Common Central Nervous System Tumors Research Articles

1235 Using Supervised Machine Learning to Validate a Novel Scoring System for the Prediction of Disease Remission of Functional Adenomas Following Transsphenoidal Resection

INTRODUCTION: Functional pituitary adenomas are common primary central nervous system tumors with potent systemic endocrinological effects. Postoperatively, remission rates range from 65-98%. METHODS: 392 adult patients who underwent primary resection of a functional pituitary adenoma at the three Mayo Clinic between 2006-2022 were retrospectively reviewed. Multivariate logistic regression was performed to identify variables predictive of disease remission. Variables found statistically significant on multivariate analysis were incorporated into our proposed pituitary-SCHEME score. Machine learning models were implemented to compare the accuracy of the pituitary-SCHEME score against the multivariate models. After training (314 patients) and cross-validation of the machine learning models, an independent testing set of 78 patients was performed. SPSS V27 and R4.2.1 were used for statistical analyses. RESULTS: 261 (66.6%) patients achieved post-operative biochemical remission. On multivariate analysis gross-total resection and Knosp-Grade 0,I,II adenomas were predictive of disease remission following resection, while macroadenomas (adenoma > 10mm), male sex, mammosomatotroph and Mixed Growth-Hormone + Prolactin adenomas were predictive of continued disease. In machine learning models, without Pituitary-SCHEME score, the K-Nearest Neighbors (KNN) model achieved the highest accuracy at 75.6% followed by Naive Bayes model. An increase in model sensitivity was achieved with inclusion of Pituitary-SCHEME score with the Linear-Discriminant-Analysis (LDA) model achieving the highest accuracy at 86.9%, followed by the Classification and Regression Trees (CART) model. The random forest model had the largest AUC-ROC among models with and without pituitary-SCHEME score. Model prediction accuracy (with vs. without pituitary-SCHEME score) were found to be statistically different based on Wilcoxon rank sum testing (p < 0.0001). CONCLUSIONS: The novel pituitary-SCHEME score, which incorporates perioperative and endocrinological measures, has promise as a clinical tool to predict patient outcomes following surgical resection of functional adenomas.

Dexamethasone in Patients with Glioblastoma: A Systematic Review and Meta-Analysis.

Glioblastomas are the most common primary central nervous system (CNS) tumors. Although modern management strategies have modestly improved overall survival, the prognosis remains dismal, with treatment side effects often impinging on the clinical course. Glioblastomas cause neurological dysfunction by infiltrating CNS tissue and via perifocal oedema formation. The administration of steroids such as dexamethasone is thought to alleviate symptoms by reducing oedema. However, despite its widespread use, the evidence for the administration of dexamethasone is limited and conflicting. Therefore, we aimed to review the current evidence concerning the use and outcomes of dexamethasone in patients with glioblastoma. We performed a systematic review and meta-analysis according to the PRISMA-P guidelines. We performed a restricted search using the keywords "Dexamethasone" and "Glioblastoma" on PubMed, Web of Science, Cochrane Library, and Academic Search Premier. We included studies reporting on overall survival (OS) and progression-free survival (PFS) in glioblastoma patients receiving higher or lower dexamethasone doses. The risk of bias was assessed using ROBINS-I. We performed a meta-analysis using a random effects model for OS and PFS. Twenty-two retrospective studies were included. Higher doses of dexamethasone were associated with poorer OS (hazard ratio 1.62, confidence interval 1.40-1.88) and PFS (1.49, 1.23-1.81). OS remained worse even when studies corrected for clinical status (1.52, 1.38-1.67). Despite the widespread use of dexamethasone in glioblastoma patients, its use is correlated with worse long-term outcomes. Consequently, Dexamethasone administration should be restricted to selected symptomatic patients. Future prospective studies are crucial to confirm these findings.

302 Targeted Inhibition of the Epigenetically Activated miR-483-5p IGF-2 Pathway as a Novel Therapeutic Strategy for Meningioma

INTRODUCTION: Meningioma is the most common primary central nervous system tumor. These are usually treated by surgical resection with curative intent, however gross total resection is not always feasible and there are many cases of recurrent and refractory disease despite adjuvant radiotherapy. Presently, there is no effective pharmacotherapeutic options for these tumors. METHODS: Small RNA sequencing was performed on meningioma tumor samples to study grade-dependent changes in microRNA expression. Gene expression was analyzed by chromatin marks, qRT-PCR and western blot. miRNA modulation, anti-IGF-2 neutralizing antibodies, and inhibitors against IGF1R were evaluated in a tumor-derived primary cultures of meningioma cells. RESULTS: Meningioma tumor samples showed high, grade-dependent expression of miR-483-5p, associated with high mRNA and protein expression of its host gene IGF-2. Inhibition of miR-483-5p reduced the growth of cultured meningioma cells, whereas a miR-483 mimic increased cell proliferation. Similarly, inhibition of this pathway with anti-IGF-2 neutralizing antibodies reduced meningioma cell proliferation. Small molecule tyrosine kinase inhibitor blockade of the IGF-2 receptor (IGF1R) resulted in rapid loss of viability of cultured meningioma tumor-derived cells, suggesting that autocrine IGF-2 feedback is obligatory for meningioma tumor cell survival and growth. The observed IGF1R-inhibitory IC50 for GSK1838705A and Ceritinib in cell-based assays along with the available pharmacokinetics data predicted that effective drug concentration could be achieved in vivo as a new medical treatment of meningioma. CONCLUSIONS: Meningioma cell growth is critically dependent on autocrine miR-483/IGF-2 stimulation and the IGF-2 pathway provides a new feasible meningioma treatment target.

Abstract 1174: Incorporation of multisector analysis into the design of personalized DNA vaccines for patients with newly diagnosed glioblastoma

Abstract Glioblastoma (GBM) is the most common malignant central nervous system (CNS) tumor in adults. Despite multimodality treatment including surgery, radiation, and chemotherapy, patients with GBM have a median survival of less than 2 years. Recent clinical trials have reported promising results using cancer vaccines to stimulate a tumor-directed immune response in several histologies. The majority of trials targeted tumor neoantigens derived from a single tumor sample, which limits the antigen pool in spatially heterogeneous cancers like GBM. Our group previously implemented multisector sequencing into the design of personalized peptide vaccines to increase the candidate pool of targetable neoantigens (NCT03422094). Although the peptide vaccine treatment was successful in stimulating an effector T cell response, it was limited by a long turnaround time from vaccine design to administration and a low peptide production rate. Therefore, we incorporated multisector sampling into the design of a personalized DNA-based GBM vaccine (NCT04015700). An average of 33% of the candidate targetable neoantigens were spatially restricted to a single sampled region, which would have been missed without multisector sequencing. DNA-based vaccines are potentially advantageous over peptide-based vaccines because they enable a higher neoantigen payload and faster manufacturing time with potent immunogenicity. Here, we report the results from 9 subjects enrolled onto the study. Spatially distinct tumor regions were subjected to whole exome sequencing (WES) and RNA-sequencing (RNA-seq), data from which were used to identify neoantigens through the pVACseq algorithm (http://pvactools.org). An average of 32 neoantigens were included in each DNA vaccine, compared to an average of only 9 for the peptide vaccine, and the turnaround time from date of surgery to administration of the DNA vaccine was about half the time. Three subjects had radiographic evidence of tumor progression prior to vaccination, highlighting the aggressive nature of GBM and the need for short manufacturing timeframes. PBMCs pre- and post-DNA vaccination were collected from 7/9 subjects. All subjects presented detectable responses and 6/7 tested revealed a sustained increment in T cell reactivity against tumor neoantigens post-treatment by IFN-γ ELISpot. Intracellular staining showed a neoantigen-specific antitumor CD8/CD4 T cell cytolytic (CD69+, CD107a+) and proliferative (Ki67+) profile. Post-vaccination tumor resections were performed for 2 subjects who also were treated with PD1 blockade upon progression, providing an opportunity to explore vaccine-induced changes in the tumor microenvironment. Herein, we demonstrate the advantages of incorporating multisector sequencing into the development of DNA-based GBM vaccines and provide insights into the resulting immune responses. Citation Format: Elizabeth A. Garfinkle, Katherine E. Miller, Alexandra J. Livingstone, Renzo Perales-Linares, Neil Cooch, Alfredo Perales-Puchalt, Sarah Rochestie, Joann Peters, Niranjan Y. Sardesai, William E. Gillanders, Elaine R. Mardis, Gavin P. Dunn, Tanner M. Johanns. Incorporation of multisector analysis into the design of personalized DNA vaccines for patients with newly diagnosed glioblastoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 1174.

Retrospective study of CNS tumors in a tertiary care centre in Western Odisha - A 4 year study

Central nervous system (CNS) tumors comprise nearly 3% of all malignancies world-wide whereas in India it accounts for about 2%. In recent years there has been an increase in CNS tumors with new potential risk factors being observed. The aim of the present study is to highlight the histopathological spectrum of brain tumors in a single tertiary care centre in Western Odisha.This retrospective histopathological analysis of CNS tumors was conducted in the Department of Pathology, VIMSAR, Burla, Odisha, India from October 2016 to September 2020. In the span of 4 years, a total of 94 neurosurgical biopsies were studied. Histopathological examination of routinely processed tissue and hematoxylin and eosin (H&E) stained sections of corresponding cases were thoroughly examined. Immunohistochemistry (IHC) was done whenever required. Thereafter an approach was made to diagnose the cases, based on WHO classification system of 2016.A wide range of histopathological spectrum of CNS tumors was observed and was classified according to the WHO classification system of 2016. The primary CNS tumors were graded from Grade I to Grade IV. The most common CNS tumor in our study we found to be Astrocytic tumors (21 cases, 22.34%) followed by Schwannoma (19 cases, 20.21%) and meningiomas (18 cases, 19.14%). The incidence was more among males (59.51%) as compared to females (40.4%). This study provides an information regarding the prevalence of disease in Western Odisha. Use of modern imaging technique helps to a major extent in making a provisional.

Liquid Biopsy for Glioma Using Cell-Free DNA in Cerebrospinal Fluid.

Glioma is one of the most common primary central nervous system (CNS) tumors, and its molecular diagnosis is crucial. However, surgical resection or biopsy is risky when the tumor is located deep in the brain or brainstem. In such cases, a minimally invasive approach to liquid biopsy is beneficial. Cell-free DNA (cfDNA), which directly reflects tumor-specific genetic changes, has attracted attention as a target for liquid biopsy, and blood-based cfDNA monitoring has been demonstrated for other extra-cranial cancers. However, it is still challenging to fully detect CNS tumors derived from cfDNA in the blood, including gliomas, because of the unique structure of the blood-brain barrier. Alternatively, cerebrospinal fluid (CSF) is an ideal source of cfDNA and is expected to contribute significantly to the liquid biopsy of gliomas. Several successful studies have been conducted to detect tumor-specific genetic alterations in cfDNA from CSF using digital PCR and/or next-generation sequencing. This review summarizes the current status of CSF-based cfDNA-targeted liquid biopsy for gliomas. It highlights how the approaches differ from liquid biopsies of other extra-cranial cancers and discusses the current issues and prospects.

Pediatric spinal ependymoma with chromothripsis of chromosome 6: a case report and review of the literature

BackgroundEpendymomas are the third most common central nervous system tumor in the pediatric population; however, spinal ependymomas in children are rare. Ependymomas affecting the spinal cord most frequently occur in adults of 20–40 years of age. The current World Health Organization classification system for ependymomas is now composed of ten different entities based on histopathology, location, and molecular studies, with evidence that the new classification system more accurately predicts clinical outcomes.Case presentationWe present the case of a 16-year-old Caucasian female patient with a history of type 2 neurofibromatosis with multiple schwannomas, meningioma, and spinal ependymoma. Chromosome analysis of the harvested spinal ependymoma tumor sample revealed a 46,XX,−6,+7,−22,+mar[16]/46,XX[4] karyotype. Subsequent OncoScan microarray analysis of the formalin-fixed paraffin-embedded tumor sample confirmed + 7, −22 and clarified that the marker chromosome represents chromothripsis of the entire chromosome 6 with more than 100 breakpoints. Fluorescent in situ hybridization and microarray analysis showed no evidence of MYCN amplification. The final integrated pathology diagnosis was spinal ependymoma (central nervous system World Health Organization grade 2 with no MYCN amplification.ConclusionThis case adds to the existing literature of pediatric patients with spinal ependymomas and expands the cytogenetic findings that may be seen in patients with this tumor type. This case also highlights the value of cytogenetics and microarray analysis in solid tumors to provide a more accurate molecular diagnosis.

Terson’s Syndrome due to Ependymoma: A Rare Case Report

Abstract
 Introduction : Terson's syndrome is often associated with subarachnoid hemorrhage. Other reported causes, include trauma, tumors, hypertension, perioperative and postoperative intracranial hemorrhage, or increased intracranial pressure. This case demonstrates a unique pathogenesis of Terson's syndrome.
 Case Illustration : A 14-year-old boy presented with the blurred vision on both eyes 3 weeks ago, accompanied with nausea, vomiting, and headache, with normal blood pressure measurement (126/80mmHg). He also had a history of head injury. His visual acuity was 6/20 uncorrected with pinhole on both eyes. Both intraocular pressures within normal limits. The anterior segment showed bilateral mid-dilated reactive pupil. Funduscopy revealed bilateral papilledema with peripapillary hemorrhage, similar to retinal vein occlusion, which is suggestive with Terson’s Syndrome. Magnetic Resonance Imaging (MRI) scan showed an ependymoma mass. We consulted this case with Pediatric Neurosurgeon, who planned for ventriculoperitoneal shunt with craniotomy tumor removal.
 Discussion : Terson's syndrome now defined as any intraocular hemorrhage associated with intracranial hemorrhage or elevated intracranial pressures. In this case, the etiology was thought to be increased intracranial pressure, which may be caused by ependymoma. Ependymoma is one of the most common central nervous system tumors in children. Intraocular hemorrhage in Terson’s syndrome is often self-limiting, but ependymoma needs neurosurgical intervention, which has lower survival rates for children with posterior fossa tumors.
 Conclusion : There are still controversies regarding the pathogenesis of Terson's syndrome. Not the occlusion, but the compression of the central retinal vein, by the increased pressure of cerebrospinal fluid due to high intracranial pressure, which increases the retinal venous pressure and causes retinal hemorrhage.

Etomidate inhibits tumor growth of glioblastoma by regulating M1 macrophage polarization.

Glioblastoma (GBM) is a common primary central nervous system tumor. Although the multimodal integrated treatment for GBM has made great progress in recent years, the overall survival time of GBM is still short. Thus, novel treatments for GBM are worth further investigation and exploration. This study aimed to investigate the effects of etomidate on GBM tumor growth and the underlying mechanism. A xenograft tumor model was established and treated with etomidate to assess tumor growth. Immunohistochemistry (IHC) assay evaluated the positive rate of Ki67 cells in tumor tissues. Cell counting kit (CCK)-8 and EdU assays accessed the cell viability and proliferation. Immunofluorescence (IF) staining detected the distribution of macrophage markers in tumor tissues. The percentages of M1- and M2-like macrophages in tumor-associated macrophages (TAMs) and co-culture system (macrophages and GBM cells) were detected using flow cytometry. Macrophage polarization-related genes were measured using reverse transcription-quantitative polymerase chain reaction (RT-qPCR). Etomidate treatment inhibited the tumor growth, and increased the CD86+ cells but decreased the CD206+ cells in TAMs. The gene expression of M1 markers was increased in TAMs of etomidate-treated mice, whereas that of M2 markers was decreased. Moreover, etomidate treatment increased the number of CD86+ M1-like macrophages co-cultured with tumor cells but decreased that of CD206+ M2-like macrophages, with the upregulation of M1 markers and downregulation of M2 markers. Etomidate inhibited GBM tumor growth by promoting M1 macrophage polarization, suggesting a new insight into the clinical treatment of GBM.

Liquid biopsy evaluation of circulating tumor DNA, miRNAs, and cytokines in meningioma patients.

Liquid biopsy is a non-invasive method used to detect cancer and monitor treatment responses by analyzing blood or other bodily fluids for cancer biomarkers. Meningiomas are the most common primary central nervous system tumors, and biomarkers play a crucial role in their diagnosis, prognosis, and treatment monitoring. The World Health Organization (WHO) classifies meningiomas based on tumor grades and molecular alterations in genes such as in NF2, AKT1, TRAF7, SMO, PIK3CA, KLF4, SMARCE1, BAP1, H3K27me3, TERT promoter, and CDKN2A/B. Liquid biopsy, specifically cell-free DNA (cfDNA) analysis, has shown potential for monitoring meningiomas as it can detect ctDNA release in the blood, unaffected by the blood-brain barrier. MicroRNAs (miRNAs) have also been found to be deregulated in various cancers, including meningiomas, presenting potential as diagnostic biomarkers. Additionally, studying cytokines in the tumor microenvironment may aid in establishing prognostic or diagnostic panels for meningiomas. In the present study we analyzed the DNA coming from both the plasma and tumor samples, in addition to analyze miRNA-21 and cytokines in the plasma of 28 meningioma patients. Our findings indicate that the detection of ctDNA in the plasma of meningioma patients is feasible. However, it's important to note that certain challenges persist when comparing plasma DNA analysis to that of tumor tissues. In our study, we observed a paired identification of mutations in only one patient, highlighting the complexities involved. Furthermore, we successfully identified miR-21 and cytokines in the plasma samples. Notably, our analysis of Interleukin 6 (IL-6) unveiled higher expression in the clear cell subtype compared to the other types. Despite the ongoing research, the clinical implementation of liquid biopsy in meningiomas remains somewhat limited. Nevertheless, our promising results underscore the need for further investigation.

Intraoperative Touch Imprint Cytology of Brain Neoplasms: A Useful High-Diagnostic Tool in 93 Consecutive Cases; Differential Diagnoses, Pitfalls, and Traps.

Intraoperative cytological examination of central nervous system (CNS) lesions was first introduced in 1920 by Eisenhardt and Cushing for rapid evaluation of neurosurgical specimens and to guide surgical treatment. It is recognized that this method not only confirms the adequacy of biopsy in CNS samples but also indicates the presence and preliminary diagnosis of lesional tissue. A total of 93 patients who underwent touch imprint cytology (TIC) for CNS tumors or lesions between 2018 and 2023 were included in the study. All cases were correlated with the final histopathological diagnosis, and pitfalls and difficulties encountered with discrepancies were noted. The most common primary CNS tumors were gliomas and meningiomas, while secondary (metastatic) tumors were predominantly lung, breast, and gastrointestinal system carcinomas. Sensitivity, specificity, positive predictive value, and negative predictive value for diagnosis with TIC were 94.1%, 100%, and 61.5%, respectively. Final histopathological diagnosis by TIC was made in 88 cases (94.6%) and the discrepancy was found in 5 cases (5.37%). Three of the five discrepancies (3.2%) were haematolymphoid malignancies (two lymphomas and one plasma cell neoplasia), one glioblastoma, and one hemangioblastoma case. TIC is a fast, safe, and inexpensive diagnostic tool used during intraoperative neuropathology consultation. Awareness of the pitfalls of using this method during intraoperative consultation will enable high-diagnostic accuracy.

Impact of molecular genetic profle of meningiomas on the clinical course and recurrence using combined modality treatment

Introduction. Meningioma is one of the most common central nervous system tumors, accounting for 39.7 % of all primary brain tumors. The tumor originates from arachnoid meningothelial cells and is characterized by a wide range of histological types classified into 15 subtypes. The histological classification of meningiomas allows us to predict meningioma behavior and the risk of disease recurrence, as well as to define treatment strategies. However, clinical outcomes in histological subgroups of patients are often inconsistent with the histological grade of malignancy. Thus, a more reliable method is needed both to determine the histological subtype of the tumor and to predict the clinical course of the disease with the potential for targeted treatment.The purpose of the study was to summarize the available data on the effect of results of the genomic and proteomic tumor analysis on carcinogenesis with the relationship between the mutational changes and noninvasive diagnosis, treatment and the course of the disease.Material and Methods. Literature search was carried out in the PubMed, Elibrary system, publications were included mainly from 2010 to 2023. with the identification of articles by the keyword “genetic analysis of meningiomas” and synonyms. 550 articles were found, of which 55 were used to write a literature review.Conclusion. The study of the molecular genetic profile of meningiomas will improve the classification and establish a correlation with MRI data, the course of the disease and prognosis.

CSF cytology of common primary CNS neoplasms categorized by CNS WHO 2021.

The detection of neoplastic cells in cerebral spinal fluid (CSF) is pivotal for the management of patients with central nervous system (CNS) tumours. This article delves into the CSF cytological characteristics of common CNS neoplasms, aligning with the 2021 World Health Organization (WHO) classification of CNS tumours. A retrospective review of CSF specimens positive for primary CNS neoplasms was performed at three tertiary medical centres. Only cases that had histopathologic confirmation and/or molecular workup were included. Common primary CNS neoplasms seen in CSF cytology specimens include medulloblastoma, (non-WNT/non-SHH as well as SHH-activated and TP53 mutant), pineoblastoma, atypical teratoid/rhabdoid tumour (AT/RT), IDH-wildtype glioblastoma, and primary diffuse large B-cell lymphoma of the CNS. Ependymomas and germinomas can also have CSF involvement but are less common. Although the typical histologic architecture of these tumours may not be preserved in the CSF, unique cytomorphologic features such as nuclear moulding, nuclear pleomorphism, rhabdoid cells, prominent nucleoli and rosette formation can still be appreciated. Adopting the updated terminology and correlating cytologic observations with molecular findings will streamline the diagnostic process, reducing the complexities and ambiguities pathologists often encounter when analysing CSF specimens for potential primary CNS neoplasms.

Deep-learning model for diagnostic clue: detecting the dural tail sign for meningiomas on contrast-enhanced T1 weighted images.

Meningiomas are the most common primary central nervous system tumors, and magnetic resonance imaging (MRI), especially contrast-enhanced T1 weighted image (CE T1WI), is used as a fundamental imaging modality for the detection and analysis of the tumors. In this study, we propose an automated deep-learning model for meningioma detection using the dural tail sign. The dataset included 123 patients with 3,824 dural tail signs on sagittal CE T1WI. The dataset was divided into training and test datasets based on specific time point, and 78 and 45 patients were comprised for the training and test dataset, respectively. To compensate for the small sample size of the training dataset, 39 additional patients with 69 dural tail signs from the open dataset were appended to the training dataset. A You Only Look Once (YOLO) v4 network was trained with sagittal CE T1WI to detect dural tail signs. The normal group dataset, comprised of 51 patients with no abnormal finding on MRI, was employed to evaluate the specificity of the trained model. The sensitivity and false positive average were 82.22% and 29.73, respectively, in the test dataset. The specificity and false positive average were 17.65% and 3.16, respectively, in the normal dataset. Most of the false-positive cases in the test dataset were enhancing vessels, misinterpreted as dural thickening. The proposed model demonstrates an automated detection system for the dural tail sign to identify meningioma in general screening MRI. Our model can facilitate and alleviate radiologists' reading process by notifying the possibility of incidental dural mass based on dural tail sign detection.

MiRNA-660-3p inhibits malignancy in glioblastoma via negative regulation of APOC1-TGFβ2 signaling pathway

ABSTRACT Glioblastoma as the most common and aggressive central nervous system tumor in adults. Its prognosis and therapeutic outcome are poor due to the limited understanding of its molecular mechanism. Apolipoprotein C-1 (APOC1) as a member of the apolipoprotein family that acts as a tumor promoter in various cancers. MicroRNA (miRNA) can silence gene expression and suppress tumor progression. However, the role of APOC1 and its upstream miRNA has not been explored in glioblastoma. Two glioblastoma cell lines (U87 and U251) were used to explore the role of APOC1 and its upstream miRNA-660-3p in glioblastoma tumorigenesis in vitro. Cells with APOC1/miRNA-660-3p overexpression or knockdown were assessed for their proliferation, migration, and invasion in vitro, and tumorigenesis in vivo. Gene and protein expression was assessed by qRT-PCR and western blot, respectively. Cell proliferation was assessed by the MTT assay and the EdU and Ki67 staining. Cell migration and invasion were assessed by the transwell assay. Tumorigenesis in vivo was assessed in U87 cells with a xenograft mouse model. APOC1 was overexpressed in glioblastoma compared with normal peritumoral tissue and was inversely related to patient prognosis. APOC1 overexpression promotes cell proliferation, migration, and invasion in vitro. APOC1 inhibition reduced tumor growth in vivo. miRNA-660-3p inhibits tumorigenesis by directly targeting APOC1. Mechanistically, APOC1 drives the malignancy of glioblastoma by activating the TGFβ2 signaling pathway. miRNA-660-3p suppresses tumorigenesis by targeting APOC1. Therefore, miRNA-660-3p/APOC1 axis can serve as potential intervention targets in managing glioblastoma progression.

EPID-01. ANTINEOPLASTIC, RADIATION, AND SYNCHRONICITY EFFECTS ON BRAIN METASTASIS SURVIVAL: A RETROSPECTIVE POPULATION-BASED STUDY

Abstract INTRODUCTION Brain metastases (BM) are the most common central nervous system tumors. The impact of oncological treatment on the prevention of BM is not well-defined. We report the effects of chemotherapy and radiotherapy directed at primary cancer on synchronous and metachronous BM survival. METHODS A large nationwide multi-institutional claims-based platform (TriNetX Diamond Network) was queried. Patients diagnosed during 2013-2023 with the 15 most common primary cancers that metastasize to the brain were included. Metachronous was defined as BM diagnosed > 2 months after primary cancer. Cohorts were propensity score matched for age, extracranial metastasis, and adjuvant therapy. Kaplan-Meier plots were used to compare survival. RESULTS 113,827 (38%) patients with synchronous and 187,036 (62%) with metachronous BM were identified. Patients with synchronous BM had 26 months shorter median survival compared to metachronous BM (11 vs. 37 months, HR 2.17, 95%CI 2.14-2.19, P< 0.0001). However, no survival advantage was observed from the time of BM diagnosis (11 vs. 12 months, HR 1.06, 95%CI 1.05-1.08, P=0.411). Antineoplastic treatment prior to BM improved median BM-free survival by 13 months (4 vs. 18 months, HR 1.66, 95%CI 1.77-1.82, P < 0.0001) and median OS by 17 months (25.15 vs. 42.26 months, HR 1.48, 95%CI 1.46-1.51, P< 0.0001). Radiation therapy prior to BM incurred a significant but smaller increase in median BM-free survival by 6 months (5 vs. 11 months, HR 1.27, 95%CI 1.26-1.29, P< 0.0001) and median OS by about 3 months (30.13 vs. 32.82 months, HR 1.06, 95%CI 1.04-1.08, P < 0.0001). CONCLUSION Once BM is diagnosed, the synchronicity of diagnosis does not predict survival. Antineoplastic and radiation treatment directed at primary cancer may improve BM-free survival and OS. Studies characterizing the BM-free effects of molecular markers, chemotherapy, and radiotherapy are necessary to improve screening, prevention, and treatment.

EXTH-57. THE IGF-2 SIGNALING PATHWAY IS A PROMISING MENINGIOMA TREATMENT TARGET

Abstract Meningioma is the most common primary central nervous system tumor often causing serious complications while there is no effective medical treatment. We developed a tumor-derived primary culture model featuring tumor cells with retained PDG2S lineage marker as well as non-arachnoid cells mimicking the tumor cell microenvironment. We used this model to test the relevance of miRNA differentially expressed in meningioma tumor samples identified by small RNA sequencing. We found that in all meningiomas studied, there was activation of the IGF2/miR-483 locus with high expression of both miR-483-5p and IGF2. Inhibition of miR-483-5p reduced the growth of cultured meningioma cells, whereas a miR-483 mimic increased cell proliferation. Anti-IGF2 neutralizing antibodies reduced meningioma cell proliferation. Small molecule tyrosine kinase inhibitor blockade of the IGF2 receptor (IGF1R) resulted in rapid loss of viability of cultured meningioma tumor-derived cells. Autocrine IGF2 feed-back appears to be obligatory for meningioma tumor cell survival and growth. Inhibition of this circuit with IGF1R small molecule tyrosine kinase inhibitors or receptor-binding antibodies as well as anti-IGF2 neutralizing antibodies may have therapeutic potential for meningioma.

NIMG-76. A DEEP LEARNING ALGORITHM FOR FULLY AUTOMATED VOLUMETRIC MEASUREMENT OF MENINGIOMA BURDEN

Abstract PURPOSE Meningiomas are the most common primary central nervous system tumor. A subset of these tumors is multiply recurrent despite aggressive treatment with surgery or radiation and causes significant morbidity and mortality. Longitudinal measurement of meningioma burden on post-contrast MRI is the basis of treatment response assessment. As per Response Assessment in Neuro-Oncology (RANO), estimates of tumor size are based on the product of bidirectional diameters of enhancing tumor. However, these 2D segmentations as well as manual volumetric segmentations have high rates of intra- and inter-rater variability, which prohibits accurate longitudinal assessment of tumor size. A rapid and reproducible quantitative method for determining meningioma volume is needed to expedite response assessment in clinical trials. To address this unmet need, we developed a deep learning algorithm that enables fully automated 3D segmentation and volumetric assessment of meningioma burden. METHODS 351 post-contrast T1-weighted brain MRIs from 86 patients with meningioma were obtained from Massachusetts General Hospital and Dana-Farber Cancer Institute. The cohort was unique compared to prior DL segmentation models as it encompassed diverse clinical scenarios (e.g., meningioma of all grades, post-operative and post-radiated meningioma). The MRIs were resampled to 1 mm isotropic resolution and preprocessed using N4 bias field correction and zero-mean intensity normalization. The dataset was split 70%/15%/15% for training/validation/testing on a per patient level. The training data were used with manually generated tumor segmentations to train a convolutional neural network (CNN) with a U-Net architecture and the Dice loss function. RESULTS The median Dice score was 0.6758 on the test set. Additional work is ongoing to optimize performance, with primary focus directed toward improved data preprocessing and ground truth segmentation as the variability in segmentation quality contributed to the lower Dice score, highlighting the need to develop a less biased and more reliable tool to segment meningiomas.

Pediatric low-grade glioma: State-of-the-art and ongoing challenges.

The most common childhood central nervous system (CNS) tumor is pediatric low-grade glioma (pLGG), representing 30%-40% of all CNS tumors in children. Although there is high associated morbidity, tumor-related mortality is relatively rare. pLGG is now conceptualized as a chronic disease, underscoring the importance of functional outcomes and quality-of-life measures. A wealth of data has emerged about these tumors, including a better understanding of their natural history and their molecular drivers, paving the way for the use of targeted inhibitors. While these treatments have heralded tremendous promise, challenges remain about how to best optimize their use, and the long-term toxicities associated with these inhibitors remain unknown. The International Pediatric Low-Grade Glioma Coalition (iPLGGc) is a global group of physicians and scientists with expertise in pLGG focused on addressing key pLGG issues. Here, the iPLGGc provides an overview of the current state-of-the-art in pLGG, including epidemiology, histology, molecular landscape, treatment paradigms, survival outcomes, functional outcomes, imaging response, and ongoing challenges. This paper also serves as an introduction to 3 other pLGG manuscripts on (1) pLGG preclinical models, (2) consensus framework for conducting early-phase clinical trials in pLGG, and (3) pLGG resistance, rebound, and recurrence.

Vascularization ability of glioma stem cells in different three-dimensional microenvironments.

Glioblastoma (GBM) is among the most common and aggressive adult central nervous system tumors. One prominent characteristic of GBM is the presence of abnormal microvessels. A significant correlation between angiogenesis and prognosis has been observed. Accurately reconstructing this neovascularization and tumor microenvironment through personalized in vitro disease models presents a significant challenge. However, it is crucial to develop new anti-angiogenic therapies for GBM. In this study, 3D bioprinted glioma stem cell (GSC)-laden hydrogel scaffolds, hybrid GSC hydrogels and cell-free hydrogel scaffolds were manufactured to investigate the vascularization ability of GSCs in varying 3D microenvironments. Our results demonstrated that the bioactivity of GSCs in the 3D bioprinted GSC-laden hydrogel scaffold was preferable and stable, and the amounts of vascular endothelial growth factor A and basic fibroblast growth factor were the highest in the microenvironment. When the three different models were co-cultured with human umbilical vein endothelial cells, the expression of angiogenesis-related markers was the most abundant in the bioprinted GSC-laden hydrogel scaffold. Additionally, xenograft tumors formed by bioprinted GSC-laden hydrogel scaffolds more closely resembled human gliomas regarding color, texture and vascularization. Notably, in xenograft tumors derived from 3D bioprinted GSC-laden hydrogel scaffolds, the number of human CD105+ cells was significantly higher, and human endothelial vascular lumen-like structures were observed. This indicates that the 3D bioprinted GSC-laden hydrogel scaffold is a suitable model for mimicking the glioma microenvironment and studying tumor angiogenesis.