bluuebunny/crossref_metadata_2025 huggingface dataset:
NCOG-21. ADJUVANT RADIATION THERAPY IN ATYPICAL MENINGIOMA TREATMENT DOES NOT IMPROVE PROGRESSION FREE SURVIVAL OR OVERALL SURVIVAL: A RETROSPECTIVE COHORT STUDY
Authors: Kagithala Dheeraj , Rademacher Anneliese , Pawloski Jacob , Latack Katie , Fadel Hassan , Dallo Florence , Snyder James , Lee Ian , Robin Adam
Published: November 2024

Treatment of atypical meningiomas (AMs) presents a challenge due to their aggressive nature and tendency to recur. While there is clear evidence for the role of surgical resection of AMs, the use of adjuvant radiation therapy (ART) is a topic of ongoing debate. The aim of this study is to explore the impact of ART following surgical resection of AMs. The primary outcomes of interest are progression free survival (PFS) and overall survival (OS). Records were reviewed for all patients treated for Ams at our institution between January 1, 2014 and January 1, 2024. Patients were grouped into two cohorts, those who were initially treated with surgical resection only and those who also received adjuvant RT. PFS and OS were compared between the two groups using Kaplan Meier curves and Log Rank test. Additionally, multivariable cox proportional hazard models were used to adjust for age, MIB, and resection Simpson grading. There were 76 patients who were initially treated with surgery only and 23 patients who had surgery and ART. No significant difference in PFS or OS was observed between the groups (p=0.3522 and p=0.3636, respectively); including after adjusting for age, MIB, and Simpson grading (HR= 1.55 [0.64-3.76], p= 0.330; and HR = 0.95 [0.31-2.93] p= 0.934, respectively). On multivariate analysis, MIB >10 was associated with a significant difference in PFS (HR=2.76 [1.15-6.59], p=0.023). With ART, PFS was 91% at 12 and 60% at 36 months (versus 89% and 57%, respectively, with surgery only). OS was 95% at 12 and 88% at 36 months (versus 91% and 85%, respectively, with surgery only). In this series, ART was not observed to significantly improve PFS or OS compared to surgery alone. Larger series are needed to determine if there is a subset of patients who benefit from ART.
NCOG-28. SERUM PROTEIN BIOMARKERS LINKED TO NEURODEGENERATIVE PROCESSES ARE ELEVATED IN GLIOMA PATIENTS AND ASSOCIATED WITH SEVERITY OF NEUROLOGIC SYMPTOMS
Authors: Hsieh Emory , Mendoza Tito , Raval Dhaivat , Kauss McKenzie C , Slattery Kaitlynn , Wright Michelle L , Davis Tara S , Choi Ann , Reinhart Kimberly , Miller Hope , Vera Elizabeth , Penas-Prado Marta , Gilbert Mark R , Armstrong Terri S , Guedes Vivian A
Published: November 2024

BACKGROUND

Glioma patients frequently report neurologic symptoms, adding to the complexity of cancer management and negatively impacting quality of life. However, mechanisms associated with the development of neurologic symptoms in glioma patients remain unclear. Pathological changes in the brain of glioma patients might result in elevated peripheral blood levels of proteins previously linked to central nervous system (CNS) damage and neurodegeneration, including neurofilament light chain (NfL), tau, and glial fibrillary acidic protein (GFAP). Here, we tested the hypothesis that the circulating levels of these proteins in blood are elevated in glioma patients and associated with the severity of neurologic symptoms.

METHODS

Patients (n=73) were enrolled in a natural history study (NCT02851706, PI T. Armstrong). Healthy subjects (n=39) were recruited by the National Institutes of Health Clinical Center Blood Bank. Neurologic symptom severity and walking interference were assessed using MD Anderson Symptom Inventory-Brain Tumor (MDASI-BT). Serum proteins were analyzed using ultrasensitive assays (Meso Scale Discovery).

RESULTS

Participants were predominantly white (patients 74%, healthy subjects 67%) and male (patients 58%, healthy subjects 54%). The median age was 44 (range=24,74) for patients and 49 (range=19,78) for healthy volunteers. No significant differences in age, sex, or race were observed between patients and healthy subjects. Serum levels of NfL (p<0.0001), GFAP (p<0.0001), and tau (p<0.0001) were higher in glioma patients when compared to healthy subjects. Patients with walking interference had higher levels of GFAP (p=0.003), NfL (p=0.003), and tau (p=0.004), and those who reported numbness had higher levels of GFAP (p=0.012).

CONCLUSIONS

These findings suggest that serum levels of protein markers of neurodegeneration are elevated in glioma patients and associated with the presence of neurologic symptoms. Blood-based biomarkers have the potential to shed light on the mechanisms underlying symptoms and offer a non-invasive alternative for monitoring CNS damage that impact patient outcomes.
NCOG-31. NEUROCOGNITIVE OUTCOME FOLLOWING AWAKE CRANIOTOMY FOR INSULAR GLIOMA RESECTION: IMPACT OF SURGICAL APPROACH AND TUMOR CLASSIFICATION
Authors: Noll Kyle , Bander Evan D , de Almeida Romulo A Andrade , Seaman Scott , Banu Matei , Clark Victoria E , Suki Dima , Wefel Jeffrey S , Bradshaw Mariana , Ferguson Sherise , Weinberg Jeffrey S , Prabhu Sujit S , Lang Frederick F
Published: November 2024

BACKGROUND

Insular glioma resection harbors similar risk of neurocognitive function (NCF) decline as other tumor locations. However, differences in outcomes according to transsylvian versus transcortical surgical approach and tumor classification remain unknown.

METHODS

53 patients with newly diagnosed insular glioma (47% high-grade; 23% GBM; 75% left hemisphere) underwent awake craniotomy for resection (transsylvian, 64%; transcortical, 36%). Patients completed neuropsychological testing preoperatively and <2 months postoperatively (M interval=23.7 days). Tumor location was described with Berger-Sinai zones collapsed into anterior (I and/or IV), posterior (II and/or III), superior (I and/or II), and inferior (III and/or IV) groups. Tumor extension was characterized with the Pitskhelauri system into insula only, insula with extension (lobar or medial), and predominantly (>50%) extra-insular groups. Result: Decline (z-score change<-1.0) on at least 1 test occurred in 85% of patients with largest effect (partial η2) in memory (.29–.44) and verbal fluency (.39). There was no interaction with approach on any NCF change score, though transcortical was associated with more frequent fluency decline (61% vs. 26%, p=.014). Left hemisphere tumor was associated with poorer outcome on 6/12 tests (all p<.01). Predominantly extra-insular tumors showed greater reductions in fluency (M=-1.21, SD=0.90) than insula only tumors (M=-0.10, SD=0.76; p=0.024). Number of Berger-Sanai quadrants involved was inversely associated with change in executive functioning (r=-0.34, p=.018). Poorer executive function outcome was also found in anterior (M=-0.61, SD=1.41) versus posterior tumors (M=0.86, SD=1.51; p=.014), and recognition memory outcome worse for inferior (M=-2.44, SD=1.81) than superior lesions (M=-0.31, SD=1.47; p=.021).

CONCLUSIONS

NCF decline is common in the early term following resection of insular glioma. While risk of verbal fluency decline may be greater for transcortical surgeries, outcomes were largely similar across approaches. In addition to hemisphere, tumor extension and insular zone localization may inform domain-specific risk of NCF decline following resection.
NCOG-32. RELATIONSHIPS BETWEEN INTRAOPERATIVE TASK-BASED GAMMA BAND ELECTROCORTICOGRAMS, DIRECT ELECTRICAL STIMULATION, AND COGNITIVE-LINGUISTIC OUTCOME FOLLOWING AWAKE BRAIN TUMOR RESECTION
Authors: Noll Kyle , Tasnim Israt , Asman Priscella , Swamy Chandra , Connelly Katherine , Muir Matthew , Hall Matthew , Pellizzer Guiseppe , Ince Nuri , Prabhu Sujit
Published: November 2024

BACKGROUND

As an adjunct to direct electrical stimulation (DES), intraoperative electrocorticography (ECoG) can aid detection of language-eloquent cortex. However, it is unclear how surgical impact upon mapping findings relates to cognitive-linguistic outcomes.

METHODS

Ten patients underwent awake craniotomy for tumor resection with ECoG and DES language mapping. Mapping utilized iPad stimulus presentation coupled to an electrode array capable of both recording ECoG activity and delivering DES. Time-frequency gamma band activations were visualized (Early, Long, Late, Double Peak) for 3 naming paradigms (Object, Action, Auditory). DES was also conducted for each task. Mapping results were overlayed on postoperative MRI to examine proximity to parenchymal trauma (cavity, sulcal displacement). Patients completed cognitive-linguistic testing [WAB-R (N=3) or Neuropsychological Assessment (N=7)] prior to surgery and <2 months postoperatively. Patients with persisting aphasia at 6-month follow-up were also identified.

RESULTS

Postoperative language decline was found in 50% of patients, with 30% showing worsening (>1SD) in Naming and Phonemic Fluency, and 60% in Semantic Fluency. Surgery impacted ECoG features in 60% of patients and DES arrest sites in 30%. A trend was observed where Early and Late Object naming ECoG features were associated with Semantic Fluency decline [rpb(5)=-.69, p=.067]. Arrest during Auditory naming DES <1 cm of surgical effect was associated with decline in Abstraction [rpb(5)=-.83, p=.042; FET, p=.029] and Semantic Fluency [rpb(5)=-.87, p=.012; FET, p=.024]. Excluding the 3 transsulcal surgeries, arrest during Auditory naming DES <1 cm of resection was associated with general language decline [FET, p=.047]. All 3 patients with persisting aphasia had Auditory naming arrest <1 cm of resection and 2/3 patients had Object naming ECoG features resected.

CONCLUSIONS

While preliminary, results suggest that surgical proximity to ECoG and DES mapping results may inform risk of surgically-acquired cognitive-linguistic decline. Findings support the potential of multimethod-multitask intraoperative language mapping.
NCOG-36. CLINICAL AND DEMOGRAPHIC CHARACTERISTICS PREDICT POSTOPERATIVE BEHAVIORAL DYSFUNCTION FOLLOWING HIGH-GRADE (WHO 2-4) GLIOMA RESECTION
Authors: Ambati Vardhaan , Kaur Jasleen , Hervey-Jumper Shawn
Published: November 2024

BACKGROUND

Gliomas have the highest incidence (85%) of cancer-related cognitive and behavioral impairments. Few studies have explored preoperative clinical and demographic drivers/predictors of postoperative behavioral impairment.

METHODS

We analyzed prospectively collected data from patients 1) who underwent glioma (WHO 2-4) resection and 2) who had postoperative Flanker testing, an assessment of inhibitory control and selective attention (NIH Toolbox Cognition Battery). Patients whose age-adjusted Flanker score (last follow-up) was less than the cohort mean were classified as having “poor” outcomes. Univariate analysis, multivariate logistic, and LASSO regressions were performed to identify drivers of poor outcomes.

RESULTS

In total, 43 patients (mean age at diagnosis 45.9 [range 18-77] years, 35% female) met inclusion criteria. The average age-adjusted Flanker score was 83.3±13.6; twenty (46.5%) patients had below-average scores. On univariate analysis, there were no significant differences in demographic factors (age, sex, education, employment) and tumor characteristics (grade, location). Multivariate logistic regression identified having high school versus higher degree (OR:1.6x10^4, p=0.017), WHO Grade 4 versus Grade 2 (OR:2.36, p=0.026), and parietal lesion (OR:1.6x10^3, p=0.034) as risk factors, while increased age (OR per 1-year increase:0.71, p=0.009) and dominant language hemisphere lesion (OR 0.002, p=0.048) were protective against poor behavioral outcome. LASSO regression (efficiently narrows down predictors) identified higher WHO grade (4 vs. 2), lower education (high school vs. higher), and insular and parietal lesions as predictive of poor outcomes. Increased age at diagnosis, frontal lobe lesions, and lesions on the dominant language hemisphere were protective.

CONCLUSION

Lower education status, higher WHO grade, and insular and parietal lesions are risk factors for poor behavioral outcomes postoperatively following glioma resection. In contrast, increased age, frontal lobe lesions, and dominant language hemisphere lesions were positive prognostic factors. Neuro-oncologists may use these findings to preoperatively counsel patients and tailor care plans with necessary postoperative support.
NCOG-43. THE APPLICATION OF INDUCTION CHEMOTHERAPY COMBINED WITH RADIOTHERAPY IN YOUNG ADULTS WITH CNS GERM CELL TUMORS
Authors: Liu Hao , Nahm Josh , Ware Cornelius , Hsu Sigmund , Amsbaugh Mark , Blanco Angel , Zhu Jay-jiguang
Published: November 2024

BACKGROUND

Central nervous system (CNS) germ cell tumors are rare brain neoplasms, accounting for approximately 0.3-0.5% of all CNS tumors. A combination of radiotherapy and chemotherapy is the standard of care (SOC) in pediatric patients. However, there is no SOC for young adult or adult patients. This study evaluates a regimen of induction chemotherapy followed by radiation in treating young adults with CNS germ cell tumors.

METHOD

Nine young adult patients diagnosed with pure CNS germinomas were identified in our institution. They underwent a treatment regimen of induction chemotherapies that were planned for four cycles and consisted of bleomycin (three doses per cycle), cisplatin (five doses per cycle) and etoposide (five doses per cycle) followed with whole brain and/or ventricular radiotherapy. The patients’ overall survival (OS), neurological function (including cognition), and adverse events (AE) were analyzed.

RESULT

Among the nine patients (seven males and two females), the median age is 20 years (range: 17-33 years). They received bleomycin, cisplatin and etoposide (median: two cycles, range: 1-4), and subsequent radiotherapy with plans based on tumor location by radiation oncologists, with a median radiotherapy dose of 45 Gy (range: 36-50.4). Seven patients had a complete response after chemotherapy. The median OS is 53 months (range: 39-121). There is no identifiable cognitive impairment by neurological exam. All patients experienced at least one, reversible, grade 3 AE of myelosuppression. All patients return to their normal baseline including employment. Results of neuropsychological evaluation and all AEs will be presented at the conference.

CONCLUSION

Induction chemotherapy followed by radiotherapy is potentially safe and effective with manageable and reversible side effects from chemotherapy without cognitive and functional impairment in the nine young adult patients with CNS germ cell tumors. A prospective study of this approach in a clinical trial setting is warranted.
NCOG-44. EXPLORING THE IMPACT OF PRE-OPERATIVE MAJOR DEPRESSIVE DISORDER ON POSTOPERATIVE OUTCOMES IN PATIENTS UNDERGOING SURGICAL EXCISION OF MENINGIOMAS
Authors: Sallese Greta , Kandhadai Anuttham , Brindley Paul
Published: November 2024

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-47. DEFINING PERIOPERATIVE RISK FACTORS IN STEREOTACTIC BRAIN BIOPSIES AMONG DIFFERENT HISTOLOGIC DIAGNOSES
Authors: Tripathy Arushi , Harake Edward , Saleh Sara , Al-Holou Wajd
Published: November 2024

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 < 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= <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<0.001). Of the 15 cases of symptomatic hemorrhage, there was a significantly greater representation of glioma patients (p<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.
NCOG-49. EFFICACY OF POSTOPERATIVE RADIOTHERAPY AFTER GROSS TOTAL RESECTION FOR INTRACRANIAL SOLITARY FIBROUS TUMORS: A SYSTEMATIC REVIEW AND META-ANALYSIS
Authors: Min Kwon Sae , Na Min Kyun
Published: November 2024

BACKGROUND

The efficacy of postoperative radiotherapy (PORT) after gross total resection (GTR) for intracranial solitary fibrous tumors (SFT) remains unclear as previous studies yielded inconsistent results. Therefore, this study aimed to clarify this uncertainty using a comprehensive meta-analysis. By evaluating and synthesizing data from relevant studies, we sought to investigate the role of PORT, as compared with surgery alone, in survival outcomes after GTR of intracranial SFT.

METHODS

We conducted a systematic literature search, adhering to PRISMA guidelines, using Medline, Embase, and the Cochrane Library to identify relevant literature. The outcomes of interest included progression-free survival (PFS), overall survival (OS), and metastasis-free survival (MFS) at 3, 5, and 10 years, respectively. Differences between the two cohorts (GTR+PORT vs. GTR only) were estimated by calculating the hazard ratios. Results. Twelve studies, including data from 419 patients (PORT, n = 225 vs. surgery only, n = 194), were selected for meta-analysis. Pooled hazard ratios revealed that the PORT cohort showed sustained superiority in both PFS and OS over the surgery-only cohort after GTR of the tumor. These results were consistent with those of a subgroup analysis that focused on grade 2 and 3 intracranial SFT. However, no significant improvement was observed in MFS with PORT addition. Conclusion. The present study underscores the importance of PORT in enhancing the PFS and OS of patients with intracranial SFT after GTR. These findings suggest that PORT should be considered an effective treatment strategy for all patients with intracranial SFT, irrespective of the extent of resection.
EXTH-01. EFFICACY OF PERAMPANEL AGAINST GLIOBLASTOMA CELLS
Authors: Yamamuro Shun , Nishide Takuma , Nara Kaoru , Aida Yumi , Yazawa Genki , Ohyama Kentaro , Ozawa Yoshinari , Yoshimura Sodai , Sano Emiko , Yoshino Atsuo
Published: November 2024

We investigated the antitumor effect of perampanel, which is the AMPA-type glutamate receptor antagonist widely used as an antiepileptic drug in Japan, on glioblastoma cells both in vitro and vivo. Commercially available glioblastoma cell lines (A-172, AM-38, T98G, U-138MG, U-251MG and YH-13) and newly established glioblastoma cell line 0125-DGC were used in the experiments. First, the antitumor effect of perampanel was evaluated by cell counting assay. The number of surviving cells after administrating drugs (perampanel, carbamazepine, sodium valproate, levetiracetam, and temozolomide) was counted. The cell proliferation inhibitory effect was observed in all cell lines after administration of perampanel and temozolomide. The antitumor effect was greater when perampanel and temozolomide were used together than when they were used alone. Next, we investigated the mechanism of the antitumor effect of perampanel on glioblastoma cells using FACS, western blotting, RT-PCR, and transwell assay. The expression levels of apoptosis-related proteins and mRNAs on glioblastoma cells were increased after administration of perampanel. Furthermore, perampanel demonstrated the inhibitory effect on the migration of glioblastoma cells. Finally, we evaluated the antitumor effect of perampanel in vivo. U-87MG cells were transplanted into the brains of immunodeficient mice, and these mice were treated by perampanel and/or temozolomide. The transplanted mice were divided into an untreated control group, a perampanel treatment group, a temozolomide treatment group, and a combination treatment group. As a result, survival times were significantly prolonged in all treatment groups compared to the untreated control group. Notably, survival times in the combination therapy group was significantly longer than in the monotherapy group. These results revealed that perampanel exhibits antitumor effects on glioblastoma cells by inducing apoptosis and suppressing cell migration ability. Furthermore, perampanel may enhance the antitumor effect of temozolomide for glioblastoma when it used as combination therapy.
EXTH-06. DEVELOPMENT OF ANTISENSE OLIGONUCLEOTIDE THERAPY AGAINST ZFTA-RELA EPENDYMOMA
Authors: Laboe Nicholas , Gee David , Bertrand Kelsey , Agnihotri Sameer , Mack Stephen
Published: November 2024

Treatment for ependymoma (EPN), the third most common pediatric brain tumor, has not changed in the last 30 years, consisting of surgery and radiotherapy. When EPNs relapse, there are very limited therapeutic options, thus highlighting a dire need for more effective treatment for these tumors. Over 95% of supratentorial EPN are driven by ZFTA fusion oncoproteins, the most common variant being ZFTA-RELA. ZFTA fusion oncoproteins (FO) alone are sufficient to drive tumors in murine models. We hypothesize that: these tumors continue to depend on ZFTA-RELA expression, and that the FO represents a lead target for therapeutic development.

RESULTS

To assess this dependency, we utilized CRISPR-Cas9 mediated knockout (KO) of ZFTA-RELA oncoproteins from a series of patient derived cell lines as compared to control cells. We found that ZFTA FO driven patient models were dependent upon ZFTA FO expression, and KO led to impaired cellular proliferation. To determine whether a reduction in FO protein levels would also be sufficient to reduce tumor growth, we screened a series of antisense oligonucleotides (ASOs) for ZFTA FO knockdown efficiency in patient-derived cell lines. We quantified knockdown efficiency by western blot and selected the top-performing ASOs targeting a functionally important zinc finger domain of ZFTA. Top-performing ASOs reduced tumor cell proliferation in single dose experiments by 50%, while a non-targeting ASO treated population was unaffected. Repeated ASO doses over 96 hours saw a 75% reduction compared to a 10% reduction in the non-targeting group.

CONCLUSION

Our findings suggest that ZFTA-RELA drives tumor initiation and continued maintenance and proliferation of EPN. Tumor proliferation can be slowed by reducing FO levels below a required threshold. ASO therapy, potentially in combination with translation inhibitors, is one promising route for targeted treatments in this aggressive EPN subtype and could be expanded against other EPN driver proteins such as EZHIP.
EXTH-13. COMBINED ANTI-ANGIOGENIC TREATMENT TO INCREASE INTRATUMORAL PERSISTENCE OF CAR T-CELLS IN LUNG CANCER BRAIN METASTASES
Authors: Blobner Jens , Eberle Constantin , Dengler Laura , Beck Alexander , Müller Katharina J , Teske Nico , Xu Tao , Karschnia Philipp , Ishikawa-Ankerhold Hellen , Thon Niklas , Tonn Joerg-Christian , Subklewe Marion , Kobold Sebastian , Harter Patrick N , Buchholz Veit R , von Baumgarten Louisa
Published: November 2024

BACKGROUND

Metastatic lung cancer, especially when it spreads to the brain, shows a devastating prognosis. Immunotherapeutic approaches including CAR T-cells show promise in hematologic malignancies. However, the presence of immunosuppressive factors within the tumor microenvironment and physical barriers like elevated interstitial pressure due to dysfunctional tumor vessels are one of the main obstacles especially in solid tumors. Evaluation of the potential synergy between anti-angiogenetic drugs and CAR T-cells in this context are an ongoing investigation.

METHODS

Here, we set up an immunocompetent syngeneic orthotopic cerebral metastasis model in mice by combining a chronic cranial window with repetitive intracerebral two-photon laser scanning microscopy (TPLSM). This model allows in vivo characterization of fluorescent tumor cells and CAR T-cells on a single cell level over time. Intraparenchymal injection of red fluorescent EpCAM-transduced Lewis Lung carcinoma cells (EpCAM/tdtLL/2 cells) followed by injection of EpCAM-directed or undirected CAR T-cells into the adjacent brain tissue was performed. Additionally, aVEGF-A combined with aVEGF-R2 and the respective isotype control were injected intraperitoneally.

RESULTS

Compared to undirected CAR T-cells, mice receiving EpCAM-directed CAR T-cells showed higher intratumoral CAR T-cell densities after intraparenchymal injection. This finding was accompanied with reduced tumor growth and eventually translates into a survival benefit. However, intratumoral CAR T-cell numbers diminish over time indicating insufficient persistence inside of the tumor microenvironment. Additional anti-VEGF-A/VEGF-R2 treatment results in reduced tumor growth after EpCAM/GFPCAR T-cell and GFPT-cell treatment, respectively. Interestingly, in vivo imaging reveals higher intratumoral CAR T-cell numbers after anti-angiogenic treatment compared to isotype controls pointing towards enhanced CAR T-cell persistence resulting in a survival benefit.

CONCLUSION

Collectively, our findings indicate that locally injected CAR T-cells may safely induce relevant anti-tumor effects in brain metastases from lung cancer. Additional anti-angiogenic treatment provides a mechanism to enhance intratumoral CAR T-cell persistence and reduce tumor growth.
EXTH-16. UNBIASED DISCOVERY OF SYNERGISTIC VULNERABILITIES AGAINST GLIOBLASTOMA: AN INNOVATIVEIN VIVO CRISPR PROFILING PLATFORM TO UNLEASH THE POWER OF TUMOR-TARGETED CYTOKINE THERAPY
Authors: Sakic Irma , Uijttewaal Esther C H , De Luca Roberto , Puca Emanuele , Weller Michael , Neri Dario , Elling Ulrich , Weiss Tobias
Published: November 2024

BACKGROUND

Glioblastoma poses a formidable challenge due to its intricate intra- and intertumoral heterogeneities and its associated immunosuppressive milieu. The standards of care have limited activity, and no major advances have been made in decades. One promising avenue is tumor-targeted cytokine-based therapies, particularly L19-TNF, which is undergoing clinical trials in Europe and the US for patients with newly diagnosed and recurrent glioblastoma. However, there is still an opportunity to find safer and more tolerable combination partners to improve the efficacy of L19-TNF immunotherapy. To address this challenge, we employed a cutting-edge in vivo CRISPR screening approach to identify synergistic vulnerabilities with a focus on druggable targets.

METHODS

We systematically investigated the dependencies of tumor growth and key signaling pathways under the pressure of L19-TNF immunotherapy in the CT-2A orthotopic murine glioma model. We used an innovative in vivo CRISPR screening approach that enables timed sgRNA activation to mitigate off-target effects and overcome orthotopic tumor cell implantation challenges, such as the bottleneck of cell engraftment.

RESULTS

We first conducted a genome-wide in vivo screen and identified 400 top-scoring candidate genes, which we subsequently tested again in a targeted in vivo screen to refine our drug selection process. Through this, we uncovered novel and previously unexplored druggable targets for glioblastoma. Out of these, we validated four promising target-specific drugs in preclinical glioblastoma models in downstream in vivo experiments. In addition, we investigated modes of action and resistance.

CONCLUSION

Our research marks a significant advancement in pursuing novel treatment strategies for glioblastoma. We have unveiled a range of synergistic combinations and paved the way for the rational design of combinatory treatment approaches to maximize the therapeutic efficacy of L19-TNF immunotherapy, laying the groundwork for future clinical translation.
EXTH-20. EXPLORING EUPHOL’S THERAPEUTIC EFFECT IN ADULT AND PEDIATRIC BRAZILIAN HIGH-GRADE GLIOMAS PRE-CLINICAL MODELS
Authors: Baroni Mirella , Tshikawa Leticia , Megid Raquel , Scremim Flavia , Gomes Izabela , Teixeira Gustavo , Lopes Luiz Fernando , Mançano Bruna , Polverini Allan , Lombardi Ismael , Junior Carlos , Teixeira Silvia , Reis Rui
Published: November 2024

High grade gliomas (HGG) are among the most aggressive brain tumors affecting both adults and children. Adult HGG (aHGG) account for almost 25% of all brain tumors in adults, with glioblastoma (GBM) being the predominant subtype. Pediatric HGG (pHGG), though less common, accounts for 3-15% of primary brain tumors in children and exhibits distinct genetic profiles compared to aHGG. Standard treatment for HGG in both adults and pediatric patients includes maximal surgical resection followed by temozolomide (TMZ)-based chemotherapy and radiation therapy. Our group previously reported that euphol, a natural compound derived from the sap of Euphorbiaceae family plants, exerts cytotoxicity effects on glioma cells. In this study, we investigated the therapeutic potential of euphol in primary cell cultures and xenograft models derived from six Brazilian HGG patients, including three adults and three pediatrics. In vitro, euphol exposure significantly reduced cell viability reduction, clonogenic capacity, and migration, while enhancing apoptosis in all six primary cultures. Additionally, euphol sensitized glioma cells to TMZ, resulting in a synergistic cytotoxic effect. In vivo, euphol reduced tumor growth in both GBM and pHGG models, and prolonged the survival of mice in the GBM orthotopic experiment. These findings highlight the promising therapeutic potential of euphol for treating high-grade gliomas in both adult and pediatric populations.
EXTH-22. TARGETING MITOCHONDRIAL PROTEASE IN DIFFUSE GLIOMAS
Authors: Kim Olga , Sergi Zach , Yu Guangyang , Li Qi , Lu Peng , Hsia Ru-Ching , Robey Robert , Chari Raj , Wang Herui , Tran Bao , Andresson Thorkell , Gottesman Michael , Liu Zhenggang , Graves Lee , Iwanowicz Edwin , Wu Jing
Published: November 2024

BACKGROUND

Targeting mitochondrial function has emerged as a promising therapeutic strategy in cancer treatment. TR107 is characterized as a specific activator of caseinolytic protease proteolytic subunit (ClpP) in the mitochondria, potentially affecting oncogenic pathways. Here, we investigated the effects of TR107 on adult malignant gliomas, IDH-wildtype and IDH-mutant

METHODS

We utilized patient-derived glioma cells to determine the efficacy of TR107 with cell viability, proliferation, cell cycle, and apoptosis assays. Immunofluorescent staining and electron microscopy (EM) were employed to uncover organelle morphological changes upon treatment. Mitochondrial function and ATP production were assessed in live cells utilizing Seahorse analysis. Global proteomics and RNA sequencing were performed to identify treatment-induced dysregulated pathways in glioma cells

RESULTS

Both IDH-wildtype and IDH-mutant glioma cell lines were highly sensitive to TR107, showing at least 100 times lower IC50 compared to the related compound ONC201. Genetic knock out of ClpP revealed that the growth inhibitory effects of TR107 are ClpP-dependent. Interestingly, IDH-mutant cell lines showed a more profound disintegration of mitochondrial morphology and dysregulation of mitochondrial function evidenced by an enhanced suppression of oxidative phosphorylation, mitochondrial complexes expression, mtDNA copy number, complex I activity, and ATP production, compared to IDH-wildtype cells. Six days of treatment with TR107 led to a complete inhibition of cell growth and up to 97% of cell death in IDH-mutant cells, while 50% of IDH-wildtype cells remained viable. Western blot, EM, and RNAsequencing analyses uncovered autophagy as a potential pro-survival mechanism in IDH-wildtype cells. Importantly, multiple metabolic and DNA repair-related pathways were affected by the treatment, suggested by global proteomics and RNA sequencing. Finally, TR107 was not affected by ABC transporters, supporting its potential use in brain tumor patients

CONCLUSION

TR107 demonstrated potent cytotoxic effects in patient-derived glioma cells by disrupting mitochondrial structural and functional integrity. TR107 efficacy in vivo is under investigation.
EXTH-24. THERAPEUTIC TARGETING OF MISLOCALIZED NUCLEAR ENVELOPE PROTEINS INMYC-DRIVEN GROUP 3 MEDULLOBLASTOMA
Authors: Suk Yujin , Ibañez-Vega Jorge , Chaudhry Iqra , Rossotti Martin , Subapanditha Minomi , Miletic Petar , Custers Stefan , Escudero Laura , Delaidelli Alberto , Nakashima Takuma , Xiao Yuxi , Moffat Jason , Suzuki Hiromichi , Sorensen Poul , Henry Kevin , Venugopal Chitra , Krenciute Giedre , Singh Sheila
Published: November 2024

Medulloblastoma (MB) is the most common, malignant pediatric brain tumour comprised of four distinct molecular subgroups (WNT, SHH, Group 3, and Group 4). A subset of Group 3 MB tumors harbors focal amplifications of the MYC oncogene (MYC-G3MB) and are particularly prone to tumour recurrence due to their highly proliferative nature linked to its embryonic stem cell-of-origin and programming. We discovered that LBR, an inner nuclear transmembrane protein, while present in all cells at the nuclear envelope (NE), is aberrantly presented to the cell surface in MYC-G3MBs. Transcriptomic profiling of publicly available datasets identified significant NE protein enrichment in MYC-G3MB compared to normal tissue and high expression during fetal development that dampens postnatally and in adult samples. Immunohistochemistry analysis of LBR on patient tumors was able to significantly prognosticate overall and progression free survival. Flow cytometry analysis identified LBR cell surface expression in MYC-G3MBs with low to no expression in human neural stem cells and other MB subgroups. High resolution microscopy of endogenously tagged LBR revealed cell surface presentation to be linked to ER-like vesicles that directly trafficked to the cell surface in MYC-G3MBs. Transcriptomic analysis of LBR cell surface positive and negative cells identified LBR to be linked to mitotic processes and mislocalization was significantly enriched following exposure to chemotherapy and radiation in vitro and in vivo. Therefore, we demonstrate that LBR is an ideal therapeutic target for patients facing treatment-refractory MB and have generated single domain antibodies (sdAb) to develop LBR-CAR T cells. Validation of LBR sdAbs demonstrate on-target binding and comparable affinity and avidity to commercial LBR antibodies. There is an undeniable paucity of targets for MB patients stemming from the lack of neoantigens and genomic aberrations in pediatric tumors. The preclinical development and validation of novel immunotherapeutic targets such as LBR provides alternative therapies for patients otherwise facing palliation.
EXTH-28. DEVELOPING A NOVEL INJECTABLE IMMUNOTHERAPEUTIC GEL FOR ENCAPSULATION OF NATURAL KILLER CELLS FOR POST-SURGICAL GLIOBLASTOMA TREATMENT
Authors: Huang Chiungyin , Chen Pinyuan , Wei Kuochen
Published: November 2024

Malignant brain tumors are one of the leading causes of death among all cancers. Approximately 40,000 people are diagnosed with malignant brain tumors every year. Among these patients, 15,000 cases are glioblastoma (GBM) with a very poor prognosis; even after aggressive surgical resection and adjuvant chemo/radiotherapy, the median survival is only 14.6 months. The major reason for poor prognosis is the blood-brain barrier, which prevents therapeutic agents from reaching the target area. Therefore, there are only a few choices of drugs available for brain tumor treatment. To date, temozolomide (TMZ) and the Gliadel wafer have been clinically used as standard chemotherapy agents after brain tumor resection. However, drug resistance to TMZ and the poor drug diffusion rate of the Gliadel wafer still result in ineffective suppression of residual cancer cells. To overcome the above-mentioned difficulties in clinical brain tumor treatment, in situ self-crosslinking multifunctional hydrogels was developed to carry natural killer cells (NK cells) and radiosensitizers as a novel brain tumor treatment system. Unlike traditional hydrogels catalyzed by pH value or temperature, this new system is stable and consistent as an immune cell carrier. We used fibrinogen, thrombin, and alginic acid as the backbone of the in situ self-crosslinking hydrogel, tested the properties of the synthesized hydrogel, and analyzed the gel-formation time and swelling rate. The release rate of NK cells was also examined. In a brain tumor animal model, the use of hydrogel-NK cells significantly inhibited tumor proliferation and prolonged animal survival time. In conclusion, this therapeutic hydrogel carrying NK cells can serve as a novel post-operation adjuvant therapeutic tool for malignant brain tumors.
EXTH-32. DUAL TARGETING OF CD155/TIGIT AND PD-L1/PD-1 IMMUNE CHECKPOINTS POTENTIATES NATURAL KILLER CELL-MEDIATED CYTOTOXICITY IN MEDULLOBLASTOMA
Authors: Monnikhof Matthijs , Schakelaar Michael , Meulenbroeks Chris , Quist Matthias , Perzolli Alicia , Selten Aimee , Koster Celeste , Maassen Daniëlle , Canelo Alba Montoro , Fredriks Maureen , Kaludjerovic Vela , Meeldijk Jan , Pijnappel Emma , Rebel Heggert , van Kempen Sven , Crnko Sandra , Frederico Aniello , Wesseling Pieter , Calkoen Friso , van der Lugt Jasper , ten Broeke Toine , Kool Marcel , Bovenschen Niels
Published: November 2024

Medulloblastoma (MB) is one of the most prevalent pediatric brain malignancies and makes up approximately 20% of all primary brain tumors in children. Current treatment options are not curative for about 30% of patients and leave survivors with an impaired quality of life. Immune checkpoint inhibition can offer a novel targeted therapy but largely remains understudied in MB. The aim of this study was to determine whether immune checkpoint inhibition can be used as a novel targeted therapy in MB. We used MB cell lines, MB patient-derived xenograft (PDX) organoid models, and primary patient-derived MB tissue to study immune checkpoints and their blockade to target MB. We identified the expression of immune checkpoint protein TIGIT on immune cells and its high-affinity ligand CD155 in medulloblastoma patient-derived tissues, cell lines, and PDX MB organoids. In addition, while MB shows weak, if any, PD-L1 protein expression, we found that MB cells can upregulate PD-L1 expression upon stimulation by natural killer (NK) cells via interferon-γ as a putative immune evasive strategy. Subsequent immunotherapeutic interventions with FDA-approved antibodies Tiragolumab (anti-TIGIT), Durvalumab (anti-PD-L1), and their combination potentiated primary NK cell activation and killing of MB cell lines and PDX-derived MB organoids. These data propose a translatable and novel immunotherapeutic strategy for patients diagnosed with MB.
EXTH-35. REPURPOSING OF CLINICALLY APPROVED GLUTAMATE ANTAGONISTS TO TREAT GLIOBLASTOMA
Authors: Uriach Dasca Julia , Marashli Samuel , Holland Eric C , Weller Michael , Wirsching Hans-Georg
Published: November 2024

The neurotransmitter glutamate plays a fundamental role in promoting epilepsy and tumor progression in glioblastoma. Glioblastoma cells secrete glutamate into the tumor microenvironment via the cystine-glutamate antiporter system Xc, leading to neuronal hyperexcitability, excitotoxicity, and tumor cell invasion. Additionally, glutamatergic neuroglioma synapses drive glioma progression in preclinical tumor models. To pharmacologically counteract effects of glutamate in glioblastoma, we employed a triple combination of anti-glutamatergic drugs: gabapentin, sulfasalazine, and memantine, which target glutamate synthesis, release, and post-synaptic signaling, respectively. In genetically engineered murine glioblastoma models, daily treatment with this triple combination prolonged median survival. This survival benefit was not observed with single or double drug combinations, nor with the standard antiepileptic drug levetiracetam, indicating the potential synergy and efficacy of this drug combination beyond merely treating epilepsy. Importantly, these preliminary results support the rationale for the ongoing phase Ib/II randomized clinical trial GLUGLIO, which explores the efficacy of combined gabapentin, sulfasalazine, and memantine in conjunction with standard chemoradiotherapy in patients with newly diagnosed glioblastoma (NCT05664464).
EXTH-50. THYROID HORMONE-INDUCED DIFFERENTIATION: A PROMISING THERAPEUTIC STRATEGY FOR MEDULLOBLASTOMA
Authors: Yang Yijun , Valdes-Rives Silvia , Ronsley Rebecca , Leary Sarah , Wechsler-Reya Robert , Yang Zeng-jie
Published: November 2024

Medulloblastoma (MB) is the most common malignant brain tumor in children, consisting of four major subgroups (WNT, SHH, Group 3, and Group 4) that differ in genetic/epigenetic profiles and prognoses. Despite current therapy, a significant proportion of patients still succumb to MB. Moreover, survivors often suffer severe side effects from aggressive treatments. Therefore, improved strategies to treat MB are urgently needed. MB tumor cells retain the capacity for differentiation and can undergo terminal differentiation, after which they lose their proliferative and tumorigenic capacity. This suggests that MB can potentially be treated by inducing tumor cell differentiation. However, the mechanisms underlying MB tumor cell differentiation remain unclear. Our recent studies reveal that thyroid hormone (TH) plays a critical role in promoting tumor cell differentiation in MB. Reduced TH levels free the TH receptor, TRα1, to bind to EZH2 and repress the expression of NeuroD1, a transcription factor that drives tumor cell differentiation. Increased TH levels reverse the EZH2-mediated repression of NeuroD1 by disrupting the binding between EZH2 and TRα1, thereby stimulating tumor cell differentiation and reducing MB growth. Importantly, triiodothyronine (T3, active form of TH) inhibits the growth of both SHH- and Group 3 tumors, suggesting that the tumor-inhibitory effect of T3 is not restricted by MB subgroups. Additionally, this effect is significantly enhanced by concurrent chemotherapy. These findings establish an unprecedented association between TH signaling and MB pathogenicity, providing solid evidence for TH as a promising therapeutic modality for MB treatment.
EXTH-51. ENHANCING GLIOBLASTOMA TREATMENT: ALLOGENEIC CAR-T CELLS OVERCOMES FUNCTIONAL DEFICITS OF PATIENT-DERIVED AUTOLOGOUS PRODUCTS
Authors: Vaseem Shaikh Muhammad , Salim Sabra K , Maich William T , Ananad Alisha , Wei Jeffrey , Subapanditha Minomi K , Suk Yujin , Singh Manoj , Tabunshchyk Zoya , Chen Katie , Vora Parvez , Venugopal Chitra , Moffat Jason , Singh Sheila K
Published: November 2024

Glioblastoma (GBM) is the most common primary brain malignancy in adults, with a dismal prognosis despite an intensive standard of care. Recently, chimeric antigen receptor T-cell (CAR-T) therapy has shown promising outcomes in treating liquid malignancies. However, clinical trials targeting various tumor antigens in GBM failed to show durable clinical benefit. Though this may stem from various tumor-intrinsic immune evasion strategies typical of GBM, there has been little work investigating whether the problem lies in the quality of the CAR-T products treatment itself. Currently, CAR-T cells for clinical studies are produced in an autologous setting, where T-cells are extracted from patients, engineered ex-vivo, and then re-infused. However, peripheral T-cells taken from GBM patients have shown qualitative and functional deficits, which may contribute to suboptimal treatment outcomes. Thus, we aimed to explore whether CAR-Ts generated from GBM patients had any functional deficits in comparison to healthy donors, utilizing our previously validated CD133 CAR-T. In this study, we show pre-treatment exhaustion, poor tumor control, and reduced survival advantage in autologous, patient-derived CD133-targeting CAR-T cell products using an orthotopic xenograft model of human GBM. To address the functional and logistical considerations of autologous therapy, we also sought to generate an “off-the-shelf” allogeneic CD133 CAR-T. Using CRISPR gene editing technology, we generated TCR-knockout CAR-T cells with comparable pre-clinical efficacy to our healthy donor derived autologous models. Ultimately, this work highlights the need to reevaluate autologous CAR-T therapy for GBM and consider allogeneic approaches as biologically-informed therapeutic alternatives.