tbuckley/cabot-search huggingface dataset:
RADT-46. RADIOSURGERY DOSE REDUCTION FOR BRAIN METASTASES ON IMMUNOTHERAPY (RADREMI):A PROSPECTIVE PILOT STUDY
Authors: Charles Curtis, Michael Weisman, Shearwood McClelland, Ryan Rhome, Paul Anthony, Namita Agrawal, Tim Lautenschlaeger, Richard Zellars, Aaron Kamer, Nasser Hanna, Yong Zang, LaKeisha Boyd, Kevin Shiue
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND The combination of immunotherapy and single-fraction stereotactic radiosurgery (SRS) for treatment of metastatic brain disease has yielded symptomatic radiation necrosis rates as high as 16%. The aim of this study was to evaluate the toxicity of dose reduced stereotactic radiosurgery (SRS) in patients receiving concurrent immune checkpoint inhibitors (ICI). METHODS RADREMI is a prospective, single arm, phase 1 pilot study evaluating adults with 1-10 brain metastases on MRI receiving ICI within 30 days of treatment. SRS was delivered using dose reduction: 18 Gy for lesions 0-2 cm, 14 Gy for lesions 2.1-3 cm, and 12 Gy for lesions 3.1-4 cm. Patients were evaluated at 6-months with regard to symptomatic radiation necrosis, defined as a 6-month rate of clinical symptomatology requiring steroid administration, bevacizumab, and/or operative intervention concomitant with advanced and routine brain imaging findings consistent with radiation necrosis. RESULTS Between 2019 and 2023, 18 eligible patents were entered with 12 evaluated. All patients were treated within the 18 Gy cohort. The median follow up was 13.82 months. The median number of brain metastases treated was 1.5 (inner quartiles 1, 3) with up to 7 lesions treated. The proportion of patients who experienced symptomatic radiation necrosis by 6 months was calculated with the 95% confidence interval tested against a historical proportion of 16%. The incidence of symptomatic radiation necrosis at 6 months was 1 of 12 (0.083; 95% CI: 0.002, 0.385; p-value 0.234) following SRS. CONCLUSIONS Our findings of dose reduced SRS with concurrent ICI unfortunately did not have statistical significance regarding symptomatic radiation necrosis. This was likely due to the small number of evaluable patients. The secondary endpoint of local control is currently under review. Dose reduced SRS with concurrent ICI warrants further studies to evaluate toxicity and local control.
SURG-29. EXTENDED RESECTION IMPROVES PATIENT SURVIVAL OUTCOMES AFTER GROSS-TOTAL RESECTION OF GLIOBLASTOMA
Authors: Kazuhiro Tanaka, Hiroaki Nagashima, Shunsuke Yamanishi, Yoshihiro Muragaki, Takashi Sasayama
Journal: Neuro-Oncology (2024)

Abstract In recent years, the effectiveness of extended resection (ER) beyond the contrast-enhanced (CE) lesion has been reported as a surgical strategy for glioblastoma. This study was to determine whether ER of FLAIR-hyperintense area beyond the CE tumor affected the overall survival (OS) and progression-free survival (PFS) of patients with glioblastoma after gross-total resection (GTR). From October 2019 to March 2022, a total of 62 patients who underwent resection of glioblastoma (GBM) at Kobe University Hospital were retrospectively examined. Volumetric measurements of the CE area and surrounding FLAIR-hyperintense area were performed, and clinical variables related with OS and PFS were analyzed. In total, 33 patients with GBM who underwent GTR of the CE tumor met the inclusion criteria. The mean volume of CE tumor and FLAIR hyperintensity area before resection was 36.5 cm3 and 77.2 cm3 respectively. The mean excision rate of FLAIR-hyperintense area was 18.2%. Removal rates of 20% or more in the FLAIR-hyperintense region significantly increased OS and PFS (p=0.040 and 0.026, respectively). In multivariate analysis, age ≥ 65 years (HR 2.73; 95% CI 1.09–7.22; p=0.032) were associated with shorter OS, but ER ≥ 20% (HR 0.41; 95% CI 0.17–0.99; p=0.049) and MGMT promotor methylation (HR 0.36; 95% CI 0.15–0.85; p=0.020) were associated with longer OS. ER of FLAIR-hyperintense lesions of 20% or more in glioblastoma contributed to prolonging patient survival. It is necessary to validate the effect of ER in prospective clinical trials.
CSIG-24. BRAIN MICROENVIRONMENT-DEPENDENT NEURODEVELOPMENTAL LINEAGE PLASTICITY PROMOTES ADAPTATION TO ONCOGENE INHIBITION IN MALIGNANT GLIOMAS
Authors: Dimitri Cadet, Cassidy Andrasz, Nicholas Bayley, Elisa Fazzari, Elizabeth Fernandez, Quincy Okobi, Thomas Graeber, Aparna Bhaduri, Timothy Cloughesy, David Nathanson
Journal: Neuro-Oncology (2024)

Abstract Phenotypic plasticity drives non-genetic tumor adaptation in response to various microenvironmental and therapeutic pressures, consequently promoting tumor heterogeneity and progression. In malignant gliomas, the intrinsic and extrinsic mechanisms underlying phenotypic lineage plasticity and its contribution to drug resistance remain unclear. The epidermal growth factor receptor (EGFR) is frequently altered in glioma and serves as a critical regulator of normal radial glia (RG) cells – multipotent progenitors that give rise to cortical neurons and glia in the developing brain. Here, through interrogation of a large panel of diverse glioblastoma (GBM) patient-derived gliomaspheres and orthotopic xenografts, we find that enrichment of RG-like cells is significantly correlated with responses to pharmacological ablation of EGFR, highlighting EGFR as a crucial lineage survival factor for a population of malignant RG-like cells in GBM. Single-cell RNA sequencing and quantitative proteomics reveal that adaptation to EGFR inhibition is linked to a temporal contraction in RG-like cells and concomitant increase in lineage-restricted neuronal and oligodendrocyte progenitor (NPC/OPC)-like states exclusively in the orthotopic brain environment. This lineage transition is coupled to heightened RAS signaling gene expression programs and sustained activation of MAPK signaling, despite robust and durable inhibition of EGFR activation. Furthermore, constitutively active MEK – but not AKT – is sufficient to rescue tumor proliferation under EGFRi, suggesting that the brain microenvironment modulates RAS-MAPK oncogenic signaling to drive lineage transitions following EGFR blockade. Collectively, these results highlight a critical link between oncogenic signaling and neurodevelopmental lineage plasticity in malignant gliomas, presenting a compelling therapeutic opportunity to block tumor cell state transitions for more durable tumor responses in the native glioma tumor microenvironment.
SURG-30. SURVIVAL AND OUTCOMES ANALYSIS OF PATIENTS TREATED WITH LASER INTERSTITIAL THERMAL THERAPY FOR LARGE-VOLUME GLIOBLASTOMA
Authors: Chandler Berke, Maxon Knott, Khushi Shah, Adham Khalafallah, Cameron Rivera, muhammet gurses, Ashish Shah, Ricardo Komotar, Michael Iva
Journal: Neuro-Oncology (2024)

Abstract INTRODUCTION Laser interstitial thermal therapy (LITT) has shown increased patient survival and outcomes in glioblastoma multiforme (GBM). However, its safety and survival in large-volume GBM tumors has been poorly elucidated. OBJECTIVE To evaluate the use of LITT in large-volume GBMs. METHODS A retrospective cohort of adult patients with grade IV IDH-wt GBM measuring ≥ 10 cm3 who were treated with LITT was compared to a control group with volumes &amp;lt;10 cm3. A Kaplan-Meier analysis, followed by a Cox-proportional hazards model with overall survival (OS) as the timeline and death as the event, were performed with volume group, mFI-11 score, 30-day readmission, age at surgery (AOS), recurrent vs. primary lesions, and EOA as covariates. RESULTS The cohort consisted of 46 large-volume patients (mean: 22.0 cm3, STD: 10.8) with a mean age of 63 years and 57% male predominance, compared to 41 controls (mean: 4.4 cm3, STD: 2.8). Lesions were primary in 78% and 60%, and recurrent in 22% and 40%, of the large and small-volume groups, respectively. Kaplan-Meier analysis showed no significant survival difference between the large (OS=245 days) and small-volume (OS=358 days) groups (p=0.261). No covariate showed significant risk of hazard in the large compared to small-volume cohorts (p&amp;gt;0.05). Across the entire cohort, mFI-11 score, recurrent lesions, and EOA showed no significance as individual predictors of death (p&amp;gt;0.25). AOS (p&amp;lt;0.005) and 30-day readmission (p&amp;lt;0.005) showed significantly increased hazard for the entire cohort. Importantly, volume group did not significantly increase hazard (1.16 [0.68, 1.98], p=0.60). CONCLUSION This is the first study evaluating the safety and efficacy of LITT in large-volume GBMs, specifically, with a larger cohort than any existing analysis sub-grouped by volume. We show LITT can be safe and efficacious, without significantly increased mortality compared to in small-volume GBMs.
EXTH-43. ANTI-GLIOMA ACTIVITY OF BIMODAL CGAS-AGONISTIC AND STAT3-INHIBITORY SPHERICAL NUCLEIC ACIDS
Authors: Akanksha Mahajan, Corey Dussold, Seunghyun Kim, Rachel Jarvis, Serena Tommasini, Connor Forsyth, Lisa Hurley, Chad Mirkin, Alexander Stegh
Journal: Neuro-Oncology (2024)

Abstract Activation of the cGAS-STING (cyclic GMP-AMP synthase-stimulator of Interferon Genes) pathway enhances T cell activation and infiltration into tumors, reversing the immunosuppressive phenotype of myeloid cells. Targeting the STING receptor with synthetic cyclic dinucleotide (CDN) ligands offers a promising immunotherapeutic strategy for lymphocyte-depleted, myeloid cell-enriched tumors like Glioblastoma (GBM). However, this approach is constrained by the structural instability of CDNs and the presence of immune-evasive, STING-inhibitory mechanisms in the tumor microenvironment (TME), particularly those driven by the master transcriptional regulator STAT3 (Signal Transducer and Activator of Transcription 3). To activate cGAS anti-tumor responses and simultaneously inhibit STAT3-driven immunosuppression in the GBM TME, we developed Spherical Nucleic Acids (SNAs) consisting of a nanoparticle core densely functionalized with radially oriented stem-loop dsDNA oligonucleotides containing a guanine repeat element flanked by palindromic STAT3 decoy sequences. In vitro studies demonstrated that these SNAs effectively activate cGAS and inhibit STAT3 in reporter cell lines, exhibit high-affinity binding to both the cGAS enzyme and STAT3 proteins, and downregulate IL-6-induced STAT3 transcriptional targets. Furthermore, intratumoral injection of these bimodal SNA architectures induced type I interferon (IFN) and proinflammatory cytokines, activated T cells and B cells, and natural killer cells; and reprogrammed immunosuppressive tumor-associated macrophages (TAMs). Importantly, bimodal SNAs showed profound sex-based differential pharmacological action with therapeutic benefits seen in females but not in male mice in aggressive immune checkpoint-resistant murine glioma models. In the absence of cGAS transcriptional changes, western blot and flow cytometry analysis revealed that cGAS protein levels were approximately twice as high in female BMDMs (bone marrow-derived macrophages) and TAMs than males. In summary, our study establishes bimodal SNAs as a first-in-class, single-entity nucleic acid therapeutic capable of targeting multiple pathways for the immunological reprogramming of the GBM TME.
NCMP-14. RADIOGRAPHIC RESPONSE TO BEVACIZUMAB IN TREATING RADIATION NECROSIS AND ASSOCIATED EDEMA IN BRAIN TUMORS
Authors: kang hee ahn
Journal: Neuro-Oncology (2024)

Abstract OBJECTIVE This study evaluates the efficacy of bevacizumab in treating radiation necrosis (RN) and associated perilesional edema in brain tumors. We aimed to measure changes in radiologic volumes and clinical performance following treatment. MATERIALS AND METHODS We retrospectively reviewed patients treated with radiation therapy and/or stereotactic radiosurgery between September 2017 and August 2023. We identified 10 metastatic brain tumors and one glioblastoma with symptomatic RN. Diagnosis was primarily through MRI, with one case confirmed pathologically. All patients received bevacizumab (7.5 mg/kg every 3 weeks). Volumes of RN and perilesional edema were measured using gadolinium-enhanced T1-weighted and T2-weighted/FLAIR MRI, respectively, analyzed with Brainlab software. Volume changes and clinical symptoms, graded by the ECOG Performance Status (PS) scale, were recorded. RESULTS The minimal follow-up was 4 months. The 11 patients received a median of 2 bevacizumab cycles (range, 2-3). Pre-treatment median volumes (ranges) were: tumor/RN 5.45 cc (2.66-13.56), perilesional edema (T2, FLAIR) 53.93 cc (7.46-115.32), 58.01 cc (15.18-131.2). Post-treatment median volumes (ranges) were: tumor/RN 2.5 cc (2.23-7.23), perilesional edema (T2, FLAIR) 4.05 cc (3.08-11.18), 7.38 cc (2.887-17.647). Median percentage volume reductions were: tumor 39%, RN 38%, perilesional edema (T2, FLAIR) 80%, 79%. Significant reductions in edematous volumes were observed. Pre-treatment ECOG PS median was 2 (range 2-3); post-treatment ECOG PS median remained 2 (range 2-3). Clinical performance improved in most patients, with two exception where deterioration occurred after the third cycle despite initial improvement. CONCLUSION Bevacizumab is effective in reducing RN and perilesional edema, particularly within the first two cycles of treatment. Most patients showed clinical improvement, though further research is needed to optimize treatment and understand long-term outcomes.
TMIC-45. CYTOMEGALOVIRUS PP65 ANTIGEN EXPRESSION FOLLOWING PP65-SPECIFIC DENDRITIC CELL VACCINATION IN MATCHED PRIMARY AND RECURRENT GLIOBLASTOMA SPECIMENS
Authors: Tarek Bou Dargham, Zuowei Su, Sergio Pina-Oviedo, Michael Brown, Sarah Cook, Diane Satterfield, Stevie Threatt, Weihua Xie, Pam Norberg, Mustafa Khasraw, Roger E McLendon, Gerald E Archer, John H Sampson, Duane A Mitchell, Charles Cobbs, Sean Lawler, Kristen Batich
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Human cytomegalovirus (HCMV) expression in glioblastoma (GBM) has been corroborated by multiple independent laboratories. HCMV genes have been directly linked to GBM cell proliferation, invasion, and angiogenesis. The HCMV tegument protein pp65 has served as a tumor-specific antigen in serial pp65 RNA-pulsed autologous dendritic cell (DC) vaccine trials. Here we report pp65 expression in matched primary and recurrent GBM samples from those trials following pp65-DC vaccination. METHODS Paired GBM specimens were collected from patients receiving pp65-DC vaccines according to ATTAC and ATTAC-GM clinical trials (NCT00639639). Of 23 treated patients, 9 cases were available for analysis. Formalin-fixed paraffin-embedded specimens were mounted on glass slides and stained for pp65 via immunohistochemistry (IHC). CD31 served as a control for tissue quality and to investigate the role of pp65 co-staining in the tumor perivascular niche. RESULTS Of 9 available cases, 5 were excluded due to poor tissue quality/absent CD31 staining on aged slides. Among the remaining four cases, three showed pp65 staining in non-vascular and perivascular areas within both primary and recurrent samples. However, recurrent specimens of these positive cases demonstrated a clear reduction in both intensity and distribution of pp65 staining within non-vascular regions but retained a strong positivity within the perivascular space. The fourth case showed absent pp65 staining and only weakly positive CD31 staining in both primary and recurrent specimens. Necrotic areas within pp65-positive slides showed minimal to no pp65 staining. CONCLUSIONS This study confirms HCMV pp65 expression in both primary and recurrent GBM following pp65-DC vaccination, with an interesting phenomenon of retained pp65 expression specifically in the perivascular niche. These findings support the role of HCMV in GBM angiogenesis and tumor progression as well as mechanisms of immune evasion following single antigen vaccine platforms. Our study reinforces the importance of tissue quality for proper HCMV detection in GBM.
NCOG-38. LAMOTRIGINE MONOTHERAPY ASSOCIATES WITH IMPROVED PROGRESSION-FREE AND OVERALL SURVIVAL IN HIGH-GRADE GLIOMA
Authors: Ryan Rilinger, Akshay Sharma, Marina Feldman, Lydia Guo, Josephine Volovetz, Matthew Grabowski, Mina Lobbous
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND High-grade gliomas (HGG) are aggressive brain tumors with notoriously poor prognoses and high symptomatic burden, including seizures in 30-60% of HGG cases. Despite negative impacts to quality of life, positive seizure history at presentation and during the disease course has been shown to associate with improved overall survival. Further, recent preclinical studies have suggested a link between neuronal hyperexcitation and more rapid glioma progression. We hypothesized anti-seizure medication (ASM) therapy may suppress neuronal excitation and therefore help prolong survival. To this aim, we characterized the association of various ASM therapies with survival and seizure control. METHODS Retrospective review of 413 patients with co-occurring HGG and clinically diagnosed epileptic activity. Multivariable linear regression was used to assess the impact of ASM quantity (monotherapy versus polytherapy) and type (specific ASMs as well as ASM class) on progression-free survival (PFS) and overall survival (OS). Logistic regression was used to assess the impact of ASM quantity and type on likelihood of achieving seizure remission. Additional variables in the regressions included age, treatment exposure (radiation therapy, cytotoxic chemotherapy, or targeted chemotherapy), and extent of surgical resection (gross total resection versus all other surgeries). Kruskal-Wallis tests were used to compare median survival between multiple groups. RESULTS ASM monotherapy and polytherapy demonstrated comparable survival outcomes. Among patients who received ASM monotherapy, only lamotrigine demonstrated a significant association with improved survival with PFS and OS (P = &amp;lt;0.001 for both). No specific drug or drug class demonstrated greater likelihood of achieving seizure remission. CONCLUSION Lamotrigine demonstrates a unique association with improved outcomes that is neither shared by other ASMs nor explained by ASM drug class, without any decline in likelihood of achieving seizure remission. Optimization of ASM therapy may enhance survival outcomes without compromising seizure control.
TMIC-69. HUMAN ORGANOID TUMOR TRANSPLANTATION IDENTIFIES FUNCTIONAL GLIOBLASTOMA MICROENVIRONMENTAL COMMUNICATION MEDIATED BY PTPRZ1
Authors: Weihong Ge, Ryan Kan, Can Yilgor, Elisa Fazzari, Patricia Nano, Daria Azizad, Matthew Li, Joyce Ito, Christopher Tse, Andrew Tum, Jessica Scholes, Kunal Patel, David Nathanson, Aparna Bhaduri
Journal: Neuro-Oncology (2024)

Abstract Glioblastoma, the most aggressive form of primary brain cancer, is driven by both intrinsic cellular properties and extrinsic factors from the tumor microenvironment (TME). Here, we leverage our novel human organoid tumor transplantation (HOTT) system to explore how external cues modulate glioblastoma cell type specification, heterogeneity, and migration. Comparing the single-cell transcriptomes of HOTT and matched primary tumors, we found that HOTT recapitulates not only core features of major patient tumor cell types but also those of peritumor non-neoplastic cell types. This enables us to explore tumor-TME interactions and identify PTPRZ1, a receptor tyrosine phosphatase implicated in brain tumor migration, as a key mediator in intercellular communication. This finding was further confirmed by interrogation of published datasets from patients containing non-neoplastic microenvironmental cells. PTPRZ1 activation, resulting from the reactivation of developmental programs in both the tumor and its TME, highlights the relevance of the organoid system for modeling the GBM microenvironment. Moreover, HOTT uniquely allows for perturbations in either patient tumors or their microenvironments, or both, to verify PTPRZ1 function. Tumor knockdown of PTPRZ1 confirmed its role in promoting tumor migration and maintaining progenitor identity. Surprisingly, environmental PTPRZ1 knockdown in human cortical organoids before tumor transplantation inhibited tumor migration and promoted differentiation, even without direct tumor manipulation. Overall, this fundamental result demonstrates that a single treatment delivered to the tumor and its TME can exert opposite effects on the tumor. Consequently, it underscores the necessity of studying human glioblastoma within a human microenvironment context, such as HOTT, especially when evaluating therapeutic efficacy in GBM, as effective treatments must address both the tumor and its complex TME, rather than the tumor alone.
SURG-58. COLD ATMOSPHERIC PLASMA (CAP) CAUSES SELECTIVE TUMOR CELL DEATH VIA APOPTOSIS AND FERROPTOSIS IN MALIGNANT GLIOMA CELLS
Authors: Sophie Peeters, Wi Kim, Amber Armellini, Blake Haist, Weihong Ge, George Ayad, Zhitong Chen, Richard Obenchain, Can Yilgor, Geoffrey Owens, Andrea Tamayo, David Nathanson, Robert Prins, Aparna Bhaduri, Richard Wirz, Anthony Wang
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND High-grade gliomas (HGGs) are primary brain tumors associated with significant morbidity and mortality, and despite advances in neuro-oncology, the prognosis remains poor. Cold atmospheric plasma, a novel experimental anti-cancer therapeutic tool, is a near-room temperature ionized gas generated at atmospheric pressure. It has many promising results in vitro and in vivo with a variety of cancers. CAP cytotoxicity appears to be selective to cancer cells without significant damage to surrounding healthy tissues. We aim to evaluate the efficacy of CAP in generating tumor-selective cytotoxicity against high-grade glioma. METHODS B16, U87, GL261, patient derived high grade glioma, human neural stem cells (LM-NSC008) and astrocytes (NHA hTERT) were treated with CAP. Proliferation and propidium iodide (PI)/annexin V flow cytometry assays were employed to quantify cytotoxicity, cell cycle phases and apoptosis. Cells were pre-treated with ferroptosis inhibitors Ferrostatin-1 and Deferoxamine (DFO) in rescue assays. Cerebral organoids were transplanted with fluorescent tumor cell lines and stained with cleaved caspase-3, ki67 and transferrin receptor. RESULTS CAP induces dose dependent cell death in all glioma cell lines tested. CAP induces an accumulation of intracellular ROS, most prominent in glioma cells. CAP-mediated cell death involves apoptosis and ferroptosis. CAP selectively leads to apoptosis in tumor implanted organoids and leads to decreased proliferation in malignant and non-malignant cells. CAP leads to a shift into G0 phase of all treated cells, malignant and non-malignant. CONCLUSIONS CAP treatment induces dose-dependent increases in ROS and apoptosis in HGG lines tested more significantly than in NHAs and hNSCs. CAP induces decreased proliferation and G0 phase cell cycle arrest in all CAP-treated cells. CAP-mediated cytotoxicity was significantly mitigated with DFO pre-treatment in HGG cells, suggesting that ferroptosis plays a critical role in the mechanism of CAP treatment in HGG. CAP led to selective glioma cell death in tumor implanted cerebral organoids.