Diffuse Astrocytoma Research Articles

MYB/MYBL1-altered gliomas frequently harbor truncations and non-productive fusions in the MYB and MYBL1 genes

Astrocytomas that harbor recurrent genomic alterations in MYB or MYBL1 are a group of Pediatric-type diffuse low-grade gliomas that were newly recognized in the 2021 WHO Classification of Tumors of the Central Nervous System. These tumors are described in the WHO classification as harboring fusions in MYB or MYBL1. In this report, we examine 14 consecutive cases in which a MYB or MYBL1 alteration was identified, each with diagnostic confirmation by genome-wide DNA methylation profiling (6 Angiocentric gliomas and 8 Diffuse astrocytomas, MYB- or MYBL1-altered), for their specific genomic alterations in these genes. Using RNA sequencing, we find productive in-frame fusions of the MYB or MYBL1 genes in only 5/14 cases. The remaining 9 cases show genomic alterations that result in truncation of the gene, without evidence of an in-frame fusion partner. Gene expression analysis showed overexpression of the MYB(L1) genes, regardless of the presence of a productive fusion. In addition, QKI, a recognized fusion partner common in angiocentric glioma, was generally up-regulated in these 14 cases, compared to a cohort comprising >1000 CNS tumors of various types, regardless of whether a genomic alteration in QKI was present. Overall, the results show that truncations, in the absence of a productive fusion, of the MYB(L1) genes can likely drive the tumors and have implications for the analysis and diagnosis of Angiocentric glioma and Diffuse astrocytoma, MYB- or MYBL1-altered, especially for cases that are tested on panels designed to focus on fusion detection.

MO27-5 Concurrent leiomyosarcoma and diffuse astrocytoma in a Li-Fraumeni syndrome patient: a case report

MO27-5 Concurrent leiomyosarcoma and diffuse astrocytoma in a Li-Fraumeni syndrome patient: a case report

Current progress of anti‑PD‑1/PDL1 immunotherapy for glioblastoma (Review).

Glioblastoma (GBM) is the most common central nervous system malignancy in adults. GBM may be classified as grade IV diffuse astrocytoma according to the 2021 World Health Organization revised classification of central nervous system tumors, which means it is the most aggressive, invasive, undifferentiated type of tumor. Immune checkpoint blockade (ICB), particularly anti‑programmed cell death protein‑1 (PD‑1)/PD‑1 ligand‑1 immunotherapy, has been confirmed to be successful across several tumor types. However, in GBM, this treatment is still uncommon and the efficacy is unpredictable, and <10% of patients show long‑term responses. Recently, numerous studies have been conducted to explore what factors may indicate or affect the ICB response rate in GBM, including molecular alterations, immune expression signatures and immune infiltration. The present review aimed to summarize the current progress to improve the understanding of immunotherapy for GBM.

Anatomical and subcortical invasiveness in diffuse low-grade astrocytomas differ between IDH status and provide prognostic information.

Diffuse astrocytomas preferentially infiltrate eloquent areas affecting the outcome. A preoperative understanding of isocitrate dehydrogenase (IDH) status may offer opportunities for specific targeted therapies impacting treatment management. The aim of this study was to analyze clinical, topographical, radiological in WHO 2 astrocytomas with different IDH status and the long-term patient's outcome. A series of confirmed WHO 2 astrocytoma patients (between 2005 and 2015) were retrospectively analyzed. MRI sequences (FLAIR) were used for tumor volume segmentation and to create a frequency map of their locations into the Montreal Neurological Institute (MNI) space. The Brain-Grid (BG) system (standardized radiological tool of intersected lines according to anatomical landmarks) was used as an overlay for infiltration analysis of each tumor. Long-term follow-up was used to perform a survival analysis. Forty patients with confirmed IDH status (26 IDH-mutant, IDHm/14 IDH-wild type, IDHwt) according to WHO 2021 classification were included with a mean follow-up of 7.8 years. IDHm astrocytomas displayed a lower number of BG-voxels (P < 0.05) and were preferentially located in the anterior insular region. IDHwt group displayed a posterior insular and peritrigonal location. IDHwt group displayed a shorter OS compared with IDHm (P < 0.05), with the infiltration of 7 or more BG-voxels as an independent factor predicting a shorter OS. IDHm and IDHwt astrocytomas differed in preferential location, number of BG-voxels and OS at long follow-up time. The number of BG-voxels affected the OS in IDHwt was possibly reflecting higher tumor invasiveness. We encourage the systematic use of alternative observational tools, such as gradient maps and the Brain-Grid analysis, to better detect differences of tumor invasiveness in diffuse low-grade gliomas subtypes.

Optimal treatment strategy for low-grade spinal cord astrocytoma: a retrospective, multicenter analysis by the Neurospinal Society of Japan

OBJECTIVE Primary spinal cord gliomas are rare, and among these astrocytomas (WHO grade II) are much rarer. The optimal treatment strategy thus remains unclear. The authors conducted a multicenter study led by the Neurospinal Society of Japan (NSJ) to analyze treatment policies and outcomes. The aim was to present optimal treatment methods for spinal cord astrocytoma and to identify predictors of better outcomes. METHODS Among 1033 consecutive cases of spinal cord intramedullary tumors treated surgically at 58 centers affiliated with the NSJ, 57 patients were diagnosed with diffuse astrocytoma (WHO grade II) and were enrolled in the present study. Among these 57 patients, treatment methods, outcomes, and tumor proliferation rate as evaluated by the MIB-1 staining index (SI) were analyzed, and the optimal treatment method for spinal cord astrocytomas (grade II) was determined. In addition, the authors searched for factors predicting better treatment outcomes. RESULTS Treatment for spinal cord astrocytoma comprised three methods: surgery alone in 30 patients, adjuvant radiation therapy in 13 patients, and adjuvant chemoradiotherapy in 13 patients. One patient who did not undergo surgery was excluded from survival analysis. Treatment with surgery alone or surgery with radiotherapy was associated with significantly longer overall and progression-free survivals than that with adjuvant chemoradiotherapy. Patients treated with radiation therapy had a higher MIB-1 SI than those treated with surgery alone. The extent of tumor resection tended to correlate with longer survival. In contrast, postoperative neurological worsening showed the inverse order. Adjuvant chemoradiotherapy was associated with the shortest survival in both total cases and recurrent cases. The optimal cutoff value of MIB-1 SI for predicting longer survival by surgery alone was less than 4.0%. CONCLUSIONS The optimal treatment for spinal cord astrocytoma is maximal tumor resection without neurological impairment. When some tumor remains in patients with an MIB-1 SI less than 4.0%, a wait-and-see approach is optimal. If the MIB-1 SI is higher than 4.0%, local radiation therapy is recommended. Adjuvant chemotherapy is not recommended for the treatment of grade II spinal cord astrocytoma.

Vorasidenib-Induced Trichomegaly and Hypertrichosis: a New Side Effect in a Patient with Diffuse Astrocytoma.

Vorasidenib, an oral dual inhibitor targeting mutant enzymes isocitrate dehydrogenase 1 and 2, is utilized in the management of diffuse low-grade gliomas. Despite limited documentation of its adverse events, we present the case of a 44-year-old male who exhibited trichomegaly and hypertrichosis of body hair, eyebrows, and eyelashes following one month of vorasidenib treatment. Notably, the patient experienced diffuse hair regrowth on the scalp, including in areas affected by severe androgenetic alopecia. This report holds significance as it highlights a previously unreported side effect, thereby enhancing our understanding of emerging therapies for brain tumors and their associated adverse reactions.

The Role of Radiotherapy, Chemotherapy, and Targeted Therapies in Adult Intramedullary Spinal Cord Tumors.

Intramedullary primary spinal cord tumors are rare in adults and their classification has recently evolved. Their treatment most frequently relies on maximal safe surgical resection. Herein, we review, in light of the WHO 2021 classification of central nervous system tumors, the knowledge regarding the role of radiotherapy and systemic treatments in spinal ependymomas, spinal astrocytomas (pilocytic astrocytoma, diffuse astrocytoma, spinal glioblastoma IDH wildtype, diffuse midline glioma H3-K27M altered, and high-grade astrocytoma with piloid features), neuro-glial tumors (ganglioglioma and diffuse leptomeningeal glioneuronal tumor), and hemangioblastomas. In spinal ependymomas, radiotherapy is recommended for incompletely resected grade 2 tumors, grade 3 tumors, and recurrent tumors not amenable to re-surgery. Chemotherapy is used in recurrent cases. In spinal astrocytomas, radiotherapy is recommended for incompletely resected grade 2 astrocytomas and grade 3 or 4 tumors as well as recurrent tumors. Chemotherapy is indicated for newly diagnosed high-grade astrocytomas and recurrent cases. In hemangioblastomas not amenable to surgery, radiotherapy is an effective alternative option. Targeted therapies are playing an increasingly important role in the management of some intramedullary primary spinal cord tumor subtypes. BRAF and/or MEK inhibitors have demonstrated efficacy in pilocytic astrocytomas and glioneuronal tumors, belzutifan in von Hippel-Lindau-related hemangioblastomas, and promising results have been reported with ONC201 in diffuse midline glioma H3-K27M altered.

AB048. Evidence of effectiveness of neoadjuvant camrelizumab and apatinib in patients with recurrent high-grade gliomas.

Recurrent high-grade glioma (HGG) is a challenge with limited treatment options and a poor prognosis. We conducted an open-label phase II study: neoadjuvant camrelizumab and apatinib in patients with recurrent high-grade gliomas (NCT04588987), and interim analysis showed very promising results. We are further searching for evidence of the effectiveness of this strategy. Patients with recurrent HGG received neoadjuvant treatment with camrelizumab (intravenous injection 200 mg on day 1) and apatinib (oral 250 mg per day on days 1-7), and 14 days later received surgery for recurrent tumor resection. Sequential therapy began 2 weeks after surgery with the biweekly camrelizumab (200 mg) and 4 weeks after surgery with the daily apatinib (250 mg) until investigator assessed progressive disease or unable to tolerate toxicity. The primary endpoint was overall survival (OS). When patients suspected progress during per-protocol treatment, re-surgery for resection of lesion was done, and the tissue was further examined. Between October 9, 2020, and March 30, 2024, 24 patients were enrolled [19 glioblastomas, one World Health Organization (WHO) grade 4 diffuse astrocytoma, three anaplastic astrocytoma, and one anaplastic oligodendroglioma]. Nineteen patients with interim analysis data, and showed the median progression-free survival (PFS) was 4.8 months [95% confidence interval (CI): 4.4-5.2], the median OS was 12.9 months (95% CI: 9.3-16.4) respectively, with a median follow-up time of 17.5 months (95% CI: 9.0-26.1). There were two patients who suspected progress and received second surgery. One patient showed real tumor progression with active tumor cells. While another patient the histology revealed mainly necrosis with inflammatory cells. Five patients initially showed increased enhancement on magnetic resonance imaging (MRI) but without increased symptoms, and showed continuous improvement when receiving further treatment. This immuno-target combination neoadjuvant therapy in recurrent HGG demonstrated encouraging efficacy and revealed some evidence of efficacy, and worth to further investigate.

AB094. Association of body mass index with grading and survival of glioma patients.

Glioma is the second most common type of brain tumor, representing 24% of all brain tumor cases. The role of body mass index (BMI) on glioma remains unclear, with conflicting findings regarding the association between higher BMI and the risk of developing certain brain tumors. Glioblastoma, an aggressive and malignant form of glioma with limited treatment options and a poor prognosis, has been linked to BMI in some studies, suggesting that individuals with higher BMIs may have an elevated risk of glioblastoma development. However, a comprehensive understanding of the mechanisms underlying this relationship and its extent is still needed. The study aimed to investigate the correlation between BMI and the grading and survival of glioma patients. A retrospective cross-sectional analysis was conducted on 117 histologically confirmed glioma patients at Dr. Sardjito General Hospital in Yogyakarta, Indonesia. Clinical data were collected from medical records. BMI was calculated by measuring weights (kg) and dividing it by squared heights (m2). The statistical analysis focused on assessing the association between BMI, tumor grade, and patient survival. Among 117 glioma patients, glioblastoma was the most prevalent tumor type (48.7%; n=57/117), followed by diffuse astrocytoma (22%; n=26/117). The remaining cases included anaplastic ependymoma, anaplastic oligodendroglioma, and pilocytic astrocytoma. Most patients were male (61%), with an average age of 47.5 years, age ranges between 20 and 79 years. The majority had grade IV of World Health Organization (WHO) classification (58%, n=68/117), while only two patients were classified as grade I. The average BMI was 23.5 kg/m2, indicating overweight status for the Asian population, with more than half of the patients being overweight or obese (54%, n=63/117). Additionally, ten patients were underweight. There was a trend of higher BMI being associated with higher grading and survival. However, no significant association between BMI and tumor grade (P=0.23) or survival (P=0.26) was found. Although no significant associations were found between BMI, tumor grade, and survival in glioma patients, further studies are warranted. The high prevalence of overweight and obesity among patients should be further investigated to provide valuable insights for patient management and care.

Pathological Evaluation of Diffuse Gliomas Using IDH1 and ATRX in a Resource-Limited Setting.

Classification of gliomas based on tumor histology remains the gold standard in the diagnosis and prognosis of gliomas. However, the recent World Health Organization (WHO) classificationhas included molecular studies for diagnosis and prognostication. Immunohistochemical markers such as isocitrate dehydrogenase 1 (IDH1) and alpha thalassemia/mental retardation syndrome X-linked (ATRX)can be used for the diagnosis andprognosis of the majority of gliomas. We aim to study the frequencies of IDH1 and ATRX mutations in diffuse gliomas using surrogate immunohistochemical markers and correlate histopathological findings of gliomas with immunohistochemical findings. This was a retrospective study of one-year duration from January 2022 to December 2022, conducted in the department of pathology. Relevant data was retrieved from medical records. Histopathology blocks were collected and sent for immunohistochemical studies using tissue microarray for IDH1 and ATRX. Qualitative data were expressed in percentages and proportions. The difference in proportion was calculated using the chi-square test, and a p-value of <0.005 was taken as significant. A total of 51 cases of diffuse gliomas were included in the study. The frequency of IDH1-positive diffuse astrocytomas was 33 (64.7%), and loss of ATRX was seen in 12 (23.5%) cases. Immunohistochemistry serves as a surrogate marker to detect molecular alterations in diffuse gliomas.

A Four-Grade Astrocytoma Classification System with Optimal Feature Selection Using Ant Colony Optimization Algorithm

An efficient Four-Grade Astrocytoma brain tumor classification is proposed in this research work. The work highlights the optimal feature selection using a hybrid combination of Ant Colony Optimization (ACO) algorithm and machine learning techniques, leading to better classification accuracy. A diverse set of features including spatial and frequency domain features will provide better discrimination of patterns. ACO provides a robust and efficient mechanism for exploring the vast space of possible feature subsets. A total of 135 features are extracted including Tamura features, Gabor Wavelet Features, Coiflet Wavelet Coefficients, Speeded Up Robust Features, and GLCM features. Ant Colony Optimization is used to find out the optimum set of features. The selected feature set is used for training a Decision Tree classifier, where the Astrocytoma MRI images are categorized into four grades of astrocyoma namely, pilocytic astrocytoma, diffuse astrocytoma, anaplastic astrocytoma and glioblastoma multiforne. Classification is also performed using KNN classifier, SVM classifier and Ensemble Bagged Tree Classifier. Performance metrics like accuracy, sensitivity, specificity, precision and FScore are utilized to evaluate the proposed system’s performance. It is found out that the decision tree classifier outperforms the other classifiers. Thus this integrated approach of ACO with machine learning classifiers results in improved Astrocytoma classification performance aiding clinicians in making accurate treatment decisions.

Deep Residual Learning-Based Classification with Identification of Incorrect Predictions and Quantification of Cellularity and Nuclear Morphological Features in Digital Pathological Images of Common Astrocytic Tumors.

Interobserver variations in the pathology of common astrocytic tumors impact diagnosis and subsequent treatment decisions. This study leveraged a residual neural network-50 (ResNet-50) in digital pathological images of diffuse astrocytoma, anaplastic astrocytoma, and glioblastoma to recognize characteristic pathological features and perform classification at the patch and case levels with identification of incorrect predictions. In addition, cellularity and nuclear morphological features, including axis ratio, circularity, entropy, area, irregularity, and perimeter, were quantified via a hybrid task cascade (HTC) framework and compared between different characteristic pathological features with importance weighting. A total of 95 cases, including 15 cases of diffuse astrocytoma, 11 cases of anaplastic astrocytoma, and 69 cases of glioblastoma, were collected in Taiwan Hualien Tzu Chi Hospital from January 2000 to December 2021. The results revealed that an optimized ResNet-50 model could recognize characteristic pathological features at the patch level and assist in diagnosis at the case level with accuracies of 0.916 and 0.846, respectively. Incorrect predictions were mainly due to indistinguishable morphologic overlap between anaplastic astrocytoma and glioblastoma tumor cell area, zones of scant vascular lumen with compact endothelial cells in the glioblastoma microvascular proliferation area mimicking the glioblastoma tumor cell area, and certain regions in diffuse astrocytoma with too low cellularity being misrecognized as the glioblastoma necrosis area. Significant differences were observed in cellularity and each nuclear morphological feature among different characteristic pathological features. Furthermore, using the extreme gradient boosting (XGBoost) algorithm, we found that entropy was the most important feature for classification, followed by cellularity, area, circularity, axis ratio, perimeter, and irregularity. Identifying incorrect predictions provided valuable feedback to machine learning design to further enhance accuracy and reduce errors in classification. Moreover, quantifying cellularity and nuclear morphological features with importance weighting provided the basis for developing an innovative scoring system to achieve objective classification and precision diagnosis among common astrocytic tumors.

The significance of clinical and morphological characteristics of spinal cord astrocytomas in the choice of surgical tactics

Objective — to determine the factors affecting the dynamics of the neurological status in the postoperative period in patients with intramedullary spinal cord astrocytomas (SCA) in order to improve the results of their surgical treatment. Materials and methods. Between 2010 and 2019, we conducted a retrospective study on the surgical treatment outcomes of 39 SCA patients operated on at the SI “Romodanov Neurosurgery Institute of the National Academy of Medical Sciences of Ukraine”. The age of the patients ranged from 19 to 67 years, with an average age of 41.4 years. Out of the total, 25 patients (64%) were men and 14 patients (36%) were women. We observed cervical localization in 11 (28%) clinical cases, thoracic localization in 25 (64%), and conus medullaris in 3 (8%). All patients underwent a comprehensive clinical and instrumental examination using magnetic resonance imaging with intravenous enhancement, computed tomography, and spondylography. The dynamics of neurological symptoms were evaluated using the modified McCormick before surgery, at the time of the patient’s hospital discharge, and during follow‑up examinations. Results. Total removal of SCA was performed in 7 (18%) patients, subtotal in 25 (64%), and partial in 7 (18%). Pilocytic astrocytoma (PA) (World Health Organisation (WHO) grade I) was detected in 19 (49%) patients, diffuse astrocytoma (DA) (WHO grade II) in 17 (43%), and anaplastic astrocytoma (AA) (WHO grade III) in 3 (7%). Partial regression of neurological symptoms was noted in 29 (74%) patients, the neurological status remained at the preoperative level in 6 (15%) patients, and a slight increase in the neurological deficit was noted in 4 (10%) patients. Age &lt;60 years is significantly more frequently associated with the growth of PA, while age &gt;60 years is significantly more frequently associated with the growth of AA. The duration of anamnesis (&lt; 1 year and &gt;1 year) and the degree of radicality of the operation were identified as significant factors that can influence the neurological status in the late postoperative period, mainly in patients with PA and DA. However, such factors as tumour location and the degree of infiltration of nearby structures are not statistically significant. AA is associated with an unfavourable prognosis across all important criteria. Conclusions. The most important determinants of SCA prognosis are preoperative and postoperative neurological condition, resection extent, and histological grade. Patients with minor neurological damage at the time of surgery, those under the age of 60, and those with highly differentiated SCA had the greatest surgical treatment outcomes. Assessment of the preoperative neurological status and determination of the histological type of the tumour are important factors in choosing the optimal surgical tactics, which сan improve treatment outcomes and the quality of life in SCA patients.

EPID-03. CURE FRACTION AND LONG TERM SURVIVAL ESTIMATES FOR PEDIATRIC CENTRAL NERVOUS SYSTEM TUMORS IN EUROPE – RESULTS OF THE POPULATION-BASED EUROCARE PROJECT

Abstract BACKGROUND Time trends in cure fractions and up-to-date long-term survival have not been reported for clinically relevant groups of pediatric central nervous system (CNS) tumors although it provides important information for planning long-term clinical follow-up. METHODS We analyzed data on 15,242 children (&amp;lt;15 years) diagnosed with a CNS tumor between 1998-2013 from 31 European countries with follow-up until 31/12/2014. Cure fraction, the proportion of patients not anymore at risk of dying from progression or relapse was estimated using a mixture cure model with a parametric cancer survival curve function and assuming constant long-term mortality from other causes, including other cancers. Additionally, model-based up-to-date 15-year observed survival (OS) was estimated for the period 2010-2013. RESULTS The cure fraction for ependymomas increased from 65% in 1998-2001 to 79% in 2010-2013. However, as a result of the high long-term mortality rate of 16 per 1000 surviving patients per year, ependymomas had an estimated 15-year OS of 62%. For diffuse astrocytomas the cure fraction increased 6 percent-points to 84%, and 15-year OS was 74%. Cure fraction for glioblastomas increased from 15% to 20%. Long-term mortality for surviving glioblastoma patients was null resulting in a comparable projected 15-year OS of 20%. For medulloblastomas the cure fraction increased with 4 percent-points to 56% in 2010-2013, and a comparable 15-year OS of 56%. AT/RTs including PNETs together with high-grade gliomas (HGGs) were the only groups for which the cure fraction did not change over time: 34% and 24%, respectively. Estimated 15-year OS was 28% for AT/RTs including PNETs and 19% for HGGs. CONCLUSIONS As a result of high long-term mortality, the difference between cure fraction and 15-year OS was the highest for ependymomas and diffuse astrocytomas. Further investigation into underlying reasons (e.g., late effects of treatment) are needed to reduce the extra risk of deaths.

LGG-11. UNDERSTANDING THE TRANSCRIPTIONAL HETEROGENEITY OF PEDIATRIC LOW-GRADE GLIOMAS AND ITS IMPLICATION FOR TUMOR PATHOPHYSIOLOGY

Abstract BACKGROUND Pediatric low-grade gliomas (pLGGs) are the most frequent brain tumors in children and comprise a heterogeneous group of tumors with different locations, histologic subtypes, ages at presentation, and clinical behavior. Tumors frequently respond to treatment with chemotherapy or radiation therapy, but they can regrow after a period of quiescence, requiring further therapy. Thus, a deeper understanding of the molecular processes involved in these tumors is required to develop therapeutic strategies that are effective against their disease mechanisms. METHODS To better understand the cellular behaviors of this heterogenous group of tumors, we have employed single-cell and single-nuclei RNA sequencing technologies to analyze a large-scale dataset (&amp;gt;250,000 cells) of 55 pLGGs across many histological subtypes (pilocytic astrocytoma, pleomorphic xanthoastrocytoma, pilomyxoid astrocytoma, DNET, ganglioglioma, RGNT, diffuse astrocytoma, SEGA, glioneuronal, oligodendroglioma). RESULTS Analysis of this data identified a heterogenous population of cell types and cell states, detecting mature and progenitor-like astrocytes and oligodendrocytes, as well as cells exhibiting senescence or cycling programs. Moreover, we identify a significant immune infiltrate, comprised primarily of microglia. In addition to heterogeneity within pLGG tumors, heterogeneity between LGG subtypes represents another layer that stratifies pLGG biology. We performed a compositional analysis of the cell types present in these tumors and compared transcription signatures and gene expression programs across shared cellular populations of histologically and genetically distinct pLGGs. Finally, we used spatial transcriptomic data to investigate and annotate the cellular architecture of multiple pLGGs with BRAF mutations and draw comparisons to findings from our single-cell and single-nuclei transcriptomic analysis. CONCLUSIONS Our analysis of human pLGGs at the single-cell and single-nuclei resolution provides critical insight into the heterogenous biological activities that constitute these tumors.

QOL-42. ANALYSIS OF LATE EVENTS AFTER RADIATION THERAPY FOR PRIMARY PEDIATRIC BRAIN TUMORS

Abstract BACKGROUND Late events after radiation therapy for primary brain tumors consist of secondary malignant neoplasms (SMN) and tumor recurrences. The incidence and biology of late events are not very well described. Therefore, we aimed to identify late events in our institutional cohort and describe their biology. METHODS A retrospective chart review of all irradiated pediatric brain tumor patients treated between 2000 and 2015 at our institution was performed to obtain demographics and clinical data of late events. Late events were defined as intracranial intraaxial SMN or tumor recurrence occurring later than 3 years after radiation therapy. A whole-genome methylation array was employed to identify the methylation class of the late event. RESULTS In the observed period, 267 patients received some form of cranial radiotherapy for primary brain tumor; high-grade glioma (HGG, n=66), medulloblastoma (n=74), ependymoma (n=50), germ-cell tumors (GCT, n=22), low-grade glioma (LGG, n=24), and other diagnoses (n=31). Out of the 174 patients who were alive and without an event after 3 years from the radiation therapy, 30 developed late events (16.8%), and 27 of them were histologically verified. Verified late events consisted of 8 SMNs (29.6%) and 19 primary tumor recurrences. SMNs were mainly radiation-induced gliomas (RIG, n=7) and one atypical teratoid/rhabdoid tumor (ATRT) after craniopharyngioma. All RIG tumors clustered with the “pediatricHGG_RTK1” methylation class. Tumor recurrences consisted of medulloblastomas (Group 4 and Wnt), ependymomas (PFA and ST_ZFTA), GCTs, gliomas (one NF1-associated HGG, one H3-altered thalamic glioma, one diffuse astrocytoma with BRAF-V600E mutation), and craniopharyngiomas. The overall survival rate 5 years after a late event was 39.7%, with a worse survival rate for SMN patients (14.3%) compared to those with recurrences (44.9%) (p=0.05). CONCLUSIONS Late events affected 16.8% of long-term survivors. Strikingly, SMNs represented almost 30% of late events and were associated with a very poor prognosis.

LGG-08. DIFFUSE ASTROCYTOMA IN A PATIENT WITH POSSIBLE MBD4-ASSOCIATED NEOPLASIA SYNDROME (MANS)- EXPANDING THE SPECTRUM OF MANS-ASSOCIATED NEOPLASM

Abstract BACKGROUND MBD4-associated neoplasia syndrome (MANS) is a recently identified genetic syndrome characterized by the development of colorectal polyps, acute myeloid leukemia, and uveal melanoma, with an elevated mutation burden. MANS is attributed to bi-allelic germline variations in the MBD4 gene. METHOD We present a case of a pediatric patient with diffuse astrocytoma WHO-grade II and bi-allelic germline variations in the MBD4 gene. CASE REPORT A previously healthy 10-year-old female with a significant family history of high-grade IDH wild type-glioma in the deceased older brother presented with vague symptoms and was found to have abnormal brain MRI with multiple foci of subcortical FLAIR/T2 hyperintensity involving the right frontotemporal lobe, left frontal lobe, and left thalamus. She had intact neurologic exam findings and was followed with serial brain MRIs. Over the next 2 years, she continued to be asymptomatic, but her MRI showed an increase in the size of her brain lesions. Following a stereotactic biopsy of the right temporal lesion, a diagnosis of diffuse astrocytoma (WHO-grade II) was confirmed. Molecular analysis showed point mutations in IDH1, TP53, and PTEN genes, along with LOH at 17p (including TP53 gene), and outline gene expressions for NTRK2, OLIG2, GRM3, FGF1, SOX8, MBP, MGMT genes. Given the low grade of the tumor and the absence of tumor-related symptoms, a decision was made to continue monitoring with serial MRIs. Whole exome sequencing identified germline bi-allelic missense variations in the MBD4 gene, specifically C.1405A&amp;gt;G and C.1573A&amp;gt;C. Both parents were found to be heterozygous for one of these mutations. CONCLUSION The significance of MBD4 mutation remains unknown in our patient, but bi-allelic variations coupled with the presence of a brain tumor and positive family history raise concerns about MANS in our patient. Additional studies are needed to elucidate the potential association between brain tumors and MANS.

OTHR-20. MINIMALLY-INVASIVE MOLECULAR DIAGNOSIS OF INFILTRATING BRAINSTEM GLIOMAS THROUGH CEREBROSPINAL FLUID CELL-FREE DNA SEQUENCING

Abstract BACKGROUND Accurate molecular diagnosis of infiltrating brainstem tumors, including diffuse midline gliomas and IDH mutant astrocytomas, is essential for prognostication and optimal therapy. Surgical biopsy of the brainstem carries risk of permanent neurological deficits and may yield insufficient or non-diagnostic tissue. We hypothesized that minimally invasive “liquid biopsy” analyzing circulating tumor cell-free DNA (cfDNA) in cerebrospinal fluid (CSF) could represent an alternative molecular diagnostic modality. METHODS We performed MSK-IMPACT, a New York State Department of Health authorized hybridization capture-based next-generation panel DNA sequencing clinical assay on 44 CSF samples from 37 unique patients with brainstem tumors. Ages at time of CSF collection ranged from 1–47 years (median: 29 years). For samples in which diagnostic alterations could not be detected, we performed a series of secondary analyses for known hotspot mutations such as H3F3A, IDH1/2, and BRAF, including manual review for mutant reads below the official clinical reporting threshold, as well as droplet digital PCR (ddPCR). RESULTS Among 44 samples included in this study, 10/44 (23%) samples had mutations detected by MSK-IMPACT using standard clinical calling criteria and 14 of the remaining 34 samples (41%) had supporting evidence of a diagnostically relevant mutation based on manual review. Testing by ddPCR was performed on 11 samples (based on DNA availability), uncovering 4 additional mutations. Overall positive diagnostic yield was 64% (28/44). In biopsied patients, CSF confirmed disease-defining mutations in 80% (16/20) of CSF samples, including H3F3A K28M (9/10; 90%) and IDH1/2 (5/6; 83%). Among 24 unbiopsied patients, a disease-defining mutation was identified in 60% (15/25) of CSF samples. CONCLUSIONS Analysis of CSF cfDNA in patients with brainstem tumors has a high diagnostic yield and obviates the need for tissue biopsy in a majority of patients. A tiered testing approach using next-generation sequencing and ddPCR assays helps maximize diagnostic information and sensitivity.

HGG-36. ASSESSMENT OF CHROMOSOMAL ABERRATIONS IN DIFFUSE ASTROCYTOMAS OF CHILDHOOD USING THE ARRAY COMPARATIVE GENOMIC HYBRIDIZATION (ACGH+SNP) TECHNIQUE – PRELIMINARY STUDY

Abstract BACKGROUND Comprehensive knowledge of the genomic changes underlying cancer is a key basis for diagnosis, prognosis and targeted therapies. With recent advances, the technique of comparative genomic hybridization (aCGH+SNP) facilitates genome-wide screening for genome copy number changes and rapid examination of numerical and structural chromosomal changes, as well as loss of heterozygosity at high resolution down to several tens of kilobases. METHODS The study included 12 patients aged 6 months to 15 years, operated on at the Department of Pediatric Neurosurgery in Krakow due to paediatric-type diffuse gliomas (according to WHO classification 5th Ed). Tumor tissue samples were collected from all included participants as remnants of routine examination. Pangenomic profiling of diffuse astrocytomas was performed with using SurePrint G3 Cancer CGH+SNP Kit 4x180K (Agilent, Santa Clara USA) at the Molecular Genetics Laboratory of the University Children’s Hospital in Krakow. Genomic DNA was extracted automatically from deep-frozen tumor tissue. Descriptive statistics were used to describe the basic characteristics of the data included in the study due to the small number of participants. RESULTS Of the 12 tumors examined by microarray, 5 patients had abnormalities in the form of diffuse high grade gliomas. In 1 patient, only numerical changes in chromosomes were observed, in 1 case only structural chromosomal abnormalities were detected. Combined numerical and structural aberrations were presented in 3 samples. Additionally, we detected 1 case of triploidy and 1 case of loss of heterozygosity. CONCLUSIONS Significant changes were observed in paediatric-type diffuse high-grade gliomas. Interestingly, we detected new undescribed alterations that were not only of a chromosomal nature, but also concerned individual genes. This may constitute the basis for further research aimed at establishing new diagnostic and prognostic markers, as well as effective therapy. A limitation of this study is the small patient sample, and further research is recommended.

Socioeconomic disparities impact on the outcome of patients with diffuse and anaplastic astrocytoma: A SEER analysis of pediatric and adult populations.

e14024 Background: Astrocytoma is a rare form of brain tumors that affects both pediatrics and adults. In this study we assessed the effect of socioeconomic disparities on the outcome of patients diagnosed with astrocytoma in the pediatric and adult settings. Methods: We queried the Surveillance, Epidemiology, and End Results (SEER) registry for patients diagnosed with diffuse and anaplastic astrocytoma between 2000 and 2020. Data were collected on age at diagnosis, tumor site, annual household income, urban/rural residence and time of death. The chi-squared test was used to assess the association between two categorical variables, the Mann-Whitney U test and the Kruskal-Wallis test were used for continuous data that were non-normally distributed. The Kaplan-Meier method was used for survival analysis. Statistically significant differences between the curves were estimated using the 2 tailed log-rank test. Results: Among 27,438 patients (males: 55.4%), 9.5% were under 18, 36.5% were 19-45, 23.7% were 45-60, and 30% were over 60. Ethnicity was 14.3% Hispanic, 6.7% Black, and 73.7% White. Common tumor sites were frontal lobe (30.4%), temporal lobe (20.4%), and parietal lobe (10.6%). 39% had income &gt;$75K and 11.2% lived in rural areas. Median survival was the highest in patients under 18 (15.8 years), declining with age to 2.8 years for those over 60 (P&lt;0.0001). Surgery improved outcomes across all ages. Pediatric patients who had surgery lived 2.7 years longer on average (12.8 vs 10.1 years, p&lt;0.001), while adults who had surgery saw a 4.1 year gain (8.8 vs 4.7 years, p&lt;0.001). Higherhousehold income (&gt;$75k) improved survival across ages. The median OS for pediatric patients with higher income is 16.4 years compared to 15.5 years for patients with lower income with p= 0.02. For adult patients mean survival was 8.9 years for those who had higher income compared to 8 years for patients with lower income with p&lt;0.001. Location didn't impact pediatric outcomes (15.8 vs 15.8 years), but adults in non-metropolitan areas had lower survival (6.9 vs 8.5 years, p&lt;0.001). Conclusions: Age, surgery, household income and geographic location influenced the survival of patients with diffuse and anaplastic astrocytoma. Surgery was a key factor positively impacting both pediatric and adult populations. Household income similarly affects outcomes across age groups, with younger patients generally experiencing better outcomes.