Common Central Nervous System Tumors Research Articles

BIOS-02. CLINICAL OUTCOMES OF OVER 600 PATIENTS WITH GLIOBLASTOMA TREATED AT A CANADIAN TERTIARY CENTER IN THE PAST 15 YEARS: A COMPARATIVE ANALYSIS WITH THE PIVOTAL STUPP TRIAL

Abstract Glioblastoma is the most common malignant primary central nervous system tumor in adults and is associated with a poor prognosis. The benefit of adding concomitant followed by adjuvant temozolomide to radiotherapy after maximal safe resection was demonstrated by Stupp and colleagues in 2005 and has since remained the standard of care. This regimen conferred a statistically significant benefit with a 2-year survival rate of 26.5% compared to 10.4% in patients treated with radiotherapy alone. Our primary goal was to retrospectively assess the clinical outcomes of patients with glioblastoma treated at our institution over the past 15 years by comparing the overall survival (OS) and progression-free survival (PFS) from our cohort to data from the pivotal trial. Our secondary objective was to create a comprehensive database with clinical and pathological information in order to identify predictive and prognostic factors. We reviewed the clinical records of patients treated for glioblastoma from January 2005 to November 2019 at our center. We extracted data on survival and calculated OS and PFS using the Kaplan-Meier method. 617 patient charts were reviewed, out of which 17 were excluded because of missing data. The remaining 600 patients were included. Baseline demographic information was similar to that of the Stupp cohort, with the exception of a larger proportion of patients aged 50 or above (76% versus 69%, respectively). The median OS at our center was 14.3 months, 95% confidence interval [12.8-15.2], which was comparable to that of the original trial (14.6 months [13.2-16.8]). PFS was better in our cohort at 6 months (74.2% [70.7-77.7] versus 53.9% [48.1-59.6]) and 12 months (36.3% [32.5-40.2] versus 26.9% [21.8-32.1]), and comparable thereafter. Our study confirms that the data from the Stupp trial are reproducible in a Canadian academic center setting. Our database will allow us to explore potentially new predictive factors.

High expression of NLRP12 predicts poor prognosis in patients with intracranial glioma.

Intracranial gliomas are the most common primary central nervous system tumors in humans, and glioblastoma multiforme is the most malignant intracranial glioma. The nucleotide-binding domain leucine-rich repeat (NLR)-containing family are crucial regulators of inflammatory and innate immune responses. NLRP12 codes for the monarch-1 protein, which regulates immune responses in humans. Data from a next-generation sequencing database indicated that NLRP12 expression is increased in glioma cells. However, the relationship between NLRP12 levels and gliomas is unclear. To explore the role of NLRP12-related translation factors and proteins in glioma, we evaluated the clinical data and paraffin sections from glioma patients. The expression of NLRP12 was evaluated using immunohistochemical analysis, and clinical parameters were analyzed using chi-square and Kaplan-Meier survival tests. The degree of malignancy and prognosis highly correlated with NLRP12 levels. In addition, the siRNA-mediated downregulation of NLRP12 in glioma cell lines decreased proliferation, invasion, and migration. The levels of VEGF, N-cadherin, and cyclin D1 were downregulated after knockdown of NRLP12 in glioma cell lines, as observed using western blotting in vitro. Knockdown of NLRP12 attenuated the tumor progression in vivo. The expression of NLRP12 may be an independent prognostic factor and a potential target for the treatment of intracranial glioma.

Machine learning based survival prediction in Glioma using large-scale registry data.

Gliomas are the most common central nervous system tumors exhibiting poor clinical outcomes. The ability to estimate prognosis is crucial for both patients and providers in order to select the most appropriate treatment. Machine learning (ML) allows for sophisticated approaches to survival prediction using real world clinical parameters needed to achieve superior predictive accuracy. We employed Cox Proportional hazards (CPH) model, Support Vector Machine (SVM) model, Random Forest (RF) model in a large glioma dataset (3462 patients, diagnosed 2000-2018) to explore the most optimal approach to survival prediction. Features employed were age, sex, surgical resection status, tumor histology and tumor site, administration of radiation therapy (RT) and chemotherapy status. Concordance index (c-index) was employed to assess the accuracy of survival time prediction. All three models performed well with prediction accuracy (CI 0.767, 0.771, 0.57 for CPH, SVM, RF models respectively) with the best performance achieved when incorporating RT and chemotherapy administration status which emerged as key predictive features. Within the subset of glioblastoma patients, similar prediction accuracy was achieved. These findings should prompt stricter clinician oversight over registry data accuracy through quality assurance as we move towards meaningful predictive ability using ML approaches in glioma.

Preclinical Efficacy and Toxicology Evaluation of RAC1 Inhibitor 1A-116 in Human Glioblastoma Models.

Simple SummaryMalignant gliomas are the most common primary central nervous system tumors in adults. Currently, this disease is associated with poor prognosis and is virtually incurable. There is a need to find novel targets and treatments to improve patient survival. This study shows the preclinical evaluation of 1A-116, a Rac1 inhibitor that showed in vitro antitumor activity on glioma cells. We also evaluated 1A-116 in vivo, showing a favorable toxicological profile and antitumor efficacy in an intracranial mouse tumor model. Altogether, our study provides important evidence of 1A-116 as a signal transduction-based precision therapy for glioma and also increases the evidence of Rac1 as a key molecular target in cancer.Malignant gliomas are the most common primary central nervous system tumor in adults. Despite current therapeutics, these tumors are associated with poor prognosis and a median survival of 16 to 19 months. This highlights the need for innovative treatments for this incurable disease. Rac1 has long been associated with tumor progression and plays a key role in glioma’s infiltrative and invasive nature. The aim of this study is to evaluate the 1A-116 molecule, a Rac1 inhibitor, as targeted therapy for this aggressive disease. We found that targeting Rac1 inhibits cell proliferation and cell cycle progression using different in vitro human glioblastoma models. Additionally, we evaluated 1A-116 in vivo, showing a favorable toxicological profile. Using in silico tools, 1A-116 is also predicted to penetrate the blood–brain barrier and present a favorable metabolic fate. In line with these results, 1A-116 i.p daily treatment resulted in a dose-dependent antitumor effect in an orthotopic IDH-wt glioma model. Altogether, our study provides a strong potential for clinical translation of 1A-116 as a signal transduction-based precision therapy for glioma and also increases the evidence of Rac1 as a key molecular target.

The differential usage of molecular machinery in brain cancer patients with iron-enriched glioma environments.

Gliomas are neuroepithelial tumors in the brain or spinal cord that arise from glial or precursor cells and include astrocytomas, oligodendrogliomas, and ependymomas. They are the most common malignant primary central nervous system tumors, representing 75% of cases in adults and 24% of all cases of primary brain and CNS tumors [1,2].

Response assessment in pediatric craniopharyngioma: recommendations from the Response Assessment in Pediatric Neuro-Oncology (RAPNO) Working Group.

Craniopharyngioma is a histologically benign tumor of the suprasellar region for which survival is excellent but quality of life is often poor secondary to functional deficits from tumor and treatment. Standard therapy consists of maximal safe resection with or without radiation therapy. Few prospective trials have been performed, and response assessment has not been standardized. The Response Assessment in Pediatric Neuro-Oncology (RAPNO) committee devised consensus guidelines to assess craniopharyngioma response prospectively. Magnetic resonance imaging is the recommended radiologic modality for baseline and follow-up assessments. Radiologic response is defined by 2-dimensional measurements of both solid and cystic tumor components. In certain clinical contexts, response to solid and cystic disease may be differentially considered based on their unique natural histories and responses to treatment. Importantly, the committee incorporated functional endpoints related to neuro-endocrine and visual assessments into craniopharyngioma response definitions. In most circumstances, the cystic disease should be considered progressive only if growth is associated with acute, new-onset or progressive functional impairment. Craniopharyngioma is a common pediatric central nervous system tumor for which standardized response parameters have not been defined. A RAPNO committee devised guidelines for craniopharyngioma assessment to uniformly define response in future prospective trials.

Head MRI imaging profile of meningioma according to WHO 2016 grading

Magnetic resonance imaging (MRI) of meningiomas is essential in predicting their histopathological grade. Meningiomas are the second most common central nervous system neoplasm in adults, usually benign, originating from arachnoid cap cells and categorized according to the WHO classification as benign (grade I), atypical (grade II), and anaplastic (grade III). The study aims to determine the head MRI imaging profile in preoperative meningioma patients confirmed by pathologic results according to WHO 2016 grading. A retrospective study was conducted from January 2017 to March 2022 with 30 samples of meningioma patients who underwent surgery. Preoperative head MRI and pathologic examination were done and tumor location, border, edge, and size were confirmed with pathology results according to WHO 2016 grading. Most patients were 41-50 years old, female (100%), mostly WHO grade I histopathology with transitional type. The most common locations were convexity meningiomas, with the most MRI characteristics of well-defined borders, regular edges, size 0-3 cm, with hypointense T1, hyperintense T2, hyperintense T2 FLAIR, restricted diffusion on DWI, type 2 DCE, homogeneous enhancement pattern, and the most feeding arteries originated from the meningeal artery.

Effect of glioma-derived immunoglobulin on biological function of glioma cells

IntroductionGlioma is the most common and most invasive primary central nervous system tumour, and it is urgent to develop new specific therapeutic targets. Studies have confirmed that epithelial-derived tumour cells promote tumour cell proliferation and metastasis by secreting a large number of immunoglobulins (Igs), but the role of tumour-derived Igs in glioma has never been reported. MethodsThe Gene Expression Profiling Interactive Analysis and Chinese Glioma Genome Atlas databases were used to analyse the Ig transcription and its correlation with the prognosis of patients with glioma. Immunohistochemistry and immunofluorescence were used to detect the protein expression of IgG and IgM in the glioma tissues of patients and glioma cell lines. When IgG was knocked down by small interfering RNA or knocked out by CRISPR-Cas9, the function of proliferation and migration of glioma cells were analysed by CCK-8, clone formation, wound healing, and transwell assays. Changes in proteins and their phosphorylation in signalling pathways were detected by western blotting. The nude mouse subcutaneous tumour-bearing model was established to analyse the effect of IgG in vivo. ResultsThe transcriptional level of IgG was pretty high in glioma tissues and was positively correlated with high WHO grade, recurrence, and poor prognosis. The expression of IgG and IgM was found in tumour tissues and human glioma cell lines U87 and U251, and the main expression form was secreted. Decreased IgG inhibited the proliferation and migration of glioma cells. Knockout or knockdown of IgG downregulated the phosphorylation of the key molecules in the MAPK and PI3K/Akt pathway through the HGF/SF-Met or FAK/Src pathway. In vivo tumourigenesis mouse model confirmed that reduced IgG expression inhibited glioma growth. ConclusionIg was expressed in glioma tissues and cell lines, and a high expression level predicted a poor prognosis of patients. Glioma-derived IgG promoted glioma cell proliferation and migration through the HGF/SF-Met or FAK/Src pathway.

Current and promising treatment strategies in glioma.

Gliomas are the most common primary central nervous system tumors; despite recent advances in diagnosis and treatment, glioma patients generally have a poor prognosis. Hence there is a clear need for improved therapeutic options. In recent years, significant effort has been made to investigate immunotherapy and precision oncology approaches. The review covers well-established strategies such as surgery, temozolomide, PCV, and mTOR inhibitors. Furthermore, it summarizes promising therapies: tumor treating fields, immune therapies, tyrosine kinases inhibitors, IDH(Isocitrate dehydrogenase)-targeted approaches, and others. While there are many promising treatment strategies, none fundamentally changed the management of glioma patients. However, we are still awaiting the outcome of ongoing trials, which have the potential to revolutionize the treatment of glioma.

P11.55.B Postoperative MRI is able to detect an unexpected residual tumor after surgery of brain metastases: experience from 5 specialized centers

Abstract Background Brain metastases (BM) constitute the most common central nervous system tumors. The treatment options of BM consist of surgery, radiotherapy, radiosurgery, chemotherapy, and immunotherapy. Regarding surgery in BM, the extent of resection (EOR) represents a crucial factor for patient prognosis. However, first studies using postoperative MRI demonstrated that an unexpected residual tumor after surgery of BM is not uncommon despite these tumors were considered to be well-demarcated. The aim of this study was thus to investigate in a large cohort including multiple neurosurgical centers the EOR following BM resection, potential risk factors for incomplete resection and postsurgical follow-up data. Material and Methods In the current retrospective study conducted at 5 specialized neurosurgical centers in Austria, we included patients with BM resection and available postoperative MRI. The EOR following BM resection was determined by postoperative MRI (complete vs incomplete resection). Additionally, the data on the intraoperative judgement of the EOR of the performing neurosurgeon were collected. Moreover, potential factors for incomplete resection including tumor localization, tumor volume, primary tumor, pattern of contrast media enhancement on imaging and tumor eloquence were investigated. Finally, the rate of local progression of BM after initial surgery was analyzed in the follow-up period and overall survival data were collected. Results Altogether, 548 patients with 649 surgically treated BM were included. According to postoperative MRI, complete resection was achieved in 407 (66%) of 649 BM and incomplete resection in 176 (29%) of 649 BM. Misjudgment of the EOR by the neurosurgeon was found in 25% of cases and resulted in an unexpected residual tumor which was evident on postoperative MRI in 122 (22%) BM. Preoperative tumor volume was significantly larger in incompletely resected BM. Moreover, local progression was significantly more common in cases with incompletely resected BM and was also associated with shorter overall survival. Conclusion Our data of this study including multiple centers indicate that postoperative MRI is capable to detect a relatively high rate of unexpected residual tumors following resection of BM. Since local progression was more common in BM with residual tumors and this was associated with shorter survival, special attention should be paid to achieve a complete tumor resection.

P02.04.A Preoperative neutrophil, thrombocyte and monocyte to lymphocyte ratios as independent prognostic factors for patient survival in WHO 2021 glioblastoma multiforme

Abstract Background Glioblastoma (GBM) is the most common malignant primary central nervous system (CNS) tumor. It is a fast-growing and extremely aggressive malignancy with a short postoperative survival time of little more than a year. The tumor-immune system interactions are complex and can be measured as local phenomena - e.g., tumor-infiltrating lymphocytes, or as systemic events - e.g., lymphopenia, neutropenia, etc. with cell numbers allowing for estimation of the type of immune reaction against the tumor. Material and Methods A retrospective non-clinical approach was utilized for the means of the study. Patients with a histologically and molecular verified GBM, corresponding to the guidelines of 2021 WHO CNS tumor classification, diagnosed in a three-year interval (February 2018-2021) in a single tertiary healthcare institution were included. Patients with infectious, inflammatory, autoimmune, and hematological diseases, as well as those with malignancy in another location, were excluded. Data regarding patient demographics, and preoperative peripheral blood cell counts (neutrophils, platelets, and monocytes in a ratio to lymphocytes) were compared with postoperative patient survival. Preoperative ratios were calculated as absolute values. For cutoff values we used generally accepted ones - >4 for neutrophil to lymphocyte (NLR), >200 for thrombocyte to lymphocyte (TLR), and >0.25 for monocyte to lymphocyte ratios (MLR). Results were statistically analyzed with MedCalc version 19.7.1 and the Kaplan-Meier method. Results A total of 22 patients fit the established criteria, with a male to female ratio of 2.14:1, mean age of 66.23 years, and mean survival of 255.72 days (8.04 months, range 24-801 days). Eight patients had an elevation of NLR and five of PLR, with no statistical correlation to survival. Six patients had an increase in MLR with a statistically significant (p=0.0044) shorter postoperative survival. Synergic increase in NLR and PLR did not show significance, while synergic increase with MLR showed no added benefit, as did comparison within MGMT promoter methylation groups. Conclusion Elevation in NLR, PLR, and MLR is a good independent prognostic marker for postoperative patient survival in histologically and mutationally verified GBM. Acknowledgments * contributed equally to the work and should be considered co-first authors.Financing: Medical University - Varna Scientific Fund, grant number 19010 and National scientific fund - young researchers (Republic of Bulgaria) grant number 2990/07.06.2021 Ethical approval: Medical University - Varna committee on scientific ethics approval protocol number 93/21.05.2020

Intracranial meningiomas: clinical, intrascopic and pathomorphological causes of recurrence (literature review)

Introduction. Meningiomas are the second most common central nervous system (CNS) tumors in adults. most meningiomas are benign tumors. Anaplastic and atypical meningiomas account for 25% and have a high recurrence rate even after radical tumor resection and radiotherapy. The prognosis of patients with anaplastic meningiomas remains disappointing; most of them die within the first 2 to 5 years after surgery. Purpose: to discuss the challenges in diagnosis and treatment of recurrent meningiomas, to identify the causes of tumor progression, and to assess the clinical features and radiographic findings as well as specific pathomorphological and molecular genetic characteristics. material and methods. We searched for publications in the Pubmed, EMBASE, Cohrane Library and eLibrary databases published between January 2000 and January 2019 on the issue of recurrent intracranial meningiomas, in particular atypical and anaplastic meningiomas. Results. The review systematizes data on the prognostic factors for survival, relapse-free period, and disease progression. particular attention was paid to the radical resection of the tumor and the assessment of the grade of anaplasia. The current data on radiotherapy and drug therapy were presented. the controversial issues of approaches to the assessment of morphological prognostic criteria were discussed. The current knowledge on the most common genetic mutations in meningiomas, the prospects for their study and use for targeted therapy were presented. Conclusion. The management of meningioma still presents some unresolved issues. There are no optimal standards for diagnosis and treatment of patients with meningiomas that would take into account biological characteristics, including growth characteristics and molecular genetic profile. There are no clear prognostic criteria for recurrence and continuity in further management after surgical treatment, which affects the mortality rate and quality of life in this category of patients. New fundamental data that will determine a different strategy in the treatment of intracranial meningiomas are needed.

Weighted Gene Co-Expression Network Analysis and Support Vector Machine Learning in the Proteomic Profiling of Cerebrospinal Fluid from Extraventricular Drainage in Child Medulloblastoma.

Medulloblastoma (MB) is the most common pediatric malignant central nervous system tumor. Overall survival in MB depends on treatment tuning. There is aneed for biomarkers of residual disease and recurrence. We analyzed the proteome of waste cerebrospinal fluid (CSF) from extraventricular drainage (EVD) from six children bearing various subtypes of MB and six controls needing EVD insertion for unrelated causes. Samples included total CSF, microvesicles, exosomes, and proteins captured by combinatorial peptide ligand library (CPLL). Liquid chromatography-coupled tandem mass spectrometry proteomics identified 3560 proteins in CSF from control and MB patients, 2412 (67.7%) of which were overlapping, and 346 (9.7%) and 805 (22.6%) were exclusive. Multidimensional scaling analysis discriminated samples. The weighted gene co-expression network analysis (WGCNA) identified those modules functionally associated with the samples. A ranked core of 192 proteins allowed distinguishing between control and MB samples. Machine learning highlighted long-chain fatty acid transport protein 4 (SLC27A4) and laminin B-type (LMNB1) as proteins that maximized the discrimination between control and MB samples. Machine learning WGCNA and support vector machine learning were able to distinguish between MB versus non-tumor/hemorrhagic controls. The two potential protein biomarkers for the discrimination between control and MB may guide therapy and predict recurrences, improving the MB patients’ quality of life.

The first-in-class ERK inhibitor ulixertinib shows promising activity in mitogen-activated protein kinase (MAPK)-driven pediatric low-grade glioma models.

Pediatric low-grade gliomas (pLGG) are the most common pediatric central nervous system tumors, with driving alterations typically occurring in the MAPK pathway. The ERK1/2 inhibitor ulixertinib (BVD-523) has shown promising responses in adult patients with mitogen-activated protein kinase (MAPK)-driven solid tumors. We investigated the antitumoral activity of ulixertinib monotherapy as well as in combination with MEK inhibitors (MEKi), BH3-mimetics, or chemotherapy in pLGG. Patient-derived pLGG models reflecting the two most common alterations in the disease, KIAA1549:BRAF-fusion and BRAFV600E mutation (DKFZ-BT66 and BT40, respectively) were used for in vitro and in vivo (zebrafish embryos and mice) efficacy testing. Ulixertinib inhibited MAPK pathway activity in both models, and reduced cell viability in BT40 with clinically achievable concentrations in the low nanomolar range. Combination treatment of ulixertinib with MEKi or BH3-mimetics showed strong evidence of antiproliferative synergy in vitro. Ulixertinib showed on-target activity in all tested combinations. In vivo, sufficient penetrance of the drug into brain tumor tissue in concentrations above the in vitro IC50 and reduction of MAPK pathway activity was achieved. In a preclinical mouse trial, ulixertinib mono- and combined therapies slowed tumor growth and increased survival. These data indicate a high clinical potential of ulixertinib for the treatment of pLGG and strongly support its first clinical evaluation in pLGG as single agent and in combination therapy in a currently planned international phase I/II umbrella trial.

Incidence and survival of benign, borderline, and malignant meningioma patients in the United States from 2004 to 2018.

Meningioma is the most common primary central nervous system tumor, and its incidence is increasing. A systematic epidemiological and clinical analysis is required to better estimate its public health impact and understand its prognostic factors. Data were obtained from the Surveillance, Epidemiology, and End Results (SEER) database from 2004 to 2018 for all types of meningiomas without an age restriction. Age-adjusted incidence rates (IRs) and 95% confidence intervals were estimated according to sex, age, race, ethnicity, and tumor location. Kaplan-Meier analysis and multivariate Cox proportional hazard models were used to analyze the overall survival (OS). The competing risk regression model of Fine-Gray was used to analyze cause-specific survival. Data from a total of 109 660 meningioma patients were analyzed. A majority of patients were older than 60 years, and only 0.41% of patients were 0-19 years. The meningioma IRs were higher in females, Black, and non-Hispanic patients than in males, White, and Hispanic patients, respectively, and IRs increased with age. The ratio of IRs for females to males was 2.1 and also increased with age, peaking at 3.6 in the 45-49-year-old group. Older and male patients with all types of meningiomas, Black patients with benign and borderline meningiomas, and patients with larger borderline and malignant meningiomas showed poorer prognosis. For all meningioma types, surgical resection improved survival. The reported incidence rates and survival trends covered all demographics and subtypes of meningiomas. Older age, male sex, Black race, and tumor size may be important prognostic factors for meningioma cases, and tumor resection can substantially improve survival among meningioma patients.

Caspase 8 Expression Patterns in Meningiomas: A Tissue Microarray Digital Image Analysis.

Background: Caspases (cysteine-aspartic proteases) represent a family of enzymes that critically influence cell homeostasis by being involved in inflammation and apoptosis mechanisms. Meningiomas demonstrate the most common intracranial primary central nervous system tumors in adults worldwide.Aim: Our purpose was to explore the role of caspase 8 expression in meningiomas’ pathological features.Materials and methods: A total of 50 meningioma cases were included in the study, comprising a broad spectrum of histopathological sub-types. An immunohistochemistry assay was applied on tissue microarray cores followed by digital image analysis.Results: Overexpression of caspase 8 protein was observed in 21/50 (42%) cases, whereas the rest of them (29/50, 58%) demonstrated moderate to low levels of the molecule. Caspase 8 overall expression was statistically significantly correlated to grade of the examined tumors and to mitotic index (p=0.001,p=0.002, respectively).Conclusions: Caspase 8 aberrant expression is observed in meningiomas associated with their differentiation grade and mitotic activity. Targeted therapeutic strategies focused on enhancing caspase 8 expression and also inducing the overall apoptotic activity should be a very promising approach in rationally handling sub-groups of meningioma patients.

Abstract 5392: Magnolol induces apoptosis and inhibits invasion ability via suppression of STAT3 signaling in glioblastoma multiforme cells

Abstract Magnolol is a phenolic compound extracted from magnolia officinalis, exhibited anti-tumor potential against many types of cancers. Magnolol has also recognized as an anti-inflammation agent which can downregulate several inflammation signals transduction. Glioblastoma multiforme (GBM) is the most common central nervous system (CNS) tumor and associated with poor prognosis among adults due to rapid growth and aggressive invasion. However, the treatment efficacy of current standard therapy for GBM is remaining unsatisfied. Nevertheless, whether magnolol may suppress GBM progression and its underlying mechanism has not been elucidated. Thus, the purpose of this study was to investigate the mechanism and therapeutic efficacy of magnolol on GBM.First of all, we validated the potential treatment targets of GBM with the GEPIA (Gene Expression Profiling Interactive Analysis) analysis and Western blotting assay. GEPIA data indicated the PKCδ/STAT3 signaling pathway as a potential target of GBM that may affect patient survival. In our results, magnolol can effectively suppress the phosphorylation and the nuclear translocation of STAT3 in GBM cells. Then, we used the MTT assay to investigate the cytotoxicity of GBM cells after various dose of magnolol treatment. We also detected the extrinsic/intrinsic apoptosis induction ability of magnolol on GBM cells. This study also demonstrated that magnolol may significantly trigger the loss of mitochondrial membrane potential, and the activation of cleaved caspase-3, -8 and -9. Transwell invasion and wound healing assays was used to identify the suppression of migration and invasion effects of magnolol on glioblastoma cells. Meanwhile, tumor invasion and migration ability and the associated genes, including MMP9 and uPA, were all diminished by magnolol treatment. In sum, our results demonstrated that magnolol suppressed GBM progression may be associated with the inactivation of PKCδ/STAT3 signaling transduction. Citation Format: Sin-Rong Lee, Yuan Chang, I-Tsang Chiang, Fei-Ting Hsu. Magnolol induces apoptosis and inhibits invasion ability via suppression of STAT3 signaling in glioblastoma multiforme cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5392.

LGG-32. Integrated biologic, radiologic and clinical analysis of pediatric low-grade gliomas during and after targeted therapy treatment

BACKGROUND: Pediatric low grade gliomas (pLGGs) are the most common central nervous system tumor in children, characterized by driver alterations in the RAS and MAPK pathways. Genomic advances have facilitated use of molecular targeted therapies, however their long-term impact on tumor behavior remains critically unanswered. METHODS: We performed an IRB-approved, retrospective chart and imaging review of pLGGs treated with off-label targeted therapy at Dana-Farber/Boston Children’s Cancer and Blood Disorders Center from 2010 to 2020. Volumetric analysis was performed for BRAFV600E and BRAF fusion/duplication driven pLGG subsets. RESULTS: Fifty-five patients were identified (dabrafenib n = 15, everolimus n = 26, trametinib n = 11, and vemurafenib n = 3). Targeted agent was used as first or second-line therapy for 58% (32/55). Median duration of targeted therapy was 0.79 years (0.01 – 4.87), and overall median follow-up was 2.50 years (0.01 – 7.39). The 1-year, 3-year, and 5-year EFS from targeted therapy initiation were 62.1%, 38.2%, and 31.8%, respectively. Mean volumetric change for BRAFV600E mutated pLGG on BRAF inhibitors was -54.11%, and median time to best volumetric response was 8.28 months (n = 12). Median time to largest volume post-treatment was 2.86 months. Mean volumetric change for BRAF fusion/duplication pLGG on MEK inhibitors was +7.34% with median time to best volumetric response of 6.71 months (n = 7). Median time to largest volume post-treatment was 2.38 months. CONCLUSIONS: Our integrated clinical and volumetric data suggest the majority of patients receiving BRAF inhibitors or trametinib achieve reduction in tumor volume while on therapy and that tumor stability can be achieved following targeted therapy cessation. Moreover, volumetric analysis shows promise as a tool to assess targeted therapeutic response in pLGGs.

LGG-04. Clinical and molecular characterization of metastatic pediatric low grade gliomas

BACKGROUND: Despite being the most common central nervous system tumor in children, ≤5% of pediatric low grade gliomas (pLGG) present with metastases. Due to their rarity, there is a paucity of clinical and molecular data in metastatic pLGGs. To address the need, we analyzed a cohort of 22 patients with pLGG followed at Texas Children’s Hospital who presented with metastatic disease. RESULTS: The predominant histology was pilocytic astrocytoma (16/22, 73%); average age at diagnosis was 4 years 11 months. The most common sites of primary disease were optic pathway/chiasm (7/22, 32%) and suprasellar (5/22, 23%). Metastatic disease was most commonly noted in the leptomeninges (12/22, 55%). 16/22 patients (73%) were treated with up-front medical therapy following tumor biopsy/resection, the majority with carboplatin-based therapy; the remaining 6 patients received only surgery up-front. Only 2/22 patients (9%) did not progress after their initial treatment with an average follow-up of 42 months. 14 patients (14/22, 64%) had continued disease progression after at least 2 therapeutic interventions; however, only 3 patients (3/22, 14%) eventually received craniospinal radiation. 10 patients (10/22, 45%) received treatment with an agent targeting the mitogen-activated protein kinase (MAPK) pathway. 20/22 patients (91%) were alive at last follow-up (average 72 months). 4/21 patients (19%) harbored a BRAF V600E mutation while 7/20 (35%) had a BRAF::KIAA1549 duplication/fusion. 8/20 patients (40%) were wildtype for both analyzed molecular alterations in BRAF. 8 patients had germline whole exome sequencing performed and all were negative for pathogenic/likely-pathogenic variants related to their clinical phenotype. Methylation analyses are pending on patients with available tumor tissue. CONCLUSION: In our cohort of patients with metastatic pLGG, most tumors progressed despite numerous therapeutic regimens, but the overall survival was >90%. 40% of patients were wild type for the 2 most common MAPK alterations seen in pLGG.

GCT-15. Multi-institutional analysis and literature review of central nervous system germ cell tumors in patients with Down syndrome

Abstract BACKGROUND: A standard-of-care has not been established for the management of patients with Down syndrome (DS) who develop primary central nervous system (CNS) germ cell tumors (GCTs) – the most common CNS neoplasm in DS – despite being more susceptible to treatment-related adverse events. METHODS: Data from large academic institutions were collected and a comprehensive review of the medical literature was conducted. RESULTS: Ten patients from six institutions (five USA, one Brazil) were reviewed. Additionally, thirty-one patients were identified in the literature from 1975-2021. Of the 41 total patients, mean age was ten years (range, birth to 35 years); males were predominant (61%). Basal ganglia were the most common tumor location (n=12; 29%), followed by posterior fossa (n=7; 17%). Sixteen patients had non-germinomatous germ cell tumors (NGGCTs) (39%), 14 had pure germinomas (34%), and eight had teratomas (20%); histology was unreported for two (5%). Nine patients (22%) experienced disease relapse, of which four died from tumor progression (one germinoma versus three teratoma). Fifteen patients (37%) experienced treatment-related complications - seven died (four germinoma versus three NGGCT). Of the germinoma patients, two died from chemotherapy-related sepsis, one from post-surgery cardiopulmonary failure, and one from Moyamoya following radiation-therapy (RT) only. Of the NGGCT patients, one died from chemotherapy-related sepsis, one from post-surgical infection, and one from pneumonia following surgery/chemotherapy/RT. Three-year overall survival (OS) was 66% for all histological types - 62% germinoma, 79% for NGGCT, and 53% for teratoma. Three-year OS for patients who received RT or chemotherapy was 71% and 75% respectively. Twenty-seven patients remain alive at latest follow-up (mean follow-up from diagnosis: 46.8 months). CONCLUSIONS: Patients with DS treated for CNS GCTs are at an increased risk of treatment-related adverse events. A different therapeutic approach may need to be considered for this patient population to mitigate treatment-related complications and long-term neurocognitive sequelae.