tbuckley/cabot-search huggingface dataset:
CSIG-28. DISSECTING THE FUNCTIONAL IMPAIRMENT OF WILD-TYPE P53 IN HUMAN GLIOBLASTOMA
Authors: Leopoldo A García-Montaño, Yamhilette Licón Muñoz, Frank Martinez, Kandee Gallegos, Christian A Bowers, Huining Kang, Sara G M Piccirillo
Journal: Neuro-Oncology (2024)

Abstract Glioblastoma (GBM) is the most common malignant brain tumor in adults and is characterized by heterogeneous nature, invasive potential, and poor treatment response. Work from The Cancer Genome Atlas (TCGA) identified the tumor suppressor gene TP53 as a GBM driver. In contrast to several cancers, only ~35% of GBM cases carry mutations in TP53. Work from our lab showed that TP53 mutations emerge as ‘late’ events during GBM growth. Therefore, we hypothesized that wild-type (wt) p53 function is impaired in GBM. We used the TCGA data of 591 GBM patients to compare the clinical and molecular characteristics of wt and mutant TP53 patients. Gene expression data were analyzed to compare the correlation of TP53 with the expression of key p53 regulators and identify differentially expressed regulators between our groups. Furthermore, we evaluated the expression of p53 and selected regulators in patient-derived cells (PDCs) and control lines with known TP53 status. Our results show that wt TP53 patients live less than mutant patients and both groups respond similarly to treatment. No differences in age, sex, race, TP53 levels, and MGMT methylation status were observed between the groups. Gene expression analyses revealed that MAPK8, a p53 activator, negatively correlates with TP53 in the wt group. Moreover, ~21% of p53 regulators are differentially expressed between wt and mutant patients. Among these, we selected SIRT3, a p53 repressor, for experimental validation. We verified the p53 genetic status of PDCs through western blot and confirmed Sirt3 expression in wt and mutant TP53 PDCs. By CRISPR-Cas9-based genomic editing, we are currently evaluating the impact of SIRT3 knockout in GBM-PDC and patient-derived xenografts. We expect that SIRT3 knockout will restore p53 function in the wt group. In conclusion, our results suggest that p53 function is impaired in wt patients and provide insights into mechanisms affecting its activity.
NCOG-47. DEFINING PERIOPERATIVE RISK FACTORS IN STEREOTACTIC BRAIN BIOPSIES AMONG DIFFERENT HISTOLOGIC DIAGNOSES
Authors: Arushi Tripathy, Edward Harake, Sara Saleh, Wajd Al-Holou
Journal: Neuro-Oncology (2024)

Abstract INTRODUCTION Stereotactic brain biopsies (SBB) are critical for diagnosing neoplastic central nervous system pathologies including gliomas, metastatic carcinomas (cA), and lymphomas. While SBB-related complications have been cited in the literature, we sought to characterize the perioperative risk factors/outcomes. METHODS We conducted a retrospective review of 615 patients who underwent a SBB at the same tertiary academic hospital between 2000-2020. Logistic regression was conducted across all recorded variables to assess the relative impact on intra/postoperative complications, and Kaplan-Meier curves were calculated to assess probability of 1-year hospice enrollment. RESULTS Of the 615 patients, the average (+/- SD) age was 56+/- 19 years with 286 (46.5%) female patients and the following histological groups: glioma (n=422), lymphoma (n=74), and metastatic cA (n=22). Complications included intraoperative bleeding (7.1%), general postoperative hemorrhage (34%), symptomatic postoperative hemorrhage (3.3%), and discharge-to-hospice (6.8%). General hemorrhage and discharge-to-hospice were most common in glioma (p &amp;lt; 0.001) and lymphoma patients (p=0.003), respectively. Independent risk factors for general hemorrhage included medical history (mental status deficits, glioma, GBM; p= 0-0.02) and biopsy characteristics (parietal lobe, subcortical, eloquent, M8 hole, multiple depths; p= 0-0.05). Preoperative systematic workups and history of lymphoma were independently associated with lower hemorrhage risk (p= &amp;lt;0.001). Risk factors for hospice discharge included preoperative deficits (gait, speech, and mental status; p=0.001-0.05) and postoperative complications (prolonged ICU, UTI, pneumonia; p&amp;lt;0.001). Of the 15 cases of symptomatic hemorrhage, there was a significantly greater representation of glioma patients (p&amp;lt;0.001) with 67% GBM patients and 50% with multiple-depth biopsies. These patients had similar probability of 1-year hospice enrollment compared to non-hemorrhagic patients (p= 0.92). DISCUSSION While complication rates were relatively similar among different histological categories, perioperative risk factors broadly differed based on the type of complication. Understanding perioperative risk factors in SBB may help inform surgical decision making and prognostication.
TMOD-25. UTILIZING PRIMARY MACROPHAGES AS AN IMPROVED SERUM-FREE IN VITRO MODEL OF TUMOR-ASSOCIATED MACROPHAGES IN GLIOBLASTOMA
Authors: Hasan Alrefai, Amr Elkholy, Benjamin Lin, Manoj Kumar, Taylor Schanel, Lauren Nassour-Caswell, Joshua Anderson, Patricia Hicks, Erin Ahn, C Ryan Miller, Christopher Willey
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Tumor-associated macrophages (TAMs) account for up to 40% of tumor mass in glioblastoma and over 70% of the immune cells contained therein. TAMs influence glioblastoma (GBM) growth, invasion, and resistance to therapy. Unfortunately, in vitro macrophage models typically employ immortalized cell lines, such as THP-1, which require serum for their growth and maintenance, and are often stimulated with IL-4/13 to mimic TAM function in vitro. Unfortunately, THP-1-derived macrophages do not readily adopt the M2 state and may be poor TAM models. METHODS The buffy coat from peripheral blood was isolated from healthy donor blood and plated in RPMI 1640 supplemented with 10% human serum and 50ng/mL of M-CSF. 25 ng/mL of M-CSF was added on day 3. The macrophages were washed, lifted, and plated in serum-free X VIVO-15 supplemented with M-CSF. Afterwards macrophages were left in an M0 (resting) state, or polarized towards an M1(pro-inflammatory) by stimulating with LPS/IFNγ, M2 (anti-inflammatory) by polarizing with IL-4/13, or TAM state by co-culturing with GBM patient-derived xenolines. Macrophage polarization was characterized through cytokine arrays, invasion, angiogenesis, and phagocytosis assays, comparing them to M0, M1, and M2 macrophages. RESULTS M1-polarized THP-1 macrophages displayed an increase in M1-associated markers, such as CD80 and HLA-DR (p&amp;lt;0.0001); however, M2-polarized THP-1 macrophages did not display an increase in the M2-associated surface marker, CD206 (p = 0.6167). Interestingly, M1-polarized peripheral blood mononuclear cell (PBMC)-derived macrophages displayed increases in the M1-associated markers, CD80 and CD369 (p&amp;lt; 0.01). Additionally, M2-polarized PBMC-derived macrophages displayed increases in CD206 (p&amp;lt;0.0001). Interestingly, TAMs derived from either THP-1s or PBMCs did not closely align with either polarization state using cell-surface markers, dPCR, or cytokine arrays. CONCLUSIONS We have demonstrated a serum-free method of generating a TAM model by polarizing primary macrophages towards a GBM-supportive phenotype that differs molecularly and functionally from M0, M1, and M2 macrophages.
NCOG-04. MEMORY TRACT SPARING USING DIFFUSE TENSOR IMAGING IN RADIATION PLANNING OF PRIMARY BRAIN TUMORS
Authors: Ory Haisraely, Arnaldo Mair, Yaavoc Lawerence, Alicia Taliansky
Journal: Neuro-Oncology (2024)

Abstract INTRODUCTION Radiation therapy (RT) is a critical treatment modality for both primary and metastatic brain tumors, yet approximately 30% of patients experience cognitive decline post-radiotherapy. This cognitive toxicity is linked to low radiation doses affecting neural stem cells in the hippocampal dentate gyrus. Hippocampal Avoidance (HA)-Whole Brain Radiotherapy (WBRT) combined with Memantine has shown promising outcomes in preserving cognitive function and quality of life (QOL) in patients with brain metastases, suggesting it should be the standard of care for those with good performance status and no hippocampal metastases. METHODS We conducted a prospective trial approved by the IRB (SMC0307-23), including patients aged 18 and above with primary brain tumors post-resection or biopsy. Exclusion criteria included multifocal glioma crossing to the other hemisphere. RT was delivered to a total dose of 60Gy in 30 fractions with concomitant TMZ. Diffusion tensor imaging (DTI) was performed to map hippocampal-associated white matter tracts. Memory fiber tracts and hippocampi were contoured and integrated into RT planning using Eclipse treatment planning software. Dosimetric analyses compared two plans: one with memory fiber constraints and one without. RESULTS Twelve patients with low-grade gliomas were included, with successful contouring of memory fibers and hippocampi. VMAT treatment plans met dose constraints for memory fibers, with an average mean dose of 10.1 Gy. The average MoCA score before RT was 27.1 and 26.4 at six months post-treatment, with a p-value of 0.07. Excluding one patient, the scores were 27.1 and 26.6, respectively (p=0.13). CONCLUSION MRI planning using DTI for memory fiber detection and incorporation into RT planning via VMAT techniques enables hippocampal and associated white fiber sparing, potentially preserving cognitive function. Preliminary cognitive data are promising, supporting the need for further validation in a larger cohort.
NCOG-44. EXPLORING THE IMPACT OF PRE-OPERATIVE MAJOR DEPRESSIVE DISORDER ON POSTOPERATIVE OUTCOMES IN PATIENTS UNDERGOING SURGICAL EXCISION OF MENINGIOMAS
Authors: Greta Sallese, Anuttham Kandhadai, Paul Brindley
Journal: Neuro-Oncology (2024)

Abstract INTRODUCTION Meningiomas are prevalent brain tumors that can cause significant morbidity for patients. Major depressive disorder (MDD), especially in the setting of other medical conditions, is associated with poor prognoses and increased mortality. This study aims to investigate whether pre-operative MDD is a risk factor for postoperative mortality and cognitive impairment in patients with meningiomas undergoing surgical excision. METHODS A retrospective cohort study was conducted using the TriNetX database including adults undergoing craniotomy for meningioma excision, one group comprising patients with pre-operative MDD and the other without. Propensity-score matching was performed to control for age, sex, race, ethnicity, history of cognitive impairment, neurodegenerative diseases, other psychiatric disorders, and socioeconomic barriers to care. Primary outcomes were postoperative mortality, depressive episodes, and cognitive impairment measured within 5 years postoperatively. RESULTS After matching, the study included 289 patients per cohort. Postoperative mortality rates for patients with pre-operative MDD compared to those without were similar (11.42% vs 9.69%, RR: 1.179, 95% CI: 0.732-1.898). Patients with MDD had a significantly higher prevalence of postoperative depressive episodes compared to those without MDD (64.71% vs 38.06%, RR: 1.7, 95% CI: 1.434-2.015). There were no statistically significant differences between the two groups in the prevalence of attention and concentration deficits (5.88% vs 4.15%, RR: 1.417, 95% CI: 0.689-2.913), cognitive communication deficits (8.99% vs 6.57%, RR: 1.368, 95% CI: 0.775-2.416), or executive function deficits (3.46% vs 3.46%, RR: 1, 95% CI: 0.423-2.366). CONCLUSION This study suggests no significant relationship between pre-operative MDD and post-operative mortality and cognitive deficits in patients undergoing meningioma resection. However, the risk of experiencing a depressive episode within 5 years post-operation is very high, especially in those with pre-operative MDD. Therefore, preoperative psychiatric evaluation and postoperative monitoring in patients with meningiomas and MDD are crucial. Further research is warranted to elucidate underlying mechanisms and relationships.
NCOG-03. DESCRIPTIVE ANALYSIS AND OUTCOME COMPARISON BETWEEN PATIENTS WITH GLIOBLASTOMA MULTIFORME WHO RECEIVE 15 VERSUS 30 FRACTIONS OF RADIOTHERAPY: A RETROSPECTIVE CHART REVIEW
Authors: Joshua Gnanasegaram, Gregory Paulin, Ethan Kutanzi, Maria Kalyvas, Melinda Mushonga, Sofia Genta, Teresa Purzner, James Purzner, Katie Goldie, Timothy Olding, Fabio Ynoe de Moraes
Journal: Neuro-Oncology (2024)

Abstract The morbidity and efficacy of abbreviated radiotherapy (RT) courses for Glioblastoma (GB) in patients over 60 years have been studied, however, outcomes in younger patients are not yet well-described. This study aims to characterize the outcomes of patients receiving either a standard versus abbreviated RT course. A retrospective chart review at Kingston Health Sciences Centre from June 2014 to March 2021 included patients with GB receiving either 40Gy in 15 fractions (Fr) or 60Gy in 30Fr. Data on age, ECOG score, and concurrent chemotherapy (Temozolomide, TMZ) were collected. Outcomes compared were treatment completion, hospital admission during treatment, progression-free survival (PFS), and overall survival (OS). Records of 156 patients (median age 61 years, range 25-87 years) were reviewed. Of these, 89 received 30Fr and 67 received 15Fr (p=0.51). MGMT methylation was recorded in 54 (35%) patients; of these, 27 received 15Fr and 27 received 30Fr. Median follow-up was 12 months. While PFS did not significantly differ between 15Fr vs. 30Fr (6 vs. 11 months, respectively; p=0.08), OS was significantly different (8 vs. 16 months, respectively; p&amp;lt;0.001). Patients receiving 15Fr vs 30F tended to have higher ECOG scores (p&amp;lt;0.001) and were older (median: 71 [range 45-87] vs. 57 [range 25-69] years; p&amp;lt;0.001). Individuals receiving TMZ were more likely to receive 30Fr (67.5% vs. 32.5% for 15Fr; p&amp;lt;0.001). Completion rates were higher for 30Fr (94.3%) than 15Fr (83.6%; p=0.03). Hospital admission rates did not differ (p=0.51). In summary, patients receiving 15Fr (40Gy) typically have poorer functional status, are less likely to receive chemotherapy, and less likely to complete treatment compared to those receiving 30Fr. Hospital admission rates during treatment are low (13%) and similar for both groups. OS, but not PFS, is better for patients receiving 30Fr compared to 15Fr.
EXTH-69. DEVELOPMENT OF A NOVEL, HUMAN ANTIBODY TO IMPROVE ONCOLYTIC VIRUS THERAPY FOR GLIOBLASTOMA
Authors: Sara Murphy, Jwala Sivaccumar, Leike Li, Jessica Swanner, Cole Lewis, Jiaqi Li, Tae Jin Lee, Upasana Sahu, Kimberly Rivera-Caraballo, Karina Vazquez-Arreguin, Ningyan Zhang, Ashok Sharma, Zhiqiang An, Balveen Kaur
Journal: Neuro-Oncology (2024)

Abstract Glioblastoma (GBM) is the most aggressive, malignant, primary brain tumor with abysmal overall survival. GBM is regarded as an “immune cold” tumor due to poor immune cell infiltration and immunosuppressive signaling in the tumor microenvironment (TME). Oncolytic herpes virus (oHSV) therapy has emerged as a possible therapeutic avenue for solid tumors such as GBM. We have observed that oHSV-treated tumor cells release extracellular ATP (eATP) which functions as immunostimulatory signaling molecule. In the TME, eATP is rapidly hydrolyzed into immunosuppressive adenosine by ectoenzymes CD39 and CD73. Using global CD73 knock out (CD73KO) mice or a function-blocking murine antibody, we found that blocking CD73 activity improves oHSV therapy in vivo. Intracranial tumor-bearing CD73KO mice respond significantly better to oHSV therapy than wild type (WT). These long-term survivors also rejected a subsequent tumor challenge, demonstrating development of a memory response. scRNA-seq revealed significantly increased immune cell infiltration in CD73KO mice compared to WT. We evaluated cellular crosstalk using CellChat and uncovered a major CCL-directed signaling pathway in the CD73KO mice. Furthermore, we identified a novel, human CD73 antibody from panning an scFv phage display library derived from human tonsils. This antibody, Ab6, demonstrated functional inhibition of purified CD73 and very high binding affinity for CD73. Co-culture of human GBM cells treated with OV and Ab6 and donor PBMCs resulted in increased tumor cell death. Additionally, human DCs exposed to Ab6 and OV-treated conditioned media were better able to activate T cells. To evaluate in vivo efficacy of this novel antibody, we have generated custom humanized CD73 knock-in mice wherein human CD73 has replaced murine CD73. We are currently evaluating the efficacy of Ab6 and oHSV in these mice against intracranial glioma. These results will support the translation of Ab6 as a potential immune therapeutic to add to the arsenal against brain tumors.
NCOG-02. ASSESSING THE INFLUENCE OF ADJUVANT INTERSTITIAL BRACHYTHERAPY ON MALIGNANT BRAIN TUMOR PATIENTS: INSIGHTS FROM THE NATIONAL READMISSION DATABASE
Authors: Kevin Sun, Ping Zhu, Truong Do, Clark Chen
Journal: Neuro-Oncology (2024)

Abstract Interstitial brachytherapy (IB) is a form of surgically administered radiotherapy involving the implant of radioactive seeds into the resection cavity after tumor excision. Advances in IB for brain cancers have revived interest in this treatment platform. However, the impact of this therapy on hospital quality measures remains poorly characterized. Here we utilized the National Readmission Database (NRD) to address this gap in knowledge. We identified patients with malignant brain tumors who had undergone either craniotomies (C) for tumor resection or craniotomies augmented with adjuvant interstitial brachytherapy (C+IB) in the National Readmission Database (NRD, 2010-2018). Propensity-score weighting and survey regression techniques were used for analysis. Over the study period, the number of craniotomies with adjuvant interstitial C+IB steadily decreased. For brain metastasis (BM) patients, C+IB and C patients exhibited comparable length of hospital stay (IRR:0.95, CI95:0.61-1.50, p=0.838) and routine discharge to home or self-care (OR:1.01, CI95:0.86-1.18, p=0.918). However, primary brain tumor (PBT) patients who underwent C+IB showed longer hospital stay (IRR:1.43, CI95:1.03-1.99, p=0.032) and are less likely to undergo routine discharge (OR: 0.38, CI95:0.20-0.74, p=0.005) relative to the C cohort. Despite these differences, C+IB and C patients showed comparable 30- or 90- day readmission risk. The profile of readmission diagnoses was also similar. Cost-analysis suggests that IB increased the median total charge by $19,184 (p=0.003). Our analysis suggests that adjuvant interstitial brachytherapy did not alter hospital course/readmission risk for brain metastasis patients. However, PBT patients who underwent this therapy showed longer hospitalization and increased likelihood for non-routine discharge.
SURG-51. DECOMPRESSIVE HEMICRANIECTOMY IN HIGH-GRADE GLIOMA PATIENTS: CLINICAL AND RADIOGRAPHIC OUTCOMES
Authors: Maria Diaz, Adela Joanta-Gomez, Mary Welch, Guy McKhann, Michael Sisti, Andrew Lassman
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Decompressive hemicraniectomy (DHC) is an uncommonly needed treatment in high-grade gliomas (HGG), most used for refractory increased intracranial pressure (ICP) from vasogenic edema, mass effect, or related complications. Outcomes and imaging following DHC are not well described. METHODS We retrospectively identified cases of DHC for HGG at our institution since 2019. RESULTS Three patients with HGG underwent DHC (2 females, ages 39-70) for newly diagnosed (2 patients) or recurrent tumor (1 patient). Causes of increased ICP were tumor/vasogenic edema (2 patients) or abscess (1 patient). Subsequent cranioplasty was performed in 2 patients: at 1.8 months after DHC in one patient, and at 8.6 months in another patient who developed sinking skin flap syndrome (SSFS). SSFS presented as progressive worsening of tumor-related neurologic deficits after completion of radiation therapy with no change in imaging, followed by frank signs of increased ICP 8 months after DHC. Two patients died of disease progression (5.3 months and 9.1 months after DHC), and one patient remains alive at 13.5 months (patient with SSFS; neurologic deficits virtually resolved after cranioplasty repair). Imaging will be described for all patients. CONCLUSION DHC can be a life-saving intervention in HGG. When feasible, early cranioplasty should be considered to avoid complications, including SSFS, which may present with neurological deficits without corresponding imaging change.
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: Cinzia Scarpini, Dawn Ward, Poe Phyu, Ibrahim Jalloh, Nicky Thorp, Benjamin Fisher, Emile Hendriks, Lyndsay Salisbury, James Nicholson, Thankamma Ajithkumar, Gail Horan, Amos Burke, Nicholas Coleman, Kieren Allinson, Matthew Murray
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND In Europe, bifocal germinoma is diagnosed based on typical age (&amp;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 (&amp;gt;300-fold reduction from diagnosis). EVD removed and septostomy performed; biopsy confirmed germinoma only (&amp;lt;5% cells) with &amp;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.