tbuckley/cabot-search huggingface dataset:
OS07.9.A NETWORK ANALYSIS IDENTIFIES CSF2RA’S GENETIC COMMUNITY AS A REGULATOR OF PROGRESSION IN THE INVASIVE REGION OF HIGH GRADE GLIOMA
Authors: V Stevens, M Flick, C P Sereduk, C L Plaisier, R F Barajas, L S Hu, K Kannan, N L Tran
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND High-grade glioma (HGG) is the most common and aggressive form of primary brain cancer with poor prognosis. Standard of care surgery employs Magnetic Resonance Imaging to identify the contrast enhancing (CE) core for resection, typically leaving behind a non-enhancing (NE) invasive rim of tumor which invariably contributes to recurrence. Recent multi-omics analyses identified predominant neuronal and immune signatures within NE tumor, which could provide key insights for combatting recurrence. We present the novel application of graph network analyses to integrate multi-omic data from a unique dataset of multi-regional spatially-localized CE and NE biopsy samples from a large cohort of patients with HGG. MATERIAL AND METHODS 159 IDH-wildtype tumor biopsy samples from NE and CE regions of 74 glioma patients were profiled by RNA sequencing. Differentially expressed genes (DEGs) across NE and CE samples (n = 1159) were determined using the EdgeR package, and represented as nodes within a Neo4j graph network. Samples were hierarchically clustered for each gene (method = median), and edges were generated between gene nodes sharing ≥ 1 sample. Modularity optimization was used to identify communities of densely connected nodes. Genes occurring exclusively within NE communities were localized by cell type using external single-cell RNA sequencing datasets and identified as source node candidates for NE network random walks. These were performed with CSF2RA nodes as source (walk length = 5; 10,000 walks/source node). Random walks traversing samples with significantly elevated CSF2RA expression (one-tailed test) were kept for analysis. Genes occurring at high frequency (one-tailed test) within random walks were ranked by correlation with CSF2RA expression in NE samples and analyzed by gene set enrichment analysis (GSEA) for biological processes using clusterProfiler. RESULTS CSF2RA, an immune signaling receptor gene, was upregulated (logFC = 0.789) in NE samples and uniquely occurred within NE communities. We show its differential expression within the immune-enriched Glycolytic/Plurimetabolic (GPM) glioma subtype and confirm its enrichment in myeloid populations across single cell HGG datasets. NE network random walks identified 46 DEGs associated with CSF2RA. GSEA revealed upregulation of proliferative and metabolic signatures and downregulation of signaling pathways within CSF2RA’s network. CONCLUSION CSF2RA’s genetic network in NE tumor represents a potential mechanism for immunologic facilitation of glioma progression within this region. Given the expression of CSF2 ligand by glioma cells, which plays a crucial role in recruiting myeloid cells during peripheral cancer progression, modulating the expression of key genes in the CSF2RA network may be a promising approach for perturbing the crosstalk signals between immune and tumor cells in the NE region.
KS02.7.A LONGITUDINAL SINGLE-CELL ANALYSES IDENTIFY DRIVERS OF GENETIC, EPIGENOMIC, AND CELLULAR EVOLUTION IN IDH-MUTANT GLIOMA
Authors: K C Johnson, A Spitzer, F S Varn, M Nomura, L Garofano, T Chowdhury, K J Anderson, F D’Angelo, L Bussema, S Gritsch, Y Oh, H Moon, S Paek, F Bielle, A Laurenge, A Di Stefano, B Mathon, A Picca, M Sanson, A Lipsa, F Hertel, Z Zhao, Q Wang, T Jiang, B Hermes, N Sanai, A Golebiewska, S P Niclou, J Huse, W Yung, A Lasorella, M L Suvà, A Iavarone, I Tirosh, R G Verhaak
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Hotspot mutations in the IDH genes serve as tumor-initiating events that define a subset of adult diffuse glioma that can further be divided into either oligodendroglioma or astrocytoma subtypes. 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. MATERIAL AND METHODS 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. RESULTS 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. CONCLUSION 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.
P27.16.A PREDICTIVE ROLE OF INTRACRANIAL PD-L1 EXPRESSION IN A REAL-WORLD COHORT OF NSCLC PATIENTS TREATED WITH IMMUNE CHECKPOINT INHIBITION FOLLOWING BRAIN METASTASIS RESECTION
Authors: S Murad, D Wasilewski, J Onken, P Höricke, J Bukatz, A Früh, Z Shaked, M Misch, A Kühl, O Klein, F Ehret, D Kaul, H Radbruch, D Capper, P Vajkoczy, D Horst, N Frost, P Bischoff
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Emerging evidence suggests that treatment of NSCLC brain metastases with immune checkpoint inhibitors (ICIs) is associated with response rates similar to those of extracranial disease. Programmed death-ligand 1 (PD-L1) tumor proportion score (TPS) serves as a predictive biomarker for ICI response. However, the predictive value of brain metastasis specific (intracranial) PD-L1 TPS is not established. We investigated the role of intra- and extracranial PD-L1 TPS in NSCLC patients treated with ICI following brain metastasis resection. MATERIAL AND METHODS Clinical data from NSCLC patients treated with ICI following brain metastasis resection (n = 64) were analyzed. PD-L1 TPS of brain metastases (n = 64) and available matched extracranial tumor tissue (n = 44) were assessed via immunohistochemistry. Statistical analyses included cut point estimation via maximally selected rank statistics, Kaplan-Meier estimates, and multivariable Cox regression analysis for intracranial progression-free survival (icPFS), extracranial progression-free survival (ecPFS), and overall survival (OS). RESULTS PD-L1 expression was found in 54.7% of brain metastases and 68.2% of extracranial tumor tissues, with a median intra- and extracranial PD-L1 TPS of 7.5% (0 - 50%, IQR) and 15.0% (0 - 80%, IQR), respectively. In matched tissue samples, extracranial PD-L1 TPS was significantly higher than intracranial PD-L1 TPS (p = 0.013). Optimal cut points for intracranial and extracranial PD-L1 TPS varied according to outcome parameter assessed. Notably, patients with a high intracranial PD-L1 TPS (&amp;gt; 40%) exhibited significantly longer icPFS as compared to patients with a low intracranial PD-L1 TPS (≤ 40%). The cut point of 40% for intracranial PD-L1 TPS was independently associated with OS, icPFS and ecPFS in multivariable analyses. CONCLUSION Our study highlights the potential role of intracranial PD-L1 TPS in NSCLC, which could be used to predict ICI response in cases where extracranial tissue is not available for PD-L1 assessment as well as to specifically predict intracranial response.
P27.18.A RADIOGRAPHIC AND CLINICAL RESPONSE OF SACRAL WHO GRADE 2 MYXOPAPILLARY EPENDYMOMA WITH PROTON BEAM RADIATION AND TEMOZOLOMIDE WITHOUT SURGICAL RESECTION
Authors: A Valerius, U Sener, P Rose, W Breen, E Lehrer, A Thomsen, D Baykal
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Myxopapillary ependymomas (MPE) are slow-growing tumors of the spine typically involving the medullary conus and cauda equina. MPE is regularly managed with surgical resection with radiation therapy reserved for cases where gross total resection cannot be achieved. Management of inoperable cases represents a clinical challenge. No systemic therapy is approved for treatment of MPE. Addition of chemotherapy may improve outcomes for cases not amenable to resection. MATERIAL AND METHODS We report feasibility and preliminary efficacy of combination treatment with proton beam radiation therapy and temozolomide chemotherapy for a patient with large, unresectable MPE. RESULTS A 19-year-old female presented with one year of gradually worsening hip and back pain despite treatment with physical therapy. MRI Lumbar spine identified a destructive and expansile T2-heterogenous and hyperintense intraosseous mass (14 x 12 x 13 cm) with extraosseous expansion involving the sacrum, coccyx, and left SI joint with abnormal soft tissue enhancement extending along the posterior spine. No additional lesions were identified on neuro-axis imaging. Biopsy of the mass was consistent with a WHO grade 2 myxopapillary ependymoma. Standard treatment of care would include complete surgical resection. Unfortunately, this would require a morbid procedure in an en block fashion with immediate and permanent loss of bowel, bladder, sexual, and ambulatory function in a young patient whose primary symptom was pain and mild weakness. It was therefore elected to treat the patient in an unconventional approach and begin with proton beam radiation therapy (59.4 Gy in 33 fractions) with concurrent temozolomide followed by 6 cycles of adjuvant temozolomide. Mild clinical improvement and significant radiographic response were achieved (size reduced to 8 x 7 x 11 cm). CONCLUSION This case suggests a potential role for use of proton radiation therapy with concurrent and adjuvant temozolomide for management of myxopapillary ependymoma not amenable to surgical resection.
P27.17.B PRIMARY CNS LYMPHOMA IN YOUNGER PATIENTS: ANALYSIS OF A MONOCENTRIC COHORT RECEIVING THE MODIFIED BONN PROTOCOL AS PRIMARY THERAPY
Authors: T Zeyen, J Weller, M Schneider, A Potthoff, C Schaub, L Röver, U Herrlinger, N Schäfer
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Polychemotherapy based on high-dose methotrexate (HD-MTX) is generally regarded ad standard therapy for newly diagnosed, younger patients with primary CNS lymphoma (PCNSL). Combination partners for HD-MTX vary between protocols (rituximab, ifosfamid (IFO), cytarabine (AraC), thiotepa (TT)). The type of consolidation therapy is even more variable (whole brain radiotherapy, high-dose therapy with stem cell rescue (HD-ASCT), continuation of standard-dose chemotherapy +/- intrathecal therapy). Successfull protocols are associated with a long-term survival (&amp;gt;5years) rate of substantially more than 50%. We here report the retrospective analysis of our monocentric cohort treated with the modified Bonn protocol. MATERIAL AND METHODS All consecutive patients aged &amp;lt;65 years who were newly diagnosed with PCNSL between 2012-2021 and recieved at least 1 cycle of the modified Bonn protocol as first-line therapy were included in this retrospective analysis. The modified Bonn protocol comprised 3 courses of rituximab/HD-MTX/IFO, implantation of an intraventricular catheter followed by consolidation therapy with 2 courses of HD-AraC and 2 courses of HD-MTX/IFO including intrathecal MTX and AraC in each course. Progression-free survival and overall survival were evaluated. RESULTS Forty patients with a median age of 58 years (range 38-64) and a median KPS of 80% (range 30-100) were included. Twenty-three patients (57.5%) had multiple cerebral lesions. Thirty-eight patients (95%) reached intrathecal consolidation therapy and 36 (90%) completed all seven courses of therapy. Grade 3/4 toxicity (CTCAE v5) was observed in 21 patients (52.5%); among those, nine had an infection grade 3/4 (22.5%). After a median follow-up (mFU) of 54.7 months (IQR 25-99.5 months), the median progression-free survival was 102.8 months (95%CI 0-211.5) and the 2-year progression-free survival rate was 55%. The 5-year overall survival rate was 80% (median not reached). Sixteen patients developing refractory/relapsed PCNSL received second line therapy using the modified Freiburg protocol (AraC/TT +/- HD-MTX/rituximab followed by HD-ASCT). A second relapse has been observed in 6 of these 16 patients so far (mFU 48.7 months). CONCLUSION First line treatment of PCNSL with the modified Bonn protocol is highly effective. Overall survival rates compare well with other seemingly more toxic PCNSL protocols in younger patients. In patients with relapsed/refractory disease, second line therapy according to the modified Freiburg protocol appears to be affective.
P27.19.A RAPID EARLY PROGRESSION IN GLIOBLASTOMA: A CASE-CONTROL EVALUATION OF CLINICAL OUTCOMES AND ADVANCED IMAGING BIOMARKERS
Authors: M Waqar
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND In glioblastoma patients, Rapid Early Progression (REP) refers to tumour growth between the time of surgery and postoperative chemoradiotherapy. It has a high incidence although relatively little is known about the phenomenon. The aim of this study was to characterise REP using clinical and advanced imaging data in the context of a case control study, to control for key confounders. We only included patients undergoing gross-total resection (GTR) to eliminate bias from extent of resection. MATERIAL AND METHODS Ethical approval was obtained. We reviewed an institutional database of newly-diagnosed glioblastomas undergoing GTR (2015-2021). Supratentorial IDH-wildtype glioblastomas were included with magnetic resonance imaging (MRI) scans available at the postoperative and radiotherapy planning time points. REP was defined as a nodular increase in enhancement located within/around the surgical cavity, occurring within 6 weeks of surgery, that was not accounted for by areas of diffusion-restriction on the postoperative MRI scan. Patients with REP were propensity-score matched to a control group based on clinical features. REP and control cases were compared on the basis of: clinical outcomes such as overall survival (OS) and progression-free survival (PFS; progression was defined as post-chemoradiotherapy progression); and advanced imaging using radiomics applied to preoperative T1 post contrast/Fluid Attenuated Inversion Recovery (FLAIR) sequences (Pyradiomics package) and the Apparent Diffusion Coefficient (ADC) derived from diffusion-weighted MRI. RESULTS 60 patients undergoing GTR were included. 8 cases met the definition of REP such that the overall incidence after GTR was 13%. REP cases were matched to 16 control patients. After matching, there was no significant difference in baseline variables between REP and control cases except preoperative performance status, which was worse in REP cases (median Eastern Cooperative Oncology Group [ECOG] 2 vs. 1). REP was associated with a shorter median OS (9 vs. 17 months, p = 0.038) and PFS (5 vs. 9 months, p = 0.029). The incidence of REP was higher in patients over 65 (6/22, 27%) and significantly fewer REP patients in this category received radical postoperative chemoradiotherapy versus controls (Fisher’s Exact, p=0.023). REP and control cases had similar radiomic profiles and there was no significant difference in mean ADC between the groups in enhancing (p=0.99) or non-enhancing FLAIR hyperintense regions (p = 0.67). CONCLUSION REP cases had a worse performance status from diagnosis and received less radical postoperative chemoradiotherapy protocols compared to controls, yielding a significantly shorter median OS/PFS. Our results highlight that REP is a significant prognostic variable yet does not have a distinct biomarker. Our ongoing work will explore potential tissue biomarkers of REP.
JS04.4.A SHORTENING THE TURNAROUND TIME FROM SURGERY TO COMPLETE MOLECULAR DIAGNOSIS
Authors: S Halldorsson, H Leske, R M Nagymihaly, A Patel, F Sahm, E O Vik-Mo
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND The neuropathological assessment of central nervous system (CNS) tumors often necessitates extensive molecular analyses to arrive at a diagnosis consistent with the WHO CNS classification (2021). Key diagnostic indicators include the epigenetic profile of the tumor, MGMT methylation status, gene amplifications, deletions, duplications, gene fusions, and point mutations. Achieving comprehensive classification typically involves multiple distinct analyses, including NGS gene panels, fluorescent in situ hybridization (FISH), pyrosequencing, Sanger sequencing, and methylation bead arrays. The emergence of the nanopore long-read sequencing enables whole-genome sequencing (WGS) of a tumor sample, consolidating all diagnostically relevant information into a single analysis. MATERIAL AND METHODS DNA from fresh-frozen tissue from 52 CNS tumors was sequenced retrospectively using nanopore Promethion flow cells. Basecalling, methylation calling and mapping to reference genome was performed during sequencing over a period of 72 hours. Once sequencing was completed, copy-number variations (CNVs), structural variants (SVs) and single-nucleotide variants (SNVs) were called using the Epi2me software suite. Methylation on CpG sites overlapping the EPIC 850K array were extracted and used for classification using the MNP-flex platform. All relevant findings were compared to results from the routine diagnostic work-up. RESULTS Nanopore WGS provided on average 35x coverage after 72 hours of sequencing on a single flow cell. The average turnaround time from obtaining a tumor biopsy to producing a report was five days. Classification based on the methylation profile was concordant with molecular pathology in 46 of 52 cases (88%). Three cases were classified as control tissue, characterized by low tumor-cell content, while four cases displayed discordance with the initial classification. All relevant gene-fusion events and amplifications were successfully identified in the nanopore data, with two additional relevant findings reported that had not been previously detected. Seventy-three clinically relevant SNVs were reported in the nanopore data matching previous findings while seven SNVs were unreported, six of which were from samples with low tumor content. CONCLUSION Nanopore whole-genome sequencing showed high concordance with traditional methods for CNS tumor classification. It holds potential for improving diagnostic accuracy and shortening the turnaround time from surgery to complete molecular diagnosis.
P27.13.B INSIGHTS INTO PARANEOPLASTIC NEUROLOGICAL SYNDROMES IN THE ERA OF MODERN ONCOLOGICAL TREATMENTS
Authors: A Taliansky, D N Zohar
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND The paraneoplastic neurological syndromes (PNS) are an uncommon phenomenon with diverse clinical manifestations. The diagnosis of PNS is often challenging because of the broad range of clinical manifestations and the difficulties in the detection of antibodies (AB) that are confirmatory for the diagnosis. Recently published Updated Diagnostic Criteria for PNS improved the efficacy and accuracy of clinical practice but leaves a “gray zone”. The utilization of immunotherapy is rapidly expanding, but the safety and the efficacy of the immunotherapy in PNS patients are unclear as well. Managing PNS is challenging, as there is no consensus on the type of immunomodulatory therapy and the indications for advanced treatment lines. MATERIAL AND METHODS We retrospectively evaluated the data about the case of PNS treated in the neurology department and Neuro-oncology unit at Sheba MC Israel. RESULTS 68 years old male was hospitalized at July 2022 with C7-T3 myelopathy syndrome. The evaluation was negative excluding protein 75 mg/dl and mild pleocytosis, but negative cytology. There was clinical improvement after Methylprednisolon treatment. At March 2023 the patient admitted with acute onset of Lt. hemiparesis and Lt. hemihypoesthesia that developed three weeks after COVID-19 infection. PNS panels of high-risk and low-risk AB in serum and CSF were negative. The Brain MRI showed Rt. thalamic and internal capsule lesion that was hyperintense in FLAIR sequence and homogeneously enhanced by contrast in T1 sequence. The lesion was diagnosed as TUMEFACTIVE demyelinating lesion. Transient clinical and radiological response on steroids treatment was reached. The systemic evaluation revealed the Rt. axillary mass that was diagnosed as BRAF V600E mutated melanoma and case was diagnose as probable PNS. The treatment by BRAF and MEK inhibitors was started and sustained clinical and radiological neurological improvement and oncological complete response were reached. CONCLUSION Many questions arise while making therapeutic decisions that relate to PNS. One of those is the question of if cancer therapy alone is sufficient and if it is possible to skip the advanced immunomodulatory treatment lines, because immunosuppression constitutes an aggravating prognostic factor for oncological outcome. New targeted oncological therapies have a short time to response which makes this therapeutic approach possible and our case illustrates the concept.