tbuckley/cabot-search huggingface dataset:
NCOG-24. CHARACTERIZING NEUROTOXICITY ASSOCIATED WITH SYSTEMIC CHEMOTHERAPY IN PATIENTS WITH BREAST CANCER USING DOMAIN-SPECIFIC INTRA-INDIVIDUAL NEUROCOGNITIVE VARIABILITY
Authors: David Sheppard, Kyle Noll, Catherine Sullaway, Jeffrey Wefel
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Systemic chemotherapy is associated with neurotoxicity and neurocognitive functioning (NCF) changes. Intra-individual neurocognitive variability (IIV) is an index of NCF spread/dispersion across neuropsychological tests and can be elevated in patients with breast cancer (BC) after systemic chemotherapy. This study investigated longitudinal IIV changes within NCF domains after chemotherapy to determine whether: (1) IIV for NCF domains are more sensitive to changes than traditional mean-based metrics, and (2) whether changes in domain-specific IIV are associated with changes in mood disturbance or quality of life (QOL). METHODS Prior to and during/shortly after chemotherapy, 37 women with BC were administered a standardized NCF battery including tests within domains of attention/speed of information processing (A/SoP), learning/memory (L/M), and executive functions (EF). Within each domain, the coefficient of variation (CoV) was computed using the standard deviation of normatively-adjusted T-scores while adjusting for intra-individual mean. Patients were assessed for QOL using Functional Assessment of Cancer Therapy-Breast and mood using the STAI and BDI. RESULTS Paired samples t-tests revealed that mean NCF performances declined for L/M (t[36])=-4.44,p&amp;lt;.001,Hedge’s g=.70) and improved for A/SoP (t[36]=3.21,p=.003,g=.29), while CoV increased/worsened for L/M (t[36]=3.82,p&amp;lt;.001,g=.76) but did not change for A/SoP (t[36]=-0.05,p=.959,g=.01). There was no change in EF mean or CoV (ps &amp;gt;.10). No domain mean or IIV change was associated with mood changes (ps&amp;gt;.10). Mean NCF changes were not associated with QOL (ps &amp;gt;.10). Increased/worsened L/M CoV was associated with improved FACT-Breast scale QOL (ρ=.40,p=.020). CONCLUSIONS Both mean- and IIV-based NCF worsened for learning/memory. Discrepancies between mean and IIV change for attention/speed of information processing may be due to differential susceptibility to practice effects. Unexpected associations between learning/memory IIV changes and QOL require further investigation. Future studies are needed to examine NCF dispersion changes across treatment status and in other cancer populations.
EPCO-46. SPATIAL TRANSCRIPTOMICS ANALYSIS OF GLIOBLASTOMA REVEALS THREE DISTINCT REGIONAL PROGRAMS OF T-CELL INFILTRATION
Authors: William L Wang, Yiyun Chen, Chiu Ho Mo, Zinaida Good, Elena Sotillo, Crystal L Mackall
Journal: Neuro-Oncology (2024)

Abstract Glioblastoma (GBM) resists T-cell killing by developing an immunosuppressive tumor microenvironment. Transcriptomic technologies, such as single-cell RNA sequencing (scRNA-seq), have characterized immune cell phenotypes and putative cell-cell interactions in GBM. However, the tumor microenvironment surrounding T-cells is still not well characterized, motivating the need for spatial analyses. Two publicly-available GBM spatial transcriptomic datasets were analyzed, with one discovery cohort (N=18) and one validation cohort (N=12). Using cell deconvolution with a scRNA-seq reference dataset, areas of high T-cell infiltration were identified and clustered into regional programs based on transcriptomic signatures. To highlight which ligand-receptor interactions are most prominent in these regional programs, a novel spatial enrichment algorithm was applied. The impact of spatially enriched ligand-receptor interactions on overall survival was evaluated using bulk RNA-sequencing data from The Cancer Genome Atlas (TCGA). Three distinct T-cell regional programs (transitional, immunosuppressive, and infiltrative) were found across both the discovery and validation cohort. The infiltrative T-cell regional program resided on the periphery of the tumor with a neural progenitor phenotype (NRGN, VSNL1, SLC17A7). In contrast, the immunosuppressive T-cell region had a higher proportion of malignant cells and a greater mesenchymal tumor signature (ANXA1, CD44, complement pathway). Furthermore, ligand-receptor enrichment analysis showed that the immunosuppressive region had higher tumor and tumor-associated macrophage (TAM) signaling towards CD4 T-cells along the collagen, midkine, and osteopontin pathways. TCGA survival analysis showed that higher collagen and midkine signals were associated with worse overall and disease free survival. Our results identified three distinct regional programs in GBM and highlight a set of signaling pathways associated with T-cell suppression. Our findings suggest that the disruption of these pathways could reduce immunosuppressive signals from tumor and TAMs to T-cells. Subsequent validation with spatial proteomics data in glioblastoma is ongoing.
PATH-68. THE CLINICAL AND PROTEOMIC CLASSIFICATION FOR THE PRECISION TREATMENT STRATEGY OF CHORDOMA
Authors: Tong Meng
Journal: Neuro-Oncology (2024)

Abstract Chordoma is a rare and heterogeneous mesenchymal malignancy, with distinct clinical and biological behaviors. Till now, its comprehensive clinical-molecular characteristics and accurate molecular classification remain obscure, leading to numerous diagnostic and therapeutic challenges. In this research, we enroll a large cohort of chordoma (102 patients) and describe their clinical, imageological and histopathological features. Through tandem mass tag-based proteomic analysis and nonnegative matrix factorization clustering, we classify chordoma into the following three molecular subtypes: bone microenvironment dominant, mesenchymal derived, and mesenchymal to epithelial transition mediated pattern. The three subtypes exhibit discrete clinical prognosis and distinct biological attributes of osteoclastogenesis and immunogenicity, oxidative phosphorylation, and receptor tyrosine kinase activation, suggesting targeted therapeutic strategies of Denosumab, S-Gboxin and Anlotinib, respectively. Notably, these approaches demonstrate positive treatment outcomes for each subtype in vivo and in vitro, as well as in patient-derived xenograft models. Altogether, this work sheds light on the clinical-proteomic characteristics of chordoma that deepens our understanding of this rare disease and provides candidate precision treatment strategy for chordoma according to molecular classification, underscoring their potential for clinical application.
CTNI-12. TIRABRUTINIB FOR RECURRENT/REFRACTORY PRIMARY CENTRAL NERVOUS SYSTEM LYMPHOMA –A SINGLE-INSTITUTION RETROSPECTIVE ANALYSIS–
Authors: Fumiyuki Yamasaki, Ushio Yonezawa, Akira Taguchi, Shumpei Onishi, Iori Ozono, Novita Ikbar Khairunnisa, Nobutaka Horie
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Tirabrutinib is a second-generation, highly selective oral Bruton’s tyrosine kinase inhibitor and approved for the treatment of recurrent/refractory primary central nervous system lymphoma (PCNSL) in Japan. We reviewed our single institution experiments of tirabrutinib. MATERIALS AND METHODS Our institutional review board approved this retrospective study. Twenty-eight patients with recurrent or refractory PCNSL treated with tirabrutinib at our institution between 2020 and 2024 were included. Information regarding the patient’s age, gender, imaging findings, pathological results, including immunostaining findings, and treatment information, including chemotherapy and radiation therapy, was obtained from medical records. RESULTS Tirabrutinib was administered to 14 patients with recurrent cases (20-85 years old, median 69.5 years old, 9 males and 5 females), 14 with refractory cases (59-87 years old, median 74 years old, 9 males and 5 females). Three male patients received rechallenge with tirabrutinib against re-relapsed. We assessed the effectiveness of tirabrutinib and observed complete response (CR) in 12 cases, partial response (PR) in 1 case, and progressive disease (PD) in 1 case among refractory patients. In recurrent cases, we observed CR in 8 cases, PR in 1 case, stable disease (SD) in 3 cases, and PD in 2 cases. In rechallenge for re-relapsed cases, we observed CR in 2 cases and PD in 1 case. The progression-free survival following beginning of tirabrutinib was 12.95 months for refractory cases and 8.2 months for recurrent cases. The overall survival was 25 months for refractory cases and 12.8 months for recurrent cases. One patient each experienced CTCAE grade 3 interstitial pneumonia or liver failure, both of which improved after discontinuing the medication. Four patients exhibited grade 1-2 skin rashes. CONCLUSIONS Tirabrutinib demonstrates efficacy and high tolerability for the treatment of recurrent/refractory PCNSL in real-world settings.
TMOD-35. EGFRVIII OVEREXPRESSION AND LOSS OF MOUSE SPECIFIC CDKN2A IN GLIAL CELLS LEADS TO SPONTANEOUS GLIOMAGENESIS IN A NOVEL MOUSE MODEL
Authors: Olivia Singh, Mathew Voisin, Mira Li, Hafsah Ali, Qingxia Wei, Andrew Gao, Sameer Agnihotri, Kelly Burrell, Mark Wilson, Shirin Kamiri, Severa Bunda, Kenneth Aldape, Gelareh Zadeh
Journal: Neuro-Oncology (2024)

Abstract A new mouse model for the classical subtype of human glioblastoma (GBM) has been bred using Cre-mediated EGFRvIII overexpression and homozygous p19-ARF deletion, the mouse homolog of human p14ARF/CDKN2A, in GFAP expressing cells. Transgenic mice develop intraparenchymal and/or leptomeningeal brain lesions with some spinal cord invasion as early as 1 month old and 95% of mice die by 6 months due to hydrocephalus and/or paralysis. Mice with high grade tumors have worse survival and similar features to human classical GBM such as necrosis, high levels of mitosis and infiltration of tumor cells into normal brain. Immunohistochemical analysis confirms EGFRvIII overexpression and p19-ARF loss in Cre-expressing cells, along with patchy positive GFAP and high proliferation by Ki67. Bulk RNA sequencing reveals GEC3 tumors cluster closely with human classical GBM and have significant upregulation of downstream markers in the JAK/STAT and P13K/AKT pathways. Adherent and neurosphere primary culture of dissociated tumors indicate that tumor cells maintain EGFRvIII expression in culture and generate xenograft tumors by 3 weeks after intracranial injections into NODSCID mice. Xenograft tumors are reminiscent of the primary tumor, with similar histopathological features and immunohistochemical staining. Our spontaneous glioma model is a powerful tool for future studies focused on the role of the immune microenvironment on glioma recurrence and resistance.
PATH-07. CLINICAL AND RADIOGRAPHIC FEATURES OF DIFFUSE GLIOMA MOLECULAR SUBTYPES IN ACCORDANCE WITH THE 2021 CNS5 WHO CLASSIFICATION
Authors: Jasmin Jo, Mark Mondia, Josephine Arewa, Andrew How, James Patrie, Nicholas Dueck, Reed Gilbow, Andrew Goschka, David Joyner, Sohil H Patel, M Beatriz Lopes, David Schiff
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND The incorporation of molecular parameters into WHO CNS5 has led to reclassification of many gliomas. We undertook to describe presenting clinical and radiographic features of diffuse adult gliomas according to CNS5 category. METHODS We reviewed pathology reports, clinical and MRI data at presentation of 972 adult patients with glioma diagnosed between 1/2010-2/2022. Continuous variables were presented as median; categorical variables as numbers and percentages, and comparison were performed using chi-square test. RESULTS 736 patients had sufficient data for CNS5 re-classification and were included in the analysis: Grade 2 IDH-mutant (IDHmut) astrocytoma (A2) n=69, grade 3 IDHmut astrocytoma (A3) n=37, grade 4 IDHmut astrocytoma (A4), n=32, grade 2 oligodendroglioma (O2) n=60, grade 3 oligodendroglioma (O3) n=23, and grade 4 IDH-wildtype glioblastoma (GBM) n=515. Age at presentation significantly differed between grade 2&amp;3 gliomas and grade 4 (mean age:39 versus 61.7; p&amp;lt;0.001); A4 were also younger than GBM (39.8 versus 63.1). A majority in all categories except grade 2 gliomas were male. Seizure was more common in IDHmut gliomas than GBM (58.4% versus 31.8%;p&amp;lt;0.001), while cognitive impairment was more common in GBM than in IDHmut gliomas (64.4% versus 34.4%;p&amp;lt;0.001) and in A4 (64% versus 40.6%;p=0.013). Focal deficits at presentation were more frequent in GBM than in IDHmut gliomas (74.2% versus 30.5%;p&amp;lt;0.001), but not significantly different compared to A4 (74.2% versus 58.1%;p=0.06). Contrast enhancement on MRI was more frequent in GBM compared to IDHmut gliomas (93% versus 48%;p&amp;lt;0.001), but similar frequency with A4 (93% versus 96%;p=1.00). The minimum ADC was significantly higher in IDHmut glioma including A4 than GBM(p&amp;lt;0.001). Calcification was more common in oligodendroglioma than astrocytoma and GBM (p&amp;lt;0.001), and more frequent in A4 than GBM(p=0.016). CONCLUSION Significant differences in the clinical presentation and radiologic features exist among CNS5 glioma subtypes, informing potential diagnosis, management and prognosis at initial presentation.
PATH-14. UTILITY OF DNA METHYLATION ANALYSIS IN HISTOLOGICALLY-CONFIRMED PA PATIENTS WITH POOR PROGNOSIS
Authors: yasuki suruga, Kaishi Satomi, Yoshihiro Otani, Kentaro Fujii, Joji Ishida, Atsuhito Uneda, Nobushige Tsuboi, Keigo Makino, Shuichiro Hirano, Naoya Kemmotsu, Ryoji Imoto, Ryo Mizuta, Yusuke Tomita, Takao Yasuhara, Kana Washio, Hiroyuki Yanai, Yuko Matsushita, Yuko Hibiya, Akihiko Yoshida, Koichi Ichimura, Shota Tanaka
Journal: Neuro-Oncology (2024)

Abstract INTRODUCTION Pilocytic astrocytoma (PA) is a circumscribed low-grade astrocytic glioma, generally considered to be associated with a good prognosis. However, some PA patients experience unfavorable outcomes; advanced age was known as an independent poor prognostic factor. This study retrospectively reviewed PA patients and conducted molecular analyses for elderly patients. METHODS We analyzed data from 29 histologically confirmed PA patients treated at a single center from 2002 to 2021 and conducted integrated molecular analyses including DNA methylation profiling for elderly PA patients. RESULTS The median age at diagnosis was 14 years (range 3-82 years), with 4 patients (14%) being elderly (patients≥60years old). Elderly patients had significantly worse progression-free survival and overall survival. DNA methylation analysis was performed on 2 of the 4 elderly patients. Despite histological diagnoses of PA, methylation profiling classified one case as high-grade astrocytoma with piloid features (methylation class scores below 0.3 in both v11b4 and v12.5) and the other as glioblastoma, IDH-wildtype (score over 0.5 in both v11b4 and v12.5), using classifiers from the German Cancer Research Center and t-SNE analysis. CONCLUSION Elderly patients with PA morphology showed unfavorable outcomes in this cohort. In those patients, DNA methylation profiling revealed the possibility of high-grade astrocytic tumors, including newly defined entities.
NCOG-36. CLINICAL AND DEMOGRAPHIC CHARACTERISTICS PREDICT POSTOPERATIVE BEHAVIORAL DYSFUNCTION FOLLOWING HIGH-GRADE (WHO 2-4) GLIOMA RESECTION
Authors: Vardhaan Ambati, Jasleen Kaur, Shawn Hervey-Jumper
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Gliomas have the highest incidence (85%) of cancer-related cognitive and behavioral impairments. Few studies have explored preoperative clinical and demographic drivers/predictors of postoperative behavioral impairment. METHODS We analyzed prospectively collected data from patients 1) who underwent glioma (WHO 2-4) resection and 2) who had postoperative Flanker testing, an assessment of inhibitory control and selective attention (NIH Toolbox Cognition Battery). Patients whose age-adjusted Flanker score (last follow-up) was less than the cohort mean were classified as having “poor” outcomes. Univariate analysis, multivariate logistic, and LASSO regressions were performed to identify drivers of poor outcomes. RESULTS In total, 43 patients (mean age at diagnosis 45.9 [range 18-77] years, 35% female) met inclusion criteria. The average age-adjusted Flanker score was 83.3±13.6; twenty (46.5%) patients had below-average scores. On univariate analysis, there were no significant differences in demographic factors (age, sex, education, employment) and tumor characteristics (grade, location). Multivariate logistic regression identified having high school versus higher degree (OR:1.6x10^4, p=0.017), WHO Grade 4 versus Grade 2 (OR:2.36, p=0.026), and parietal lesion (OR:1.6x10^3, p=0.034) as risk factors, while increased age (OR per 1-year increase:0.71, p=0.009) and dominant language hemisphere lesion (OR 0.002, p=0.048) were protective against poor behavioral outcome. LASSO regression (efficiently narrows down predictors) identified higher WHO grade (4 vs. 2), lower education (high school vs. higher), and insular and parietal lesions as predictive of poor outcomes. Increased age at diagnosis, frontal lobe lesions, and lesions on the dominant language hemisphere were protective. CONCLUSION Lower education status, higher WHO grade, and insular and parietal lesions are risk factors for poor behavioral outcomes postoperatively following glioma resection. In contrast, increased age, frontal lobe lesions, and dominant language hemisphere lesions were positive prognostic factors. Neuro-oncologists may use these findings to preoperatively counsel patients and tailor care plans with necessary postoperative support.
CTNI-24. WF-1801: SINGLE ARM PILOT STUDY OF RAMIPRIL FOR PREVENTION OF RADIATION-INDUCED COGNITIVE DECLINE IN GLIOBLASTOMA PATIENTS RECEIVING CHEMORADIOTHERAPY
Authors: Christina Cramer, Emily Dressler, Sydney Smith, Brandi Page, Jeffrey Wefel, Mark Gilbert, Stephen Rapp, Edward Ip, Stephanie Pugh, Ashley Summrall, Kathryn Weaver, Glenn Lesser, Michael Chan
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Patients with glioblastoma (GBM) experience cognitive decline after chemoradiation. Radiation therapy (RT) to the brain creates chronic inflammation believed to contribute to cognitive decline. Ramipril counteracts neuroinflammatory changes in pre-clinical models when given during RT. METHODS This prospective single arm study (WF-1801) coordinated by the Wake Forest NCI Community Oncology Research Program (NCORP) Research Base assessed feasibility, tolerability, and potential efficacy of using ramipril in patients with GBM. Eligibility and treatment paradigms mirrored NRG/RTOG 0825 allowing for outcomes from the placebo arm to be used for comparison. Participants took ramipril during 6 weeks of chemoradiation with temozolomide and for 3 months after RT. Patients completed cognitive testing (HVLT-R, TMT, and COWA) and patient-reported outcomes at baseline, RT completion, and 1 and 4 months after RT. Co-primary endpoints were retention rate (compliance with 75% doses and completion of cognitive testing) and change in cognitive composite score 1 month after RT. RESULTS 75 participants were accrued between 3/25/2019 and 11/14/23: 65% were male, 89% White, median age 63 years. The NRG/RTOG 0825 placebo cohort (n=247) was younger (median 57, p&amp;lt;0.0001) with more White participants (95%, p=0.04). The overall retention rate in WF-1801 was 48% (one-sided 95% CI: 38%-100%); 61% completed &amp;gt;=75% of doses; 57% completed cognitive testing at all time points. The median (range) change in cognitive composite score 1 month after RT was 0.01 (-82.6, 13.0) reflecting an improvement from baseline. However, this was not significantly different from the NRG/RTOG 0825 placebo group median of 0.10 (-48.2, 8.6); p=0.49. CONCLUSION The overall retention rate fell short of our pre-specified endpoint of &amp;gt; 65%; however, medication compliance was high and well-tolerated in retained patients. Future investigations could identify patient subsets who may benefit more from concurrent ramipril. WF-1801 (NCT03475186) funded by UG1CA189824. NRG/RTOG-0825 (NCT00884741) funded by U10CA180868 and U10CA021661.
SURG-23. ESTABLISHMENT OF AN APPROPRIATE GLIOMA SURGERY SYSTEM CONSIDERING MOLECULAR AND FUNCTIONAL BOUNDARIES
Authors: Ryuta Saito, Kazuya Motomura, Fumiharu Ohka, Shoichi Deguchi, Yoshiki Shiba, Junya Yamaguchi, Tomohide Nishikawa, Yuji Kibe, Hiroki Shimizu, Sachi Maeda
Journal: Neuro-Oncology (2024)

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