bluuebunny/crossref_metadata_2025_split huggingface dataset:
EPCO-50. MOLECULAR DETERMINANTS OF CENTRAL NERVOUS SYSTEM TROPISM AND PROGRESSION IN COLORECTAL CANCER
Authors: Gui Chengcheng , Walch Henry , Mueller Kirin , Skakodub Anna , Miao Emily , Khatri Ishaani , Kumar Rahul , Mazzeo Michel Padilla , Shen Junchao , Cooper Claire , Hsu Audree , Patel Roshal , Ilica A Turan , Eichholz Jordan , Yu Kenny , Wilcox Jessica , Manca Paolo , Yu Yao , Yamada Yoshiya , Imber Brandon , Maron Steven , Foote Michael , Chatila Walid , Yaeger Rona , Schultz Nikolaus , Pike Luke 
Published: November 2024

Abstract

BACKGROUND
Brain metastases (BM) from colorectal cancer (CRC) are associated with dismal prognosis, but little is understood regarding their molecular characteristics. We identified genomic features that predispose to brain tropism, differentiate BM from extracranial disease, and predict early intracranial progression (IP) after BM-directed therapy.

METHODS
We analyzed next-generation sequencing (NGS) of tumor biopsies from three subgroups of CRC patients: patients with BM (BM+, n=379), patients with extracranial metastases (EM) but without BM (BM-/EM+, n=3968), and patients without metastatic disease (BM-/EM-, n=1061). NGS was performed with MSK-IMPACT, a targeted panel of &gt;300 genes. First, we compared genomic alterations in primary tumors (PT) among the BM+, BM-/EM+, and BM-/EM- subgroups. Second, we focused on patients in the BM+ subgroup who received stereotactic radiosurgery (SRS) for limited BM, comparing tumor genomic alterations from different anatomic sites: BM (n=32), EM (n=62), and PT (n=68). Third, we focused on the 32 resected BM, identifying genomic alterations that predicted early IP, defined as new BM, leptomeningeal disease, or enlargement of existing BM, within 6 months of postoperative SRS.

RESULTS
PT of BM+ patients demonstrated lower rates of microsatellite instability, increased frequency of BRAF alterations, and fewer APC alterations compared with PT of BM-/EM+ and BM-/EM- patients. Among BM+ patients, SMAD4, MYC, and CDK8 alterations were enriched among resected BM specimens, compared with EM and PT specimens. Resected BM of patients with early IP demonstrated increased frequency of SMAD4 alterations, particularly biallelic SMAD4 loss, and decreased frequency of MYC alterations, compared with resected BM of patients without early IP.

CONCLUSION
Alterations in key driver genes are associated with initial development and progression of CRC BM. BRAF alterations are enriched in PT of patients who develop BM. SMAD4 alterations are enriched in BM compared to extracranial disease and furthermore predict early IP after BM-targeted therapy.
ANGI-01. EXTRANEURAL METASTATIC EPENDYMOMA: DISTANT METASTASIS TO THE PLEURA, LUNGS, LYMPH NODES, AND BONE
Authors: Guirguis Mina , Jiang Zhixin , Cai Chunyu , Youssef Michael 
Published: November 2024

Abstract
Ependymomas are neuroepithelial tumors arising from ependymal cells surrounding the cerebral ventricles that account for 1.6-1.8% of primary CNS tumors. They rarely metastasize to extraneural structures, with one study reporting an incidence of 6.2% with a mean time from diagnosis to extraneural metastasis of 75.6 months. This spread, when it does occur, has been reported to occur to the lungs, lymph nodes, liver, and bone. We describe the case of a patient with recurrent WHO Grade III ependymoma, ZFTA::RELA fusion positive, with extraneural metastatic disease to the thoracic spine, lungs, and pelvic bones. He was treated with multiple surgical resections, radiation therapy, and salvage chemotherapy for his extraneural metastasis to the lungs, bone, pleural space, and lymph nodes. His functional and respiratory statuses declined until he ultimately developed pneumonia, status epilepticus, then spontaneous respiratory arrest, which resulted in his passing away. Salvage chemotherapy for ependymoma has unclear mortality benefit and more research must be done to determine how best to treat patients with extraneural metastases, particularly those who fail traditional treatment with resection and radiation therapy.
ANGI-03. GLIOMA STEM CELLS INDUCE VASECTASIA – A NON-ANGIOGENIC BRAIN TUMOUR NEOVASCULARIZATION PROCESS DRIVEN BY INTERCELLULAR EGFR TRANSFER THROUGH EXTRACELLULAR VESICLES
Authors: Rak Janusz , Spinelli Cristiana , Adnani Lata , Wong Fang Cheng , Meehan Brian , Montermini Laura , Huang Sidong , Kim Minjun , Nishimura Tamiko , Croul Sidney , Nakano Ichiro , Riazalhosseini Yasser 
Published: November 2024

Abstract
Tumour neovascularization in glioblastoma (GBM) is abundant, abnormal and poorly understood, and it likely involves multiple co-existing mechnanisms with distinct modes of regulation. Since glioma stem cells (GSCs) engage in bidirectional interactions with the vasculature we dissected the resulting vascular responses elicited by either proneural (PN), or mesenchymal (MES) GSC subtypes established from patients isolates and able to drive progression of orthotopic intracranial xenografts in mice. We report here that while PN-GSCs elicited mostly angiogenesis-type vascular capillary growth processes, their MES-GSC counterparts elicited non-angiogenic growth of enlarged vessels (vasectesia), paradoxically associated with reduced blood vessel density. Vasectasia was dependent on the expression of oncogenic EGFR/EGFRvIII by MES-GSCs, and on the related kinase/signalling activity, as EGFR/EGFRvIII gene disruption and Dacomitinib treatment suppressed formation of large blood vessels in vivo and resulted in a preponderance of a small calliber (angiogenic) vasculature throughout xenografts. Notably, the analysis of spatial transcriptomes and single cell RNA sequencing revealed distinct molecular traits of endothelial cells asociated with vasectasia and angiogesis, the former enriched in Birc5, but depleted for angiogenic tip cell markers (Vegfr2, Apln). Mechnaistically, vasectasia was linked to the intercellular transfer of EGFR from MES-GSCs to endothelial cells resulting in ectopic activation of EGFR signalling in the endothelial cell bacground, both in vitro and in a model of in vivo blood vessel recruitment into implanted matrigel pellets. Simultaneous pharmacological blockade of both, angiogenesis (anti-VEGR2) and vasectasia (Dacomitinib) lead to a marked increase in survival of mice with aggressive GBM lesions initiated by MES-GSCs. We suggest that, vasectasia driven by intercellular transfer of oncogenic EGFR may represent a new, subtype-specific mechanism of GBM neovascularization, and a plausible target for agents aiming to modify vascular tumour microenvironment.
ANGI-04. DISTINCT EXPRESSION OF TARGET MOLECULES BETWEEN TUMOR CELLS IN CEREBROSPINAL FLUID AND LEPTOMENINGES FOR LEPTOMENINGEAL METASTASIS
Authors: Kijima Noriyuki , Achiha Takamune , Kuroda Hideki , Tachi Tetsuro , Murakami Koki , Kishima Haruhiko 
Published: November 2024

Abstract

PURPOSE
Metastatic brain tumor frequently present with leptomeningeal metastasis. The leptomeningeal metastasis is usually diagnosed by cerebrospinal fluid (CSF) cytology and/or contrast enhanced magnetic resonance imaging. However, it remains to be known whether tumor cells from CSF faithfully represent the tumor cells of leptomeniges. Therefore, this study aimed to clarify the transcriptome differences between tumor cells from cerebrospinal fluid, and spinal cords

METHODS
MDA-MB-231 cells labeled with GFP and luciferase were injected into the right ventricle of immunodeficient mice. Tumor cells from cerebrospinal fluid, and spinal cords were sorted and analyzed the transcriptome differences by RNA sequencing,

RESULTS
RNA sequencing analysis showed distinct transcriptome profiles between tumor cells from cerebrospinal fluid and spinal cord. Genes related to ECM receptor interaction and PI3K-Akt signaling pathway such as COL1A1, COL1A2, THBS1 were significantly highly upregulated in tumor cells from spinal cord compared to those from CSF

CONCLUSIONS
Tumor cells from spinal cord had different characteristics in transcriptome from those from CSF. Different therapeutic strategies might be needed to regulate tumor cells from spinal cord and those from CSF.
ANGI-06. CEREBROSPINAL FLUID MAY BE THE MOST IMPORTANT PATHWAY FOR BRAIN METASTASES: A DATA-DRIVEN HYPOTHESIS AND CLINICAL IMPLICATIONS
Authors: Tuohy Kyle , Dowd Richard , Ouyang Tao , Thamburaj Krishnamoorthy , Aregawi Dawit , Olmez Inan , Mansouri Alireza , Glantz MIchael 
Published: November 2024

Abstract

INTRODUCTION
Hematogenous spread of brain metastases represents conventional wisdom. However, compelling physiologic evidence suggests that brain metastases may reach the CNS by way of the CSF either via the choroid plexus or directly from the bone marrow. We provide clinical evidence that invasion of brain parenchyma occurs through the CSF, and we model the therapeutic implications of this novel hypothesis.

METHODS
First, we assessed whether brain metastases were contiguous with a CSF space in 204 consecutive patients using pre-treatment MRI. Then, CSF was examined for malignant cells in 66 consecutive brain metastasis patients. Next, we contoured normal brain MRIs of 3 patients to calculate the percentage of brain within 5 mm of a CSF space. Finally, we queried an international neoplastic meningitis registry for patients with brain metastases to evaluate response to intra-CSF chemotherapy alone.

RESULTS
In 204 consecutive patients with brain metastases, the mean number of metastases was 4.63 (SD 6.26), and 85% of metastases touched a CSF space. In 67% of patients, all metastases touched a CSF space. In our consecutive cohort of 66 patients with CSF analysis, 44% with one, 46% with two, 63% with three, and 71% with &gt;3 metastases had malignant cells in the CSF (R2=0.93, p=0.04). Brain contouring revealed that up to 75% of the brain parenchyma lies within 5 mm of a CSF space. Seven of 10 patients with both brain and CSF metastases receiving only intrathecal chemotherapy experienced disappearance or substantial reduction in the size of their metastases.

CONCLUSIONS
This data suggest that brain metastases may access the CNS through the CSF. Intrathecal chemotherapy can reach most brain metastases and can produce objective responses. We suggest that the CSF should be monitored in all patients with, or at risk for, brain metastases, and true cures may require treatment of the CSF space.
ANGI-11. SEX DIFFERENCES IN SOX2 GLIOBLASTOMA EXPRESSION OUTSIDE MRI-DEFINED CONTRAST ENHANCEMENT AT AUTOPSY
Authors: Bobholz Samuel , Lowman Allison , Aaronsen Daniel , Winiarz Aleksandra , Duenweg Savannah , Flatley Michael , Nath Biprojit , Kyereme Fitzgerald , Connelly Jennifer , Mrachek Kelly , Krucoff Max , Banerjee Anjishnu , LaViolette Peter 
Published: November 2024

Abstract

INTRODUCTION
Sex-determining region Y-box 2 (SOX2) has recently been used as a marker for pluripotency to identify cellular glioblastoma invasion pathologically. This can be used to identify areas of tumor invasion consisting of sparse individual cells, likely highlighting the furthest margin of tumor invasion. This study aligned large format SOX2 stained tissue samples to conventional MRI to determine demographic factors that impact the presence of SOX2 positive invasion outside the T1 contrast-enhanced tumor margin.

METHODS
The cohort for this study consisted of 36 IDH-wildtype glioblastoma patients (23 male, 13 female, mean age=61.9). Tissue samples from areas of suspected tumor invasion and normal tissue were collected at autopsy, stained for SOX2, digitized at 40X resolution, and automatically segmented for SOX2 positive staining cell percent (SOX2+%) at MR resolution using a color deconvolution algorithm. Contrast enhanced T1 scans from acquisitions close to death were annotated manually for tumor presence and aligned to the T2-weighted FLAIR image. Tissue data was then aligned to MR images using a custom in-house software that relies on manually defined control points to generate a nonlinear transform that warps tissue into MR space while correcting for tissue shrinkage. Mean SOX2+% was computed for each patient outside of contrast enhancement and compared across age and sex as demographic factors.

RESULTS
Males were found to have a higher SOX2+% than females outside contrast enhancement (t=2.09, p=0.045), while no association with age was observed (r=0.146, p=0.397).

CONCLUSIONS
Sex differences were observed for non-enhancing SOX2 positivity, which may relate to the more aggressive tumors identified in male patients in some studies. Further research into the mechanisms behind sex differences in tumor growth patterns and molecular characteristics impacting the infiltration of tumor beyond the MR defined region is needed.
BIOM-07. SURVIVAL-ASSOCIATED GENETIC VARIATIONS IN TAIWANESE GLIOBLASTOMA MULTIFORME PATIENTS - A RETROSPECTIVE NGS STUDY
Authors: Huang Yu-FEN 
Published: November 2024

Abstract
This retrospective study, conducted at Taichung Veterans General Hospital in Taiwan, employed Next-Generation Sequencing (NGS) technology to analyze genetic variations associated with survival in patients with glioblastoma multiforme (GBM). The study encompassed 30 newly diagnosed GBM patients, divided into two groups based on survival duration: long-term (over two years) and short-term (under two years). The findings are outlined below: Key Mutations: Significant mutations included CHEK2, IDH1, and TP53, along with variations in the TERT promoter and TP53 RNA splicing sites. Correlation Between Mutations and Survival: Contrary to Western data, TP53 mutations were more prevalent in the long-term survival group, suggesting that regional genetic differences may influence GBM prognosis. Therapeutic Effectiveness: The application of bevacizumab was significantly associated with improved survival rates, indicating its potential efficacy in treatment. The study highlights the critical role of personalized medicine in the treatment of GBM in Taiwan and points to the necessity of further research into the genetic characteristics and treatment responses of GBM patients in Taiwan and potentially other non-Western regions. These insights underline the importance of continuing to explore effective personalized treatment strategies and enhancing our understanding of genetic determinants in diverse populations. Moreover, the prevalence of certain mutations in Taiwanese patients, which differ from those commonly observed in Western populations, prompts a reevaluation of global treatment frameworks and suggests the potential for region-specific therapeutic protocols. The implication of these findings extends beyond immediate clinical applications, providing a foundation for future clinical trials and research into genetic markers that could dictate treatment choices. In conclusion, this study not only underscores the importance of individualized treatment plans based on genetic profiling but also highlights the variations in genetic mutations across different populations, which could have profound implications for the management of GBM worldwide. Further investigation into these disparities and their implications on treatment efficacy is essential for advancing GBM treatment and improving patient outcomes globally.
BIOM-08. LEVERAGING CSF PROTEOMICS TO OPTIMIZE CNS LYMPHOMA MANAGEMENT
Authors: Mansouri Alireza , Wilding Hannah , Aastha Aastha , Mikolajewicz Nicholas , de Filho Leonardo Macedo , Glantz Michael , Kislinger Thomas 
Published: November 2024

Abstract

INTRODUCTION
Despite exquisite responses to initial therapy for CNS lymphoma (CNSL), relapse is common and overall responses are disappointing compared to other non-CNS diffuse large B-cell lymphomas. Incorporation of multi-agent intraventricular chemotherapy (MAIVC) alongside systemic therapy is novel. Identification of minimally-invasive biomarkers of response to MAIVC are necessary but lacking. The objectives of this study were to 1) identify baseline cerebrospinal fluid (CSF)-based proteomic predictive biomarkers of MAIVC treatment response and 2) identify tumor burden markers for longitudinal monitoring of MAIVC treatment response in CNSL.

METHODS
A cohort of patients with primary or secondary CNSL that were treated with MAIVC at Penn State Health (2015-2021) was included. Each MAIVC cycle was administered via Ommaya reservoir and included a 2-drug combination comprised of methotrexate, rituximab, cytarabine, etoposide, topotecan, gemcitabine, or thiotepa. Patient-matched CSF was sampled at pre- and post-therapeutic endpoints and profiled using shotgun proteomics. Patients were grouped by treatment response status. Early responders were defined as patients that achieved malignant cell-free CSF within 6 MAIVC cycles, whereas never responders were those patients that i) did not achieve malignant cell-free CSF by endpoint or ii) required salvage surgery or radiation during MAIVC.

RESULTS
59 patients were included (21 primary; 38 secondary CNSL) with a median age of 66 years (range 25-90) and median number of MAIVC cycles of 8 (range 2-23). A proteomic-based classifier, comprised of SGCE, LCP1 and AGRN, discriminated between early and never responders with an AUROC of 0.95. Comparison of CSF at baseline (&lt;3 cycles MAIVC) vs. post-treatment (&gt;12 cycles MAIVC) identified H3F3A, YWHAE, LCP1, CA1 and GAPDH as tumor burden biomarkers.

CONCLUSION
Here we developed a proteomic signature capable of predicting CNSL patient response to MAIVC, with potential to improve clinical decision making. Furthermore, the biomarkers associated with tumor burden represent important indicators of treatment response. Ongoing efforts are underway to evaluate these candidates as actionable therapeutic targets.
BIOM-11. PROGNOSTIC VALUE OF H3K27ME3 AND EZH2 IN ASTROCYTOMA, IDH-MUTANT
Authors: Onishi Shumpei , Yamasaki Fumiyuki , Amatya Vishwa Jeet , Yonezawa Ushio , Taguchi Akira , Ozono Iori , Khairunnisa Novita Ikbar , Go Yukari , Takeshima Yukio , Horie Nobutaka 
Published: November 2024

Abstract

BACKGROUND
H3K27 trimethylation (H3K27me3), catalyzed by EZH2, regulates gene expression through epigenetic mechanisms. H3K27me3 is used as a surrogate marker in pathology for diffuse midline glioma, ependymoma. However, the clinical value of H3K27me3 and EZH2 in astrocytoma, IDH-mutant has not been reported. The aim of this study was to evaluate the clinical significance of H3K27me3 and EZH2 in astrocytoma, IDH-mutant.

METHODS
A total of 30 patients with astrocytoma, IDH-mutant treated at our institute were included. The patients were divided into 2 groups according to the expression of immunohistochemistry (IHC) for H3K27me3. The following factors were analyzed; age, WHO grade, IHC for EZH2, CDKN2A status, ki67-index and extent of resection. The CDKN2A status was diagnosed by IHC for MTAP and was confirmed by NGS-based CGP test in some cases. Kaplan–Meier analysis and Cox regression analysis were performed to analyze overall survival (OS) and progression-free survival (PFS).

RESULTS
According to WHO classification 2021, astrocytomas were classified as follows: WHO grade2: 20 cases, grade 3: 2 cases, grade 4: 8 cases. Seventeen patients were identified as H3K27me3 positive, while fourteen patients were classified as H3K27me3 negative. The proportion of WHO grade 3 or 4 and ki-67 index were significantly higher in the H3K27me3 positive group (p=0.0011, 0.0036, respectively). OS and PFS were significantly longer in H3K27me3 positive group (p=0.0379, 0.0025). Furthermore, in the analysis of WHO grade 2/3, double-positive expression of H3K27me3 and EZH2 showed significantly shorter PFS and OS than the other group (p=0.0114 and 0.0068, respectively). In Cox regression analysis, H3K27me3 showed the highest likelihood ratio for OS (p=0.01061).

CONCLUSIONS
In Astrocytoma, IDH-mutant, the H3K27me3 positive group showed poor prognosis than H3K27me3 negative group. In addition, patients with double-positive expression of H3K27me3 and EZH2 demonstrated more unfavorable prognosis. H3K27me3 and EZH2 could be prognostic markers for astrocytoma, IDH-mutant.
BIOM-18. MAPPING TUMOR HABITATS IN IDH-WILD TYPE GLIOBLASTOMA: INTEGRATING MR IMAGING, PATHOLOGIC, AND RNA DATA FROM IVY GLIOBLASTOMA ATLAS PROJECT
Authors: Park Ji Eun , Lee Ho-Su , Lee Dongjun , Yoon Shinkyo , Song Sang Woo , Kim Young-Hoon , Hong Chang Ki , Kim Jeong Hoon , Kim Ho Sung 
Published: November 2024

Abstract

BACKGROUND
To identify biologic correlates and spatially validate intratumoral subregions (tumor habitat) using diffusion-weighted and dynamic susceptibility contrast-imaging on a comprehensive pathology map of the isocitrate dehydrogenase (IDH)-wild type whole glioblastoma sample using the Ivy Glioblastoma Atlas Project (Ivy GAP).

METHODS
Complete data of 20 patients with 168 slides of IDH-wild type glioblastoma were obtained from the IvyGAP (http://glioblastoma.alleninstitute.org/). On MRI, tumor habitats were defined using voxel-wise clustering of apparent diffusion coefficient (ADC) and cerebral blood volume (CBV) maps for contrast-enhancing lesion (CEL) and peritumoral non-enhancing lesion (NEL). On pathology slides, normalized areas of leading edge (LE), infiltrating tumor (IT), cellular tumor (CT), hypervascular lesion (CThypervascular), and perinecrotic lesion (CTperinecrotic) were obtained. Gross specimen pictures were co-registered on MRI images for co-localization and correlation between MRI tumor habitats. Pathologic areas were calculated using Pearson’s correlation coefficient. RNA sequencing of 67 RNA-seq samples was assessed using 4 Neftel subtypes and further correlated with pathology.

RESULTS
Six tumor habitats were correlated: hypervascular, hypovascular cellular, and hypovascular hypocellular habitats for CEL and NEL. CT was strongly correlated with hypovascular cellular habitat in CEL (C2, r = 0.238, p =.005). IT was strongly correlated with hypovascular cellular habitat in NEL (C5, r = 0.294, p =.017). CThypervascular was correlated with hypervascular habitat in NEL (r = 0.195, p =.023). CTperinecrotic was correlated with imaging necrosis (r = 0.199, p =.005). Astrocyte-like subtypes were positively correlated with IT (r = 0.256, p &lt;.001), while mesenchymal-like subtypes were positively correlated with CTperinecrotic area (r = 0.246, p &lt;.001).

CONCLUSION
Pathologically matched tumor subregions were cellular tumor with hypovascular cellular habitat in CEL and infiltrative tumor with hypovascular cellular habitat in NEL. Identification of the most aggressive tumor portion, and infiltrative tumor portion using non-invasive imaging can be achieved using MRI tumor habitats.