tbuckley/cabot-search huggingface dataset:
PATH-46. DETECTION OF CDKN2A/B HOMOZYGOUS DELETION BY DNA METHYLATION AND DNA NEXT GENERATION SEQUENCING: A COMPARISON
Authors: Kristyn Galbraith, Neha Dhasmana, Chanel Schroff, Sam McLennan, Yiying Yang, Guomiao Shen, Matija Snuderl
Journal: Neuro-Oncology (2024)

Abstract CDKN2A/B homozygous deletion status is critical for grading of several central nervous system (CNS) tumors, including IDH mutant astrocytoma, pleomorphic xanthoastrocytoma, and meningioma. CDKN2A/B status can be assed using variety of methods, but the accuracy varies due to technical and analytical variables. Here we sought to compare sensitivity of CDKN2A/B homozygous deletion detection by NGS and DNA methylation array derived copy number analysis. We retrospectively analyzed 100 CNS tumors diagnosed at NYU Langone Health between 2020 and 2023. All tumors were profiled by whole genome DNA methylation profiling using the Illumina EPIC array. Copy numbers were analyzed using the ‘conumee’ R package and visual inspection. Next-generation sequencing (NGS) analysis was performed by NYU Langone Genome PACT, a 510(k) FDA cleared (K202304) matched tumor-normal 607 gene panel. Variant allele frequency of canonical driver mutations was used to molecularly estimate tumor cell content. Discrepant cases were assed using targeted qPCR. Our cohort of 100 CNS tumors included glioblastoma (N=75), IDH mutant astrocytoma (N=14), oligodendroglioma (N=4), pleomorphic xanthoastrocytoma (N=2), meningioma (N=1), infantile hemispheric glioma (N=1), central neurocytoma (N=1), diffuse midline glioma K27-altered (N=1), and anaplastic pilocytic astrocytoma (N=1). By DNA methylation, CDKN2A/B homozygous deletion was detected in 54 cases, hemizygous deletion was detected in 13 cases, and no deletion was detected in 33 cases. By NGS, CDKN2A/B homozygous deletion was detected in 31 cases, hemizygous deletion was detected in 28, and no deletion was detected in 41 cases. DNA methylation detected a homozygous deletion in 23 cases that were not detected by NGS. All cases of homozygous deletion detected by NGS were also detected by DNA methylation. DNA methylation derived copy number assessment is more sensitive for CDKN2A/B homozygous deletion than next generation sequencing.
NCOG-31. NEUROCOGNITIVE OUTCOME FOLLOWING AWAKE CRANIOTOMY FOR INSULAR GLIOMA RESECTION: IMPACT OF SURGICAL APPROACH AND TUMOR CLASSIFICATION
Authors: Kyle Noll, Evan D Bander, Romulo A Andrade de Almeida, Scott Seaman, Matei Banu, Victoria E Clark, Dima Suki, Jeffrey S Wefel, Mariana Bradshaw, Sherise Ferguson, Jeffrey S Weinberg, Sujit S Prabhu, Frederick F Lang
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Insular glioma resection harbors similar risk of neurocognitive function (NCF) decline as other tumor locations. However, differences in outcomes according to transsylvian versus transcortical surgical approach and tumor classification remain unknown. METHODS 53 patients with newly diagnosed insular glioma (47% high-grade; 23% GBM; 75% left hemisphere) underwent awake craniotomy for resection (transsylvian, 64%; transcortical, 36%). Patients completed neuropsychological testing preoperatively and &amp;lt;2 months postoperatively (M interval=23.7 days). Tumor location was described with Berger-Sinai zones collapsed into anterior (I and/or IV), posterior (II and/or III), superior (I and/or II), and inferior (III and/or IV) groups. Tumor extension was characterized with the Pitskhelauri system into insula only, insula with extension (lobar or medial), and predominantly (&amp;gt;50%) extra-insular groups. Result: Decline (z-score change&amp;lt;-1.0) on at least 1 test occurred in 85% of patients with largest effect (partial η2) in memory (.29–.44) and verbal fluency (.39). There was no interaction with approach on any NCF change score, though transcortical was associated with more frequent fluency decline (61% vs. 26%, p=.014). Left hemisphere tumor was associated with poorer outcome on 6/12 tests (all p&amp;lt;.01). Predominantly extra-insular tumors showed greater reductions in fluency (M=-1.21, SD=0.90) than insula only tumors (M=-0.10, SD=0.76; p=0.024). Number of Berger-Sanai quadrants involved was inversely associated with change in executive functioning (r=-0.34, p=.018). Poorer executive function outcome was also found in anterior (M=-0.61, SD=1.41) versus posterior tumors (M=0.86, SD=1.51; p=.014), and recognition memory outcome worse for inferior (M=-2.44, SD=1.81) than superior lesions (M=-0.31, SD=1.47; p=.021). CONCLUSIONS NCF decline is common in the early term following resection of insular glioma. While risk of verbal fluency decline may be greater for transcortical surgeries, outcomes were largely similar across approaches. In addition to hemisphere, tumor extension and insular zone localization may inform domain-specific risk of NCF decline following resection.
NCOG-22. ELDER AGE INSTEAD OF LOW EDUCATION PREDICTS POOR LANGUAGE FUNCTION IN RECURRENT LEFT HEMISPHERIC DIFFUSE GLIOMA PATIENTS
Authors: Pi-Cheng Cheng, Kuo-Chen Wei, Pin-Yuan Chen, Ko-Ting Chen
Journal: Neuro-Oncology (2024)

Abstract PURPOSE Language processing is multifactorial, requiring interactions between cognitive functions and connections of cerebral cortexes and subcortical fibers in dominant hemisphere. Previously, we identified distinct patient factors and tumor characters influencing language performance in treatment-naïve diffuse glioma. In this study, we aimed to investigate predictive factors between treatment-naïve and recurrent patients with diffuse glioma. MATERIALS AND METHODS Grade 2 to 4 diffuse glioma patients who underwent awake surgery with completed preoperative language assessment were included. The Chinese version of the short-form Boston Diagnostic Aphasia Examination (sfBDAE) was used for language testing. Patient age, sex, education level, tumor grade, language pathway involvement, T1 contrast enhanced (C+), and FLAIR (T2) volume were selected as variables. Univariate and multivariate logistic regression analysis were used on language function impairment. The statistical significance was defined as a p-value less than 0.05 by SPSS20.0. RESULTS 50.7% of all awake surgeries (112 of 221) in 171 patients had repeated operations in the retrospective cohort. Comparing to treatment-naïve patients, patients with recurrent tumor had higher academic year (p=0.016), more subventricular zone invasion (p=0.03), and more subcortical language pathway involvement (p=0.035), whereas showed no difference on language performance. In language function analysis, low education was the sole predictive factor for poor language function in treatment-naïve patients. In sharp contrast with low education, elder age factor was exclusively correlated with poor language function in recurrent patients. Furthermore, times of craniotomy was also an independent predictive factor in recurrent group. CONCLUSIONS Neurocognitive reserve is considered a protective factor against brain damage. Both age and education level are critical factors for cognitive reserve. Whether the phenomenon of a distinct and mutually exclusive patient factor affecting language function between treatment-naïve and recurrent diffuse glioma patients could be explained by the model of cognitive reserve necessitate more study.
TMIC-59. ENTANGLED: THE INTERPLAY OF CELLULAR PLASTICITY AND NEURONAL SIGNALING IN BRAIN CANCER PROGRESSION
Authors: Sasi S Senga
Journal: Neuro-Oncology (2024)

Abstract The interplay between two recently proposed hallmarks of cancer, namely dedifferentiation/transdifferentiation and altered neuronal signaling, may dictate the spatiotemporal coupling between neurons and astrocytes. Synaptic activity correlates with brain cancer progression and further influences the directionality of metabolites. Through phenotypic plasticity, brain parenchymal cells may dedifferentiate in a manner that determines the directionality of metabolites, thereby altering plasticity and exerting selective pressure on the immune microenvironment within the brain. Therapeutic advancements in brain cancers, including maximizing surgical resection margins and Chimeric Antigen Receptor (CAR) T-cell therapy, have their own limitations. Thus, understanding the interplay between dedifferentiation/transdifferentiation and its role in dictating altered neuronal signaling to modulate the brain tumor microenvironment may provide novel targets for improving prognosis and limiting therapeutic toxicity.
PATH-44. CLINICAL AND RADIOGRAPHIC PREDICTORS OF PROGNOSIS IN ASTROCYTOMA, IDH-MUTANT, WHO GRADE 4
Authors: Aleksandra B Lasica, Zhou Lan, Julie J Miller, Alyssa Russ, Catharina Westergaard, Eudocia Q Lee, Ugonma Chukwueke, Luis Nicolas Gonzalez Castro, Jose Ricardo McFaline Figueroa, Elisa Aquilanti, Lakshmi Nayak, Rameen Beroukhim, Tracy Batchelor, Vihang Nakhate, Tyler Lanman, Juan Pablo Ospina Botero, Natalie Stec, David A Reardon, Patrick Y Wen, Gilbert Youssef
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Astrocytoma, IDH-mutant, WHO grade 4, are classified as a separate entity in the 2021 WHO classification of central nervous system tumors and have been poorly characterized in the literature. In this study, we report on the clinical outcomes in a large cohort of newly diagnosed grade 4 IDH-mutant astrocytoma. METHODS We retrospectively identified adult patients with astrocytoma, IDH-mutant, WHO grade 4, treated for their initial diagnosis at Dana-Farber Cancer Institute and Massachusetts General Hospital between 2010 and 2021. Clinical, molecular, and radiological characteristics were recorded, and their association with overall survival (OS) and progression-free survival (PFS) was measured by a log-rank test. If a proportional hazard assumption was violated, we compared the median OS and PFS between groups by the bootstrap method instead. RESULTS We identified 140 patients, with a median age at diagnosis of 37.9 years (range: 19-87) and male predominance (60.7%). MGMT promoter was methylated in 51.4%, and CDKN2A/B homozygous deletion was present in 40 cases (28.6%). Most tumors showed enhancement on the preoperative scan (n=108; 77.1%). Seventy percent of patients had subtotal resection, 25.7% had a gross total resection, and 4.3% had a biopsy. Most patients received standard chemoradiation followed by adjuvant temozolomide (n=103; 73.6%). The median OS was 6.9 years (95% CI: 4.5-9.2), and the median PFS was 3.3 years (95% CI: 2.1-4.4). OS and PFS were not associated with MGMT promoter methylation or the presence of enhancement on the preoperative scan. CDKN2A/B homozygous deletion was associated with worse OS (5.5 vs. 7.8 years, log-rank test-based p-value=0.036) but had no association with PFS (3.4 vs 2.6 years, bootstrap method-based p-value=0.488). CONCLUSIONS In our cohort of astrocytoma, IDH-mutant, WHO Grade 4, CDKN2A/B homozygous deletion had a negative prognostic impact, whereas MGMT promoter methylation status and enhancement on the preoperative scan did not affect survival outcomes.
NCOG-23. CLINICIAN AND PATIENT REPORTED OUTCOMES IN YOUNG ADULTS WITH GLIOBLASTOMA: RESULTS FROM A MULTIMODAL PROSPECTIVE STUDY
Authors: Javeria Raheem, Katrina Roberto, Aimee Chan, Aimee Theriault, Mikayla Machado, Inga Granovskaya, Andrea Wong, Eirena Calabrese, James Perry, Mary Jane Lim-Fat
Journal: Neuro-Oncology (2024)

Abstract The median age for glioblastoma (GBM) is 65 years old, however, younger patients have a similarly dismal prognosis. The adolescent and young adult (AYA) population (15-39 years) is a unique and understudied population. Our study aimed to identify survivorship needs in adult patients in AYA population (&amp;lt;40 yrs) with GBM through analysis of patient and clinician-reported outcomes (PROs and CROs). The Molecular, Imaging and Neurological assessment Database (MIND-CNS) captures Neurological Assessment in Neuro-Oncology (NANO) scores, MDASI-BT and FACIT-SP12 responses at first clinic visit and follow-ups for patients with GBM. We tested associations of the two age groups (18-39 vs. 40 years and older) with each domain of NANO, MDASI-BT and FACIT-SP12 at baseline and at follow-up visits using multivariate logistic regression models, adjusting for MGMT promoter methylation and extent of resection. There were 104 patients with GBM enrolled, including 11 young adults, (median =30 years) and 93 older adults (median =65 years). Young and older adults scored similarly in the domains of NANO, MDASI-BT, and FACIT-SP12 at baseline. MDASI domains at follow-up showed statistically significant lower scores on weakness, fatigue, distress, irritability, drowsiness, and disturbed sleep in younger vs. older adults (adjusted p&amp;lt;0.05). Younger adults had less difficulty with memory and concentration, and their symptoms interfered less with work, walking, and overall enjoyment of life. They also reported feeling more peaceful, finding greater comfort and strength in their faith and beliefs. A comparison of NANO score at baseline and progression will be performed at data maturation. While PROs were similar at baseline, young adults reported lower severity in their physical symptoms and higher spiritual well-being compared to older adults at follow-up visits, highlighting different survivorship experiences. Data maturation will allow for deeper analysis to better inform supportive strategies.
TMIC-15. GUT MICROBIOTA CONTROLS NEUROFIBROMATOSIS-1 (NF1) OPTIC GLIOMA GROWTH THROUGH IMMUNE CIRCUIT MODULATION
Authors: Jit Chatterjee, Xuanhe Qi, Megan Ouyang, Rui Mu, Xuanwei Li, Stephanie L Bozeman, Talia Eligator, Lawrence A Schriefer, Rachel Rodgers, Megan T Baldridge, David H Gutmann
Journal: Neuro-Oncology (2024)

Abstract Changes in the gut microbiome can have profound effects on the nervous system through modulation of T cell and microglia function. Since our prior studies demonstrated that T cells and microglia positively regulate low-grade glioma growth through the establishment of T cell-microglia immune circuit, we sought to explore the impact of changes in the gut microbiota on tumor biology. For these studies, genetically engineered Neurofibromatosis type 1 (NF1) optic glioma (Nf1-OPG) mice were raised in a germ-free environment or treated with antibiotics to deplete gut bacteria. First, we demonstrated that Nf1-OPG mice raised in a germ-free (gnotobiotic) environment or treated with specific antibiotics lacked optic gliomas and had improved OPG-induced retinal pathology (increased retinal nerve fiber layer thickness). Second, germ-free and antibiotic-treated Nf1-OPG mice gavaged with fecal microbiota from Nf1-OPG mice raised in a standard barrier facility restored optic glioma growth. Third, we showed that both germ-free and antibiotic-treated Nf1-OPG mice exhibited reduced intra-tumoral CD8+ T cell content resulting from decreased microglia chemokine production. Fourth, we discovered a gut-brain paracrine axis whose interruption reduced optic glioma growth and attenuated retinal nerve fiber layer thinning. Collectively, these findings establish a mechanistic relationship between the gut microbiota and brain tumor growth relevant to potential therapeutic interventions for pediatric low-grade gliomas.
NCOG-16. A PROSPECTIVE OBSERVATIONAL STUDY OF CLINICAL PROFILE, COURSE AND OUTCOME OF PRIMARY BRAIN TUMOR AT A TERTIARY CARE CENTER
Authors: Monik Patel, Vivek patel, Ankita Parikh
Journal: Neuro-Oncology (2024)

Abstract Primary brain tumors include tumor arising from neuro-epithelial cells, cranial nerves, meninges, germ cells, pituitary gland, and blood-forming organs. These tumors can present with either generalized or focal signs and symptoms.General symptoms are due to raised intracranial pressure (headache, vomiting). Focal symptoms are due to the compression of a structure or destruction (focal neurological deficits). The aim of this study is to analyze the clinical profiles of pediatric and adult brain tumor patients. Data of primary brain tumor patients who were diagnosed from 1st December 2019 to December 2021 were prospectively collected and analysed. In our study of 61 patients, the majority of patients had GBM (32.8%) and astrocytoma (31.1%) and medulloblastoma (11.5%). Less common histologies ependymomas (9.8%), meningioma (6.6%), brain stem glioma (3.3%), oligodendrogliomas (3.3%) and germinoma (1.6%). Out of 19 astrocytomas, 10 were of low grade (1 or 2), while 9 were of high grade (3 or 4).The majority (61.7%) of gliomas were of high grade, while the remaining 38.3% were of low grade. The majority (57.5%) of patients received multimodal treatment,26.2%received dual modality (surgery and RT), while the remaining 16.3% received single modality, either surgery or RT. Most (86.9%) of the patients treated with radiotherapy as a part of a single or multimodal treatment. A significant percentage of patients (77.1%) received concurrent and adjuvant temozolamide-based chemotherapy. Primary brain tumors have a different profile in pediatric patients. Among pediatric patients, the median age was 11.8 years, with male predominance. This study concludes that primary brain tumors have a different profile among adults and pediatric patients, with the majority of patients achieving a response to the first line therapy with an overall good tolerance for therapy.
TMIC-37. GEMISTOCYTIC TUMOR CELLS AND IMMUNE REACTIVE MICROGLIA PROGRAMMED FOR GLIAL SCARRING CHARACTERIZE T CELL CONTAINMENT IN IDH-MUTANT ASTROCYTOMA
Authors: Levi van Hijfte, Marjolein Geurts, Iris de Heer, Santoesha Ghisai, Hayri Balcioglu, Youri Hoogstrate, Wies Vallentgoed, Rania Head, Bart Westerman, Pieter Wesseling, Johanna Joyce, Reno Debets, Pim French
Journal: Neuro-Oncology (2024)

Abstract Isocitrate dehydrogenase 1/2 mutant (IDHmt) astrocytoma is considered a T cell-deprived tumor, yet little is known regarding the phenotype that relates to T cell exclusion. To aid better understanding of this mechanism, we systematically characterized the IDHmt astrocytoma immune microenvironment in a large cohort by multiplex immunofluorescence (IF) (n=75), bulk RNA sequencing (n=158), single nucleus RNA sequencing (n=7) and spatial RNA and protein profiling (n=12). We integrated and analyzed all datasets to acquire a robust characterization of the microenvironment organization and validated our results using IF stainings. We demonstrated that in IDHmt astrocytomas, T cells were contained in the perivascular space (i.e., T cell cuffs). In the tumor stroma surrounding T cell cuffs, we found a dense accumulation of gemistocytic tumor cells (GTCs), a histologically distinct tumor cell subtype. GTC-high tumors demonstrated enhanced expression of immune cell migration and activation pathways that were reliably expressed by TAMs and T cells. Notably, we found that GTCs formed a unique transcriptional cell sub-cluster that expressed markers including CD44, TNC and CRYAB, which are specific for glial scarring, a central nervous system specific mechanism for immune exclusion. Surrounding T cell cuffs, GTCs co-localized with immune-reactive microglia that expressed the chemoattractants CCL3 and CCL4. Together, co-localizing GTCs and reactive microglia expressed receptor-ligand pairs that take part in reactive astrogliosis and glial scarring, including Osteopontin – CD44 and IL-1β – IL1R1. Validation whole-slide multiplex IF stainings for this spatial relationship showed specific local accumulation of CD44 positive GTCs and TAMs around T cell cuffs in GTC-high tumors, which was absent in GTC-low tumors. Together, we show that IDHmt astrocytomas organize a network of tumor cells and leukocytes that mimics glial scarring and can aid T cell exclusion. Elucidating such specific immune exclusion mechanisms is vital for more appropriate target selection in novel immune therapies.
CNSC-26. INVESTIGATING THE ROLE OF QUAKING IN REGULATING MHC II ANTIGEN PRESENTATION IN TUMOR-ASSOCIATED MACROPHAGES OF GBM
Authors: Spring Hwang, Ailiang Zeng
Journal: Neuro-Oncology (2024)

Abstract Glioblastoma (GBM) is the most common and malignant primary brain tumor with a median survival rate of 14 months. Despite the success of immunotherapy in treating various cancer types, its efficacy remains poor in GBM. Such limitation can be attributed to the profound immunosuppressive tumor microenvironment of GBM enriched with the tumor-associated macrophages (TAMs). Quaking (Qki) is an RNA-binding protein that is mutated or deleted in more than 35% of GBM patients. Decreased levels of Qki in TAMs associates with worsened survival rates and responsiveness to immunotherapy in GBM mouse and patients. Moreover, Qki is a tumor suppressor gene in GBM and a major regulator in phagocytosis, a fundamental biological process in delivering antigens to major histocompatibility complex class II (MHC II). MHC II-restricted antigen presentation in macrophages of GBM is important in maintaining the fitness of cytotoxic and helper T cells required in anti-tumor response. However, the mechanism through which Qki regulates MHCII expression and presentation has yet to be elucidated. I hypothesize that Qki promotes MHC II expression in TAMs, thereby constraining the development and progression of GBM. In vitro assays like immunofluorescent staining, qRT-PCR, cell co-culture system, and flow cytometry will be performed involving QPP (Qk-/-Trp53-/-; Pten-/-) mouse brains, QPP cells, and mouse macrophage cell lines. A positive correlation between transcriptomic and protein expression levels of Qki, MHC II, and CIITA (a master regulator of MHC II) was confirmed in both mouse QPP and human GBM samples. Moreover, bone-marrow-derived macrophages activated by QPP cell supernatant shows upregulated levels of Qki and thus MHC II genes. A preliminary conclusion is that Qki plays a permissive role in MHCII expression in TAMs of GBM. Further downstream impact of Qki in TAMs will be evaluated in T cell activity and in transcription of MHC II in TAMs.