High-grade Tumors Research Articles

Vinblastine/prednisolone chemotherapy leads to hematological toxicity in dogs with high-grade or metastatic mast cell tumors.

To determine the myelosuppressive effects/hematological toxicities, other general toxicities, and when these occur during vinblastine/prednisolone chemotherapy in dogs bearing high-grade or metastatic cutaneous/subcutaneous mast cell tumors (MCTs). Medical records were retrospectively reviewed between November 1, 2016, and March 1, 2023. Thirty client-owned dogs with histopathologically confirmed cutaneous high-grade MCTs/metastatic subcutaneous MCTs and that subsequently completed a 12-week vinblastine/prednisolone chemotherapy protocol were included. Hematology was assessed before commencing chemotherapy and before each vinblastine treatment. The effect of each treatment upon hematological values was evaluated. Measured outcomes included the type, frequency, and severity of hematological and other more general toxicities. 24 of 30 dogs experienced at least 1 hematological toxicity, 6 experienced gastrointestinal toxicity, and 4 experienced lethargy. The most common toxicity was anemia (15/30 [50%]), with 93.3% (14/15 dogs) classified as Veterinary Cooperative Oncology Group-Common Terminology Criteria for Adverse Events grade I and 6.6% (1/15) classified as grade II. The second most common toxicity was neutropenia (14/30 [46.6%]), with 71.4% (10/14) classified as grade I and 28.6% (4/14) as grade III. The least common hematological toxicity was thrombocytopenia (4/30 [13%]), all grade I. Neutropenia mainly occurred during weeks 2 and 3; however, there was no significant decrease in neutrophil count relative to baseline. Neutrophil count increased and Hct decreased during weeks 6 to 12 of treatment when compared to baseline. No change in platelet count was observed. Vinblastine/prednisolone chemotherapy leads to hematological toxicity; however, this was mostly low-grade and did not require major intervention. Vinblastine/prednisolone chemotherapy is well tolerated in dogs bearing high-grade or metastatic MCTs.

Clinical performance of Bladder EpiCheck™ versus voided urine cytology for detecting recurrence of nonmuscle invasive bladder cancer: Systematic review and meta-analysis

BackgroundNonmuscle invasive bladder cancer (NMIBC) has a favorable prognosis but has high propensity for recurrence. Recent development in one of the urinary biomarker tests, Bladder EpiCheck™, offers a noninvasive and accurate method to detect NMIBC recurrence. In this study, we aimed to compare the diagnostic performance of Bladder EpiCheck™ with urine cytology to detect NMIBC recurrence. MethodsWe performed a systematic review search through PubMed, Embase, Cochrane Central Register of Controlled Trials, Web of Science, and Scopus from inception to July 2023. Diagnostic accuracy was defined by sensitivity, negative predictive value (NPV), specificity, and positive predictive value (PPV). ResultsA total of 6 studies involving 1588 patients were included. Bladder EpiCheck™ has a sensitivity and specificity of 0.81 (95% CI: 0.63–0.91; I2: 43%) and 0.87 (95% CI: 0.83–0.91; I2: 20%), respectively. On the other hand, urine cytology has a sensitivity and specificity of 0.63 (95% CI: 0.29–0.87; I2: 61%) and 0.97 (95% CI: 0.78–1.00; I2: 79%), respectively. EpiCheck™ has a higher NPV (0.94 (95% CI: 0.87–0.97) vs. 0.84 (95% CI: 0.80–0.87) though a lower PPV (0.62 (95% CI: 0.45–0.76) vs. 0.87 (95% CI: 0.56–0.97) than urine cytology. In our subgroup analysis, the sensitivity of Bladder EpiCheck™ for detecting high-grade tumors improved to 0.90 (95% CI: 0.83–0.94) while that for urine cytology improved to 0.72 (95% CI: 0.50–0.87). ConclusionBladder EpiCheck™ has a high sensitivity and NPV for detecting recurrence among patients with NMIBC.

Abstract C047: AGX101: Preclinical evaluation of a TM4SF1-directed tubulin inhibitor conjugate with ongoing first-in-human trial

Abstract Introduction: TM4SF1 (Transmembrane-4 L-Six-Family-Member-1) is an endothelial marker with critical roles in angiogenesis, as well as a tumor cell antigen that contributes significantly to invasion and metastasis. TM4SF1 is upregulated 20-fold in angiogenic tumor vascular endothelium compared to normal vasculature endothelium and exhibits a unique nuclear internalization pathway. AGX101 is a novel tubulin inhibitor conjugate specifically directed against TM4SF1, delivering a potent maytansinoid payload directly to the nucleus of cells within the tumor microenvironment. Delivery to both the vascular and tumor cell compartments of the tumor results in three mechanisms of action (MoAs): (1) activation of tumor immune surveillance, (2) tumor blood supply deprivation, and (3) direct tumor cell killing. Methods: TM4SF1 expression was assessed across solid tumor samples using immunohistochemistry. Safety and pharmacokinetics of AGX101 were evaluated in non-human primates, with escalating doses to determine the highest non-severely toxic dose (HNSTD). Efficacy studies were also conducted in mouse models, enabling assessment of the minimum effective dose (MED) needed to engage each of the three MoAs. The combination of HNSTD and MED enables calculation of a therapeutic index (TI). Preclinical efficacy studies used either AGX101 (in human tumor xenograft models, to study the tumor cell killing MoA) or AGXB01, a rodent surrogate of AGX101, to study vascular and immune MoAs and all three MoAs in syngeneic mouse cancer models. The potential for synergy with immune checkpoint inhibitors (ICIs) was also investigated. A first-in-human study of AGX101 in patients with advanced solid tumors with the primary objective of safety and dose-limiting toxicities (DLTs) has initiated. Results: TMFS41 is broadly expressed across solid tumors with increasing scoring intensity in higher grade tumors. In non-human primates, AGX101 exhibited a favorable safety profile, being tolerated at relatively high doses and with dose dependent, monitorable, and reversible effects. In preclinical efficacy studies, AGXB01 and AGX101 as monotherapies demonstrated robust efficacy through each of the three MoAs in multiple syngeneic, xenograft, and orthotopic tumor models in mice and rats as well as non-tumor models of angiogenesis. Measured by exposure, TI was large. Additionally, AGXB01 was shown to potentiate the effects of ICIs in syngeneic mouse models (CT26, Renca, and B16-F10), suggesting a potential synergistic approach in cancer therapy. The first dose level of AGX101 monotherapy in humans has cleared without DLTs. Conclusion: AGX101, targeting the TM4SF1 antigen, represents a promising new approach in cancer therapy. The preclinical data suggest that AGX101 could provide a significant therapeutic benefit by novel and differentiated mechanisms of action, namely selectively targeting the tumor vasculature and potentiating immune-based therapies. Further clinical development of AGX101 is ongoing. Citation Format: Ildefonso Ismael Rodriguez Rivera, Meredith S. Pelster, Shou-Ching Jaminet, Paul Jaminet, Glen J. Weiss. AGX101: Preclinical evaluation of a TM4SF1-directed tubulin inhibitor conjugate with ongoing first-in-human trial [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Tumor-body Interactions: The Roles of Micro- and Macroenvironment in Cancer; 2024 Nov 17-20; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2024;84(22_Suppl):Abstract nr C047.

Abstract B027: ISG15 modulate cancer cell mechanics and metastasis in breast cancer

Abstract Metastasis in breast cancer is a major challenge for prognosis and effective treatment, primarily because cancer cells can create an immune-suppressive microenvironment that supports their progression and spread. The physical properties of cancer cells significantly influence their metastatic potential and their interaction with the environment. Identifying targets that impact both the physical characteristics of cancer cells, and their microenvironment is crucial for tackling metastatic disease. Interferon-stimulated gene 15 (ISG15), a ubiquitin-like protein, is often overexpressed in breast cancer tissues and is associated with poor prognosis, higher tumor grade, and increased invasiveness. Despite these associations, the precise role of ISG15 and its post-translational modification, ISGylation, in cancer cell behavior and interactions with their microenvironment remains unclear. To explore this, we interrogated the biophysical role of ISG15 by using mouse modeling and in vitro loss of function approaches. We utilized whole- body ISG15-deficient mice and conducted a series of experiments to assess the impact of ISG15 on cancer cell properties and their surrounding environment. Our preliminary results indicate that cells lacking ISG15 exhibit altered physical traits, such as increased stiffness and size, which may influence their metastatic behavior. Additionally, targeting ISG15 or disrupting ISGylation enhances the susceptibility of cancer cells to immune cell-mediated destruction. In ISG15- deficient mice, we observed significantly reduced tumor growth and metastasis compared to wild-type controls. These findings suggest that ISG15 modulates critical aspects of cancer cell behavior and their interactions with the microenvironment, contributing to immune evasion and metastatic spread. Our research highlights ISG15 as a promising therapeutic target and provides a foundation for developing new strategies to prevent and treat metastatic cancer Citation Format: Mohamed Haloul, Priya Shah, Vinay Pai, Faruk Hossen, James James Lee, Ekrem Emrah Er. ISG15 modulate cancer cell mechanics and metastasis in breast cancer [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Tumor-body Interactions: The Roles of Micro- and Macroenvironment in Cancer; 2024 Nov 17-20; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2024;84(22_Suppl):Abstract nr B027.

Seizure Burden and Clinical Risk Factors in Glioma-Related Epilepsy: Insights From MRI Voxel-Based Lesion-Symptom Mapping.

Epilepsy is the most common preoperative symptom in patients with supratentorial gliomas. Identifying tumor locations and clinical factors associated with preoperative epilepsy is important for understanding seizure risk. To investigate the key brain areas and risk factors associated with preoperative seizures in glioma patients. Retrospective. A total of 735 patients with primary diffuse supratentorial gliomas (372 low grade; 363 high grade) with preoperative MRI and pathology data. Axial T2-weighted fast spin-echo sequence at 3.0 T. Seizure burden was defined as the number of preoperative seizures within 6 months. Tumor and high-signal edema areas on T2 images were considered involved regions. A voxel-based lesion-symptom mapping analysis was used to identify voxels associated with seizure burden. The involvement of peak voxels (those most associated with seizure burden) and clinical factors were assessed as risk factors for preoperative seizure. Univariable and multivariable binary and ordinal logistic regression analyses and chi-square tests were performed, with results reported as odds ratios (ORs) and 95% confidence intervals. A P-value <0.05 was considered significant. A total of 448 patients experienced preoperative seizures. Significant seizure burden-related voxels were located in the right hippocampus and left insular cortex (based on 1000 permutation tests), with significant differences observed in both low- and high-grade tumors. Tumor involvement in the peak voxel region was an independent risk factor for an increased burden of preoperative seizures (OR = 6.98). Additionally, multivariable binary logistic regression results indicated that 1p/19q codeletion (OR = 1.51), intermediate tumor volume (24.299-97.066 cm3), and involvement of the peak voxel (OR = 6.06) were independent risk factors for preoperative glioma-related epilepsy. Voxel areas identified through voxel-based lesion-symptom mapping analysis, along with clinical factors, show associations with clinical seizure burden, offering insights for assessing seizure burden for glioma patients. 4 TECHNICAL EFFICACY: Stage 1.

Clinicopathologic feature and treatment progress of high-grade ovarian neuroendocrine tumors.

High-grade Ovarian neuroendocrine tumors represent a rare subset of ovarian neoplasms characterized by aggressive behavior, poor prognosis, and early metastasis. Despite their clinical significance, the management of these tumors lacks consensus due to their low incidence. This comprehensive review encompasses literature spanning from 1991 to 2024, focusing on the clinical presentation, diagnostic criteria, differential diagnosis, prognostic indicators, treatment modalities, and recent advancements in the understanding of this condition. Notably, a substantial proportion of affected individuals present during the perimenopausal period with unilateral lesions displaying mixed histological components. Biomarkers such as CA125, CA199, and NSE hold promise for aiding in the diagnosis and screening of ovarian neuroendocrine tumors. Unfortunately, patients exhibit a dismal prognosis even diagnosed at an early stage. Primary treatment strategies predominantly involve surgical intervention coupled with etoposide-cisplatin combination chemotherapy. In cases of recurrence, second-line chemotherapeutic agents including paclitaxel, irinotecan, and doxorubicin are commonly employed alongside localized radiotherapy. While specific genetic mutations remain elusive, emerging evidence suggests potential therapeutic effect involving mTOR inhibitors, PD-1 monoclonal antibodies, and antiangiogenic agents based on isolated case reports. The exploration of representative set of mutations will help for precise targeted therapies and remains a focal point of our ongoing research efforts.

PREDICTORS OF POSTOPERATIVE COMPLICATIONS AND FUNCTIONAL OUTCOMES IN PEDIATRIC PATIENTS WITH SURGICALLY TREATED FOURTH VENTRICLE TUMOR

Background Tumors of fourth ventricle are frequently treated pathologies in pediatric neurosurgery. Data regarding predictors for permanent neurological deficits, long-term functional outcomes, cerebellar mutism (CM), the extent of resection (EOR), and oncological outcomes are scarce. We attempt to contribute to this topic with analysis of our institutional cohort. Methods A retrospective single-center study of patients aged ? 19 years who underwent primary surgical resection of fourth ventricular tumor over a 15-year period (2006–2021). Predictors analyzed included: age, gender, surgical approach, anatomical pattern, tumor grade, EOR, tumor volume, and others as appropriate. Results 106 patients were included (64 males, mean age 7.3 years). Rate of permanent neurological deficit was 24.2%; lateral tumor extension (p = 0.036) and tumor volume greater than 38 cm3 (p = 0.020) were significant predictors. Presence of deficit was the only significant predictor of reduced (less than 90) Lansky score (p = 0.005). CM occurred in 20.8% of patients and was influenced by medulloblastoma histology (p = 0.011), lateral tumor extension (p = 0.017), and male gender (p = 0.021). No significant difference between transvermian and telovelar approach in development of CM was detected (p = 0.478). No significant predictor was found for EOR. EOR was not found to be significant predictor of overall survival for both low-grade and high-grade tumors, however, gross total resection (GTR) was protective against tumor recurrence compared to near-total or subtotal resection (p &lt; 0.001). Survival was found to be better in older patients (? 7.0 years, p = 0.019). Conclusion The overall rate of postoperative complications remains high due to the eloquent localization. Older patients (&gt;7 years) have been found to have better outcomes and prognosis. Achieving GTR whenever feasible and safe has been shown to be critical for tumor recurrence. CM was more common in patients with medulloblastoma, and in patients with tumors extending through the foramen of Luschka. The telovelar approach uses a safe and anatomically sparing corridor, however, it has not been associated with a lower incidence of CM and neurological sequelae in our series, showing that each case should be assessed on an individual basis.

GLIOMA-RELATED EPILEPSY

Diffuse low-grade gliomas (LGGs), originating from glial tissue, have a propensity to progress to higher-grade tumors over time, presenting a complex challenge in clinical management. Glioma-associated epilepsy is a significant clinical indicator influencing both treatment strategies and prognostication. This study aims to assess the impact of glioma-related epilepsy on treatment outcomes and explore the current management guidelines. Material and Methods A retrospective analysis was conducted on 38 patients diagnosed with LGGs (WHO grades 2 and 3) treated in our neurosurgical department from 2013 to 2023. The focus was on glioma-related epileptic seizures, with outcomes evaluated using the Engel classification six months post-surgery. Additionally, anti-seizure medication (ASM) regimens were reviewed, and current National Institute for Health and Care Excellence (NICE) guidelines on low-grade gliomas were synthesized. Results Of the 38 patients, 30 had diffuse astrocytoma and 8 had oligodendroglioma. Among those with glioma-related epilepsy (n=25), management strategies included biopsy only (8%), gross total resection (GTR) (40%), subtotal resection (StR) (32%), and partial resection (PaR) (20%). No significant correlation was found between seizures and tumor volume, growth rate, or histological findings. However, a positive correlation between the extent of surgical resection and improved Engel outcomes was observed. Discussion Existing research suggests that early seizures may be a favorable prognostic indicator for malignant progression-free and overall survival. Epilepsy significantly impacts the quality of life for glioma patients. Exploring targeted epilepsy surgery for glioma-related seizures could potentially enhance patient outcomes and quality of life posttreatment. Conclusion Advancing approaches in epilepsy surgery for glioma-related seizures holds promise for improving patient quality of life and treatment efficacy. Further investigation into these strategies is warranted.

Abstract B071: Identifying the clinical utility of CSF as a source of liquid biopsy in pediatric brain tumors

Abstract Pediatric tumors of the central nervous system (CNS) are a leading cause of cancer-related childhood mortality. Along with imaging, it is essential to molecularly characterize tumor tissue for the diagnosis, treatment, and prognosis of these cancers. Biopsies of deeply-seeded lesions may not be possible or may carry significant risks. On the other hand, liquid biopsy, using cerebral spinal fluid (CSF), provides a minimally invasive alternative to identify and monitor tumor DNA at crucial time points, from diagnosis to follow-up. This allows for molecular diagnosis, identification of therapeutic targets, monitoring response to therapy, and early detection of recurrence or progression. The aim of our study was to assess the practicality and usefulness of liquid biopsies in a diverse group of CNS tumor patients. We used a combination of methods, including a targeted hybridization capture panel and low-pass whole genome sequencing (LP-WGS) based on the sample characteristics. We analyzed a total of 243 CSF samples from patients with CNS tumors including: low-grade glioma (LGG; N=57), high-grade glioma (HGG; N=53), medulloblastoma (MB; N=40), germinoma (CNS-GCT; N=29), and no prior biopsy (N=42). We found somatic mutations in 88% of CSF samples from HGG and 67% from LGG with known tumor DNA variants and sufficient sequencing quality. It's important to note that in LGG patients, samples collected from lumbar puncture were positive only in disseminated cases, while a higher positivity rate was found in cases where CSF was collected from ventricular spaces. Moreover, we observed positive copy number alterations (CNA) in CSF samples collected from HGG, embryonal tumors, and CNS-GCT patients at the time of diagnosis and follow-up with a sensitivity of 64%. Within our sample cohort that had an unknown or query tumor due to no prior biopsy, we were able to detect diagnostic, targetable mutations and/or a positive CNA profile in 30% of cases. This supports the utility of liquid biopsy as a diagnostic tool in in CNS lesions. This tool may also assist in monitoring for relapse in high-grade tumors. For example, in a case study, we were able to detect recurrent MB by indication of a positive CNA profile in keeping with the primary tumor CNV, six years post-surgical resection. In CNS- GCT patients, we found that LP-WGS was highly sensitive at diagnosis as we have observed similar CNV in both CSF and tumor DNA. In summary, the utility of our liquid biopsy platform in the context of CNS cancers is an impactful tool that can aid clinicians in diagnosis, treatment and monitoring disease in a minimally invasive manner. Citation Format: Liana Nobre, Mansuba Rana, Yoshiko Nakano, Ian Burns, Robert Siddaway, Richard Yuditskiy, Cyril Li, Andrew Bondoc, Anthony Liu, Uri Taboori, Cynthia Hawkins. Identifying the clinical utility of CSF as a source of liquid biopsy in pediatric brain tumors [abstract]. In: Proceedings of the AACR Special Conference: Liquid Biopsy: From Discovery to Clinical Implementation; 2024 Nov 13-16; San Diego, CA. Philadelphia (PA): AACR; Clin Cancer Res 2024;30(21_Suppl):Abstract nr B071.

Tumor-Promoted Changes in Pediatric Brain Histology Can Be Distinguished from Normal Parenchyma by Desorption Electrospray Ionization Mass Spectrometry Imaging

Background: Central nervous system (CNS) tumors are the second most frequent type of neoplasm in childhood and adolescence, after leukemia. Despite the incorporation of molecular classification and improvement of protocols combining chemotherapy, surgery, and radiotherapy, CNS tumors are still the most lethal neoplasm in this age group. Mass spectrometry imaging (MSI) is a powerful tool to map the distribution of molecular species in tissue sections. Among MSI techniques, desorption electrospray ionization (DESI-MSI) has been demonstrated to enable reliable agreement with the pathological evaluation of different adult cancer types, along with an acceptable time scale for intraoperative use. Methods: In the present work, we aimed to investigate the chemical profile obtained by DESI-MSI as an intraoperative surgical management tool by profiling 162 pediatric brain biopsies and reporting the results according to the histopathology and molecular profile of the tumors. Results: The 2D chemical images obtained by DESI-MSI allowed us to distinguish tumor-transformed tissue from non-tumor tissue with an accuracy of 96.8% in the training set and 94.3% in the validation set after statistical modeling of our data using Lasso. In addition, high-grade and low-grade tumors also displayed a distinct chemical profile when analyzed by DESI-MSI. We also provided evidence that the chemical profile of brain tumors obtained by DESI-MSI correlates with methylation-based molecular classes and specific immunophenotypes found in brain biopsies. Conclusions: The results presented herein support the incorporation of DESI-MSI analysis as an intraoperative assistive tool in prospective clinical trials for pediatric brain tumors management in the near future.

Predictive and prognostic factors in patients with Anaplastic Lymphoma Kinase: rearranged early-stage lung adenocarcinoma.

This study aimed to evaluate the predictive and prognostic factors in clinical stage I, ALK-rearranged lung adenocarcinoma following radical surgery. Additionally, it sought to compare these factors with an external cohort of ALK wild-type patients. A multicentric, retrospective, case control analysis was conducted on patients with clinical T1-2 N0 ALK-rearranged lung adenocarcinoma who underwent anatomical resection and radical lymphadenectomy. Data were collected from five high-volume oncological centers. An external cohort of ALK wild type patients was also analyzed for comparison. Survival analyses were performed using the Kaplan-Meier method, and multivariable Cox regression analysis was used to identify prognostic factors. From January 2016 to December 2022, 63 patients with ALK-rearranged lung adenocarcinoma were included. High-grade tumors (G3) significantly associated with upstaging (OR = 3.904, p = 0.04). DFS and OS were significantly improved in upstaged patients receiving adjuvant treatment (HR = 0.18, p = 0.0042; HR = 0.24, p = 0.0004, respectively). The solid or micropapillary histological subtypes were independently associated with worse DFS (HR = 3.41, p = 0.022). Comparison with 435 ALK WT patients showed worse DFS in the ALK-rearranged group (HR = 2.09, p = 0.0003). ALK-rearranged patients had higher rates of nodal upstaging, systemic, and brain recurrences. Clinical T1-2 N0 ALK-rearranged lung adenocarcinoma is an aggressive disease with a specific tropism for lymph nodes and the brain. High-grade tumors are predictive of nodal upstaging. Adjuvant treatment significantly improves DFS and OS in upstaged patients, highlighting the need for personalized preoperative staging and post-surgical management in this cohort.

BCOR-ITD Rearranged Sarcoma in the Mandible of a 5-Year-Old Child: A Case Report Highlighting Diagnostic Distinction From Odontogenic Fibromyxoma.

The 5th edition of the World Health Organization (WHO) classification of soft tissue and bone has recognized three distinct groups among Ewing-like sarcomas, namely, CIC-rearranged sarcoma, sarcomas with BCOR genetic alterations, and round cell sarcomas with EWSR1:: non-ETS fusions. Sarcomas with BCOR genetic alterations are a distinct clinicopathological group of high-grade tumors, representing 5% of small round cell tumors. BCOR-ITD rearranged tumors commonly manifest as spindle cell sarcomas and many of them display low cellularity with monomorphous cell morphology and myxoid background resembling benign fibroblastic tumors. We present an intriguing case report of a 5-year-old boy diagnosed with a moderately cellular mandibular spindle cell tumor exhibiting BCOR-ITD rearrangement which was initially misdiagnosed as an odontogenic fibromyxoma. This case report illustrates the histological and immunophenotypic findings of BCOR-ITD rearranged sarcoma, requiring a comprehensive immunohistochemical panel and additional molecular tests for accurate diagnosis.

NIMG-56. MAGNETIC RESONANCE SPECTROSCOPY IN THE POST-TREATMENT METABOLIC CHARACTERIZATION OF BRAIN TUMORS OF GLIAL ORIGIN OF CENTRAL NERVOUS SYSTEM

Abstract BACKGROUND and Purpose Central Nervous System tumors have a very low incidence worldwide, however they constitute an important source of mortality and morbidity. Treatment for these types of tumors in adults may include surgery, radiosurgery, radiation therapy, chemotherapy, and targeted treatment. These treatments in brain tumors of glial origen in adults can produce changes in the pathophysiology of the tumor. The purpose of this study was to characterize the different metabolic patterns as effect of treatment and identify tumor recurrences. Materials and METHODS A prospective study was conducted with patients with low- and high-grade tumors treated, subjecting them to the single-voxel MRS and multivoxel MRSI protocol at 1.5 T. RESULTS Of the 44 patients included, 21 were histopathologically diagnosed as low-grade tumors and 23 as high-grade tumors. Of the low-grade tumors, 11 were caracterized as low-grade (mean Cho/NAA and NAA/Cr ratios 1.49 ((p=0.036) and 0.92 (p=0.038) respectively), 8 cases presented gliosis (mean Cho/NAA and NAA/Cr ratios 1.57 (p=0.028) and 1.36 (p=0.026) respectively), and 4 cases presented radiation necrosis (mean Cho/Cr ratios 2.14 (p=0.03)), (mean Cho/Cr and NAA/Cr ratios 1.25 (p=0.01) and 1.25 (p=0.00)) respectively). Furthermore, tumor recurrence that presented high Cho/NAA ratio were observed in 11 cases. Of the high-grade tumors, 13 were caracterized as high-grade (mean Cho/NAA and Cho/Cr ratios 2.24 (p=0.026) and 4.48 (p=0.026) respectively), 13 cases presented gliosis (mean Cho/NAA and NAA/Cr ratios 1.82 (p=0.028) and 0.64 (p=0.026)) respectively) and radiation necrosis was detected in 10 cases (mean Cho/Cr ratio 1.47 (p=0.03), (mean Cho/Cr and NAA/Cr ratios 2.25 (p=0.01) and 0.97 (p=0.00) respectively). Moreover, tumor recurrence that presented high Cho/NAA ratio were observed in 9 cases. CONCLUSION MRS and MRSI contribute to identifying the recurrences, to characterizing the different metabolic patterns as an effect of the treatment and differentiate between low and high grade tumors.

TMOD-35. EGFRVIII OVEREXPRESSION AND LOSS OF MOUSE SPECIFIC CDKN2A IN GLIAL CELLS LEADS TO SPONTANEOUS GLIOMAGENESIS IN A NOVEL MOUSE MODEL

Abstract A new mouse model for the classical subtype of human glioblastoma (GBM) has been bred using Cre-mediated EGFRvIII overexpression and homozygous p19-ARF deletion, the mouse homolog of human p14ARF/CDKN2A, in GFAP expressing cells. Transgenic mice develop intraparenchymal and/or leptomeningeal brain lesions with some spinal cord invasion as early as 1 month old and 95% of mice die by 6 months due to hydrocephalus and/or paralysis. Mice with high grade tumors have worse survival and similar features to human classical GBM such as necrosis, high levels of mitosis and infiltration of tumor cells into normal brain. Immunohistochemical analysis confirms EGFRvIII overexpression and p19-ARF loss in Cre-expressing cells, along with patchy positive GFAP and high proliferation by Ki67. Bulk RNA sequencing reveals GEC3 tumors cluster closely with human classical GBM and have significant upregulation of downstream markers in the JAK/STAT and P13K/AKT pathways. Adherent and neurosphere primary culture of dissociated tumors indicate that tumor cells maintain EGFRvIII expression in culture and generate xenograft tumors by 3 weeks after intracranial injections into NODSCID mice. Xenograft tumors are reminiscent of the primary tumor, with similar histopathological features and immunohistochemical staining. Our spontaneous glioma model is a powerful tool for future studies focused on the role of the immune microenvironment on glioma recurrence and resistance.

EPCO-12. MENINGIOMA COPY NUMBER ANALYSIS IDENTIFIES OPTIMIZED SIZE THRESHOLDS AND CO-OCCURRENCE MODELS FOR INDIVIDUALIZED RISK-STRATIFICATION

Abstract Arm-level copy number alterations (CNAs) are common in meningiomas and are useful for risk-stratification, but there is no consensus regarding the optimal size threshold to define CNAs for prognostic models. Moreover, the prognostic importance of co-occurring CNA pairs and overall CNA burden in meningiomas remains incompletely understood. To address this, CNAs were analyzed in 691 retrospective meningiomas with clinical data and DNA methylation profiles from 3 international institutions. Arm-level CNAs were defined from DNA methylation profiles using iterative size thresholds ranging from 1-99% of each chromosome arm. The area under the curve (AUC) for 5-year local freedom from recurrence (LFFR) or overall survival (OS) was calculated using CNAs across size thresholds, and AUC standard deviation across thresholds was used as a measure of size-dependence. LASSO and Elastic Net Cox regressions were used to generate multi-CNA models for LFFR or OS and to identify prognostic co-occurring CNA pairs. These analyses identified 13 size-dependent prognostic CNAs in meningiomas, including loss of 1p, 3q, 4p, 4q, 6p, 6q, 9p, 10q, 12q, 14q,18q, and 22q, and gain of 1q. Regression models restricted to size-dependent CNAs improved risk stratification within strata of previously published models (Integrated score, Integrated grade), and identified prognostic CNAs not included in previous models, such as 1q gain, 7p loss, and 12q loss. Ontology analysis of genes in focal prognostic CNAs identified dysregulated STAT signaling and decreased expression of interferon-related genes from matched paired RNA sequencing. Models of size-dependent, prognostic, co-occurring CNA pairs identified 1p/22q codeletion, 1q gain/22q loss, and 9p/18q codeletion as significant predictors of LFFR. Increased CNA burden correlated with higher tumor grade and was significantly associated with worse LFFR and OS. In summary, chromosome-specific size thresholds identify prognostic arm-level CNAs and co-occurring CNA pairs in meningiomas. Thus, granular copy number analysis may improve risk stratification models for meningioma.

EPCO-26. LONGITUDINAL SINGLE-CELL ANALYSES IDENTIFY DRIVERS OF GENETIC, EPIGENOMIC, AND CELLULAR EVOLUTION IN IDH-MUTANT GLIOMA

Abstract Despite standard treatment, IDH-mutant gliomas inevitably recur. Previous studies suggest that therapeutic resistance may result from a combination of intratumoral cellular heterogeneity, epigenetic evolution, and acquired genetic alterations. However, how these multilayered molecular features interact to influence the evolutionary paths of IDH-mutant gliomas remains incompletely understood. To chart this evolution, 75 glioma samples were longitudinally collected from 35 patients (n = 13 oligodendroglioma, n = 22 astrocytoma) and profiled using single nucleus RNA sequencing, ATAC sequencing, and bulk DNA sequencing. Analysis of 331,016 nuclei (snRNA) revealed eight tumor microenvironment cell types and five pan-IDH-mutant malignant cellular states. The malignant states were distributed along a cellular hierarchy of stem-like populations (neural progenitor cell-like, oligodendrocyte progenitor cell-like, and undifferentiated) and more differentiated populations (mesenchymal-like and astrocyte-like) with cycling cells enriched in the stem-like populations. Joint open chromatin accessibility data (snATAC) was available for a subset of malignant cells (71,088 nuclei) and state-specific differentially accessible peaks supported that these states are epigenetically encoded. Across both subtypes, higher tumor grade was associated with reduced malignant cell differentiation and increased cycling populations. Between the two time points, we identified that there was a longitudinal increase in the cycling, undifferentiated, and mesenchymal-like populations with a corresponding decrease in the astrocyte-like population. Longitudinal genetic analysis revealed that 19 of 35 tumors acquired at least one of the following genetic alterations: treatment-associated hypermutation, cell cycle alteration, or large changes in copy number alterations. Importantly, tumors that acquired these key genetic alterations demonstrated significant shifts towards reduced differentiation and increased cycling populations while those tumors that did not had more stable malignant profiles. Collectively, our results suggest a common cellular hierarchy across IDH-mutant gliomas with a shift towards reduced differentiation, increased cycling populations during disease progression that is driven by acquired genetic alterations.

Impact of endogenous viral elements on glioma clinical phenotypes by inducing OCT4 in the host

IntroductionEndogenous viral elements (EVEs) are viral sequences integrated within the host genome that can influence gene regulation and tumor development. While EVEs have been implicated in cancer, their role in regulating key transcription factors in glioblastoma (GBM) remains underexplored. This study investigates the relationship between EVEs and the activation of OCT4, a critical transcription factor in GBM progression.MethodsWe utilized CancerHERVdb and HervD Atlas databases to identify potential interactions between EVEs and key genes involved in GBM. Data from 273 GBM patient samples in the TCGA database were analyzed to examine the correlation between OCT4 expression and mutations in glioma-related genes. Furthermore, glioblastoma stem cells (GSCs) were assessed for the expression levels of OCT4 and SOX2, and Pearson correlation analysis was performed.ResultsOur analysis revealed that OCT4 is a pivotal gene activated by EVEs in GBM. OCT4 expression was significantly correlated with mutations in key glioma-associated genes. Higher OCT4 levels were associated with poorer patient prognosis, higher tumor grades, and older age. Additionally, GSCs exhibited elevated expression of both OCT4 and SOX2, with a positive correlation observed between these two genes in GBM patients.DiscussionThis study highlights the potential role of EVEs in driving GBM progression through the activation of OCT4. The findings emphasize the importance of OCT4 in GBM malignancy and suggest that targeting EVE-mediated pathways may provide new therapeutic approaches for GBM treatment.

TMIC-26. IMMUNE CELL DYNAMICS WITHIN GLIOMAS: THE INFLUENCE OF GRADE AND IDH STATUS

Abstract Mutations in isocitrate dehydrogenase (IDH) are known to significantly impact the prognosis and biology of diffuse gliomas. A number of studies have compared the immune microenvironment of IDH-wildtype glioma versus IDH-mutant glioma, and have also characterized the impact of mutant-IDH on lymphocytes. However, few studies have explored how mutant-IDH may affect tumors as they progress and increase in grade, or have delved into the myeloid immune cell compartment. Thus, we sought to understand whether tumor progression affected intratumoral immune cell composition within IDH-mutant glioma, and aimed to compare IDH-mutant versus IDH-wildtype glioma in both humans and mice. Using bulk RNA sequencing, we compared paired samples from patients with IDH-mutant glioma before and after progression, focusing on differentially-expressed immunological genes and relative immune cell proportions. We also compared grade 4 IDH-mutant astrocytoma cases to IDH-wildtype glioblastoma, performing both transcriptomic and cellular analyses. Finally, we engineered murine glioma cells to test the effect of mutant-IDH alone in the tumor microenvironment. We found that multiple immune-related genes distinguish low- and high-grade IDH-mutant glioma, and that high-grade tumors contain greater proportions of suppressive myeloid cells. When comparing IDH-wildtype to IDH-mutant glioma, we found enrichment of suppressive macrophages and myeloid-derived suppressor cells (MDSC) in IDH-wildtype tumors. Finally, our murine model of IDH-wildtype versus IDH-mutant glioma mirrored many of the myeloid cell shifts observed in human tumors. Our data show that progression of IDH-mutant tumors is a significant immunological phenomenon, associated with marked alterations in the tumor immune microenvironment. We also show that IDH-mutant glioma harbors greater inflammatory signatures and fewer suppressive myeloid cells than IDH-wildtype glioma, and that engineering mutant IDH into murine tumors is sufficient to model these differences. These findings improve our understanding of key intratumoral cell populations that may be harnessed by future immunotherapeutic strategies.

SURG-23. ESTABLISHMENT OF AN APPROPRIATE GLIOMA SURGERY SYSTEM CONSIDERING MOLECULAR AND FUNCTIONAL BOUNDARIES

Abstract Gliomas are invasive tumors and cannot be cured by surgery. But surgical removal has also been proven to affect treatment outcomes. Recent advances in molecular diagnostics have identified IDH mutations, especially in lower grade gliomas, allowing the identification of so-called molecular boundaries. It is conceivable that expanded resection to the molecular border may improve treatment outcome. On the other hand, extended resection may be incompatible with functional preservation. In such cases, it is also important to consider that the impact of surgery on treatment outcome has also been proven to vary by glioma genotype. While total resection has a significant prognostic impact on survival in astrocytomas with IDH mutations, the impact on survival in oligodendrogliomas that are sensitive to chemoradiotherapy and, conversely, in high-grade tumors without IDH mutations is lower than in the former. Therefore, it is important to determine the extent of removal after considering the tumor type. In general, various surgical support devices such as surgical navigation systems, fluorescent diagnosis using 5ALA, intraoperative electrophysiological monitoring, awake functional brain mapping, and intraoperative MRI are applied during glioma surgery. In addition to these, we have developed a surgical system that also focuses on tumor subtypes by introducing preoperative tumor type prediction using AI imaging and intraoperative rapid genetic diagnosis. We have further developed intraoperative rapid genetic diagnosis to identify genetic mutations around the tumor, enabling the detection of molecular boundaries. It is now possible to remove as much as possible, considering the molecular boundary, while paying sufficient attention to preservation of brain functions. Gliomas are intractable diseases, but their treatment outcomes have steadily improved over time. We are now in an era of a tailor-made surgery based on a variety of data. Implementing “appropriate surgical procedures” we aim at further improvement of treatment outcomes.

QOL-15. PATIENT-REPORTED PHYSICAL HEALTH-RELATED QUALITY OF LIFE PREDICTS SHORT-TERM POSTOPERATIVE OUTCOMES IN A HETEROGENEOUS COHORT OF BRAIN TUMOR PATIENTS

Abstract Patient-reported outcome measures (PROMs) are increasingly used to assess patients’ perioperative health. The PROM Information System 29 (PROMIS-29) is a well-validated global health assessment instrument for patient physical health, though its utility in cranial neurosurgery is unclear. To investigate the utility of preoperative PROMIS-29 physical health (PH) summary scores in predicting postoperative outcomes in brain tumor patients. Adult brain tumor patients undergoing resection at a single institution (January 2018-December 2021) were identified and prospectively received PROMIS-29 surveys during pre-operative visits. PH summary scores were constructed and optimum prediction thresholds for length of stay (LOS), discharge disposition (DD), and 30-day readmission were approximated by finding the Youden index of the associated receiver operating characteristic curves. Bivariate analyses were used to study the distribution of low (z-score≤-1) versus high (z-score&amp;gt;-1) PH scores according to baseline characteristics. Logistic regression models quantified the association between preoperative PH summary scores and post-operative outcomes. A total of 157 brain tumor patients were identified (mean age 55.4±15.4 years; 58.0% female; mean PH score 45.5 + 10.5). Outcomes included prolonged LOS (24.8%), non-routine discharge disposition (37.6%), and 30-day readmission (19.1%). On bivariate analysis, patients with low PH scores were significantly more likely to be diagnosed with a high-grade tumor (69.6% vs 38.85%, p=0.010) and less likely to have elective surgery (34.8% vs 70.9%, p=0.002). Low PH score was associated with prolonged LOS (26.1% vs 22%, p&amp;lt;0.001), nonroutine discharge (73.9% vs 31.3%, p&amp;lt;0.001) and 30-day readmission (43.5% vs 14.9%, p=0.003). In multivariate analysis, low PH scores predicted greater LOS (odds ratio [OR]=6.09, p=0.003), nonroutine discharge (OR=4.25, p=0.020), and 30-day readmission (OR=3.93, p=0.020). The PROMIS-29 PH summary score predicts short-term postoperative outcomes in brain tumor patients and may be incorporated into prospective clinical workflows.