bluuebunny/crossref_metadata_2025_split huggingface dataset:
EPCO-59. FIRST CASE REPORT OF COMBINED GERMLINE NF1 AND BRCA2 MUTATIONS PRESENTED WITH NEUROFIBROMAS AND LIPOMATOSIS
Authors: Choi Yoon 
Published: November 2024

Abstract
Both Neurofibromatosis type 1(NF1) and BRCA2 are common tumor suppressor genes, with mutations in each associated with genetic tumor syndromes. However, it is extremely rare to observe two different germline mutations in one patient. To the author’s knowledge, this is the first case report of a patient with germline mutations in both pathological NF1 and BRCA2 genes. We report a 41-year-old male patient with neurofibromas and lipomatosis. The patient with known family history of NF1, was diagnosed with NF1 after skin biopsy at 28 years old. At 40 years old, he underwent resection of a large intrathoracic neurofibroma. For genetic confirmation, next generation sequencing test was performed on both the intrathoracic neurofibroma tumor sample and saliva sample, revealing unexpected pathological germline mutation in both NF1 and BRCA2 genes. Consequently, the patient underwent resection of multiple lesions in the chest, abdomen, and upper extremities due to concern for potential breast cancers, and pathology of these lesions predominantly showed lipomas and one angiolipoma. Patient has family members with NF1 including a maternal aunt, a maternal cousin, and one son. However, there is no family history of lipomatosis or cancers commonly associated with BRCA2 mutation such as breast, ovarian, pancreatic, or prostate cancer. While lipomas are reported in patients with NF1, it is unusual that patient does not have typical café-au-lait spots or multiple neurofibromas but instead has multiple lipomas. This unusual presentation may be related to his unique genetic condition involving germline mutations in two tumor suppressor genes. Long term follow-up with screening tests for known tumors associated with each genetic mutation will be essential.
ANGI-05. UNSUPERVISED DECONVOLUTION OF SPATIOTEMPORAL HETEROGENEITY REVEALS HIGH-RESOLUTION INVASION STATES IN GLIOBLASTOMA
Authors: Manoharan Varsha Thoppey , Abdelkareem Aly , Brown Samuel , Gillmor Aaron , Hall Courtney , Seo Heewon , Narta Kiran , Grewal Sean , Dang Ngoc Ha , Ahn Bo Young , Osz Kata , Lun Xueqing , Mahoney Douglas , Senger Donna , Chan Jennifer , Morrissy Sorana 
Published: November 2024

Abstract
Diffuse invasion of glioblastoma cells through normal brain tissue is a key contributor to tumor aggressiveness, resistance to conventional therapies, and dismal prognosis in patients. A deeper understanding of how components of the tumor microenvironment (TME) contribute to overall tumor organization and to programs of invasion may reveal opportunities for improved therapeutic strategies. Towards this goal, we applied a novel computational workflow to a spatiotemporally profiled GBM xenograft cohort, leveraging the ability to distinguish human tumor from mouse TME to overcome previous limitations in analysis of diffuse invasion. Our analytic approach, based on unsupervised deconvolution, performs reference-free discovery of cell types and cell activities within the complete GBM ecosystem. We present a comprehensive catalogue of 15 tumor cell programs set within the spatiotemporal context of 90 mouse brain and TME cell types, cell activities, and anatomic structures. Distinct tumor programs related to invasion were aligned with routes of perivascular, white matter, and parenchymal invasion. Furthermore, sub-modules of genes serving as program network hubs were highly prognostic in GBM patients. The compendium of programs presented here provides a basis for rational targeting of tumor and/or TME components. We anticipate that our approach will facilitate an ecosystem-level understanding of immediate and long-term consequences of such perturbations, including identification of compensatory programs that will inform improved combinatorial therapies.
ANGI-09. GRAPH NETWORK ANALYSIS IDENTIFIES GENETIC COMMUNITIES OF CSF2RA AND RBFOX1 AS REGULATORS OF INVASIVE HIGH-GRADE GLIOMA BIOLOGY
Authors: Flick Matthew , Stevens Victoria , Sereduk Christopher , Plaisier Christopher , Barajas Ramon , Hu Leland , Kannan Kasthuri , Tran Nhan 
Published: November 2024

Abstract

BACKGROUND
High-grade glioma (HGG) is the most common and aggressive form of primary brain cancer. Standard of care surgery employs Magnetic Resonance Imaging to identify the contrast enhancing (CE) core for resection, leaving a non-enhancing (NE) invasive rim of tumor which contributes to recurrence. Recent multi-omics analyses identified predominant neuronal and immune signatures within NE tumor. Here, we apply a graph network to integrate regionally heterogeneous data from a unique dataset of spatially-localized CE and NE biopsies from a large cohort of patients with HGG.

METHODS
RNA-sequencing of 1159 differentially expressed genes across 159 IDH-wt biopsies (74 patients) from NE/CE regions were represented as nodes in a Neo4j network. Candidate genes for network random walks occurred exclusively within NE communities detected by modularity optimization and localized by cell-type using single-cell RNA-sequencing (scRNAseq). CSF2RA and RBFOX1 were selected as sources (walk length = 5; 10,000 walks/source node). Frequently occurring genes (one-tailed test) in walks were ranked by correlation with CSF2RA/RBFOX1 expression in NE samples and analyzed by gene set enrichment analysis for biological processes (clusterProfiler). Random walk genes were visualized (DoHeatmap) against composite NE/CE scRNAseq profiles.

RESULTS
CSF2RA and RBFOX1 were upregulated in NE samples (logFC = 0.789, 1.85). Upregulation of CSF2RA, an immune receptor, in the Glycolytic/Plurimetabolic and RBFOX1, a neurodevelopmental regulator, in the Neuronal glioma subtypes were observed in NE samples (ANOVA p &lt; 0.05). CSF2RA walk genes (n=46) enriched metabolic/proliferative signatures, while RBFOX1 walk genes (n=201) showed neurodevelopmental upregulation. scRNAseq localized CSF2RA to monocytes/macrophages while RBFOX1 was expressed in distinct astrocyte/neuroepithelial populations.

CONCLUSION
CSF2RA and RBFOX1’s gene networks modulate immune and neurodevelopmental processes influencing glioma progression in NE tumor. Understanding the region-specific roles of these networks may offer strategies for targeting cells in the invasive glioma rim.
BIOM-01. CDKN2A HOMOZYGOUS DELETION HAS STRONGER PROGNOSTIC POWER THANIDH MUTATION IN CNS WHO GRADE 4 GLIOMAS
Authors: Kim Young Zoon , Da Park Hyun 
Published: November 2024

Abstract
We conducted retrospective analysis of glioma cohorts in our institute. Medical records were reviewed for 142 glioblastoma patients for 15 years, and pathological slides were examined again for the updated diagnosis according to 2021 WHO classification of CNS tumors. The IDH mutation and CDKN2A deletion were examined by NGS analysis using ONCOaccuPanel®. Traditional prognostic factors were also examined. Mean follow-up duration was 27.5 months (ranged from 4.1 to 43.5 months) and mean overall survival (OS) was 19.4 months (95% CI 16.3 – 20.9 months). After the exclusion of 4 patients with poor status of pathologic samples, total 109 glioblastoma which were diagnosed by previous WHO criteria were changed into 26 (23.9%) astrocytoma, IDH-mutant, CNS WHO grade 4 and 83 (76.1%) glioblastoma, IDH-wildtype, CNS WHO grade 4. Among them, 61 patients (56.0%) had CDKN2A deletion. Group A was classified for 59 patients with IDH-wildtype and present CDKN2A deletion, group B was classified for 16 patients with IDH-mutant and present CDKN2A deletion, group C was classified for 48 patients with IDH-wildtype and absent CDKN2A deletion, and group D was classified for 13 patients with IDH-mutant and absent CDKN2A deletion. Group A had a mean OS of 15.70 months (95% CI 13.86 – 17.54 months), group B had a mean OS of 19.37 months (95% CI 13.43 – 25.30 months), group C had a mean OS of 22.63 months (95% CI 20.10 – 25.17 months), and group D had a mean OS of 33.38 months (95% CI 29.35 – 37.40 months). Multivariate analysis showed IDH mutation (mutant vs. wildtype; HR 6.358), and CDKN2A deletion (absence vs. presence; HR 13.452). The presenting study suggest that CDKN2A deletion should play a powerful prognostic role in CNS WHO grade 4 gliomas as well as low grade glioma. Even if CNS WHO grade 4 gliomas had mutant IDH, they can have poor clinical outcome due to CDKN2A deletion.
BIOM-02. A HIGH-GRADE GLIOMA, NOT ELSEWHERE CLASSIFIED IN AN OLDER ADULT WITH DISCORDANT GENETIC AND EPIGENETIC ANALYSES
Authors: Yuen Carlen , Bao Silin , Kong Xiao-Tang , Terry Merryl , Pekmezci Melike 
Published: November 2024

Abstract
World Health Organization (WHO) Classification of Tumors of the Central Nervous System (CNS) uses integrated diagnoses, which incorporates both histologic and molecular features of the neoplasms. With each new iteration, there is refinement and expansion of the diagnostic categories. DNA methylation profiling is a powerful technique to diagnose existing CNS tumors and define new tumor types. However, challenging diagnostic cases that do not conform to the updated WHO classification remain. We present a case of a 72-year-old male with a high grade glioma (HGG) suggestive of high grade astrocytoma with piloid features (HGAP), but it did not “match” to HGAP on DNA methylation profiling, which is essential diagnostic criterion for HGAP. This resulted in an HGG, not elsewhere classified (NEC) diagnosis. This lack of classification posed additional challenges for treatment decision-making.
BIOM-09. CLINICAL EFFECT OF CD25 ON THE MTX-BASED CHEMOSENSITIVITY OF PRIMARY CENTRAL NERVUS SYSTEM LYMPHOMA
Authors: Yamanishi Shunsuke , Nagashima Hiroaki , Tanaka Kazuhiro , Sasayama Takashi 
Published: November 2024

Abstract

INTRODUCTION
Primary central nervous system diffuse large B-cell lymphoma (PCNSL) is treated with chemotherapy, mainly with high-dose methotrexate (HD-MTX), but some cases are resistant to treatment and relapse in a short period. However, a biomarker that predicts the chemosensitivity and recurrence has not yet been identified. In this study, we used surface marker analysis of tumor tissue using flow cytometry to search for biomarkers related to chemosensitivity and early recurrence.

METHODS
From 2017 to 2023, 25 patients were diagnosed with PCNSL by biopsy in Kobe University Hospital, and flow cytometry of the biopsy tissues were performed. Cerebrospinal fluid (CSF) examination including sIL2R, β2MG, and IL-10 was performed in all cases before surgery, and treatment based on methotrexate was administered postoperatively. We retrospectively analyzed patient characteristics, flow cytometry data, treatment details, response rate, time to recurrence, and overall survival.

RESULTS
The mean age of the patients was 71 (range, 37-80) years. In univariate analysis, high expression level of CD25 (interleukin-2 receptor, IL-2R) in the tissue was associated with a lower response rate to MTX-based chemotherapy (Fisher’s exact test, p=0.0072) and had a tendency of shorter time to recurrence. However, there were no significant differences in progression-free survival and overall survival. There was no correlation between expression level of CD25 in tissue and sIL-2R in CSF. Expression level of sIL-2R in CSF was independent of CD25 expression in tissue.

CONCLUSION
There are some reports that CD25 can be a prognostic factor in follicular lymphoma, but no reports in PCNSL. Here, we suggested that high expression level of CD25 in PCNSL tissue was associated to chemoresistance and early recurrence. In cases of PCNSL with high CD25 expression level, additional whole-brain irradiation and transition to tirabrutinib be considered because there are possibilities of chemoresistance and early recurrence.
BIOM-10. CLINICAL PERFORMANCE EVALUATION OF A BRAIN CANCER LIQUID BIOPSY
Authors: Cameron James , Baker Matthew , Antoniou Georgios , Brennan Paul , Butler Holly , Eustace David , Gray Ewan , Jakola Asgeir , Jenkinson Michael , Koljenovic Senada , Lazarus Alan , Mathew Ryan , Palmer David , Phang Isaac , Sala Alexandra , Weiss Tobias 
Published: November 2024

Abstract
Diagnostic delays impact the quality of life and survival of patients with brain cancer. Currently, with no blood test to assist them, clinicians must make their referral decision based on symptoms. Existing symptom-based referral guidelines inadequately stratify patients for brain imaging based on suspicion of cancer. A simple, rapid liquid biopsy placed in a primary care setting would enable more efficient triage of patients with non-specific symptoms related to brain cancer. The Dxcover® Liquid Biopsy is a rapid multi-omic liquid biopsy that interrogates a blood sample with infrared radiation and produces a distinctive signature that represents the whole biomolecular profile of the sample, and is sensitive to the hallmarks of brain cancer. The nature of the technology also allows for the diagnostic models to be tailored towards higher sensitivity (or specificity) depending on clinical priorities and international healthcare markets. In initial feasibility studies, we recruited 988 patients prospectively with non-specific symptoms associated with a brain tumor, and the algorithm detected 96% of the patients with brain tumors and 100% of glioblastomas (GBM), when tuned for greater sensitivity. EMBRACE is a prospective, observational, multicenter study, currently recruiting patients across seven sites in the United Kingdom, Belgium, Sweden and Switzerland. The study duration is 24 months and will recruit a minimum of 2200 participants. The target population is comprised of patients presenting to primary care with non-specific symptoms that are associated with brain cancer, such as headache and new onset neurological defect. The primary objective is to determine the clinical performance of the liquid biopsy for patients with brain cancer, in terms of diagnostic sensitivity and specificity. The test performance will be determined by comparing the liquid biopsy result to diagnostic imaging. Earlier and expeditious diagnoses in these patients are crucial to reduce the morbidities and mortalities associated with brain cancer. This simple, non-invasive liquid biopsy would facilitate the triage of brain tumor patients for rapid imaging.
BIOM-14. TRANSMEMBRANE WATER EFFLUX RATE (KIO) IS AN MRI-DETECTABLE BIOMARKER TO EVALUATE THE EFFICIENCY OF TTFIELDS TREATMENT ON GLIOBLASTOMA
Authors: Hu Songtao , Jia Yinhang , He Qingping , Chu Jiaqi , Wang Yongjie , Bai Ruiliang 
Published: November 2024

Abstract

BACKGROUND
Tumor Treating Fields (TTFields) has emerged as an effective treatment modality for Glioblastoma, shown to improve both OS and PFS. Yet how to monitor response to TTFields remains unclear. In this study, we proposed using transmembrane water efflux rate (kio), a non-invasive biomarker detectable in conventional MRI and reflecting cell membrane permeability, to assess the treatment efficiency of TTFields.

METHODS
U-87 MG human glioblastoma cell line were treated with TTFields at frequency of 200 kHz and varying field strengths of 0 V/cm, 0.8 V/cm, 1.2 V/cm and 1.6 V/cm using the inovitro system from Novocure. The measurement of kio was performed on a 0.5 T benchtop MRI system (Pure Devices GmbH) using a home-developed filter-exchange imaging (FEXI) sequence. Cell membrane morphology were quantitatively analysed using scanning electron microscopy. Patients with newly diagnosed glioblastoma (ndGBM) who underwent DCE-MRI before and after TTFields treatment were identified and the change of FEXI-kio value were analysed.

RESULTS
In the same frequency, the effect of TTFields on cancer cell proliferation is dependent on intensity, manifested a decrease in cell growth rate under high electric field intensity. As the TTFields electric field intensity increased, the cell membrane permeability (kio) also increased, exhibits a significant negative correlation with glioblastoma cell growth rate (p=0.031). Scanning electron microscopy reveals that TTFields can induce significant cell membrane pores, and the total surface area of membrane pores correlates significantly positively with FEXSY-kio index. DCE-MRI data obtained from 4 ndGBM before and after TTFields therapy showed that the FEXI-kio value is increased after TTFields treatment.

CONCLUSION
This study demonstrated that TTFields increases membrane permeability by inducing cell membrane holes, and kio is a promising non-invasive MRI biomarker to evaluate the efficiency of TTFields treatment.
BIOM-15. METASTATIC BIFOCAL GERMINOMA: A CASE HIGHLIGHTING DRAMATIC EARLY RADIOLOGICAL RESPONSE TO STEROIDS AND REBOUND FOLLOWING DISCONTINUATION, AND THE UTILITY OF CIRCULATING MIR-371A-3P QUANTIFICATION AND VINBLASTINE MONOTHERAPY PRIOR TO DEFINITIVE CRANIOSPINAL IRRADIATION
Authors: Scarpini Cinzia , Ward Dawn , Phyu Poe , Jalloh Ibrahim , Thorp Nicky , Fisher Benjamin , Hendriks Emile , Salisbury Lyndsay , Nicholson James , Ajithkumar Thankamma , Horan Gail , Burke Amos , Coleman Nicholas , Allinson Kieren , Murray Matthew 
Published: November 2024

Abstract

BACKGROUND
In Europe, bifocal germinoma is diagnosed based on typical age (&gt;8-10y), symptoms (diabetes insipidus), radiological appearances, and serum/CSF AFP/HCG markers below thresholds. A 12yo male presented with 4-month headaches, 3-month polyuria/polydipsia, visual and somnolence/memory issues. Weight=71.1kg; height=166cm. MRI head/spine revealed hydrocephalus and 19×14×15mm (volume=2.09cm3) enhancing pineal lesion with nodular suprasellar and septum-pellucidum soft tissue. CSF positive for malignant cells. Serum/CSF AFP/HCG markers below thresholds. Metastatic bifocal germinoma diagnosed. Dexamethasone (8mg/day=4.4mg/m2/day) commenced for raised pressure. Proton referral (craniospinal-irradiation) made, but 8 weeks to expected start; hence, external-ventricular-drain (EVD) placed and weekly vinblastine commenced (PMIDs:32642701/34520101).

METHODS
Serum/CSF placental-alkaline-phosphatase (PLAP) and miR-371a-3p measured at diagnosis and CSF longitudinally. MRI performed at d9+d19 post-vinblastine. RESULTS. At diagnosis, CSF miR-371a-3p PCR positive (raw-Cq=18.64) (PMID:37386046); serum miR-371a-3p and serum/CSF PLAP all negative. In follow-up, CSF miR-371a-3p levels fell with weekly vinblastine, consistent with treatment response; PLAP remained non-informative. Repeat CSF cytology after two vinblastine doses was negative. D9 MRI showed reduction in tumour size/enhancement [pineal lesion 13×7×12mm (0.57cm3) from 19×14×15mm] and reduced ventricular size. Dexamethasone switched to maintenance-dose hydrocortisone (10mg+5mg+2.5mg=9.7mg/m2/day). D19 MRI, however, showed increased tumour volume again (pineal=17×10×14mm; 1.25cm3), albeit less than at diagnosis, with CSF miR-371a-3p down to raw-Cq=26.92 (&gt;300-fold reduction from diagnosis). EVD removed and septostomy performed; biopsy confirmed germinoma only (&lt;5% cells) with &gt;95% inflammatory cells (lymphocytes/macrophages). Vinblastine continued until protons without further tumour-associated comorbidity; MRI pre-protons showed pineal 10×10×12mm (0.63cm3; partial-remission) and post-protons complete-remission. Conclusion. Early radiological response to dexamethasone, with rebound on maintenance hydrocortisone, presumably secondary to lymphocytic re-infiltration of tumour (PMID:18000859). Reassuringly, circulating miR-371a-3p was informative for germinoma diagnosis (confirmed by biopsy) and treatment response. Weekly vinblastine useful bridge to definitive radiotherapy, explored in upcoming MonoGerm trial.
BIOM-17. EVALUATION OF CARBONIC ANHYDRASE TYPE IX (CA IX) EXPRESSION AS TARGET FOR RADIOLIGAND THERAPY IN GLIOBLASTOMA
Authors: Mair Maximilian J , Tomasich Erwin , Polten David , Greutter Lisa , Widhalm Georg , Eckert Franziska , Wöhrer Adelheid , Berghoff Anna S , Preusser Matthias , Albert Nathalie L 
Published: November 2024

Abstract

BACKGROUND
Glioblastoma represents an unmet need in neuro-oncology. Radioligand therapies are effective and approved in extracranial malignancies such as prostate cancer and neuroendocrine tumors, but data on their use is limited in brain tumors. In addition, rational target selection in gliomas is complicated by tumor heterogeneity. In extracranial tumors, clinical trials of radionuclide treatments targeting carbonic anhydrase IX (CA IX) are ongoing.

METHODS
Tumor samples of glioblastoma (isocitrate dehydrogenase [IDH]-wildtype) were retrieved from the Neuro-Biobank of the Medical University of Vienna. Formalin-fixed, paraffin-embedded tissue specimen were stained using rabbit anti-CA IX antibody (clone EP161, Cell Marque) on a Ventana Benchmark Ultra platform (Roche Diagnostics). CA IX expression was assessed semiquantitatively.

RESULTS
Overall, 29 patient samples were included in this study. Median age at surgery was 65 years (range: 55 – 74), and 22/29 (75.9%) were male. Median overall survival (OS) reached 11.6 months (95% confidence interval: 7.3 – 16.3). In total, 24/29 (82.8%) of specimen were positive for CA IX, of whom 20/29 (69.0%) exhibited moderate to high membranous CA IX expression and 4/29 (13.8%) showed weak immunoreactivity. CA IX staining displayed pronounced spatial heterogeneity, as positive areas were primarily seen in pseudo-palisading tumor cells around necrotic foci. Patients with stronger CA IX staining tended to have longer OS (median: 14.2 months) compared to those with absent or weak CA IX expression (median OS: 6.2 months; p = 0.075). Inclusion of further samples of different glioma subtypes is ongoing.

CONCLUSIONS
CA IX could represent a promising target for radioligand therapy in glioblastoma given the strong CA IX immunoreactivity in most samples. Intratumoral heterogeneity in CA IX expression should be considered in the design of appropriate compounds and the choice of optimal radionuclides to maximize efficacy.