bluuebunny/crossref_metadata_2025 huggingface dataset:
NCOG-07. SAFETY OF ONC201 TREATMENT IN PATIENTS WITH PREVIOUSLY TREATED H3 K27M-MUTANT GLIOMA: RESULTS FROM ONC028, AN ONGOING COMPASSIONATE USE PROGRAM
Authors: Sharma Akansha , Aiken Robert , Korones David N , Koschmann Carl , Lubes Jourdan , Gardner Sharon L , Morrison Marion , Ramage Samuel C , Tarapore Rohinton S , Odia Yazmin
Published: November 2024

PURPOSE

H3 K27M-mutant diffuse midline glioma (DMG) has a poor prognosis, with a median overall survival of 1 year and no proven treatments beyond radiotherapy. ONC201 (dordaviprone), a first-in-class imipridone, previously demonstrated durable responses in patients with recurrent H3 K27M-mutant DMG. The present analysis reports safety data from ONC028, a compassionate use program (CUP) for patients with previously treated H3 K27M-mutant glioma.

METHODS

ONC028 is an expanded access program that provides ONC201 monotherapy to patients with H3 K27M-mutant glioma. Eligible patients are adults or pediatric patients with H3 K27M-mutant glioma, prior therapy including at least radiation, and adequate organ function. Patients must be ineligible for enrollment in other ongoing clinical studies evaluating ONC201. ONC201 is administered orally once weekly at 625 mg or dose-equivalent based on body weight for pediatric patients. MRIs are performed every two 28-day cycles for the initial 12 months, thereafter every 2-3 cycles. Treatment continues until disease progression, unacceptable adverse events (AEs), or withdrawal of consent. Treatment may continue post-progression at the discretion of the treating physician. Bevacizumab use for radiation necrosis or symptom management is acceptable. AEs are assessed by NCI CTCAE v5.0 criteria.

RESULTS

The 422 enrolled patients include 191 adults (45.2%) and 231 children (54.7%); 87.1% had a performance score ≥60 and the most common tumor location was the pons (57.3%). Any-causality Grade ≥3 AEs have been reported in 200 patients (47.4%). Grade ≥3 treatment-related AEs (TR-AEs) were reported in 19 (4.5%) patients; the commonest was decreased lymphocyte count, occurring in 3 (0.7%) patients. Any-causality serious AEs (SAE) were reported in 43.1% (n=182) patients. There were 10 (2.4%) patients with reports of treatment-related SAEs, the commonest were ascites, nausea, vomiting, and seizure, each occurring in 2 patients (0.2%).

CONCLUSIONS

ONC028 provides expanded access to ONC201 treatment for patients with previously treated H3 K27M-mutant glioma who are ineligible for enrollment in ongoing trials of ONC201. ONC201 treatment remains well-tolerated.
NCOG-10. LONGITUDINAL MULTIDISCIPLINARY MONITORING OF NEUROCOGNITIVE FUNCTION FOR COLLOID CYST RESECTION: THE IMPACT OF SURGERY
Authors: Tosi Umberto , Sacks-Zimmerman Amanda , Villamater Francis , Spat-Lemus Jessica , Perrine Kenneth , Souweidane Mark , Bender H Allison
Published: November 2024

Endoscopic resection of colloid cysts, a rare pathology of the third ventricle, is now accepted clinical practice. Owing to their location proximal to numerous deep gray nuclei and to the forniceal columns, colloid cysts have always been feared to cause cognitive decline, whether operated on or not. Detailed cognitive testing before and after endoscopic resection, however, has rarely been described. Thus, out objective was to determine the neurocognitive effects of endoscopic colloid cyst resection. We analyzed formal pre- and postoperative neuropsychological testing performed in 20 patients undergoing endoscopic colloid cyst resection. Performance was compared either for each individual patient on a test-by-test basis or according to aggregated neuropsychological factor scores grouped via expert census. A clinical change was defined significant if (i) reaching statistical significance, and (ii) it was greater than 1.5 times the standard deviation of the preoperative performance distribution. Overall, 20 adult patients with colloid cysts (diameter 13.3 ± 1.3 mm) underwent matched pre- and postoperative testing generating 679 data points. No patient had a significant change in cognitive performance. When neurocognitive metrics assessing cognitive functions typically subsumed by the temporal (p = 0.35), extratemporal (p = 0.20), occipitoparietal (p = 0.31), or frontal lobes (p = 0.11), no statistically significant difference was observed between pre- and postoperative cognitive performance. No significant differences emerged when factor scores were generated according to composite score of different neurocognitive domains: attention (p = 0.32), executive function (p = 0.14), language (p = 0.98), and visuospatial function (p = 0.42). In conclusion, neuropsychological testing allows for the careful longitudinal monitoring of cognitive status and the identification of patients who may benefit from pre- and postoperative cognitive rehabilitation, and should be used as a valuable surgical psychometric marker and adjuvant. No significant cognitive decline was observed, again confirming the safety of endoscopic colloid cyst resection.
NCOG-11. FACTORS PREDICTING SPEECH AND GAIT RECOVERY IN CHILDREN WITH POST-OPERATIVE POSTERIOR FOSSA SYNDROME (PFS)
Authors: Hanzlik Emily , McAfee Stuart , Scoggins Matt , Lin Tong , Raches Darcy , Conklin Heather , Szymanek Kristin , Robinson Giles , Gajjar Amar , Onar-Thomas Arzu , Bag Asim , Khan Raja
Published: November 2024

Posterior fossa syndrome/cerebellar mutism syndrome is a surgical complication of posterior fossa tumor resection, especially midline tumors. Initially thought to involve complete mutism, PFS is now recognized as a complex syndrome involving loss of language (complete [PFS1] and incomplete [PFS2]). Additional symptoms include apraxia, movement disorder, motor and coordination deficits, and emotional lability. The aim of this study was to identify factors that influence delayed speech and independent gait recovery in children with PFS. We prospectively studied 73 children ≥3 years of age with medulloblastoma who developed PFS (SJMB12, NCT01878617). Enrolled children received standardized neurologic examinations and serial imaging before, during and up to five years after completion of therapy. Neurological examinations included scale for assessment and rating of ataxia (SARA), CTCAE grading of neurologic deficits, and severity of injury to the superior cerebellar peduncles (SCP) on post-operative MRI. Median time to speech recovery was 1.4 months (range 0.3-14.3); 81% had return of speech at 3 months and 97% at 12 months. On multivariable Cox regression analysis, complete mutism (HR 0.17, p<0.0001) and inability to sit (HR 0.40, p=0.001) were associated with delayed speech return. Independent ambulation was regained by 80.8% at a median of 2.3 (range 0.3-71.3) months. 70% had a return of ambulation at 12 months and 77% at 24 months. On multivariable Cox regression analysis, complete mutism (HR 0.32, p=0.016), inability to sit (HR 0.30, p=0.002), SARA score (HR 0.94, p=0.002), and right SCP injury (HR 0.47, p=0.014) were significantly associated with delayed return of ambulation. Presence of mutism, inability to sit unassisted, higher SARA score, and right SCP injury at the time of PFS diagnosis are associated with time to recovery of speech/language and ambulation. Our findings have prognostic implications for families and to help identify children in need of more intensive interventions.
NCOG-20. RADIATION-RELATED MORBIDITY OUTCOMES IN ATYPICAL MENINGIOMA PATIENTS: A RETROSPECTIVE COHORT STUDY
Authors: Rademacher Anneliese , Kagithala Dheeraj , Pawloski Jacob , Latack Katie , Fadel Hassan , Dallo Florence , Snyder James , Lee Ian , Robin Adam
Published: November 2024

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 < 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.
NCOG-25. STEREOTACTIC RADIOSURGERY VERSUS SURGICAL MICRODISSECTION FOR JUGULAR FORAMEN SCHWANNOMAS: A RETROSPECTIVE COMPARATIVE STUDY
Authors: Akhavan-Sigari Amirhossein , Park David J , Hori Yusuke S , Persad Amit R L , Emrich Sara C , Ustrzynski Louisa , Tayag Armine , Chang Steven D
Published: November 2024

INTRODUCTION

Jugular foramen schwannomas (JFS) are rare, benign tumors arising from lower cranial nerves. Given their delicate location, surgical microdissection carries a substantial risk of neurological morbidity. Stereotactic radiosurgery (SRS) presents an alternative, particularly for smaller or residual tumors.

OBJECTIVE

This study aims to compare the outcomes and symptomatic improvements between these two treatment modalities.

METHODS

We conducted a retrospective analysis of 32 patients with JFS who underwent SRS (13 cases [40.6%]) or surgical dissection (19 cases [59.4%]) as their primary management at Stanford Medical Center between 1998 and 2024. Outcomes included progression-free survival (PFS), post-management adverse events based on common terminology criteria for adverse events (CTCAE), symptom improvement, overall survival (OS), and the necessity for secondary interventions.

RESULTS

Significant differences were observed in baseline characteristics between the SRS and surgery groups, including mean age (62.52 vs. 46.87 years, p<0.001), mean largest diameter (34.38 vs. 53.66 mm, p=0.02), and median total tumor volume (6.50 vs. 19.70 mm3, p=0.009). There were no significant differences in sex or lesion shape (dumbbell vs. non-dumbbell shaped). After adjusting for baseline characteristics, no significant differences were noted in PFS (85.71 vs. 77.77%), OS (92.3 vs 100%), symptom improvement (61.53 vs. 52.63%) or mean CTCAE grade (1.31 vs. 1.58) between the SRS and surgery groups. SRS patients had significantly lower odds of requiring secondary treatment procedures after their primary intervention as compared to those in the surgery group (OR=0.01, 95% CI: 0.0001-0.59, p=0.02).

CONCLUSION

Both SRS and surgery provide exceptional outcomes for JFS with no significant differences in PFS, OS, CTCAE grades, or symptom improvement between the two groups. However, SRS patients had lower odds of requiring secondary interventions for JFS. This is among the first studies comparing surgical microdissection and SRS for JFS. Future controlled prospective studies are necessary to derive more definitive conclusions.
NCOG-27. HIGHER LEVELS OF SERUM ICAM-1 AND IL-10 ARE ASSOCIATED WITH COGNITIVE DYSFUNCTION IN BOTH IDH-WILDTYPE AND IDH-MUTANT GLIOMA
Authors: Guedes Vivian A , Mendoza Tito , Slattery Kaitlynn , Kauss McKenzie C , Raval Dhaivat , Hsieh Emory , Wright Michelle L , Davis Tara S , Choi Ann , Reinhart Kimberly , Miller Hope , Vera Elizabeth , Penas-Prado Marta , Gilbert Mark R , Armstrong Terri S
Published: November 2024

BACKGROUND

Cognitive dysfunction is common among glioma patients, but the contribution of specific mechanisms to the development of cognitive symptoms is unclear. Circulating levels of proteins linked to neurodegeneration, inflammation, and vascular damage have been associated with cognitive symptoms in neurological diseases and aging, but their prognostic value in glioma is unknown. Here, we examined associations between cognitive symptoms and serum levels of protein biomarkers in glioma patients.

METHODS

Cognitive function was evaluated using the Montreal Cognitive Assessment (MoCA, scores ≤ 25 = cognitive dysfunction). Cytokines (interleukin-1β [IL-1β], IL-2, IL-4, IL-6, IL-8, IL-10, IL-12p70, IL-13, interferon-γ [IFN-γ], tumor necrosis factor-α [TNF-α]), and neurodegeneration (neurofilament light chain [NfL], tau, glial fibrillary acidic protein [GFAP]), and vascular damage markers (Serum amyloid A [SAA], C-reactive protein [CRP], vascular cell adhesion molecule 1 [VCAM-1], and intercellular adhesion molecule 1 [ICAM-1]) were measured using ultrasensitive assays (Meso Scale Discovery).

RESULTS

Patients (n=73) were predominantly male (58%), white (74%), with a median age of 44 (range=24,74). Cognitive dysfunction was found in 53% of the patients. Levels of NfL (p=0.035), IL-6 (p=0.006), IL-10 (p=0.007), TNF-α (p=0.035), IFN-γ (p=0.011), CRP (p=0.016), VCAM-1 (p=0.012), and ICAM-1 (p<0.001) were higher in patients with cognitive dysfunction when compared to those with normal cognition. After adjusting for isocitrate dehydrogenase (IDH) tumor mutation status, age, tumor grade, and number of surgeries, higher levels of ICAM-1 and IL-10, but not other markers, remained associated with cognitive dysfunction. MoCA scores were negatively correlated with GFAP (r=-0.24, p=0.038), IFN-γ (r=-0.31, p=0.008), IL-6 (r=-0.29, p=0.014), IL-10 (r=-0.24, p=0.039), and ICAM-1 (r=-0.39, p<0.001).

CONCLUSIONS

ICAM-1 and IL-10 levels were higher in patients with MOCA determined cognitive dysfunction, suggesting an association between cognitive symptoms and inflammation and vascular impairment in glioma patients. Future analyses in larger longitudinal cohorts are warranted to assess the predictive value of protein biomarkers.
NCOG-29. HIGHER HYPOTHALAMIC RADIATION DOSE AND FEMALE GENDER ARE RELATED TO HIGHER SELF-REPORTED FATIGUE
Authors: Neth Bryan , Alden Eva , Sener Ugur , Uhm Joon , D’Andre Stacy , Burns Terry , Amundson Adam , Routman David , Trifiletti Daniel , Vora Sujay , Mahajan Anita , Laack Nadia , Brown Paul , Breen William
Published: November 2024

BACKGROUND

Fatigue is among the most common symptoms managed by patients with cancer. Hypothalamic pituitary axis dysfunction has an established role in a subset of patients with fatigue. Our primary aim was to longitudinally assess the impact of hypothalamic radiation exposure to patient self-reported fatigue.

METHODS

We included a sample of patients who received radiation therapy treated at a single institution from 2014-2024. The PROMIS-10 questionnaire (“How would you rate your fatigue on average,” scale 1-5) was used in standard clinical practice, with measures from 6 time points over 2 years. We performed descriptive statistics. Linear mixed models were used to assess the impact of hypothalamic radiation dose on fatigue scores. Mixed models were controlled for gender, age, time, tumor category (CNS vs. non-CNS), and modality (photon vs. proton). Models were fit with random intercepts for each Patient ID.

RESULTS

1092 patients (43% female) with a median age of 54 years (range: 18-92) were included. Most patients were treated for CNS cancer (76%), with about 50% each photon and proton. Median hypothalamus radiation dose was 1306 cGy (range: 0.01-6138). Mean baseline fatigue (2.4) increased after treatment (2.7) remaining elevated at 3- and 6-months post-treatment (2.6, 2.5), returning near baseline at 1- and 2-years post-treatment (2.4, 2.3). Higher radiation dose (Estimate (SE): 0.014 (0.006), p=0.0266) and CNS cancer treatment (0.11 (0.051), p=0.0319) were significant predictors of higher fatigue in the mixed model. Male patients (-0.16 (0.042), p=0.0001) and time (-0.003 (0.0016), p=0.0398) were associated with lower fatigue. Age and treatment modality were not significant predictors of fatigue.

CONCLUSIONS

We found that higher hypothalamic radiation dose was related to more self-reported fatigue, which peaked by 6 months. This effect was seen more prominently in female patients and those treated for CNS disease. Treatment modality and age did not influence fatigue scores.
NCOG-37. SINGLE CENTER EXPERIENCE OF IDH INHIBITORS IN THE TREATMENT OF RECURRENT HIGH GRADE GLIOMAS
Authors: Garcia Catherine , Highsmith Kaitlin , Knight Stephanie , Puduvalli Vinay , Kamiya-Matsuoka Carlos
Published: November 2024

BACKGROUND

The antitumor effect of IDH inhibitors in high grade gliomas (HGG) is not well known, with conflicting views regarding the role of IDH status and the potential for resistance to DNA damage treatments. We present the outcomes of patients with HGG that were treated with IDH inhibitors at our institution.

METHODS

We performed a retrospective review of patients with IDH mutant gliomas treated with FDA approved IDH inhibitors (ivosidenib and enasidenib) in the past 5 years at our institution. One cycle of IDH inhibitor was defined as treatment for 28 days.

RESULTS

We identified 10 HGG patients (both oligodendrogliomas and astrocytomas). Median age at diagnosis was 31 years and 7 were male. Seven patients were diagnosed as WHO grade 3. Six patients were WHO grade 3 oligodendrogliomas, three WHO grade 4 astrocytomas, and one patient WHO grade 3 astrocytoma. Only one patient received enasidenib and the rest were treated with ivosidenib. Eight patients were started on IDH inhibitors after 3 recurrences. Median number of cycles was 5. One patient received 23 cycles, and one patient received 11 cycles. All patients underwent resection, 4 received chemotherapy (including temozolomide, bevacizumab, and CCNU), and 4 radiation prior to starting IDH inhibitors. One patient was treated with Tumor Treating Fields. Five patients progressed during the study follow up, and 3 patients died. Four patients are still on treatment. No serious adverse events. Median PFS after starting an IDH inhibitor was 6 months.

DISCUSSION

IDH inhibitors were well tolerated in IDH mutant HGG patients previously treated with DNA-damaging agents. It may have a role in the treatment of HGG with multiple recurrences with 3 patients showing stable disease for more than 18 months. More studies are needed to clarify the role of IDH inhibitors in patients with IDH mutant HGG.
NCOG-40. RARE ADVERSE EFFECT OF TEMOZOLOMIDE IN A 65-YEAR-OLD FEMALE WITH GLIOBLASTOMA MULTIFORME: A CASE REPORT
Authors: Jain Ujjwala , Desai Prashant
Published: November 2024

BACKGROUND

Temozolomide, an antineoplastic agent is primarily used to treat certain brain tumors, including glioblastoma multiforme (GBM). Common side effects include nausea, vomiting, constipation, loss of appetite, alopecia (hair loss), headache, fatigue, convulsions and rash. A rare (less than 1%) adverse effect includes aplastic anemia refractory to treatment. Herein we present a case of Temozolomide induced severe bone marrow suppression in a 65-year-old woman with GBM refractory to any treatment

CASE PRESENTATION

A 65-year-old female presented with dizziness and left-hand numbness. Imaging revealed a right hemisphere mass and she underwent partial resection with pathology showing GBM, IDH wildtype, with CDKN2A/B deletion. She was started on radiation therapy with concurrent temozolomide. After nearly 5 weeks of temozolomide/RT, she developed severe thrombocytopenia/neutropenia with onset of neutropenic fever and severe CMV infection, leading to her demise within a week.

DISCUSSION

Life threatening refractory cytopenias is a very rare side effect of Temozolomide with a high rate of morbidity/mortality. In the case of our patient, she initially had weekly CBC’s which were stable and hence was switched to a monthly schedule. The patient’s ANC and platelets showed a precipitous drop within a month and ended up with aplastic anemia. The development of this rare complication underscores the importance of increased awareness about this often-fatal adverse event and possibly more frequent monitoring to recognize it early, especially in these patients with an already limited life expectancy. A more tailored approach to monitoring blood work may be needed depending on patient factors.

CONCLUSIONS

Aplastic anemia refractory to treatment is a rare and life threating adverse effect of temozolomide. The frequency of checking blood work for patients on Temodar has not been definitively established with protocols ranging from once weekly to monthly. Given the potential for this fatal adverse event, it is important to develop better tools to help identify patients in whom more frequent monitoring may be necessary.
NCOG-41. COMPARATIVE ANALYSIS OF MORTALITY AND SHORT-TERM SIDE EFFECTS IN PATIENTS WITH GLIOBLASTOMA MULTIFORME TREATED WITH TEMOZOLOMIDE VERSUS TEMOZOLOMIDE PLUS BEVACIZUMAB CHEMOTHERAPY
Authors: Sallese Greta , Kandhadai Anuttham , Brindley Paul
Published: November 2024

INTRODUCTION

Glioblastoma multiforme (GBM) is a highly aggressive primary brain tumor in adults with limited treatment options and poor prognosis. Temozolomide (TMZ) chemotherapy is the standard treatment for GBM, but alternative therapies have shown limited success. Bevacizumab (BEV), a monoclonal antibody targeting vascular endothelial growth factor (VEGF), is used to restrict GBM growth and spread. This study evaluates the efficacy of combining TMZ with BEV compared to TMZ alone in managing GBM.

METHODS

A retrospective cohort study was conducted using TriNetX database data, focusing on patients diagnosed with GBM and receiving chemotherapy. Cohorts were defined by treatment: TMZ plus BEV versus TMZ alone. Propensity-score matching balanced baseline characteristics, including demographics and health conditions. Primary outcomes included mortality rates and short-term side effects within the first year of treatment, such as cognitive communication deficits, headache, dizziness, insomnia, and nausea/vomiting.

RESULTS

After matching, 922 patients were included in each cohort. There were no significant demographic differences post-matching. The mortality rate was higher in the TMZ plus BEV group compared to TMZ alone (51.30% vs. 36.98%, RR: 1.387, 95% CI: 1.249-1.541). However, TMZ plus BEV was associated with a lower incidence of cognitive communication deficits (1.95% vs. 4.34%, RR: 0.45, 95% CI: 0.26-0.779) and dizziness (7.27% vs. 10.52%, RR: 0.691, 95% CI: 0.513-0.93). No significant differences were found in headache, insomnia, or nausea/vomiting rates between the groups.

CONCLUSION

This study indicates that combining bevacizumab with temozolomide may increase mortality in GBM patients but reduce certain side effects such as cognitive deficits and dizziness. These findings emphasize the need to carefully consider the benefits and risks of different chemotherapy regimens for GBM and highlight the necessity for further research to optimize treatment strategies and improve patient outcomes.
NCOG-42. SPEECH-SPECIFIC ERRORS IN LEXICAL RETRIEVAL PREDICT GLIOMA MOLECULAR FEATURES
Authors: Kaur Jasleen , Persad Amit , Oten Sena , Hervey-Jumper Shawn
Published: November 2024

Recent work confirms that low and high-grade gliomas, remodel neural circuits which influence speech production. The extent to which speech kinetics and category of speech error during lexical retrieval may predict glioma molecular features remains unknown. Here, we extracted audiovisual speech production from 550 patients totaling over 26,400 individual stimuli to identify correlations with glioma molecular features including IDH, TERT, 1p19q co-deletion, and CDK2AB. Nonparametric statistics were used for analysis. IDH wild-type tumors were more likely to be temporoparietal, while IDH mutant tumors were more likely to be insular (p=0.02). Patients with IDH wild-type glioblastoma exhibited more errors (8.23 vs 3.79, p=0.02), with a higher occurrence of anomia (p=0.004), circumlocution (p=0.034) and general delay (p=0.04) when compared with IDH mutant WHO grade 4 astrocytoma. Binomial logistic regression identified lexical retrieval anomia, circumlocution, and initiation delays as an independent predictor of having an IDH wild-type tumor. Within the IDH mutant group, anomia (p=0.03) and articulation (p=0.014) errors were associated with malignant molecular features (after controlling for prognostic variables such as tumor volume). Binomial logistic regression identified articulation or anomia for picture naming as an independent risk predictor for WHO grade 2 gliomas with greater risk molecular features (based on Ki67 and CDK2AB). Distinct patterns of language errors were observed in patients with IDH wild-type and IDH mutant tumors. Further work is required to elucidate the functional and biological correlates of these findings.
NCOG-48. CT SCAN COMPOSITE SCORE CAN IDENTIFY GLIOBLASTOMA PATIENTS WITH WORSE OUTCOMES
Authors: Rahmani Farzaneh , Ippolito Joe
Published: November 2024

OBJECTIVE

Obesity is a risk factor for many cancer types including glioblastoma multiforme (GBM). We used CT body composition analyses to construct a sex-specific composite score that would optimally predict overall survival in GBM.

METHODS

Using a retrospective institutional cohort, we performed single slice (L3) and volumetric (L1-L5) automated body segmentation analyses on abdominal and pelvic computed tomography (CT) scans performed within 1 month of diagnosis of GBM. Multivariable Cox proportional hazards models were then used to identify variables that were independently associated with GBM overall survival. Lastly, a learning-tree algorithm was implemented to identify the relative importance of body composition metrics using a XGBoost-powered learning model. These weights were used to create sex-specific composite CT scan scores of protective and predisposing factor with relation to GBM survival. A log-rank pairwise t-test was used to compared GBM survival across patient groups stratified based on these CT composite scores.

RESULTS

Higher relative inter/intramuscular adipose tissue volume (HR(95%CI):1.9(1.01-3.06), p=0.02), visceral adipose tissue volume (HR(95%CI):2.1(1.04-4.1), p=0.04) and aortic calcification volume (HR(95%CI):2.6(1.2-5.5), p<0.001) were associated with lower GBM overall survival, while higher subcutaneous adipose tissue volume (HR(95%CI):0.4(0.2-0.8), p=0.02), iliopsoas muscle volume (HR(95%CI):0.4(0.2-0.9), p<0.001), and trabecular bone density (HR(95%CI):0.4(0.1-0.8), p=0.003) were predictive of higher GBM OS (p-value of all tests <0.05). Using quartiles of the CT scan composite predisposing and protective scores, we were able to stratify male and female participants with significantly different outcomes with regards to GBM OS (Figure). Male and female participants with higher burden of predisposing factors had significantly lower chances of survival compared to those with lower cumulative burden of these factors (Figure, p-value Q4 vs. Q1 males< 0.01 and 0.001 in females)

CONCLUSION

Using automated body segmentation analysis we optimized a CT scan composite score that was able to stratify GBM patients with worse overall survival.
NCOG-50. LONG TERM-SURVIVAL OF AN ELDERLY PATIENT WITH GIANT CELL CEREBELLUM GLIOBLASTOMA (GBM)
Authors: Ma Chunxiao , Choi Yoon Jae , Lomax Jerica , Ko Uvin , Fu Dan Beverly , Myung Joon , Kong Xiao-Tang
Published: November 2024

INTRODUCTION

Primary cerebellar glioblastoma (GBM) in adult is very rare and accounts for 1% of all GBM. Giant cell variant cerebellar GBM is even rarer. Because of the rarity, its molecular feature, the response to the standard treatment, and biological behavior of tumor progression are not well understood.

CASE REPORT

An 80 yo male presented with headache, nausea, vomiting and ataxia in 2019. Brain MRI was notable for a large enhancing cerebellar mass. Surgical resection was completed, and pathology was giant cell GBM. Molecular studies showed IDH-wildtype, CDKN2A/B copy number loss, positive TP53 G262V mutation as well as KIT and KDR amplification. The patient underwent standard 6-week concomitant temozolomide (TMZ) and radiation therapy. He only completed 3 cycles of low dose adjuvant temozolomide and two cycles of lomustine due to intolerance of both chemotherapy agents. After that the patient has been off treatment and received brain MRI surveillance over past 4 years. Two years later, his brain MRI showed new punctuate lesions in the radiation field. Suspecting the radiation necrosis; the patient underwent observation. Later, more nodular enhancing lesions developed at the outside region of the radiation field. Tumor progression was considered but the patient wished no biopsy or re-radiation. The new small nodular lesions on MRIs over past two years have behaved unusually with small fluctuations among mild progression, stabilization, or regression. His physical functions have been preserved with a Karnofsky Performance Status scale of 90% with normal cognition.

DISCUSSION

The patient, who is now 85 years old, has surpassed a 4.5-year survival mark, which is remarkable compared to the supratentorial and the cerebellar GBM with a few months’ survival mark in elderly patients. Our experience emphasizes the different behavior (good response) of a very rare giant cell cerebellar GBM to the standard treatment for newly diagnosed GBM.
EXTH-04. COMBINATION OF BEVACIZUMAB ENHANCES THE ANTI-TUMOR EFFICACY OF AD-SGE-REIC FOR GLIOMA
Authors: Otani Yoshihiro , Hattori Yasuhiko , Uneda Atsuhito , Tsuboi Nobushige , Makino Keigo , Hirano Shuichiro , Ishida Joji , Fujii Kentaro , Tomita Yusuke , Oka Tetsuo , Matsumoto Yuji , Shimazu Yosuke , Michiue Hiroyuki , Kurozumi Kazuhiko , Kumon Hiromu , Date Isao , Tanaka Shota
Published: November 2024

Reduced expression in immortalized cells/Dickkopf-3 (REIC/Dkk-3) is a tumor suppressor gene and its overexpression has been shown to exert anti-tumor effects as a therapeutic target gene in many human cancers. Recently, we revealed the anti-glioma effects of an adenoviral vector carrying REIC/Dkk-3 with the super gene expression system (Ad-SGE-REIC) and conducted the phase Ⅰ/Ⅱ a clinical trial for recurrent malignant glioma (jRCT2063190013). Anti-vascular endothelial growth factor treatments such as bevacizumab have demonstrated convincing therapeutic efficacy in patients with glioma. In this study, we examined the effects of Ad-SGE-REIC on glioma treated with bevacizumab in vitro and in vivo. Ad-SGE-REIC treatment resulted in a significant reduction in the number of invasion cells treated with bevacizumab. Western blot analyses revealed the increased expression of several endoplasmic reticulum stress markers in cells treated with both bevacizumab and Ad-SGE-REIC, as well as decreased β-catenin protein levels. In glioma-bearing mouse models, survival was extended in the combination therapy group. These results suggest that the combination therapy of Ad-SGE-REIC and bevacizumab showed anti-glioma effects by suppressing the angiogenesis and invasion of tumor cells. Combined Ad-SGE-REIC and bevacizumab might be a promising strategy for the treatment of malignant glioma.
EXTH-05. STEM CELL-BASED THERAPEUTIC STRATEGY FOR LEPTOMENINGEAL METASTASIS OF SOLID CANCERS
Authors: kitamura Yohei , Kanaya Nobuhiko , Moleirinho Susana , Tamura Ryota , Ueda Ryo , Sasaki Hikaru , Toda Masahiro , Shah Khalid
Published: November 2024

Leptomeningeal dissemination (LMD), known as carcinomatous meningitis, presents an extremely poor prognosis with an average life expectancy of 4-6 weeks. Although whole brain/spinal cord irradiation and intrathecal injection of anticancer drugs are sometimes performed, their effects are limited, so new therapeutic strategies for LMD are urgently needed. Based on the following greatest advantage of stem cell (SC) based therapeutic strategy for LMD, we tested its efficacy in LMD of various solid cancers; LMD is a condition in which cancer cells spread within a huge single space without separation, and the SCs with the characteristic of cancer tropism and chemotaxis can reach cancer cells easily; Repetitive intrathecal injection of therapeutic agents for patients is an invasive and risky procedure, but SCs can continuously secrete/release therapeutic agents into the cerebrospinal fluid after a few injections and increase local concentration of therapeutic substances. We have shown that treatment using engineered SCs may be effective treatment option against LMD from breast cancer, lung cancer, and malignant melanoma. Specifically, we reported that engineered allogeneic SCs which simultaneously targeting epidermal growth factor receptor (EGFR) and death receptor (DR) has efficacy for LMD of triple negative breast cancer and non-small cell lung cancer. Also, we reported that SCs releasing oncolytic herpes virus, granulocyte-macrophage colony-stimulating factor (GM-CSF), and single-chain variable region fragments (scFv) against programmed death receptor-1 (PD-1) has efficacy in LMD of malignant melanoma. Overall, we believe that SC therapy has the potential to become a new therapeutic option for LMD in the future.
EXTH-07. UNRAVELING THE ROLE OF SHH SIGNALING PATHWAY IN RETINOBLASTOMA
Authors: Pei Yanxin , Liu Xiao
Published: November 2024

Retinoblastoma (RB) is a pediatric cancer affecting the retina, often requiring surgical removal of one or both eyes due to the limited effectiveness of current treatments. There is an urgent need for advanced therapeutic strategies capable of effectively eliminating tumors, thereby obviating the need for surgical removal of eyes in affected children. Achieving this goal requires a deeper understanding of the cellular and molecular mechanisms governing RB initiation and progression. Using a transgenic mouse model, we identified the crucial role of the Shh signaling pathway in Rb1 mutation-induced tumorigenesis, highlighting its potential as a novel therapeutic target for RB treatment. We have observed frequent overexpression of Shh signaling proteins (SHH, GLI1, and GLI2) in human RB, correlating with aggressive clinicopathological features. GLI2 overexpression is necessary for Rb1 deletion-induced RB tumor initiation in mouse retinal progenitor cells (RPCs). These mouse intraocular tumors accurately replicate human RB at both cellular and molecular levels. Additionally, Shh pathway activation extends to normal retinal cells adjacent to human RB tumors, suggesting the involvement of Shh signaling in RB-microenvironment interactions. Importantly, our studies have identified a novel small molecular inhibitor targeting the Shh pathway, effectively inhibiting RB growth in vitro and in vivo by targeting both tumor cells and the tumor microenvironment (TME). The proposed research aims to provide unprecedented insights into the role of SHH signaling pathway in RB initiation and progression and the supporting communication network between RB tumors and TME. These outcomes have the potential to treat RB effectively while improving the well-being of young individuals with RB and those at risk of RB.
EXTH-08. IVOSIDENIB THERAPY FOR IDH-MUTANT WHO GRADE 4 ASTROCYTOMA
Authors: Owusu-Adjei Brittany , Amenta Peter , Johnson Mark , Cachia David
Published: November 2024

BACKGROUND

Isocitrate Dehydrogenase (IDH) is a commonly mutated gene in gliomas, present in approximately 10% of high-grade gliomas. Its oncometabolite, D-2-hydroxyglutarate, has been implicated in promoting gliomagenesis and epileptogenesis. IDH-1 or IDH-2 mutations confer a more favorable prognosis in gliomas than wildtype IDH, leading to the differentiation between IDH-wild type glioblastoma and IDH-mutant WHO Grade 4 astrocytoma. Although IDH-mutant WHO Grade 4 astrocytomas tend to occur in younger patients and show an improved survival, prognosis remains poor and treatment options are limited. Ivosidenib is a small molecule inhibitor of IDH-1 that has shown promise for treating low-grade IDH-mutant glioma. However, little is known about its efficacy in IDH-mutant WHO Grade 4 astrocytoma.

METHODS

We present a retrospective case of a 38-year-old male with a WHO Grade 4 astrocytoma. Molecular characterization revealed that it was IDH-mutant, MGMTp methylated, and 1p/19q co-deleted. It was treated with ivosidenib at second recurrence. He was originally treated with gross total resection, followed by radiation and 6 cycles of adjuvant temozolomide. At the time of 1st progression (approximately 19 months postoperatively), he was treated with lomustine at 90mg/m2 but progressed after 2 cycles. Here we report the effects of off label use of ivosidenib.

RESULTS

Radiological surveillance showed interval decrease in tumor size starting two months after initiation of ivosidenib. The patient remained neurologically intact and no adverse effects were observed. A review of the literature revealed only three studies analyzing the effects of ivosidenib in IDH-mutated WHO Grade 4 astrocytomas with varying results.

CONCLUSION

The INDIGO trial published last year showed evidence of efficacy in using an IDH inhibitor for low-grade gliomas. The role of these drugs in high-grade IDH-mutated gliomas is currently unknown. Further studies are needed to assess their efficacy in overall and progression free survival, specifically in IDH-mutated WHO Grade 4 astrocytoma.
EXTH-09. GENE MODIFICATION OF HEMATOPOIETIC STEM AND PROGENITOR CELLS FOR IMPROVEMENT OF IMMUNOTHERAPIES FOR MALIGNANT GLIOMAS
Authors: Font Laura Falceto , Jin Dan , Dean Bayli DiVita , Figg John , Francis Connor , Reid Alexandra , Long-James Kaytora , McDonald Brianna , Hilferty David , Mendez-Gomez Hector , Mitchell Duane , Tuerdi Zubaidan , Lauret Evelyne , Flores Catherine
Published: November 2024

Patients living with high-grade gliomas have a poor survival prognosis. Furthermore, standard of care treatment for these malignant gliomas has not significantly improved in the past decades. Our laboratory previously demonstrated that the combination of two different immunotherapies with HSPCs provided a significant survival benefit in preclinical brain tumor models, however, this therapeutic combination is still not 100% curative. We hypothesized that gene modification of HSPCs could add additional therapeutic benefit to immunotherapies for the treatment of resistant gliomas. Hematopoietic stem and progenitor cells (HSPCs) have been widely used in different clinical settings due to their ability to self-renew and differentiate into all immune cell lineages. In recent years, HSPCs have been the target of a variety of gene editing research efforts to decipher the most effective method for gene modification to use for therapeutic purposes. After comparison with previously established methods, we optimized a protocol for the successful editing of murine HSPCs and human CD34+ cells. Using Cas9 mRNA and sgRNAs in HSPCs, we achieved up to 80% reduction in gene expression. This method is superior to others due to its efficient, quick, inexpensive, and reliable nature. We also showed that, by knocking-down IL-6R in HSPCs, we can drive their differentiation into dendritic cells, while decreasing MDSCs and macrophages. Furthermore, gene-modified HSPCs are also capable of bone marrow reconstitution of lethally irradiated mice. Currently, we are testing whether the combination of gene-modified HSPCs with immunotherapy provides additional survival benefit to unmodified HSPCs with immunotherapy in a resistant murine glioma model.
EXTH-10. TARGETING EPHA3 AND EPHRIN A5: ADVANCED PRECISION THERAPY FOR GBM
Authors: Dsouza Rochelle , Skarne Niclas , Mulay Onkar , Harris Lachlan , Holton Emily , Zaman Ashraf , Akgul Seckin , Offenhauser Carolin , Alexander Hamish , Lwin Zarnie , Jeffree Rosalind , Inglis Po-Ling , Powell Joseph , Nguyen Quan , Boyd Andrew , Day Bryan
Published: November 2024

Glioblastoma (GBM) is an aggressive brain cancer and is associated with very poor prognosis. Standard treatment involves surgical resection, post-operative radiation and TMZ chemotherapy. Further research into new therapeutic approaches which target chemo-resistant tumor propagating cells, are urgently required. The EphA3 receptor is frequently elevated in GBM, particularly in the mesenchymal subtype and expressed on tumor-initiating cells (Day et al. Cancer Cell 2013). Our data in GBM tissue shows that tumor cells expressing the high-affinity EphA3 ligand, ephrin A5; are distinct from EphA3 expressing cells. The ephrin A5-positive cells express the glial differentiation marker GFAP, are less proliferative and less stem cell-like. EphA3 is expressed on the vimentin-positive, highly proliferative cell population. Single cell RNA-sequencing revealed that EphA3 and ephrin A5 are highly expressed in recurrent GBM, and are markers of MES-like and AC-like cell states respectively. Ephrin A5 over-expression in-vivo led to extension of survival in orthotopic xenograft animal models. GBM aggressiveness and downregulation of stem cell markers. Spatial transcriptomics of xenograft tumors revealed a reduction in proliferation markers including Ki67, MCM7 and PCNA. We detected an increase in expression of AC-like cell-state with a concomitant reduction of the MES-like and NPC-like cell-states. Consistently, over-expression of ephrin-A5 in primary GBM lines led to a reduction in neurosphere formation, Ki67 staining and growth rates. Thus we propose that dual targeting of EphA3 and ephrin-A5 might better capture GBM tumour heterogeneity and lead to an extension GBM patient survival. Whilst better understanding the biology of ephrinA5 expression, we also aim to validate antibody-based approaches to perform dual targeting of EphA3 and ephrin A5, leading to an extension GBM patient survival.
EXTH-14. IRREVERSIBLE TARGETING OF THE C-MYC/TOPOISOMERASE I AXIS IN GLIOBLASTOMA: DUAL INHIBITION USING A NOVEL INDENOISOQUINOLINE INHIBITOR
Authors: Walker Erin , Nusraty Sabrina , Jung Miyeon , Siddegowda Yesh Banasavadi , Oishi Masahiro , Dowling Aimee , Chowdhury Ashish , Barnes David , Brown Desmond
Published: November 2024

Glioblastoma–the most common primary CNS malignancy–is notorious for its cellular and molecular complexity and uniform fatality. Overexpression of the c-MYC and TOPOISOMERASE 1 (TOP1) oncogenes is implicated in more than 50% of human cancers. They are involved in the pathogenesis of glioblastomas with overexpression correlating with decreased overall median survival in glioblastoma patients. LMP744 is a non-camptothecin indenoisoquinoline small molecule inhibitor designed to target the C-MYC/TOP1 axis. The compound is inherently stable, has high brain penetrance, and irreversibly binds to its target providing several advantages over the camptothecin class of drugs. Human glioblastoma cells treated with LMP744 show a dose-dependent decrease in viability with LD50 ranging between 50 and 100 nM compared to 100-200µM following treatment with temozolomide in the same cell lines. Treatment results in a pro-apoptotic effect in exposed cells as well as S-phase arrest. Protein arrays and confirmatory western blots demonstrate increased CHK2 and decreased p53 and GSK-a/ß in treated cells. Orthotopic xenotransplantation via stereotactic injection of human glioblastoma cells (7×105 cells/4 µL) in nude mice showed exquisite sensitivity to LMP744 without adverse events. Administration of 20 mg/kg of LMP744 via tail vein injection resulted in total eradication of tumor signal on bioluminescent imaging. These preliminary findings suggest that LMP744–and perhaps the class of non-camptothecin indenoisoquinolones–is a promising novel candidate for glioblastoma pharmacotherapy.
EXTH-17. THERAPEUTIC EFFICACY OF B7-H3 CAR T CELLS IN PEDIATRIC HIGH-GRADE GLIOMAS WITH H3G34R/V MUTATION
Authors: Yadav Monika , Subham Siddharth , Jeppson John , Faisal Syed M , Szarejko John , Myers Doug , Akhavan David , Yadav Viveka Nand
Published: November 2024

Pediatric high-grade gliomas (pHGGs) are aggressive brain tumors responsible for significant childhood mortality. These tumors often carry mutations in the H3F3A gene, which encodes histone H3.3 proteins. However, current treatment options are limited, underscoring the need for innovative approaches. Chimeric antigen receptor (CAR) therapy, which was successful in treating certain childhood cancers, holds promise for pHGGs with H3G34R/V mutation. In this study, we examined the expression of B7-H3 in patient tumor specimens and various pHGG cell lines with H3G34R/V mutation. Data revealed substantial B7-H3 expression, confirming its potential as a therapeutic target. Co-culturing B7-H3 CAR T cells with H3G34R/V mutated KNS42 and SJ-HGG-X42 cells led to significant increase in the expression of markers associated with T cell activation (IL2, IL6, IF-γ, TNF-α) and immune responses involving cytolytic cells (Granzyme A, B, Perforin) and elevated levels of exhaustion markers (2B4, PD1, Tim3, Lag3) in comparison to mock-treated cells. We evaluated the capability of B7-H3 CAR T cells for cytolytic activity against KNS-42 and SJ-HGG-X42 cells through in vitro testing. Our results after 72 hours of co-culture revealed a strong killing potential of B7-H3 CARs against B7-H3 positive KNS-42 and SJ-HGG-X42 cells, while minimal or no killing was observed on B7-H3KO KNS-42 and B7-H3 negative MDA MD 453 cells. In vivo efficacy of B7-H3 CAR T cells in an orthotopic mouse xenograft model implanted with KNS-42 cells. B7-H3 CAR T cell treated mice showed a marked reduction in tumor burden and a substantial improvement in survival in contrast of CD19-CAR T cell treated control group. Lastly, we have developed a novel In-Utero Electroporation (IUE) immune-competent mouse model of pHGGs with H3G34R/V mutation, that enables exploration of the impact of immune suppressive tumor microenvironment on CAR T cells efficacy. In conclusion, B7-H3 emerges as a promising therapeutic target, and CAR T cells display encouraging functionality within the context of pHGGs with H3G34R/V model.