tbuckley/cabot-search huggingface dataset:
IMMU-18. IL-7 MEDIATED UPREGULATION OF VLA-4 INCREASES ACCUMULATION OF ADOPTIVELY TRANSFERRED T LYMPHOCYTES IN MURINE GLIOMA
Authors: Kirit Singh, Kelly Hotchkiss, Sarah Cook, Pamy Noldner, Ying Zhou, Eliese Moelker, Chelsea Railton, Emily Blandford, Bhairavy Puviindran, Shannon Wallace, Pamela Norberg, Gary Archer, Beth Shaz, John Sampson, Mustafa Khasraw, Peter Fecci
Journal: Neuro-Oncology (2024)

Abstract We have previously described the development of a novel brain bi-specific T cell engager (BRiTE) targeting EGFRvIII in Glioma. Despite BRiTEs impressive potency, efficacy in solid tumors is dependent on tumor-infiltrating lymphocytes (TILs). We evaluated if peripheral adoptive lymphocyte transfer (ALT) increases TILs in immunocompetent mice, even during glioma-induced sequestration. C57/Bl6 mice were implanted with 3 x 10^4 cells syngeneic glioma (CT-2AvIII) and treated with 1 x 10^7 IV CD45.1+ ALT on Day 15. The brain was divided into tumor and non-tumor bearing hemispheres and analyzed each day for exogenous (CD45.1+) CD3/4/8 counts. We observed that IL-7-expanded ALT accumulated at a higher rate within tumor versus IL-2 ALT (72-hours IL-7 median 26.66x vs IL-2 median 4.291x, p=0.0159*). Exogenous T cell entry into tumor-bearing CNS overwhelmingly consisted of CD8+ T cells, and CD45.1+ IL-7 ALT cells made up ~20% of the CD3+ population in tumor 72-hours following administration (mean 19.4%, SD ±4.53%, n=5). Survival experiments used combination ALT and anti-4-1BB therapy in the same model. Mice were treated with IV ALT on Day 5, along with 200µg of IP anti-4-1BB. IP mAb Injections were given every 3 days for 4 total cycles (D5, D8, D11 &amp; D14). Evaluation at these time points was selected as this correlated with peak sequestration of immune cells as evidenced by splenic involution. For survival studies, only combination ALT and anti-4-1BB produced significantly increased survival benefit in our CT-2AvIII model compared to ALT alone (median survival 45.5 days for combination versus 25 days in ALT only group, p=0.0134, chi-square test). These findings demonstrate the feasibility of combination ALT/antibody-based therapy in pre-clinical glioma, as well as outlining a novel approach for delivering both immune cells and antibody-based immunotherapy. Combination therapy with BRiTE and ALT will be explored in an upcoming clinical trial (NCT04903795).
CTNI-85. FINAL RESULTS FROM N2M2/NOA-20
Authors: Wolfgang Wick, Lisa-Marie Lanz, Antje Wick, Inga Harting, Susan Dettmer, Abigail Suwala, Ralf Ketter, Ghazaleh Tabatabai, Corinna Seliger, Martin Glas, Michael Burger, Marco Timmer, Florian Ringel, Iris Mildenberger, Walter Schulz-Schaefer, Mirjam Renovanz, Martin Bendszus, Felix Sahm, Michael Platten, Tobias Kessler
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND MGMT promoter methylation determines benefit from temozolomide (TMZ). Trials aiming at replacing TMZ with targeted agents in not molecularly selected patient populations have failed. Solid evaluation of the MGMT promotor methylation status is critical. METHODS The phase I/IIa umbrella trial NCT Neuro Master Match (N2M2) in patients with newly diagnosed glioblastoma aimed at showing safety, feasibility, and preliminary efficacy of targeted compounds in addition to radiotherapy. In five subtrials (alectinib, idasanutlin, palbociclib, vismogedib and temsirolimus) patients were included according to the best matching molecular alteration. Patients without matching alterations were randomized between atezolizumab, asunercept or TMZ as standard of care. Primary objective of the phase I parts of the trial was dose finding or dose validation. In the phase IIa trials, centrally determined progression-free survival at six months (PFS-6) is used as endpoint for efficacy with interim analyses for futility (H0: p=0.231). RESULTS From May 2018 through July 2022, 301 patients were enrolled and 228 treated in 13 German NOA sites. MGMT was determined locally and confirmed centrally by pyrosequencing as well as methylation arrays. The TMZ subtrial showed a PFS-6 of 18.52% (10/54 patients) (p=0.8311) and a median overall survival (mOS) of 12.1 months. Asunercept: PFS-6 of 15.4% (4/26) (p=0.8825) and mOS of 13.0 months. Atezolizumab: PFS-6 of 21.4% (9/42) (p=0.660) and mOS of 11.7 months. Palbociclib with patients demonstrating CDK4 amplification or CDKN2A/B codeletion: PFS-6 of 24.4% (10/41) (p=0.4823) and mOS of 12.6 months. Temsirolimus with patients demonstrating mTOR activation: PFS-6 of 39.1% (18/46) (p=0.0109) and mOS of 15.4 months. For the other arms, phase IIa has not been reached. CONCLUSIONS There is clinical activity of temsirolimus in patients with tumors harboring an activated mTOR pathway although this is not positively prognostic without mTOR inhibition; there is no clinical activity for asunercept and atezolizumab in not molecularly selected patients nor palbociclib in molecularly selected patients. Potential biomarkers will be discussed.
QOL-27. PATIENT REPORTED OUTCOME AND PREFERENCE AFTER CRANIOTOMY AND LASER THERMAL ABLATION: A PILOT STUDY
Authors: Isabela Peña Pino, Jiri Bartek, Clark Chen
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Laser interstitial thermal therapy (LITT) is a minimally invasive procedure that allows cytoreduction in the treatment of brain tumors and can be considered by both surgeons and patients as an alternative to craniotomy. OBJECTIVE We surveyed 27 patients who underwent both craniotomy and LITT during distinct stages of their oncology journey to assess patient reported outcomes comparing both procedures. METHODS A nine question survey was developed and validated to assess patient reported post-operative recovery, pain level, narcotic use, and procedure preference. The survey was administered to patients with WHO II-IV gliomas who underwent both craniotomy and LITT. RESULTS The survey was reviewed by independent surgeons, patient advocates, and patients in terms of face validity and showed &amp;gt;90% correlation in test-retest reliability. Our cohort had a mean age of 57 (+/- 12 years), 78% had glioblastoma. There was no significant difference in symptomatic improvement post-craniotomy or post-LITT (30% versus 4%, p=0.17). Similarly, no significance was detected in patient-reported recovery time from craniotomy (time required to return to pre-operative state, 4.3 +/- 9.1 weeks, median 2 weeks) or LITT (2 ± 2.3 weeks, median 1 week)(p=0.21). Notably, post-surgical pain (1-10 pain scale) and need for narcotic use in the first week (yes/no) after the procedure were significantly lower post-LITT (average pain score 1.7 versus 5 points, narcotic use 4% versus 81%, p&amp;lt;0.0005 for both comparisons). When asked which procedure they would choose – having experienced both craniotomy and LITT, surveyed patients overwhelmingly chose LITT over craniotomy (89% versus 11%, p&amp;lt;0.0005). Of note, the patients who preferred craniotomy experienced improved neurologic function post-craniotomy or suffered new deficits post-LITT. CONCLUSION In this pilot study, patients reported less pain and narcotic use post-LITT relative to craniotomy and generally preferred the former procedure if given the choice. Validation of these results in future studies can help inform decision making in clinical scenarios where there is equipoise between LITT and craniotomy.
NIMG-69. INTERROGATION OF GLIOBLASTOMA FATTY-ACID SYNTHESIS AND METABOLISM WITH DEUTERIUM METABOLIC IMAGING
Authors: Andrew Chang, Xia Ge, Kevin Cho, Elena Nunez, Gary Patti, Joel Garbow, Joseph Ippolito
Journal: Neuro-Oncology (2024)

Abstract Glioblastoma, an invariably lethal brain tumor, undergoes marked metabolic alterations during tumorigenesis and is extraordinarily difficult to treat. Detecting recurrence after treatment and understanding metabolic alterations within the tumor microenvironment are extremely challenging. An exciting and emerging imaging methodology, deuterium metabolic imaging (DMI), detects metabolic adaptations via non-radioactively labeled deuterated substrates. This study developed approaches to image lipid synthesis with deuterium oxide (D2O) and metabolism with D31-palmitate (D31-Pal) in glioblastoma. A fatty-acid phantom was generated for characterization of lipid DMI signal at 12 T. DMI was performed in mice orthotopically implanted with GL261 glioblastoma utilizing either orally administered D31-Pal or D2O and was correlated with pharmacokinetic metabolic measurements from mouse serum. Mice were either orally gavaged with an emulsion of D31-Pal prior to imaging or provided 16% D2O for ad libitum consumption following tumor implantation. Although D2O administration resulted in robust enrichment of lipid signal in GBM, D31-Pal uptake and metabolism were not significantly detected within intracranial tumors. Interestingly, D31-Pal uptake and metabolism were detected in normal tissues, indicating preferential utilization of fatty acids in non-neoplastic tissues. These findings suggest de novo lipogenesis within GBM, rather than uptake of administered long chain fatty acids, is the preferential pathway for cellular lipids. DMI can assist in interrogating GBM fatty-acid synthesis and metabolism, as well as furthering our understanding of lipid distribution within the body by providing a non-invasive scaffold for dynamic interrogation of fatty-acid distribution in an oncologic model. Developing a non-invasive method for characterization of tumor fatty-acid synthesis and metabolism may improve our understanding of tumor metabolism and could dynamically guide selection of patient-tailored metabolic therapies in the future.
NIMG-58. MACHINE LEARNING-GENERATED WHOLE-BRAIN RADIO-PATHOMIC TUMOR PROBABILITY MAPS WITHIN CONTRAST-ENHANCEMENT STRATIFY SURVIVAL IN GLIOBLASTOMA PATIENTS UNDERGOING GROSS-TOTAL RESECTION
Authors: Daniel Aaronson, Samuel Bobholz, Savannah Duenweg, Fitzgerald Kyereme, Allison Lowman, Biprojit Nath, Aleksandra Winiarz, Jennifer Connelly, E Kelly Mrachek, Max Krucoff, Anjishnu Banerjee, Peter LaViolette
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Even for those undergoing gross total resection (GTR), patients with WHO grade 4 glioblastoma (GBM) have poor overall survival (OS). Stratifying those who will have better OS vs. those that will not remains challenging, with conventional imaging and radiomic models falling short. This study utilizes machine learning (ML)-generated radio-pathomic models based on autopsy tissue as ground-truth to enhance prognostication through tumor probability maps (TPM) within preoperative contrast-enhancing (CE) regions of GBM. METHODS Data from the UCSF-PDGM-v2 and UPenn-GBM databases were analyzed, focusing on patients who underwent GTR with WHO 4 IDH-wildtype glioblastoma (n = 528). Preoperative tumor cellularity within CE was quantified using ML-generated TPMs, with a median threshold of 0.7242. Kaplan-Meier survival curves were employed to compare OS between patients with low (≤ 0.7242) and high (&amp;gt; 0.7242) TPM values in CE regions. Statistical significance was evaluated using log-rank tests. RESULTS Kaplan-Meier curves demonstrated significant stratification in survival outcomes based on TPM values. Patients with lower TPM values in CE regions had a median OS of 567 days, compared to 457 days for those with higher TPM values (log-rank p-value: &amp;lt; 0.001). These findings suggest that lower tumor cellularity in CE regions as assessed by TPMs correlates with improved survival, offering a more nuanced stratification than current MRI-based methods. CONCLUSION This study underscores the potential of TPM metrics as a powerful prognostic tool in GBM. The significant correlation between lower TPM values in CE regions and better median OS indicates that TPM can effectively stratify patients, aiding in clinical decision-making and personalized treatment planning. Future research is necessary to validate these findings in larger, diverse patient populations and to explore the biological mechanisms underlying these survival differences.
TMIC-11. THE EFFECTIVENESS OF VALPROIC ACID IN COMBINATION WITH TEMOZOLOMIDE FOR TREATMENT OF HIGH-GRADE GLIOMAS: A SYSTEMATIC REVIEW AND META-ANALYSIS
Authors: Eshita Sharma, Aisha Rizwan Ahmed, Paweł Łajczak, Anoushka Chatterjee, Maks Jagodzinski, Numa Rajab, Oguz Kagan Sahin, Dikshit Chawla, Oluwaseun Fagbamila, Yasmin Silva, Iago Nathan Simon Petry, Walter Fagundes
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND High-grade gliomas (HGGs) rapidly progress with a high recurrence rate and poor prognosis despite standard multimodal treatment. Valproic acid (VPA), a histone deacetylase inhibitor, sensitizes HGG to radiochemotherapy along with having potential anti-cancer mechanisms and augmenting the growth inhibitory effect of Temozolomide (TMZ). This study explores the effectiveness of VPA in combination with TMZ for treating patients with HGG. METHODS A comprehensive literature search was performed on PubMed, Scopus, Embase, and Web of Science databases and identified relevant studies (case-control, cohort, RCTs) comparing the synergistic effect of VPA during TMZ to TMZ without VPA. We investigated median overall survival (OS), Progression-free survival (PFS), and baseline MGMT methylation status to evaluate this relationship. RESULTS Our systematic review encompassed 9 studies involving 4,097 patients with HGGs (seven cohorts, one case-control, and one RCT). The pooled analysis of median OS demonstrated no statistical significance difference between VPA during TMZ and TMZ alone (MD=-3.97; 95%CI=-8.43-0.49; p=0.08). However, sub-analysis showed a statistically significant effect in studies with sample size &amp;lt;100 (MD=-5.06; 95%CI=-9.32,-0.80; p&amp;lt;0.02), and 100-200 (MD=-7.07; 95%CI=-13.15,-1.00; p&amp;lt;0.02), and those conducted before 2015 (MD=-5.62, 95%CI=-9.08,-2.17, p&amp;lt;0.01). On meta-regression analysis, no statistical significance (RC=0.82,95% CI=0.39,-2.03, p=0.18) was observed, indicating that the study year is not associated with the intervention. A separate analysis of 3 studies also showed no significant variance in the baseline percentage of patients without MGMT methylation (log OR=-0.35, 95%CI=-1.02,-0.32, p=0.30) when administering VPA during TMZ treatment (n=67) compared to TMZ alone (n=409). Additionally, VPA during TMZ does not significantly affect PFS (MD=-3.54; 95% CI=-10.18-3.10, p=0.30) compared to TMZ alone. CONCLUSIONS The concurrent use of VPA with TMZ shows no significant effect on OS and PFS, nor does it show any variance in the baseline MGMT methylation status compared to TMZ alone. However, smaller sample sizes show a significant effect. Thus, our findings emphasize the imperative for additional research aimed at refining clinical outcomes.
INNV-10. ULTRA-RAPID INTRAOPERATIVE GLIOMA TUMOR CELL QUANTIFICATION
Authors: Zacharmy Murphy, Emilia Bianchini, Andrew Smith, Lisa Koerner, Teresa Russell, David Reinecke, Yuxiu Wang, Matija Snuderl, Daniel Orringer, Gilad Evrony
Journal: Neuro-Oncology (2024)

Abstract The diagnosis and treatment of brain tumors often depends on molecular-genetic data. To date, however, there has been no intraoperative method to rapidly and iteratively utilize tumor-specific genetic alterations to guide brain tumor surgical resections, complicating intraoperative diagnosis and precluding measurement of tumor cell burdens at surgical margins. To address this gap, we developed Ultra-Rapid droplet digital PCR (UR-ddPCR), which can be completed in 15 minutes from tissue to result with an accuracy and sensitivity comparable to standard ddPCR. We demonstrate an UR-ddPCR assay for the IDH1 R132H clonal mutation that is present in many low-grade gliomas. We illustrate the clinical feasibility of UR-ddPCR by performing it intraoperatively for 49 samples from 13 glioma cases, achieving intraoperative quantification in an average of 14 minutes and 54 seconds spanning a wide dynamic range from 0.1% to 94% tumor cell percentages. We further combine UR-ddPCR measurements with UR-stimulated Raman histology intraoperatively to estimate tumor cell densities in addition to tumor cell percentages, across a wide range from &amp;lt; 1 to 1332 cells/mm2. We anticipate that UR-ddPCR, along with future refinements in assay instrumentation, will enable novel point-of-care diagnostics and the development of molecularly-guided brain tumor surgeries that improve clinical outcomes.
QOL-24. NEUROLOGIC AND NEUROCOGNITIVE OUTCOMES AMONG SURVIVORS OF INFANT-TYPE HEMISPHERIC GLIOMA (IHG)
Authors: Aditi Bagchi, Emily Hanzlik, Jason Chiang, Shelly Lensing, Martina Bryndziar, Jason Ashford, Anjali Singh, Raja B Khan, Amar Gajjar, Giles W Robinson, Arzu Onar-Thomas, Heather M Conklin
Journal: Neuro-Oncology (2024)

Abstract IHGs are large, hemorrhagic cerebral tumors associated with hydrocephalus, increased intracranial pressure, and herniation. Commonly diagnosed during early infancy, children with IHGs have an approximately 90% chance of overall survival when treated with surgery, chemotherapy, and, more recently, molecularly targeted therapies. However, there is limited understanding of long-term quality-of-life following treatment. Our study investigated long-term neurological and neurocognitive outcomes among IHG survivors. The medical database was reviewed for neurological sequelae and neurocognitive outcomes (intelligence [IQ], adaptive function, academic readiness) for 21 survivors. Median age of diagnosis and last follow-up were 0.8 (0.0-4.4) and 10.3 (4.8-17.6) years, respectively. Sixteen patients (76%) experienced atleast one neurological sequelae: 38% (8/21) had paresis/plegia; 24% (5/21) had spasticity, 26% (5/19) had abnormal speech, and 57% (12/21) had a long-term seizure disorder. Nine patients diagnosed with IHG at &amp;lt; 0.5 years had significantly higher rates of dysarthria (p = 0.019) and seizure disorders (p = 0.035) in follow-up in comparison to patients diagnosed at 0.5-1 year (n=4) and &amp;gt;1 year (n=8). Neurocognitive outcomes were available for 19 patients at a median of 6 years after diagnosis. Median IQ for the entire cohort was 68.0 (47.0-114.0), compared to normative expectations of 100 (SD = 15), with younger age at diagnosis associated with lower IQ (r = 0.36). Ten survivors experiencing seizures particularly had worse IQ scores (median 69.4 [47-101]). Survivors also had inferior outcomes in school readiness (median 46.0 [40.0-98.0]), compared to normative expectations of 100 (SD = 15), and adaptive function (median 48.0 [34.0-67.0]), compared to normative expectations of 50 (SD= 10), with younger age at diagnosis associated with lower performance for adaptive function (r = 0.45). CONCLUSION Children diagnosed with IHG have a high survival rate but experience substantial tumor-associated and treatment-related long-term morbidity. Future clinical trials should aim for better long-term quality of life for survivors through scientifically driven treatment modification.
QOL-12. ELECTRONIC ASSESSMENT OF QUALITY OF LIFE IN GLIOBLASTOMA PATIENTS USING THE EORTC-QLQ-C30/ EORTC-BN20 AND THE PROMIS SYSTEM IN CLINICAL PRACTICE
Authors: Tobias Walbert, Lonni Schultz, James Matthew Snyder, Josh D Mohn
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Patient reported outcomes are essential to guide patient-care and to maintain quality of life. We aim to further assess feasibility of computer adaptations of the Patient-Reported Outcomes Measurement Information System (PROMIS) questionnaire in the clinical setting and compare it with outcomes of the EORTC- QLQ-C30 and EORTC-BN20 questionnaires. METHODS Newly diagnosed patients with GBM were enrolled to assess feasibility. The PROMIS modules were selected to reflect the HRQoL domains assessed in the EORTC- QLQ-C30 and EORTC-BN20 questionnaires. PROMIS modules selected included anxiety, depression, fatigue, physical function, sleep disturbance, sleep-related impairment, social satisfaction role, applied cognitive ability and global health. EORTC instruments as well as PROMIS was answered to patients in the outpatient setting. Descriptive analysis was performed RESULTS 43 patients with 124 PROMIS/EORTC responses were included in this analysis. 31 patients completed the survey prior to or within 14 days of start of radiation, 12 patients completed a survey outside of the radiation window, and a total of 60 completed surveys were obtained between both patient groups. The median times to complete the EORTC-QLQ-C30 and the EORTC-BN20 surveys were 4.77 (range=2.05-18.6) and 2.63 (range=1.17- 24.83) minutes respectively. For the PROMIS instruments except global health, the median times to complete different modules ranged from 0.6- 1 minute (range= 0.15-7.77). For global health, the median time was 2.35 minutes (range= 1.02-21.12). Average time to complete all PROMIS questions was 8.65 minutes (range=3.32-66.01). CONCLUSIONS Real-time prospective assessment of the EORTC tools is similar to the PROMIS measures. While most response times were short, the ranges suggest that select patients might struggle. Patients were offered to participate online from home for convenience, but low computer literacy, limited internet access and burden of disease might limit participation.
SURG-17. SALVAGE SURGERY FOR LOCAL PROGRESSION AFTER RADIATION THERAPY OF BRAIN METASTASES
Authors: Hideyuki Arita, Toru Umehara, Koji Takano, Yoshiko Okita, Manabu Kinoshita
Journal: Neuro-Oncology (2024)

Abstract Recent advances in cancer treatments have prolonged survival after the onset of brain metastases (BM), and this trend increases the risk of local progression (LP) after radiotherapy (RT)of BM. Salvage options include surgical resection, re-irradiation and medical therapies, but there is no standard management for this clinical setting. This study aimed to evaluate the outcome of salvage surgery. We performed surgical resection for intracranial metastases in 221 cases in a single institution between Apr 2014 and Mar 2024. Of those, the data of the cases underwent initial surgery after irradiation for BM were extracted. After excluding duplicated cases and those underwent surgery within one month after irradiation, we finally analyzed 49 cases. Overall survival (OS) and local progression free survival (LPFS) were evaluated by Kaplan-Meier method. All but two cases had a history of stereotactic radiosurgery/radiotherapy for BM. Histopathological diagnosis of surgical specimens was tumor recurrence in 33 cases and radiation necrosis (RN) in 16 cases. RN cases showed longer duration between radiation and LP, when comparing with recurrent cases (median 42.3. vs. 9.3 months). OS was longer in RN cases than in tumor recurrent cases (median 68.5 vs. 26.9 months). In the recurrent cases, preoperative poor KPS (under 70), active state of extracranial lesions and RPA class were associated with shorter OS. Extent of resection, postoperative chemotherapy and local irradiation did not have significant impact on OS. Twenty cases experienced local recurrence after salvage surgery, and LPFS was 7.0 months. Any of extent of removal, postoperative chemotherapy and RT were not associated with LPFS. We reported relatively long survival after salvage surgery for local failure of BM after irradiation. Salvage surgery should be considered especially in patients with good extracranial control and performance status. High recurrence rate after salvage treatment urges the development of additional treatment approaches.