factors (TRK-A, TRK-B, and TRK-C) which are mainly involved in nervous system development. Loss of function alterations in these genes can lead to nervous system development problems; conversely, activating alterations harbor oncogenic potential, promoting cell proliferation/survival and tumorigenesis. Chromosomal rearrangements are the most clinically relevant alterations of pathological NTRK activation, leading to constitutionally active chimeric receptors. NTRK fusions have been detected with extremely variable frequencies in many pediatric and adult cancer types, including central nervous system (CNS) tumors. These alterations can be detected by different laboratory assays (e.g., immunohistochemistry, FISH, sequencing), but each of these approaches has specific advantages and limitations which must be taken into account for an appropriate use in diagnostics or research. Moreover, therapeutic targeting of this molecular marker recently showed extreme efficacy. Considering the overall lack of effective treatments for brain neoplasms, it is expected that detection of NTRK fusions will soon become a mainstay in the diagnostic assessment of CNS tumors, and thus in-depth knowledge regarding this topic is warranted.

Objective: Intradural Extramedullary (IDEM) tumors are usually treated with surgical excision. The aim of this study was to investigate the impact on clinical outcomes of pre-surgical clinical conditions, intraoperative neurophysiological monitoring (IONM), surgical access to the spinal canal, histology, degree of resection and intra/postoperative complications.Methods: This is a retrospective observational study analyzing data of patients suffering from IDEM tumors who underwent surgical treatment over a 12 year period in a double-center experience. Data were extracted from a prospectively maintained database and included: sex, age at diagnosis, clinical status according to the modified McCormick Scale (Grades I-V) at admission, discharge, and follow-up, tumor histology, type of surgical access to the spinal canal (bilateral laminectomy vs. monolateral laminectomy vs. laminoplasty), degree of surgical removal, use and type of IONM, occurrence and type of intraoperative complications, use of Ultrasonic Aspirator (CUSA), radiological follow-up.Results: A total number of 249 patients was included with a mean follow-up of 48.3 months. Gross total resection was achieved in 210 patients (84.3%) mostly in Schwannomas (45.2%) and Meningiomas (40.4%). IONM was performed in 162 procedures (65%) and D-wave was recorded in 64.2% of all cervical and thoracic locations (99 patients). The linear regression diagram for McCormick grades before and after surgery (follow-up) showed a correlation between preoperative and postoperative clinical status. A statistically significant correlation was found between absence of worsening of clinical condition at follow-up and use of IONM at follow-up (p = 0.01) but not at discharge. No associations were found between the choice of surgical approach and the extent of resection (p = 0.79), the presence of recurrence or residual tumor (p = 0.14) or CSF leakage (p = 0.25). The extent of resection was not associated with the use of IONM (p = 0.91) or CUSA (p = 0.19).Conclusion: A reliable prediction of clinical improvement could be made based on pre-operative clinical status. The use of IONM resulted in better clinical outcomes at follow-up (not at discharge), but no associations were found with the extent of resection. The use of minimally invasive approaches such as monolateral laminectomy showed to be effective and not associated with worse outcomes or increased complications.

Despite the multidisciplinary management in the treatment of glioblastomas, the average survival of GBM patients is still 15 months. In recent years, molecular biomarkers have gained more and more importance both in the diagnosis and therapy of glial tumors. At the same time, it has become clear that non neoplastic cells, which constitute about 30% of glioma mass, dramatically influence tumor growth, spread, and recurrence. This is the main reason why, in recent years, scientific research has been focused on understanding the function and the composition of tumor microenvironment and its role in gliomagenesis and recurrence. The aim of this review is to summarize the most recent discovery about resident microglia, tumor-associated macrophages, lymphocytes, and the role of extracellular vesicles and their bijective interaction with glioma cells. Moreover, we reported the most recent updates about new therapeutic strategies targeting immune system receptors and soluble factors. Understanding how glioma cells interact with non-neoplastic cells in tumor microenvironment is an essential step to comprehend mechanisms at the base of disease progression and to find new therapeutic strategies for GBM patients. However, no significant results have yet been obtained in studies targeting single molecules/pathways; considering the complex microenvironment, it is likely that only by using multiple therapeutic agents acting on multiple molecular targets can significant results be achieved.

Abstract BACKGROUND Gliomas are the most common malignant primary brain tumors. Assessment of the tumor volume represents a crucial point in preoperative and postoperative evaluation. OBJECTIVE To compare pre- and postoperative tumor volumes obtained with an automated, semi-automatic, and manual segmentation tool. Mean processing time of each segmentation techniques was measured. METHODS Manual segmentation was performed on preoperative and postoperative magnetic resonance images with the open-source software Horos (Horos Project). “SmartBrush,” a tool of the IPlan Cranial software (Brainlab, Feldkirchen, Germany), was used to carry out the semi-automatic segmentation. The open-source BraTumIA software (NeuroImaging Tools and Resources Collaboratory) was employed for the automated segmentation. Pearson correlation coefficient was used to assess volumetric comparison. Subsequently deviation/range and average discrepancy were determined. The Wilcoxon signed-rank test was used to assess statistical significance. RESULTS A total of 58 patients with a newly diagnosed high-grade glioma were enrolled. The comparison of the volumes calculated with Horos and IPlan showed a strong agreement both on preoperative and postoperative images (respectively: “enhancing” ρ = 0.99-0.78, “fluid-attenuated inversion recovery” ρ = 0.97-0.92, and “total tumor volume” ρ = 0.98-0.95). Agreement between BraTumIA and the other 2 techniques appeared to be strong for preoperative images, but showed a higher disagreement on postoperative images. Mean time expenditure for tumor segmentation was 27 min with manual segmentation, 17 min with semi-automated, and 8 min with automated software. CONCLUSION The considered segmentation tools showed high agreement in preoperative volumetric assessment. Both manual and semi-automated software appear adequate for the postoperative quantification of residual volume. The evaluated automated software is not yet reliable. Automated software considerably reduces the time expenditure.

Purpose: Current glioma diagnostic guidelines call for molecular profiling to stratify patients into prognostic and treatment subgroups. In case the tumor tissue is inaccessible, cerebrospinal fluid (CSF) has been proposed as a reliable tumor DNA source for liquid biopsy. We prospectively investigated the use of CSF for molecular characterization of newly diagnosed gliomas. Experimental design: We recruited two cohorts of newly diagnosed glioma patients, one (n=45) providing CSF collected in proximity of the tumor, the other (n=39) CSF collected by lumbar puncture. Both cohorts provided tumor tissues by surgery concomitant with CSF sampling. DNA samples retrieved from CSF and matched tumors were systematically characterized and compared by comprehensive (NGS) or targeted (ddPCR) methodologies. Conventional and molecular diagnosis outcomes were compared. Results: We report that tumor DNA is abundant in CSF close to the tumor, but scanty and mostly below NGS sensitivity threshold in CSF from lumbar puncture. Indeed, tumor DNA is 15 mostly released by cells invading liquoral spaces, generating a gradient that attenuates by departing from the tumor. Nevertheless, in >60% of lumbar puncture CSF samples, tumor DNA is sufficient to assess a selected panel of genetic alterations (IDH and TERT promoter mutations, EGFR amplification, CDKN2A/B deletion: ITEC protocol) and MGMT methylation that, combined with imaging, enable tissue-agnostic identification of main glioma molecular subtypes. Conclusions: This study shows potentialities and limitations of CSF liquid biopsy in achieving molecular characterization of gliomas at first clinical presentation and proposes a protocol to maximize diagnostic information retrievable from CSF DNA.

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Background: Glioblastoma (GBM) is the most common primary brain tumor. The extent of resection (EOR) has been claimed as one of the most important prognostic factors. Fluorescent dyes aid surgeons in detecting a tumor’s borders. 5-aminolevulinic acid (5-ALA) and sodium fluorescein (SF) are the most used. Only a few studies have directly compared these two fluorophores. Methods: A single center retrospective analysis of patients treated for GBM in the period between January 2018 and January 2021 was built to find any differences in terms of EOR, Karnofsky Performance Status (KPS), and overall survival (OS) on the use of 5-ALA, SF, or both. Results: Overall, 99 patients affected by isocitrate dehydrogenase (IDH) wild-type Glioblastoma were included. 5-ALA was administered to 40 patients, SF to 44, and both to 15. No statistically significant associations were identified between the fluorophore and EOR (p = 0.783) or postoperative KPS (p = 0.270). Survival analyses did not show a selective advantage for the use of a given fluorophore (p = 0.184), although there appears to be an advantageous trend associated with the concomitant use of both dyes, particularly after stratification by MGMT (p = 0.071). Conclusions: 5-Ala and SF are equally useful in achieving gross total resection of the enhancing tumor volume. The combination of both fluorophores could lead to an OS advantage.

High-grade gliomas are aggressive tumors that require multimodal management and gross total resection is considered to be the first crucial step of treatment. Because of their infiltrative nature, intraoperative differentiation of neoplastic tissue from normal parenchyma can be challenging. For these reasons, in the recent years, neurosurgeons have increasingly performed this surgery under the guidance of tissue fluorescence. Sodium fluoresceine and 5-aminolevulinic acid represent the 2 main compounds that allow real-time identification of residual malignant tissue and have been associated with improved gross total resection and radiological outcomes. Though presenting different profiles of sensitivity and specificity and further investigations concerning cost-effectiveness are need, Sodium fluoresceine, 5-aminolevulinic acid and new phluorophores, such as Indocyanine green, represent some of the most important tools in the neurosurgeon’s hands to achieve gross total resection.