Malignant Tumors Research Articles

NCOG-39. EXPLORING THE POTENTIAL OF STEREOTACTIC RADIOSURGERY IN THE MANAGEMENT OF MENINGIOMAS

Abstract INTRODUCTION Meningiomas present complex therapeutic challenges due to their potential impact on neurological function and quality of life. While the standard of care involves observation and surgical resection, stereotactic radiosurgery (SRS) is an alternative treatment modality. This study aimed to compare the relative efficacy of SRS and surgical resection in the management of meningiomas to inform evidence-based decision-making in this clinical context. METHODS A retrospective cohort study was conducted using the TriNetX database, comparing patients undergoing treatment for meningiomas with either stereotactic radiosurgery (SRS) or surgical resection. Cohorts were matched on comorbidities. Rates of mortality and malignant neoplasms of the brain within 5-years of treatment with either modality were compared. In addition, short-term outcomes were assessed at 3 months post-treatment. RESULTS After matching, there were 1,898 patients in each cohort. Patients receiving SRS exhibited a significantly lower risk of mortality (95% CI: 0.76-1.07) and a decreased risk of developing malignant neoplasms of the brain (RR: 0.68, 95% CI: 0.54-0.85) over 5 years, compared to surgical resection. At 3-months post treatment, patients treated with SRS demonstrated significantly lower relative risks for several outcomes, including cerebral infarction (RR: 0.27, 95% CI: 0.18-0.39), hydrocephalus (RR: 0.19, 95% CI: 0.11-0.32), cerebral edema (RR: 0.13, 95% CI: 0.10-0.18), seizures (RR: 0.27, 95% CI: 0.21-0.34), neurological deficits (RR: 0.19, 95% CI: 0.13-0.28), and post-procedural infection (RR: 0.14, 95% CI: 0.07-0.28). CONCLUSION This retrospective cohort study suggests that in the management of meningiomas, SRS may be associated with lower mortality rates, decreased risks of malignant neoplasms of the brain, and improved short-term outcomes compared to surgical resection. Further research is warranted to validate these results and explore long-term outcomes and potential adverse effects.

CNSC-45. EXTRINSIC ELECTRICAL MODULATION IMPACTS GLIOBLASTOMA TUMOR GROWTH BY DISRUPTING ITS INTERCELLULAR COMMUNICATION

Abstract Glioblastoma (GBM) is an incurable primary malignant neoplasm of the central nervous system. GBM as an electrically active neoplasm diffusely colonizes healthy brain tissues, disrupting the neurotransmission balance and causing glioma-related epilepsy (GRE) in up to 50% of patients. Interestingly, GRE is an independent favorable prognostic factor for survival in GBM. The therapeutic induction of seizure may have a previously unexplored oncologic value in GBM. We have previously reported in CT-2A-bearing mice subjected to daily extrinsic electrical modulation (EEM) diminished tumor progression and increased overall survival relative to sham-treated mice, but the mechanism by which EEM produces its anti-tumor effect remains uncertain. Therefore, GBM-bearing mice (CT-2A cells xenografted into 5-7 weeks old C57BL/6 female mice, n=5/group) received either a single EEM of 2.0 millicoulombs (mC) or sham treatment. The mice were terminated at 3 hours, 24 hours, 4, 7, and 10 days post-EEM, and tumors and contralateral brain cortex were analyzed using bulk RNA-sequencing and Sequential immunofluorescence (SeqIFTM). SeqIFTM revealed how EEM activates neuronal activity via cFOS expression and induces tumor-specific cell damage through cleaved caspase-3 expression, without affecting healthy brain tissue. Furthermore, RNA-seq performed post-EEM revealed gene expression changes of not only synapse organization markers but also of several tumor-tumor and tumor-neuron connectivity key markers, such as growth-associated protein 43 (GAP43), neuroligin-3 (NLGN3), and glutamate receptors such as GRIA4 and GRIN1 between others. However, the expression of these markers diminished significantly 96h after-EEM, indicating a reduction in intercellular electrical communication by the inhibition of the neoplasm cells electrical integration with neuronal circuits by downregulating glutamatergic receptor expression, blocking the synapse-forming protein NLGN3, and the network-connecting protein GAP43. Taken together, our findings reveal how by the disruption of these critical interactions within the tumor microenvironment though EEM impacts on GBM growth making it more susceptible to therapeutic interventions.

Comparative analysis of the expression of р16, PD-L1 in squamous cell carcinoma of the oropharynx and CUP syndrome

Introduction. metastases in the absence of a primary tumor (cancer of unknown primary (Cup) syndrome) are diagnosed in 2–4 % of malignant tumor cases. This pathology is characterized by early metastatic dissemination, weak response to conventional chemotherapy, and aggressive progression. The use of checkpoint inhibitors targeting programmed cell death protein 1 (pD-1) and its ligand (pD-L1) has shown good results in treatment of various cancers including oropharyngeal squamous cell carcinoma (OpSCC). In Cup syndrome, the effectiveness of checkpoint inhibitors is rarely investigated, and pD-L1 expression is often not measured.Aim. To compare the frequency of p16 and pD-L1 hyperexpression in OpSCC and Cup syndrome, and to analyze dependency of survival rates on the level of expression of p16, the most important prognostic marker.Materials and methods. The study included 121 patients (59 with OpSCC and 62 with Cup syndrome) who received medical treatment in the multidisciplinary medical Center “medical City” (Tyumen) and Chelyabinsk Oncological Center of Oncology and Nuclear medicine between 2019 and 2023. Immunohistochemical examination was performed using the vENTANA Benchmark gX with primary antibodies against pD-L1 (clone Sp263, uSA) and р16 (uS Biological, uSA). Statistical analysis of the data was performed using SpSS 26 software. Long-term treatment outcomes were evaluated using 1-, 3-, 5-year survival rates and median survival. Overall survival was analyzed using the kaplan-meier method. Statistical significance of the differences was evaluated using the Cox model.Results. The studied groups did not differ by sex (p = 0.472), age (р = 0.640), and N stage (р = 0.262). patient age in the whole population varied between 42 and 81 years (median age 61.89 ± 11.9 years; mean age 60.81 ± 9.8 years). pD-L1 expression rate was higher in Cup syndrome at 92 % compared to 73 % in OpSCC (statistically significant difference; р = 0.01). Analysis of the association of ORSCC and Cup syndrome with human papilloma virus showed statistically significant difference in p16 hyperexpression: patients with OpSCC had p16-positive status more frequently (53 % of cases) while patients with Cup syndrome mostly had p16-negative status (73 % of cases). mean life expectancy of patients with OpSCC and p16-positive status was 62.65 months (95 % confidence interval 54.98–70.31), minimal observation period was 12 months, maximal was 70 months. mean life expectancy of patients with Cup syndrome and positive p16 status was 66.22 months (95 % confidence interval 56.35–76.10), minimal observation period was 12 months, maximal was 70 months. No statistically significant differences in survival rates of patients with OpSCC and Cup syndrome were found (р = 0.999).Conclusion. The study showed higher pD-L1 expression in patients with Cup syndrome compared to patients with OpSCC: 92 and 73 %, respectively (р = 0.01). The obtained results highlight the importance of routine pD-L1 expression evaluation in patients with Cup syndrome. The frequency of p16 hyperexpression was higher in OpSCC compared to Cup syndrome: 53 % versus 27 % (р = 0.02) which agrees with the worldwide epidemiological data: among all malignant neoplasms of the head and neck, Hpv infection is most common in OpSCC. Therefore, it serves as an important sign of hidden oropharyngeal cancer in Cup syndrome.

Prevalence and survival of patients with nasopharyngeal malignancies (C11) (clinical and population-based study)

Introduction. In the 10th revision of the International Classification of Diseases (ICD-10), the code for malignant neoplasms of pharynx (mNN) is C11. These tumors are rare. The state statistics only presents information on morbidity. Data on mortality due to mNN are absent, they are included into the group of other causes of death. The real assessment of the effectiveness of antitumor management of mNN can only be obtained from the population Cancer Registry Database (pCR DB) of the Northwestern federal District of the Russian federation (NwfD Rf) developed by us. This database allows to determine the main analytical values of any parameter included in the case report form. The most reliable criterion of evaluation of the effectiveness of antitumor management is calculation of observed and relative 1-year and corrected 5-year survival rates of patients at the population level and in accordance with international standards.Aim. To perform first in Russia assessment of the effectiveness of antitumor management of mNN with calculation of analytical values including survival (separately for men and women) and detailed characteristics of location and histological structure.Materials and methods. The data of the International Agency for Research on Cancer (IARC), as well as reference books of the p.A. Hertsen moscow Oncology Research Institute and the N.N. petrov National medical Research Center for Oncology were used. Data processing was preformed using mS Excel 2013–2016 and STATISTICA 6.1 licensed software. Survival rates were calculated using modified EuROCARE software. The study was based on the databases of the population cancer registry of Saint petersburg and NwfD Rf developed by us. In total, 950 observations were analyzed. Results. Data obtained during investigation of the incidence and survival rates of mNN confirmed the rarity of this pathology and positive morbidity dynamics, standardized values of which decreased in Russia between 2010 and 2022 by 19.35 %, in NwfD Rf by 27.59 %. The coronavirus pandemic had a significant negative effect on the record keeping. Additionally, between 2010 and 2022 1-year survival of patients with mNN in NwfD Rf increased from 58.5 to 80.6 % (by 22.1 %); 5-year survival increased between 2000 and 2018 from 25.4 to 35.4 % (by 10 %).Conclusion. Analysis of the incidence and survival of patients with malignant neoplasm of rare location can be performed only using a database of population cancer registry of a federal district in compliance with all international rules of its maintenance. unfortunately, currently this is possible only for NwfD Rf.

NCOG-12. TREATMENT AND MORTALITY OF PRIMARY BRAIN TUMORS: A SINGLE CENTER OBSERVATIONAL STUDY OF GLIOBLASTOMAS AND ASTROCYTOMAS

Abstract Glioblastoma multiforme (GBM) is a WHO grade IV malignant tumor with a relatively poor prognosis (median survival of 15 months). Astrocytomas are WHO grade I-III tumors with a better prognosis than GBM; their median survival ranging from 2-10 years. We assessed the response to various mainstay treatment modalities in patients with GBM and astrocytoma, expecting to find that surgery and stereotactic radiation (SRS) treatment confer greater survival benefits than non-surgical and whole brain radiation (WBRT) options. We analyzed 108 patients at St. Luke’s University Health Network (SLUHN) who were previously diagnosed with a primary brain tumor consistent with GBM (90) or astrocytoma (18) prior to January 1, 2023. Mainstays of treatment were surgery with or without different radiation modalities (WBRT and SRS, and WBRT+SRS). Glioblastoma typically affected older patients (65.5), had mostly single lobe involvement (86.7%), and was predominantly located in the frontal (41.1%) and temporal lobes (37.7%). Astrocytoma was slightly younger (51.2), less often single lobe (72.2%), and mostly involved the frontal (44.4%), temporal (44.4%), and parietal lobes (33.3%). GBM found the greatest benefit from WBRT (without co-occurring SRS) with an increase of 16.4 months to 20.2 months (p=.789). Surgery, regardless of radiation status, appeared to provide the greatest benefit for patients with astrocytoma increasing average lifespan from 36.7 months to 53.6 months (p=.181). Patients with glioblastoma that underwent surgery also had increased survival of 18.2 months compared with nonsurgical patients at 12 months (p=0.097). While we were interested to see the impact these treatment modalities had on patient survival, our sample size was small and our results lacked statistical significance. Future studies with greater sample sizes would help determine whether statistical significance is correlated with meaningful clinical outcomes.

Left-sided portal hypertension caused by a solid pseudopapillary neoplasm of pancreas tail: a pediatric case report

BackgroundSolid pseudopapillary neoplasm (SPN) is a low-grade malignant tumor that occurs in 60% of all pediatric pancreas tumors. Radical tumor resection is essential; however, spleen preservation is also crucial to prevent overwhelming post-splenectomy infection. In contrast, spleen preservation is not always possible, because left-sided portal hypertension (LSPH) can cause splenic vein stenosis or occlusion induced by pancreatic tumor. We herein report on a pediatric patient of LSPH due to SPN in the pancreatic tail.Case presentationA 12-year-old girl was admitted to our hospital with left upper quadrant abdominal pain. A solid mass was palpated in the left costal region. The patient showed slight anemia (Hb: 11.8 g/dL) and elevation of inflammatory reaction (CRP: 5.98 mg/dL) without positive tumor markers. A radiological examination revealed that a 9 cm-sized mass with hemorrhagic necrosis in the pancreatic tail. Splenic venous flow was not detected and collateral draining into the left gastric vein and left renal veins were developed with splenomegaly. LSPH was involved at the time of diagnosis. The tumor was diagnosed with SPN, hence tumor resection with spleen preservation was performed. Six months after surgery, the patient developed a left quadrant abdominal pain that worsened during exercise. There was no improvement of splenic venous flow and splenomegaly. LSPH remained with splenomegaly, which possibly triggered the patient’s abdominal pain. The patient underwent splenectomy 9 months after the tumor resection. After the splenectomy, the patient’s abdominal pain disappeared without any recurrence 8-year post-surgery.ConclusionsLSPH has not been a major focus in previous SPN pediatric patients, although most symptomatic LSPH patients required splenectomy. Careful post-operative observation for LSPH is important for pediatric SPN patients.

Identification of alternative lengthening of telomeres-related genes prognosis model in hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is a common malignant tumor worldwide, characterized by high mortality. This study aimed to explore the prognostic value and function of alternative lengthening of telomeres (ALT)-related genes in HCC. Differentially expressed genes (DEGs) were identified based on The Cancer Genome Atlas (TCGA) and then intersected with ALT-related genes to obtain ALTDEGs. Risk score model was constructed using the least absolute shrinkage and selection operator (LASSO) algorithm and Cox regression and validated with Gene Expression Omnibus (GEO) datasets. The predictive efficacy of the risk score and ALTs-score was evaluated by Kaplan-Meier curves, time-ROC curves, and the nomogram analyses. The impacts of SMG5 silencing on the HCC cell behaviors were assessed by CCK-8, wound healing, and Transwell assays. A total of 500 ALTDEGs were screened and 13 genes (CDCA8, SMG5, RAD54B, FOXD2, NOL10, RRP12, CCT5, CCT4, HDAC1, DDX1, HRG, HDAC2, and PPP1CB) were identified for constructing a prognostic model. The overall survival (OS) curves, time-ROC curves, and nomograms based on the risk score or ALTs-score were developed to optimally predict the survival of HCC patients. ALTs-score was correlated with immune infiltration and confirmed its value in predicting immunotherapy outcomes. Furthermore, RT-qPCR demonstrated that eight risk signature genes were up-regulated in HCC cells. SMG5 silencing suppressed the proliferation, migration, and invasion of HCC cells. It was also found that SMG5 silencing reduced C-circle level in SNU-387 cells. We identified new ALT-related prognostic biomarkers for HCC. SMG5 knockdown inhibited the HCC progression, which might be a promising target for HCC therapy.

RepID as a potential biomarker and therapeutic target for lung neuroendocrine tumor

Neuroendocrine tumor (NET) is a rare malignant tumor, notably small cell lung cancer (SCLC), a type of lung neuroendocrine tumor, which has a survival rate of less than 7%. Although various biomarkers including CHGA (Chromogranin A), INSM1 (Insulinoma-associated protein 1), and SYP (Synaptophysin) are extensively used for the diagnostic testing of NET, their diverse specificities and sensitivities are acknowledged as limitations. Here, we demonstrate that RepID (Replication initiation determinant protein), a component of CRL4 (Cullin-RING ubiquitin E3 ligase 4), holds promise as a biomarker for identifying NET and SCLC. Analysis of the Cancer Cell Line Encyclopedia (CCLE) via the CellMinerCDB portal reveals a high correlation between RepID transcript levels and mRNA expression of NE signature genes. Additionally, RepID protein is highly expressed in SCLC patient tissues and a subset of SCLC cell lines. Viability analysis following treatment with pevonedistat and SZL-P1-41 in SCLC cell lines and human SCLC-organoid models indicates that RepID expression determines the sensitivity to CRL-targeting anti-cancer drugs. These findings suggest that RepID represents a novel biomarker for NET and SCLC, and insights from RepID research in these cancers could lead to innovative therapeutic strategies.

BIOM-26. ROLE OF EXTRA-DOMAIN B FIBRONECTIN IN MODULATING GLIOBLASTOMA CELL INVASIVE PROPERTIES

Abstract Glioblastoma (GBM) is a highly malignant tumor characterized by its resistance to current treatment modalities and high recurrence rates. Extra-domain B Fibronectin (EDB-FN), a glycoprotein not found in normal tissues but selectively expressed in the tumor microenvironment, was previously identified by our team as a promising molecular marker for brain tumors, offering potential for both prognostic prediction and therapeutic targeting. However, the specific role and mechanism of action of EDB-FN in GBM cells remain unclear. In this study, we sought to elucidate the potential role of EDB-FN and the underlying mechanisms contributing to GBM malignancy through in vitro investigations. Our findings reveal that silencing EDB-FN in GBM cells leads to a decrease in cell migration, invasiveness, extracellular matrix adhesion ability, and stem cell-like properties. Furthermore, we discovered that FAK and ERK signaling pathways play a crucial role in GBM cell progression in response to EDB-FN. This study underscores the potential of EDB-FN as a specific biomarker for GBM treatment, paving the way for future research in this area.

BIOM-76. EXPLORING CSF MICRORNA SIGNATURES AS DIAGNOSTIC BIOMARKERS IN IDH-WILDTYPE DIFFUSE GLIOMAS

Abstract The most prevalent malignant tumors of the central nervous system are adult-type diffuse gliomas. Isocitrate dehydrogenase (IDH) mutations are identified in a subset of diffuse gliomas, leading to two distinct subtypes of gliomas: IDH-wildtype and IDH-mutant. In comparison to IDH-mutant gliomas, IDH-wildtype gliomas tend to be associated with a more rapid progression and lower overall survival rates. The analysis of differentially expressed microRNAs (DE-miRNAs) in cerebrospinal fluid (CSF) of IDH-wildtype diffuse gliomas could provide an effective and non-invasive approach to assist in the early diagnosis, classification, and management of the disease. Extracellular vesicle (EV)-derived miRNAs obtained from the CSF of 11 patients with IDH-wildtype diffuse gliomas and 8 controls were analyzed by microRNA sequencing (miRNA-seq). DE-miRNAs were defined using p-value≤0.05 and absolute log2 fold change (log2FC) ≥1. Candidate DE-miRNAs were validated by qRT-PCR in 24 samples (15 IDH-wildtype vs. 9 control) using the 2-ΔΔCT method, followed by receiver operating characteristic (ROC) curve analysis. Hsa-miR-24-3p was used as the internal control. miRNA-seq analysis identified hsa-miR-484, hsa-miR-223-3p, hsa-miR-1246, hsa-miR-323a-3p, hsa-miR-106b-3p, hsa-miR-21-5p, hsa-miR-15a-5p, has-miR-15b-5p, and hsa-miR-92a-3p among the top 20 upregulated miRNAs in the CSF of patients with IDH-wildtype diffuse gliomas. Further analysis by qPCR showed that patients with IDH-wildtype diffuse gliomas had significantly higher levels of has-miR-21-5p (2.28 ± 2.33) compared to control subjects (-2.22e-007 ± 1.08, p=0.012). The ROC curve analysis revealed an area under the curve (AUC) of 0.84 (95% CI, 0.68-1.0) for has-miR-21-5p CSF levels in distinguishing IDH-wildtype diffuse gliomas from control subjects. EV-derived miRNAs in CSF, including has-miR-21-5p, have the potential to distinguish IDH-wildtype diffuse gliomas from control individuals in a minimally-invasive manner and serve as diagnostic biomarkers.

DDDR-36. LOOKING AROUND THE CORNER: PREDICTING SYNERGY OR FUTILITY TO COMBINATION OF ARSENIC TRIOXIDE PLUS MNK1 INHIBITORS IN GLIOBLASTOMA

Abstract Glioblastoma (GBM) is the most prevalent type of malignant tumor within the central nervous system. The five-year survival rate of 6.8% highlights the challenges inherent to exceptionally heterogeneous tumors that grow behind the blood brain barrier. The protracted dearth in new agents approved for GBM begs innovative strategies by which to approach clinical trials. Arsenic trioxide (ATO) is the standard of care for myelodysplasia and relapsed or refractory acute promyelocytic leukemia. ATO has an idiopathic mechanism of action, but has shown beneficial effects in other solid tumors. Across six GBM PDX models a 10-fold difference in sensitivity manifests, indicative of underlying innate sensitivity or resistance to ATO. This resistance has been previously shown to correlate with MNK1 expression. In order to sensitize PDX models innately resistant to ATO we utilized combination therapy with the MNK1 inhibitor AUM001 (AUM Biosciences, Singapore; NCT05462236). In high MNK1 expressing PDX models the combination of ATO + AUM001 induces cytotoxic synergy. Additionally, when narrowly measuring effects on the glioma stem cell population (ELDA), strong synergy was observed in models, including those failing to show such using bulk cell population viability assay. GSEA analysis revealed differential high enrichment in gene sets related to oxidative phosphorylation in the models failing to show synergy. Such criteria could act as exclusionary criteria (futility) for clinical trials by excluding such putative non-responder patients from the treatment population. Synergistic models showed enrichment in gene sets related to epithelial/mesenchymal transition, skeletal and sensory organ development, and regionalization. These signatures could serve to prioritize patient inclusion in clinical trials of ATO in combination with AUM001, enriching the fraction of responsive glioma patients. Such molecular signatures may bring precision medicine in early-stage clinical trials to advance promising new agents and combinations of agents to full FDA approval.

TMIC-64. EXPLORING ULTRASTRUCTURAL PATHOLOGY IN GLIOMAS: INSIGHTS FROM RECENT STUDIES

Abstract Glioma tumors arise from the glial cells making up to 40% of the brain tumors, and contributing up to 85% of the malignant tumors of the brain. Gliomas are a heterogeneous group of tumors classified based on various factors such as genetics, molecular profiles, etc. Glioblastoma, an aggressive form of gliomas, has incredibly low survival of only 15 months suggesting that thorough research, improved diagnostics, and therapeutics development is needed to improve the outcomes for patients with gliomas. These advancements require a critical analysis of the microenvironment of gliomas to understand the pathophysiology at play. Ultrastructural analysis (UA) using high-resolution electron microscopy offers crucial insights into the cellular and subcellular characteristics of gliomas, revealing organelle abnormalities and confirming molecular alterations. In this review, we focus on the recent developments exploring the ultrastructural pathology of gliomas. UA shows a detailed microenvironment of gliomas to reveal the abnormal presence of lipids in the intra- and extracellular environment of gliomas accompanied by the disrupted structure of the cellular membranes and organelles. The disruptions were noted in the blood vessels of the tumors displaying intriguing details regarding the formation of neovasculature and the absence of typical contents of vessel walls like endothelial cells. A comparative survey of the mitochondrial ultrastructure of gliomas with or without IDH1 mutations also reveals the role of UA in deciphering the impact of different mutations on the microenvironment level. Here, we also discuss the major implications of these findings regarding the research direction, diagnostic modalities, and therapeutic options.

Adrenocortical Carcinoma about One Case and Literature Review

Introduction: Adrenocortical carcinoma (ACC) is a rare malignant tumor that develops in the layers of the adrenal cortex with an incidence of 0.5–2 per million per year. Case report: A 40-year-old female patient, admitted for left flank heaviness, evaluation was in favour of a suspicious left adrenal tumour, the non-functional caracater was retained after a negative secretory workup. The patient was operated on with a histological appearance of metastatic ACC. Discussion and conclusion: The prognosis for these tumors is poor, since at the time of diagnosis the majority of cases are already metastatic, especially when the tumour is non-functional. The management of ACC is complex, representing a real diagnostic and therapeutic challenge.

CSIG-14. ACROLEIN INDUCES THE MIR-30A-5P/NCAM AXIS THROUGH THE AKT/GSK3Β/Β-CATENIN PATHWAY, PROMOTING GLIOMA PROGRESSION

Abstract Glioblastoma (GBM), the most aggressive brain tumor, exhibits resistance to treatment and thrives in low-oxygen (hypoxic) environments, leading to the accumulation of reactive oxygen species (ROS). Hypoxia activates the hypoxia-inducible factor (HIF)-1α pathway, enhancing tumor malignancy. Acrolein, a reactive aldehyde produced during lipid peroxidation in hypoxia, induces toxicity through DNA damage, inflammation, mitochondrial dysfunction, and oxidative stress. Our previous study found elevated acrolein levels in hypoxic glioma cells and linked acrolein-induced DNA damage (Acr-dG) with poor GBM prognosis. However, the role of acrolein in GBM progression remains unclear. This study aims to elucidate the impact of acrolein on GBM. In vitro experiments demonstrated acrolein production under hypoxia, which increased glioma cell migration and spheroid formation. RNA sequencing identified five affected pathways: cell adhesion molecules, PI3K-AKT signaling, ECM-receptor interaction, MAPK signaling, and neuroactive ligand-receptor interaction. Acrolein downregulated NCAM (neural cell adhesion molecule) via the miR-30a-5p-AKT-GSK3β/β-catenin axis in GBM cell lines and patient-derived cells. Overexpressing NCAM reduced cell migration and spheroid formation. Lower NCAM levels in GBM tissues correlated with poor patient survival. This study suggests the potential of NCAM as a therapeutic target for GBM and provides insights into early detection and treatment strategies for this malignancy.

RADT-44. EARLY CLINICAL EXPERIENCE WITH PROTON CRANIOSPINAL IRRADIATION FOR THE TREATMENT OF LEPTOMENINGEAL DISEASE

Abstract BACKGROUND Leptomeningeal disease (LMD) is a uniformly terminal event of advanced cancer with limited therapeutic options, with survival ranging from weeks to a few months. Recently, proton craniospinal irradiation (pCSI) has been demonstrated to confer a progression-free and overall survival benefit in select patients with LMD as compared to more limited site radiotherapy. Early results from an institutional experience of pCSI for patients with LMD from solid tumor malignancies are reviewed. METHODS All patients with LMD and treated with pCSI at our institution were reviewed, specifically with regards to baseline patient characteristics, radiation dosimetry parameters and clinical outcomes. RESULTS Between February 2023-April 2024, nine patients were treated with pCSI for a range of primary tumor histologies, including two with triple-negative breast cancer and one each with ER+/PR+/HER2- breast cancer, non-small cell lung cancer, small cell lung cancer, gastric cancer, esophageal cancer, pancreatic cancer and ovarian cancer. All patients received 30Gy(RBE) in 10 fractions to the craniospinal axis, with one patient receiving an intracranial boost (6Gy(RBE)). Median age and performance status was 58 years and KPS 80, respectively. Five (56%) patients underwent CSF diversion prior to pCSI, 22% of patients had undergone prior CNS-directed radiotherapy, and all patients received at least one line of systemic therapy in the metastatic setting prior to pCSI. Median survival from the first day of pCSI was 4.3 months (range 1.3-10.7mo). Median survival among patients undergoing CSF diversion prior to pCSI (n=5) was 5.3 months (vs. 2.9mo with no CSF diversion). Median survival among patients who received systemic treatment after pCSI (n=5) was 9.1 months (vs. 2.9mo for patients who did not). CONCLUSIONS Careful patient selection is imperative to identify those who will best benefit from pCSI with suggestion of patients undergoing pre-pCSI CSF diversion and receiving post-pCSI systemic therapy achieving superior survival.

PATH-51. CENTRAL NERVOUS SYSTEM METASTASES ARE GENOMICALLY DIVERGENT FROM THEIR RESPECTIVE EXTRACRANIAL SITES

Abstract INTRODUCTION Next-generation sequencing (NGS) has become standard of care in establishing the diagnosis and guiding treatment of cancers. Our understanding of genomic evolution of brain metastases (BM) and leptomeningeal disease (LMD) from solid tumor malignancies remains limited. Here we present updated data from our pilot study. METHODS We prospectively collected clinical data and NGS of seventeen patients undergoing craniotomy for symptomatic BM from solid tumor malignancies or cerebrospinal fluid (CSF) sampling for LMD. Matched systemic and CNS analyses were performed using a research-based NGS assay. When extracranial disease tissue was unavailable, liquid NGS served as a surrogate. RESULTS CNS metastases were present at initial diagnosis in 10/17 and 11/17 patients had not received systemic therapy prior to CNS tissue sampling. The predominant cancer type was NSCLC (n=11), followed by breast cancer (n=3), ovarian high grade serous carcinoma (n=1), GEJ adenocarcinoma (n=1), and basosquamous carcinoma of skin (n=1). The mean tumor mutational burden in extracranial samples was 3.65 (SD 3.34; SEM 0.97), in contrast to CNS samples 21.63 (SD 26.47; SEM 7.64). Concordant mutations in matched sampling had an increase in CNS variant allele frequency (VAF) (27.8% vs 17.3%; arithmetic difference = 10.5, p=0.054) and CNS gene copy number alterations (CNA) (2.4 copies vs 0.8 copies; arithmetic difference = 1.6, p=0.171). Known driver alterations in EGFR, KRAS and PIK3CA were retained. LMD was present in 4/17 patients, with two present at enrollment and two developing during the study. CONCLUSIONS Matched sequencing reveals CNS metastases to harbor a significantly higher TMB, retention of primary driver alterations with a trend towards higher VAF and CNA of concordant mutations. While limited by small sample size, these data indicate genetic evolution in CNS metastases regardless of prior treatment status.

CSIG-15. ACROLEIN INDUCES THE MIR-30A-5P/NCAM AXIS VIA THE AKT/GSK3Β/Β-CATENIN PATHWAY, PROMOTING GLIOMA PROGRESSION

Abstract Glioblastoma (GBM), the most aggressive brain tumor, exhibits resistance to treatment and thrives in low-oxygen (hypoxic) environments, leading to the accumulation of reactive oxygen species (ROS). Hypoxia activates the hypoxia-inducible factor (HIF)-1α pathway, enhancing tumor malignancy. Acrolein, a reactive aldehyde produced during lipid peroxidation in hypoxia, induces toxicity through DNA damage, inflammation, mitochondrial dysfunction, and oxidative stress. Our previous study found elevated acrolein levels in hypoxic glioma cells and linked acrolein-induced DNA damage (Acr-dG) with poor GBM prognosis. However, the role of acrolein in GBM progression remains unclear. This study aims to elucidate the impact of acrolein on GBM. In vitro experiments demonstrated acrolein production under hypoxia, which increased glioma cell migration and spheroid formation. RNA sequencing identified five affected pathways: cell adhesion molecules, PI3K-AKT signaling, ECM-receptor interaction, MAPK signaling, and neuroactive ligand-receptor interaction. Acrolein downregulated NCAM (neural cell adhesion molecule) via the miR-30a-5p-AKT-GSK3β/β-catenin axis in GBM cell lines and patient-derived cells. Overexpressing NCAM reduced cell migration and spheroid formation. Lower NCAM levels in GBM tissues correlated with poor patient survival. This study suggests the potential of NCAM as a therapeutic target for GBM and provides insights into early detection and treatment strategies for this malignancy.

Replenishing co-downregulated miR-100-5p and miR-125b-5p in malignant germ cell tumors causes growthinhibition through cell cycle disruption.

MicroRNAs (miRNAs) are short, nonprotein-coding RNAs, and their expression is dysregulated in malignant germ cell tumors (GCTs). Here, we investigated the causes and consequences of downregulated miR-99a-5p/miR-100-5p (functionally identical) and miR-125b-5p levels in malignant GCTs regardless of age, site, or subtype. Quantitative RT-PCR was used to assess miR-99a-5p/miR-100-5p, miR-125b-5p, and associated gene expression in malignant GCT tissues/cell lines [seminoma (Sem), yolk sac tumor (YST), embryonal carcinoma (EC)]. Cells were treated with demethylating 5-azacytidine and pyrosequencing was performed. Combination miR-100-5p/miR-125b-5p mimic replenishment was used to treat malignant GCTcells. Global messenger RNA (mRNA) targets of the replenished miRNAs were identified and Metascape used to study pathway effects. We found that expression levels of miR-99a-5p/miR-100-5p and miR-125b-5p, their respective pri-miRNAs, and associated genes from chromosomes 11 and 21 (chr11/chr21) were downregulated and highly correlated in malignant GCTcells. Treatment with 5-azacytidine caused upregulation of these miRNAs, with pyrosequencing revealing hypermethylation of their chr11/chr21 loci, likely contributing to miR-100-5p/miR-125b-5p downregulation. Combination miR-100-5p/miR-125b-5p mimic replenishment resulted in growth inhibition in Sem/YST cells, with miR-100-5p/miR-125b-5p mRNA targets enriched in downregulated genes, which were involved in cell cycle (confirmed by flow cytometry) and signaling pathways. Knockdown of the miR-100-5p/miR-125b-5p target tripartite motif containing 71 (TRIM71kd) recapitulated miR-100-5p/miR-125b-5p replenishment, with growth inhibition and cell cycle disruption of Sem/YST/EC cells. Further, replenishment led to reduced lin-28 homolog A (LIN28A) levels and concomitant increases in let-7 (MIRLET7B) tumor suppressor miRNAs, creating a sustained reversion of cell phenotype. In summary, combination miR-100-5p/miR-125b-5p mimic replenishment or TRIM71kd caused growth inhibition in malignant GCTcells via cell cycle disruption. Further studies are now warranted, including mimic treatment alongside conventional platinum-based chemotherapy.

Two-year Local and Distant Control of Malignant Peripheral Nerve Sheath Tumor (MPNST) in NF1 Patients After Multiple Recurrences: A Case Report

Malignant peripheral nerve sheath tumors (MPNSTs) are rare, biologically high-grade sarcomas that tend to recur and metastasize. The known risk factors for MPNSTs include neurofibromatosis type 1, highly aggressive MPNSTs, and dismal survival outcomes. Multimodality therapies, including surgical resection, radiotherapy, chemotherapy, targeted therapy, and combination therapy, are available. This case report describes a young woman with NF1 who was referred to us with a history of three local recurrences of MPNSTs in the proximal part of her left thigh after several surgical attempts. Successful local and distant control was achieved via preoperative radiotherapy and chemotherapy prior to the latest surgery. With preoperative RT and chemotherapy, more long-term and successful local and distant control was achieved, particularly in high-risk NF1- associated MPNST patients with a history of recurrence. Trials with larger sample sizes may show improvements in local control (LC), disease-free survival (DFS), and overall survival (OS) with neoadjuvant interventions in such patients.

Malignant Esophageal Glomus Tumor With CARMN::NOTCH2 Fusion: An Additional Tumor Underscoring the Frequent Tendency of Esophageal Glomus Tumors for Aggressive Behavior.

Malignant glomus tumors are rare tumors of pericytic origin with a propensity to develop in the upper gastrointestinal tract. Hereby we demonstrate a tumor of a 20-year-old man, who presented with dysphagia and an exophytic esophageal mass. Histologic examination of the resected mass revealed a multinodular tumor in the esophageal wall composed of epithelioid cells showing nesting and monomorphic atypia, staghorn vessels and scanty stroma. Immunohistochemically, the neoplastic cells were positive for SMA, and H-caldesmon, while desmin was negative. Collagen IV and laminin decorated a dense intercellular basal membrane meshwork. RNA-sequencing using TruSight RNA Pan-Cancer Panel revealed a CARMN::NOTCH2 fusion, that is a recurrent, frequently described and so far specific genetic alteration in glomus tumors. In spite of the adjuvant chemotherapy regimens, the patient died of disseminated metastatic disease 2 years after the diagnosis. Our patient presentation and the previous reports in the literature highlight the frequently aggressive behavior of glomus tumors arising in the esophagus.