tbuckley/cabot-search huggingface dataset:
CNSC-47. SENOLYTICS ERADICATE SENESCENT MICROGLIA IN THE BRAIN PARENCHYMA AND IMPROVE SURVIVAL IN OLDER ADULT MICE WITH GLIOBLASTOMA
Authors: Manon Penco-Campillo, Lijie Zhai, Prashant Bommi, Patience Ojo, Kristen L Lauing, Pilar Sanchez-Gomez, Douglas Anderson, Vikram Prabhu, Jigisha Thakkar, Rimas V Lukas, Derek A Wainwright
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Glioblastoma (GBM) is the most common aggressive primary malignant brain tumor in adults with a poor median survival rate. Despite the aggressive standard of care treatment combining surgical resection, chemo-, and radio-therapy, the median overall survival (OS) is only ~15-18 months. Progressively increasing subject age is inversely associated with GBM patient OS such that older adults tend to have significantly worse survival outcomes compared to younger counterparts. Senescent cells accumulate in the body during progressive aging and contribute to worse outcomes in older adult mice with GBM. Senolytics are pharmacologics that cause senescent cells to undergo cell death. OBJECTIVE To comprehensively profile the treatment effect of senolytics combined with or without immunotherapy in mice with GBM across the lifespan. METHODS Young 7-9- and older adult 97-104-week-old wild-type (WT; C57BL/6) and 110-130-week-old INK-ATTAC mice with or without intracranial SB28 cells were treated with or without brain radiation (RT), PD-1 mAb, and an IDO enzyme inhibitor with the senolytics, dasatinib + quercetin, or the AP compound that induces p16INK4A+ senescent cell death in INK-ATTAC mice (n=5/group). The quantification of beta-galactosidase positive cells by flow cytometry was performed on brain-resident neurons, astrocytes, oligodendrocytes, microglia, as well as dendritic cells, macrophages, neutrophils, T cells in the tumor and non-tumor bulk mass. Overall survival was also evaluated. RESULTS Senolytics or AP compound treatment both decrease beta-galactosidase positive microglia in the older adult brain with GBM (p&amp;lt;0.05). Combining radio- and immuno-therapy with senolytics improves overall survival of older adult mice with intracranial GBM (p&amp;lt;0.05). CONCLUSIONS Our ongoing work aims to understand how senescent microglia affect neuronal health and function in the older adult brain with GBM. KEYWORDS Glioma, senescence, senolytic.
BIOM-75. MRI FLAIR SIGNAL ASSESSMENT IN NEURO-ONCOLOGY (SANO) AS A MEASURABLE TIMEPOINT FOR INTERVENTIONAL THERAPY PRIOR TO PROGRESSION IN HIGH GRADE GLIOMAS: A WINDOW OF OPPORTUNITY
Authors: Na Tosha Gatson, Shuyi Chen, Sara Ornelas, Shane Bross
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND There are no validated clinical or radiographic assessments for response to therapy in glioblastoma (GBM). Offering interventions at the time of progression using our current assessment tools is likely too late as second-line therapies have failed to significantly delay progression and extend survival. In 2020, our team was first in the US to publish the largest and most comprehensive retrospective review identifying the T2/FLAIR MRI signal assessment protocol as an early indicator of progressive GBM. We proposed that the time of FLAIR signal abnormality within the resection cavity (RC) anticipated GBM progression by nearly 4 months and if used as a timepoint for therapeutic intervention could reshape glioma clinical trial design. METHODS To support validation of SANO, a prospective assessment of 146 GBM patients between 2019-2021 yielded 71 cases meeting resection and imaging inclusion criteria. We analyzed sequential brain MRIs from initial diagnosis to first progression for development of T2 FLAIR signal intensity (SI) within the RC as previously reported (Gatson et al 2020) and included cases with ventricle associated surgery as a comparator. PFS and OS were evaluated using Kaplan-Meier curves stratified by SI. RESULTS Development of SI occurred in 80.3% (n=57) GBM patients on average 2.8 months before RANO-assessed progression. A faster time to progression from SI development occurred in cases with ventricle associated RC. SI-positivity again portended poorer outcomes for PFS and OS as compared to SI-negative cases. Use of the eye (globe) for FLAIR assessment, instead of the ventricles, to qualitatively discern the presence of SI in ventricle associated RC. CONCLUSIONS This small prospective review supports our initial findings to validate a highly sensitive brain tumor imaging biomarker, SI, and should at least supplement existing response assessment criteria to improve declaration of GBM progression. Furthermore, use of SANO might also offer an earlier window of opportunity for salvage therapy intervention and offer new avenues for glioma clinical trial design.
RADT-09. CHEMORADIOTHERAPY WITH TEMOZOLOMIDE VS. RADIOTHERAPY ALONE IN PATIENTS WITH IDH WILD-TYPE AND TERT PROMOTER MUTATION HISTOLOGICAL GRADE 2/3 GLIOMAS: A POSTHOC ANALYSIS OF A RANDOMIZED CONTROLLED TRIAL
Authors: Peng Wang, Jing Zhang, Jin Feng, Li Chen, Yin Ren, Kaiwen Deng, Fei Liu, Xiaoguang Qiu, Yanwei Liu
Journal: Neuro-Oncology (2024)

Abstract PURPOSE In 2016, we initiated a signal center prospective randomized trial to compare chemoradiotherapy (CRT) with temozolomide (TMZ) to radiotherapy (RT) alone in patients with IDH wild-type and TERT promoter mutation histological grade 2/3 gliomas. This study demonstrated patients who received CRT had a longer median OS than those who received RT alone and found no statistical difference in PFS between the two groups. Now, we recruited more patients in the CRT group to further explore whether there were differences in PFS between patients treated with CRT and RT. Besides, we explored the effect of MGMT promoter (MGMTp) methylation status on OS and PFS in patients receiving CRT therapy in the STUPP schedule. METHODS We expanded the scope by enrolling 21 participants in the CRT group and extending the follow-up period. OS and PFS were analyzed using the log-rank test, and high-risk factors were explored through Cox regression analysis. RESULTS Patients’ median follow-up is 21.9 months. CRT group has a longer median OS (25.3 vs 17.2 months; P = 0.029, HR = 0.443) and PFS (14.6 vs 8.3 months; P = 0.0008, HR = 0.387) than the RT group. Multivariate analysis identified CRT as a favorable prognostic variable for both OS (P = 0.003) and PFS (P = 0.002). The status of MGMTp methylation did not affect OS (P = 0.560, HR = 1.30) and PFS (P = 0.75, HR = 0.88) in patients with IDH-wt/TERTp-mut receiving TMZ chemotherapy. CRT with TMZ did not significantly increase grade 3 or higher toxicities. CONCLUSIONS The long-term results confirmed that the OS and PFS benefits of the RT plus TMZ regimen exceeded those of the RT alone group in patients with IDH-wt/TERTp-mut gliomas.
STEM-13. NUCLEAR LOCALIZATION OF ALPHA-1-ANTICHYMOTRYPSIN INCREASES IN GLIOBLASTOMA FOLLOWING STANDARD OF CARE TREATMENT
Authors: Aura Figueroa González, Anna Carrano, Emily S Norton, Marissa Russo, Alfredo Quiñones-Hinojosa, Hugo Guerrero-Cázares
Journal: Neuro-Oncology (2024)

Abstract Glioblastoma (GBM) is the most common malignant primary brain tumor in adults with a median survival of 8-14 months and 5-year survival rate of 6.9%. Its aggressive nature arises mostly from molecular heterogeneity and resistance to standard of care (SOC), including radiation and temozolomide (TMZ). Recurrence is nearly inevitable, driven by highly invasive brain tumor initiating cells (BTICs). Our previous studies revealed that exposing BTICs to cerebrospinal fluid (CSF) from GBM patients increases cell migration and proliferation compared to non-cancer CSF. Transcriptomic analysis identified the upregulation of the SERPINA3 gene, which encodes alpha-1-antichymotrypsin (ACT). Silencing of SERPINA3 reduces BTIC migration and proliferation and abolishes the promigratory response to GBM-derived CSF, highlighting SERPINA3 as a potential therapeutic target. ACT has been reported to bind to DNA, although the implications of this interaction are unknown. We have previously observed higher levels of intranuclear ACT in human GBM compared to non-cancer brain tissues. We hypothesize that the nuclear localization of SERPINA3 in GBM contributes to increased malignancy, opening the possibility of therapeutically targeting its intranuclear transport. Here, we determined the intracellular localization of ACT in BTICs and GBM and compared it to non-cancer tissues. Additionally, we evaluated whether SOC affected intranuclear localization of ACT. Patient-derived BTICs were treated with TMZ, radiation, and a combination of both, to assess changes in ACT expression via Western Blot, PCR, and ICC. A decrease in cell confluency was correlated with a significant decrease (p&amp;lt;0.05) in SERPINA3 mRNA and overall protein expression when BTICs were treated with TMZ alone or in combination. Interestingly, confocal microscopy revealed a significant increase (p&amp;lt;0.05) in its nuclear localization, particularly with TMZ treatment, indicating a change in its intracellular distribution. Overall, nuclear translocation of SERPINA3 increases in response to SOC with potential implications as a treatment resistance mechanism.
CTNI-31. AI-GUIDED PERSONALIZED PRECISION RADIATION THERAPY WITH TARGETED DOSE ESCALATION FOR NEWLY DIAGNOSED GLIOBLASTOMA: A MATCHED-CONTROL STUDY
Authors: Hamed Akbari, Suyash Mohan, Anahita Fathi Kazerooni, Saima Rathore, Michel Bilello, Chiharu Sako, Jose Garcia, Cecilia Jiang, Fang Liu, Melanie Berger, Steven Brem, Spyridon Bakas, Elizabeth Mamourian, Abigail Pepin, Paul James, Jay Dorsey, Ashish Singh, Drew Parker, Ragini Verma, Quy Cao, Russell T Shinohara, Stephen J Bagley, Arati Desai, Donald M O’Rourke, MacLean Nasrallah, Michelle Alonso-Basanta, Boon-Keng Kevin Teo, Goldie Kurtz, Gaurav Shukla, Robert A Lustig, Christos Davatzikos
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND The purpose of this study was to assess the feasibility and effectiveness of AI-guided personalized precision radiation therapy (PPRT) with targeted dose escalation in enhancing outcomes for patients with newly diagnosed glioblastoma. METHODS An open-label trial was conducted at the University of Pennsylvania (NCT03477513) from August 2018 to April 2023, enrolling 20 patients with IDH-wildtype glioblastoma who underwent maximal safe resection. They were matched with a contemporaneous cohort of glioblastoma patients based on age, sex, extent of resection (EOR), O6-methylguanine-DNA methyltransferase promoter (MGMTp) methylation status, and IDH status. Propensity score matching (PSM) was employed to select the control group, utilizing one-to-four nearest neighbor matching. One patient was excluded due to concurrent treatment with tumor treating fields (TTFields). The PPRT group received personalized radiation dose escalation to 75 Gy in 30 fractions guided by AI-based predictive modeling of recurrence, along with temozolomide chemotherapy. The control group received standard-of-care chemoradiotherapy, 60 Gy in 30 fractions. A previously published and evaluated (retrospectively and prospectively) predictive AI model, which has demonstrated high predictive value for neoplastic cell infiltration and future tumor recurrence using preoperative, multi-parametric MRIs, was utilized. RESULTS Median overall survival was 24.3 months in the PPRT-temozolomide group compared to 17.5 months in the standard-of-care treatment group (hazard ratio [HR]=0.30; 95% CI: 0.16-0.57; p&amp;lt;0.001). Excluding two patients with leptomeningeal disease and bone marrow metastasis, the median survival was 35.4 months (HR=0.25; 95% CI: 0.12-0.51; p&amp;lt;0.001). CONCLUSION AI-guided PPRT for newly diagnosed glioblastoma patients demonstrated feasibility in routine clinical practice and significantly improved overall survival compared to matched controls receiving standard-of-care treatment. These findings underscore the potential of personalized precision radiation therapy, with focused dose escalation, in improving outcomes for glioblastoma patients and emphasize the need for prospective validation in a randomized controlled clinical trial.
QLTI-12. COST ANALYSIS OF EMERGENCY PROCEDURES FOR BRAIN TUMORS – WHEN YOU CAN WAIT
Authors: Aline Lariessy Campos Paiva, João Luiz Vitorino Araujo, Renan Maximillian Lovato, Jean Gonçalves de Oliveira, José Carlos Esteves Veiga
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Neurosurgery is expensive and requires advanced technology to achieve the best outcomes, especially for brain tumors. Generally patients are prepared during consultations for a brain tumor surgery, with anesthesiology, cardiology, neuropsychology and other specialties evaluations. Ideally, the hospitalization is planned before and patient is admitted only when is in good conditions. However some patients with brain tumors are evaluated in emergency department and sometimes require urgent procedures. OBJECTIVE This study aimed to estimate the direct cost of specialized care for adult neuro-oncological patients considering previous scheduled procedures versus urgent surgeries and another factors that may impact decision about nonelective procedures. METHODS This observational economic analysis describes the direct cost of care of neuro-oncological patients in Santa Casa de São Paulo, Brazil. Only adult patients with a common primary brain tumor were included. RESULTS The global mortality rate considering all patients were 12.7% and 92.3% of them occurred in nonelective procedures. Also these patients had a greater infection rate and period of hospitalization. Because of this we reviewed when a patient with brain tumor really need an urgent procedure. Despite several patients are initially diagnosed through ER investigation, probably the majority could be compensated through ambulatory consultations and after admitted with better conditions. Situations in which emergency surgery are required include acute hydrocephalus and non-compensated intracranial hypertension. CONCLUSIONS These patients usually have difficulty access to neurosurgical evaluation and so, only look for health assistance when the disease cause severe disability. Emergency surgeries were associated with an increased rate of infections and mortality. The findings of this study could be used by policymakers for resource allocation and to perform economic analyses to establish the value of neurosurgery in achieving global health goals. severe disability. KEY WORDS: costs; brain tumor; emergency; infections
QOL-05. COMPARING DISEASE-SPECIFIC QUALITY-OF-LIFE OUTCOMES OF MICROSURGERY, RADIOTHERAPY, AND OBSERVATION IN VESTIBULAR SCHWANNOMA PATIENTS: A SYSTEMATIC REVIEW AND META-ANALYSIS
Authors: Afia Salman, Shamas Ghazanfar, Unaiza Naeem, Kanwal Ashok Kumar, Aaisha Javaid, Hania Mansoor Rafi, Komal Naeem, Hassan Lucky, Rida Farhan
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Vestibular schwannoma (VS), also known as acoustic neuromas, are common tumors arising from the vestibulocochlear nerve and are located in the cerebellopontine angle. The benign tumor has a substantial impact on the patient-perceived quality of life (QoL) outcomes, which contribute to the decision regarding the ideal management plan. In this systematic review and meta-analysis, we aimed to compare the impact of microsurgery, radiotherapy, and observation on the QoL outcomes of VS patients. METHODS This study was conducted in accordance with the PRISMA guidelines and a total of four research databases were searched for eligible studies from inception to May 2024. The primary outcome of the study was the Penn Acoustic Neuroma Scale (PANQOL) total score and the secondary outcomes included the PANQOL subdomain scores. Data was pooled using the random-effects model and analyzed as OR (odds ratio) with 95% CI (confidence interval). RESULTS Compared to observation, radiotherapy was associated with superior QoL outcomes only in the face domain [MD (mean difference) = -4.59 [-7.29,-1.88]; I2= 85%; p = 0.0001], with observation being associated with superior outcomes across all others [PANQOL - total: MD = 4.94 [2.51,7.38]; I2= 85%; p = 0.0001]. Microsurgery, compared to radiotherapy, was associated with better outcomes only in the general domain [MD = -4.38 [-6.60,-2.16]; I2= 0%; p = 0.0001], with RT being associated with superior outcomes across all other domains [PANQOL - total: MD = 3.61 [1.29,5.93]; I2= 63%; p = 0.002]. Compared to microsurgery, observation was associated with superior QoL outcomes across all domains [PANQOL - total: MD = 9.22 [7.30,11.13]; I2= 64%; p = 0.0001]. CONCLUSION The findings indicate that, broadly, observation is associated with better QoL outcomes relative to both radiotherapy and microsurgery; with radiotherapy superseding microsurgery. However, the association with QoL improvement was not uniform across all domains.
IMMU-01. DE NOVO-DESIGNED BINDER-BASED CAR T CELLS ENABLE EFFECTIVE TARGETING OF GLIOBLASTOMA
Authors: Qi Xie
Journal: Neuro-Oncology (2024)

Abstract Glioblastoma is a devastating disease with poor responses to all current therapies. Chimeric antigen receptor (CAR) T cell therapy has achieved impressive success against hematological malignancies but produces responses in only a limited number of glioblastoma patients. Here, we developed a novel platform for CAR constructs using de novo designed protein binders to target tumor antigens. We firstly designed a binder CAR targeting epidermal growth factor receptor (EGFR), which is highly expressed in glioblastoma, to validate the feasibility of our platform. Our EGFR binder CAR design promoted CAR T cell proliferation, cytotoxic cytokine secretion and exhaustion resistance, leading to better antitumor performance both in vitro and in vivo. Bulk and single-cell transcriptional profiling of binder CAR T cells revealed an underlying mechanism involving enhanced effector activity and reduced exhaustion responses. Mechanismly, the binder CARs exhibited higher surface expression and greater resistance to degradation triggered by tumor antigens. Moreover, we designed and engineered a novel CD276 binder CAR T cell product and verified its antitumor function, further demonstrating the general applicability of our binder-based CAR platform. Overall, our study provides an alternative avenue for the design of a CAR antigen-binding domain to potentiate CAR T cell antitumor efficacy.
NCOG-20. RADIATION-RELATED MORBIDITY OUTCOMES IN ATYPICAL MENINGIOMA PATIENTS: A RETROSPECTIVE COHORT STUDY
Authors: Anneliese Rademacher, Dheeraj Kagithala, Jacob Pawloski, Katie Latack, Hassan Fadel, Florence Dallo, James Snyder, Ian Lee, Adam Robin
Journal: Neuro-Oncology (2024)

Abstract Atypical meningiomas present with unique challenges in management and prognosis. Given their tendency to recur, adjuvant radiation therapy (ART) is frequently utilized, however there are few reports on radiation-related morbidity in this patient population. The study aims to investigate the radiation-related complications in atypical meningioma patients treated with or without ART. The primary outcomes were the incidence and severity of RT-related morbidity. All patients treated for atypical meningiomas at our institution between January 1, 2014 and January 1, 2024 were retrospectively analyzed. Patients were grouped into two cohorts, those who were initially treated with surgical resection only and those who also received adjuvant RT. Radiation morbidity grading was assigned for all patients that received radiation treatments during their clinical course based on established grading systems. Fisher’s Exact and Kruskal-Wallis tests were used to determine associations between the two groups. There were 76 patients who were initially treated with surgery only and 23 patients who had surgery and ART. Mean length of follow-up among all patients was 55.6 months. Significantly lower rates of RT-related morbidity in the surgery only group were observed compared to the surgery and RT cohort (15.8% vs. 60.9%, p &amp;lt; 0.0001). Among patients in the surgery only cohort, 23 patients received RT at recurrence or progression. When comparing this subgroup to those who underwent ART, there was no significant difference in the severity of RT-related morbidity (p=0.2724). In this series, patients receiving ART experienced a higher incidence of radiation-related morbidity. When comparing only those who received RT, there was no difference in the incidence or severity of radiation-related morbidity between the two cohorts.
CTIM-29. TUMOR RESPONSES IN A RANDOMIZED PHASE IIB TRIAL OF A CMV VACCINE IMMUNOTHERAPEUTIC CANDIDATE (VBI-1901) IN RECURRENT GLIOBLASTOMAS
Authors: Ryan Merrell, Patrick Wen, Deborah Forst, Jessica Schulte, Yazmin Odia, Daniela Bota, Seema Nagpal, Alipi Bonm, Francisco Diaz-Mitoma, David Anderson, Andrew Lassman, Fabio Iwamoto
Journal: Neuro-Oncology (2024)

Abstract Cytomegalovirus (CMV) antigens have been reported in over 90% of GBMs. CD4+ and CD8+ T cells are most frequently directed against the gB and pp65 antigens, respectively, which are immunogenic targets in a CMV-based GBM immunotherapeutic. First-recurrent GBM patients were enrolled, with Karnofsky Performance Status of at least 70, to receive VBI-1901 (a gB/pp65 enveloped virus-like particle [eVLP]) adjuvanted with GM-CSF and given intradermally (NCT03382977). Patients were vaccinated with VBI-1901 every 4 weeks, with surveillance brain MRI scans every 6 weeks. Among 16 subjects receiving the highest dose of VBI-1901 in the Phase I/IIa portion of the study, the disease control rate was 44%, including 2 durable partial responses, which translated into a mOS of 12.9 months. Based on these results, the study was amended into a randomized study. Approximately 60 adult subjects (18 years or older) with first recurrence of WHO 2016 grade IV Glioblastoma, IDH-wildtype will be randomized at a 1:1 ratio to two open-label cohorts to receive: VBI-1901 or standard of care (SOC) treatment with lomustine or carmustine. Only subjects with a CD4/CD8 ratio ≥1 or a CD4 count of ≥ 400/uL at screening are eligible, as people with a preserved immune system are more likely to respond to immunization with VBI-1901 based on the initial phases of the study. As of May 15, 2024, 23 patients have been randomized across 6 sites. Among evaluable patients (n=13), disease control rates of 43% and 0% have been observed in the VBI-1901 and SOC arms, respectively, including 1 partial response in the VBI-1901 arm. Full enrollment (n=60) is anticipated by the end of the year across 11 sites, and updated tumor response data and select biomarkers associated previously with tumor responses will be presented.