bluuebunny/crossref_metadata_2025 huggingface dataset:
NIMG-43. ADVANCED MULTI-PARAMETRIC HYPERPOLARIZED 13C/1H IMAGING OF GBM
Authors: Autry Adam , Vaziri Sana , LaFontaine Marisa , Gordon Jeremy , Chen Hsin-Yu , Villanueva-Meyer Javier , Chang Susan , Clarke Jennifer , Xu Duan , Lupo Janine , Larson Peder , Vigneron Daniel , Li Yan
Published: November 2021

INTRODUCTION

The goal of this study was to characterize progressive and pseudoprogressive GBM using multi-parametric hyperpolarized (HP)-13C / 1H MRI.

METHODS

Dynamic HP-13C MRI was acquired from 13 patients with progressive GBM [patients (scans): 2(3) IDH-mutant; 11(13) IDH-wildtype] and 2 IDH-wildtype patients (3 scans) demonstrating pseudo-progression following intravenous injection of HP [1-13C]pyruvate. Frequency-selective echo-planar imaging (3s temporal resolution, 3.38 cm3 spatial resolution) captured [1-13C]pyruvate metabolism to [1-13C]lactate and 13C-bicarbonate in the brain. Dynamic 13C data were kinetically modeled to obtain the pyruvate-to-lactate conversion rate constant k PL and temporally summed to calculate 13C-metabolite percentiles and ratios (linearly interpolated 2x in-plane). 1H imaging included T2, post-Gd T1, perfusion (nCBV, %recovery), diffusion (ADC), and lactate-edited spectroscopy (CNI, choline-to-NAA index; 1H-lactate). The normal-appearing white matter (NAWM), non-enhancing lesion (NEL), and contrast-enhancing lesion (CEL) were segmented from 1H images. 13C-resolution masks were iteratively applied on a voxel-wise basis to evaluate 1H imaging parameters within each ROI and multi-parametric data were collectively evaluated using a mixed effects model in R.

RESULTS

Progressive IDH-mutant GBM compared to wildtype counterparts displayed increased perfusion %recovery (p < 0.001) and k PL (p < 0.01), together with reduced 1H-lactate (p < 0.001) and pyruvate percentile (p < 0.01), in the T2 lesion. Among IDH-wildtype progressive GBM, the CEL was distinguished from NEL/NAWM by increased nCBV (p < 0.05/0.001), 1H-lactate (p < 0.05/0.001); and decreased bicarbonate / lactate (p < 0.05/0.001). The CEL and NEL were collectively distinguished from NAWM by elevated CNI (p < 0.001/0.001), ADC (p < 0.05/0.001), pyruvate percentile (p < 0.001/0.001), lactate percentile (p < 0.001/0.001), and relative lactate / pyruvate (p < 0.001/0.05). Psuedo-progressive IDH-wildtype GBM displayed lower k PL (T2 Lesion; p < 0.01) and nCBV (CEL; p < 0.01) compared to progressive GBM.

CONCLUSION

HP-13C parameters can potentially augment proton imaging and demonstrated Warburg-associated metabolic alterations.
NIMG-44. PROGNOSTIC VALUE OF PH- AND OXYGEN-SENSITIVE MRI IN GLIOMA PATIENTS
Authors: Jingwen Yao , Hagiwara Akifumi , Oughourlian Talia , Wang Chencai , Raymond Catalina , Pope Whitney , Salamon Noriko , Lai Albert , Nghiemphu Phioanh , Everson Richard , Kim Won , Prins Robert , Liau Linda , Cloughesy Timothy , Nathanson David , Ellingson Benjamin
Published: November 2021

Hypoxia and tissue acidosis are two key features of the glioma microenvironment, both associated with a more aggressive phenotype through promotion of invasion, angiogenesis, and resistance to a vast number of therapies. In the current study, we demonstrate that higher levels of acidity and hypoxia in glioma are associated with worse prognosis by using simultaneous pH- and oxygen-sensitive amine chemical exchange saturation transfer spin-and-gradient echo echo-planar imaging (CEST-SAGE-EPI). A total of 159 histologically confirmed adult glioma patients (WHO grade II: N = 42; grade III: N = 38; grade IV, N = 79) were retrospectively evaluated. All patients were scanned with a custom amine CEST-SAGE-EPI MRI pulse sequence at 3T. Magnetization transfer ratio asymmetry (MTRasym) at 3ppm was used as a measure of relative acidity, R2’ was used as a surrogate of hypoxia, and their product MTRasym×R2' was used to quantify the degree of both acidity and hypoxia. Cox regression was performed to evaluate prognostic factors for OS and PFS. Univariate results suggested higher hypoxia, R2' (HR = 1.44, p = 0.0002), and higher combined measure of acidity and hypoxia, MTRasym×R2' (HR = 1.14, p = 0.0008), were associated with a shorter OS. When considering age, treatment status, and IDH mutation status as covariates, R2' and MTRasym×R2' remained significantly associated with patient OS (R2': HR = 1.27, p = 0.045; MTRasym×R2': HR = 1.17, p = 0.002). Within the treatment naïve patients, tumor acidity MTRasym, was also associated with OS (HR = 3.72, p = 0.003). R2' and MTRasym×R2' were significantly associated with PFS, both using univariate (R2': p < 0.0001; MTRasym×R2': p < 0.0001) and multivariate analyses including clinical factors (R2': p = 0.010; MTRasym×R2': p < 0.0001). In summary, tumor acidity and hypoxia measured using pH- and oxygen-sensitive metabolic MRI are significant prognostic factors in glioma.
NIMG-57. MANAGEMENT OF TECTAL GLIOMAS IN ADULTS
Authors: Tadipatri Ramya , Plasto Dinko , Hughes Jeremy , Nakaji Peter , Eschbacher Jennifer , Fonkem Ekokobe , Azadi Amir , Braun Kelly , Myers Charlotte , Ashby Lynn
Published: November 2021

BACKGROUND

Tectal gliomas (TG) are rare tumors occurring primarily in children but also found in adults during workup of various neurological symptoms. Surgery is not required in asymptomatic cases, so histopathological information is sparse. No consensus on timing of imaging surveillance or management has been established.

OBJECTIVE

We seek to standardize neuroimaging, including MRI protocol and surveillance time intervals, and clinical management of symptoms and disease progression, including surgery, radiotherapy, and chemotherapy.

METHODS

At our institution, patients with TG were identified through a search of radiology reports and clinic notes between 1989 and 2020. Initial and serial MRI exams were evaluated for tumor size, enhancement, edema, hydrocephalus, and other radiographic features. When tissue was available, cellularity, mitotic activity, and morphology were described. We documented neurological symptoms and signs potentially related to the tumor.

RESULTS

37 cases were identified: 22 female, 15 male; 5 children, 32 adults. Age of diagnosis ranged from 7 to 69 years. Presenting symptoms included headache (59%), visual symptoms (35%), and imbalance (14%), less commonly: seizure, weakness, nausea/vomiting, and dizziness. Surgical procedures included biopsy (9), resection (7), endoscopic third ventriculostomy (15), and shunt placement (11). Eight patients received radiotherapy, including IMRT, CyberKnife, GammaKnife, and Zap-X (all adults; 4 at diagnosis, 3 at progression, 1 at diagnosis and again at progression). Four patients received chemotherapy (all adults; 1 at diagnosis, 3 at progression), all with temozolomide. One additionally received bevacizumab for radionecrosis. Three patients died with progressive disease, two following treatment and one without. Of interest, 5 adult patients developed signs of parkinsonism during their follow-up period.

CONCLUSION

Management of TG encompasses both neoplastic progression and symptom control, either from local compression or infiltrative disease. We have developed an algorithm for imaging surveillance and treatment, including MRI protocol, definition of progressive disease, and indications for antineoplastic therapies.
NIMG-67. A SYSTEMATIC REVIEW ON THE DEVELOPMENT OF MACHINE LEARNING MODELS FOR DIFFERENTIATING PCNSL FROM GLIOMAS
Authors: Petersen Gabriel Cassinelli , Shatalov Julia , Brim W R , Subramanian Harry , cui Jin , Johnson Michele , Malhotra Ajay , Aboian Mariam , Brackett Alexandria
Published: November 2021

PURPOSE

Differentiating gliomas and Primary CNS Lymphomas (PCNSL) represents a diagnostic challenge with important therapeutic ramifications. MR imaging combined with Machine Learning (ML) has shown promising results in differentiating tumors non-invasively. The purpose of this systematic review is to evaluate and synthesize the findings on the application of ML in differentiating PCNSL and gliomas.

MATERIALS AND METHODS

A systematic search of literature was performed in October 2020 and February 2021 on Ovid Embase, Ovid MEDLINE, Cochrane trials, and Web of Science – Core Collection. The search strategy included keywords and controlled vocabulary including the terms: gliomas, artificial intelligence, machine learning, and related terms. Publications were reviewed and screened by four different reviewers in accordance with TRIPOD.

RESULTS

The literature search yielded 11,727 studies and 1,135 underwent full-text review. Data was extracted from 16 publications showing that 10 ML and 3 deep learning (DL) algorithms were tested. The analyzed databases had an average size of 118 patients per study. 50% of the publications validated the algorithm in an independent test cohort. The most commonly tested ML and DL algorithms were support vector machines and Convolutional Neural Networks, respectively. In internal (external) datasets, ML algorithms reached an average AUC of 89% (83%); and DL 74% (77%). Preliminary TRIPOD bias analysis yielded an average score of 0.5 (range 0.31-0.62), with most papers showing deficiencies in reporting model specifications, and funding details among other items.

CONCLUSIONS

AI-based methods for differentiating gliomas and PCNSL have been reported and show that ML methods result in accuracy = > 85%.With few studies using DL algorithms, further research into novel DL-based approaches is recommended. Additionally, most studies lack large datasets and external validation, thus increasing the risk of overfitting. Bias analysis of the published studies using TRIPOD identified reporting deficiencies, and close adherence to reporting criteria is recommended.
NCMP-05. LEFT BASAL GANGLIA/INTERNAL CAPSULE GLIOBLASTOMA WITH MEMORY LOSS FROM CONTRALATERAL RADIATION INDUCED VASCULOPATHIES
Authors: Higgins Shannon , Lassman Andrew , Lennihan Laura , Willey Joshua , Wang Tony , Sisti Michael , Shapiro Peter , Kim Esther , Koshy Amily
Published: November 2021

INTRODUCTION

Radiation induced cerebral vasculopathy encompasses a complex and broad range of effects such as ischemia, hemorrhage, vascular malformation, capillary telangiectasias, and large vessel stenosis caused by pathological reorganization of tissue after radiation exposure. Necrosis and inflammation induce damage and demyelinating changes to other vessels over the corresponding areas that may occur months to years after brain irradiation. Here we report an unusual case of hemorrhagic basal ganglia/internal capsule glioblastoma followed by contralateral basal ganglia/internal capsule acute infarct with resulting acute transient global amnesia followed by chronic memory impairment.

CASE REPORT

A 58-year old man was diagnosed with a hemorrhagic left basal ganglia/internal capsule mass after presenting with severe headaches, agitation, and vomiting. Glioblastoma (IDH wild type by sequencing, MGMT unmethylated) was identified on resection. He underwent radiotherapy and concurrent and adjuvant (12 cycles) temozolomide. Serial surveillance brain MRI scans demonstrated multiple incidental vascular abnormalities including subacute right basal ganglia/internal capsule ischemic infarct, right temporal cavernoma, and right temporal intra-parenchymal hemorrhage approximately 1, 2, and 3 years after diagnosis, respectively. Approximately 4 years after diagnosis, he presented with transient global amnesia and imaging demonstrated right basal ganglia/internal capsule ischemic stroke.

DISCUSSION

Bilateral basal ganglia/internal capsule damage from stroke has been reported as causing memory impairment (Tatemichi TK et al, Neurology 1992;42:1966-79; PMID 1407580). Here we report memory impairment from unilateral basal ganglia/internal capsule tumor and contralateral infarct following brain radiotherapy as another mechanism of neurocognitive injury. Our case highlights the significance of continuing to surveil for these findings as new neurologic symptoms may mimic tumor progression.
NCMP-13. ID8 OVARIAN CANCER MOUSE MODEL MIMICS NEUROLOGICAL SEQUELAE OF OVARIAN CANCER IN WOMEN
Authors: Lomeli Naomi , Bota Daniela , Argueta Donovan , Gupta Kalpna
Published: November 2021

OBJECTIVES

Chemotherapy-related cognitive impairment (CRCI) and chemotherapy-induced peripheral neuropathy (CIPN) are neurological complications of cancer treatment. Cisplatin is used to treat ovarian malignancies, and over 70% of women experience CRCI/CIPN during and after platinum-based chemoTx. However, over 30% of non-CNS cancer patients experience cognitive impairment prior to chemoTx. To examine the contribution of cancer itself and additional neurological impairment with chemoTx, we used an ID8 syngeneic mouse model of ovarian cancer and assessed hyperalgesia and cognition +/- cisplatin treatment.

METHODS

C57BL/6 female mice were injected intraperitoneally with 107 ID8 ovarian cancer cells or 0.9% saline. After 10d of ID8 injections, mice received cisplatin (2.3 mg/kg/day, i.p.) or 0.9% saline (OvT+CIS, OvT+VEH, respectively) for 5d, followed by 5d of rest for 2 cycles. Mechanical and cold hyperalgesia were assessed longitudinally. Cognition was assessed 28d post-chemoTx by the open field test (OFT), novel object recognition (NOR), and novel place recognition (NPR) tasks.

RESULTS

OvT+VEH and OvT+CIS mice developed an increased sensitivity to mechanical ( >200%, p< 0.001) and thermal (cold) stimuli ( >78%, p< 0.004) starting 14d post-ID8 implantation, vs non-tumor controls (CON). In the OFT, OvT+CIS mice had increased anxiogenic behavior (55%, p< 0.001) vs CON, and (46%, p< 0.05) vs OvT+VEH. In NPR, OvT+CIS had reduced discrimination (37%, p< 0.05) vs CON. OvT+VEH and OvT+CIS showed impaired discrimination (25%, p< 0.05 & 33%, p< 0.01, respectively) in NOR vs CON, with trending differences between OvT+CIS vs OvT+VEH in hyperalgesia and cognitive tasks. DISCUSSION: This is the first rodent model to demonstrate that ovarian cancer may evoke sensory and neurocognitive changes in the absence of chemotherapy. Future development of the model will address hyperalgesia and cognitive differences between OvT+VEH vs OvT+CIS. This model has potential for translational studies on the treatment of neurological sequelae of cancer and cisplatin-induced CRCI and CIPN.
OTHR-01. SNO 2020 DIVERSITY SURVEY: DEFINING DEMOGRAPHICS, RACIAL BIASES, CAREER SUCCESS METRICS AND A PATH FORWARD FOR THE FIELD OF NEURO-ONCOLOGY
Authors: Chukwueke Ugonma , Vera Elizabeth , Acquaye Alvina , Hervey-Jumper Shawn , Odia Yazmin , Klesse Laura , Dunbar Erin , Sharma Akanksha , Fonkem Ekokobe , Thomas Alissa , Werbowetski-Ogilvie Tamra , Camelo-Piragua Sandra , Gatson Na Tosha , de la Fuente Macarena , Armstrong Terri , Porter Alyx , Jackson Sadhana
Published: November 2021

BACKGROUND

Neuro-oncology has grown tremendously since 2010, marked by increasing society membership, specialized clinical expertise, and new journals. Yet, modest improvement in racial/ethnic diversity amongst clinical trial participants, researchers and clinicians led us to conduct a survey identifying opportunities to enhance diversity and inclusiveness amongst neuro-oncology professionals.

METHODS

Summer 2020, the Women and Diversity Committee of the Society for Neuro-Oncology (SNO) distributed an anonymous online survey to members and affiliates (European Association of Neuro-Oncology, Asian Society for Neuro-Oncology, Society for Neuro-Oncology Latin America and Society for Neuro-Oncology Sub-Saharan Africa). The survey captured personal and professional characteristics, biases, effective mentorship qualities, career success metrics, and suggested field/society changes. Results were analyzed by geography, profession, age, racial/ethnic and sexual identity. Standard descriptive statistics characterized the study population.

RESULTS

The 386 respondents were predominantly female (58%) with a median age range of 40-49 years (31%), White (65%), and SNO members (97%). Most worked in North America (77%) in a research profession (67%). A majority of White respondents reported never experiencing biases (64%), while the majority of non-White respondents reported unconscious biases/microaggressions, followed by a lack of/limited mentorship. Qualitative assessments showcased that personal/professional success metrics were linked to needed improvements in diversity and inclusion efforts within the neuro-oncology community. CONCLUSIONS: The prevalence of racial/ethnic biases and poor mentorship rates amongst underrepresented groups in neuro-oncology is high and potentially linked to the limited diverse representation amongst members and affiliates. These findings warrant a swift implementation of equity and inclusion practices within the neuro-oncology field.
NCOG-02. SURVIVAL AND TREATMENT OUTCOMES OF NEOPLASTIC MENINGITIS (NM)
Authors: Perison Taylor , Wheat Kayla , Gnabode Salim , Price Lori Lyn , Jeyapalan Suriya
Published: November 2021

INTRODUCTION

NM occurs in 5 - 15% of cancer patients and Overall Survival (OS) in treated patients ranges from 2-6 months. The purpose of this study was to analyze the effect of prognostic factors on OS and calculate a graded prognostic assessment (GPA) score based on tissue type, similar to the index score created for cancer patients with brain metastases (BM).

METHODS

We conducted a single center, retrospective analysis of 118 patients diagnosed between 2006 and 2018 at TMC. The prognostic factors analyzed were: Age (< = 50yo =1pt), Karnofsky Performance Status (KPS > =60 =1 pt), and no extracranial metastases (1pt). The GPA score was calculated from 0.0 - 3.0 by adding the points together. Kaplan Meier curves were used to estimate OS for primary tumors with 10 or more patients (breast, lung, leukemia, lymphoma). Cox regression analysis was used to evaluate the association of the GPA with OS.

RESULTS

The GPA analysis by tumor type included 76% of the patient population. The median OS was 5 months (breast), 2 months (lung), 7 months (leukemia), and 2 months (lymphoma). We found that leukemia (p =0.008, N = 20) and lung cancer (p =0.002, N = 20) patients showed distinct separation between GPA groups on their Kaplan Meier curves. Higher KPS was associated with increased OS (p < 0.0001) using Cox regression. DISCUSSION: The GPA algorithm was only partially successful in our NM population, which may reflect the smaller number of patients in our study compared to the studies used to create the BM GPA. TMC is a contributing institution to a large, multi-institutional, multi-national registry of patients with NM disease (Neoplastic Meningitis Registry - NeMeRe). We plan to use this larger dataset to validate our GPA score as a useful tool for predicting OS in NM patients.
NCOG-32. PROGNOSTIC IMPLICATIONS OF SIZE OF PITUITARY MACROADENOMAS: A COMPARATIVE ANALYSIS OF GIANT ADENOMAS WITH NON-GIANT MACROADENOMAS
Authors: Ghazi Sanam Mir , Tariq Muhammad Bilal , Hashmi Fauzan Alam , Tanwir Asra , Khan Ahsan Ali , Shamim Muhammad Shahzad , Angez Meher , Enam Syed Ather
Published: November 2021

BACKGROUND

In this study we compared giant pituitary adenomas (GPAs) and non-giant pituitary macroadenomas (nGPAs) on the basis of presenting complaints, surgical procedures, tumor resections and outcomes.

METHODS

A retrospective analysis (2006-2017) of pituitary macroadenomas was performed where tumors were divided into two groups; tumors greater than 4 cm were classified as GPAs while macroadenomas smaller than 4 cm were termed as nGPAs. Both GPA and nGPA had 75 patients in each group.

RESULTS

The most common complaint of all patients was visual deterioration (77.3% of patients with nGPAs and 89.3% of patients with GPAs). Visual field defects were present in 55 patients (73.3%) in the nGPA group compared to 68 patients (90.7%) in the GPA group (p=0.006). The mean volume of nGPAs was 6.3 cm3 (range 0.45 cm3 to 22 cm3 while the mean volume of GPAs was 30.1 cm3 (range 10.8 cm3 to149.4 cm3) (p=0.001). The mean extent of resection was 88.9% for nGPAs whereas the mean extent of resection was 76.7% for GPAs (p=0.03). Craniotomy was required only in the GPA group (5 patients, 6.7%) (p=0.023). Tumor recurrence/progression was seen in 9.3% of patients with nGPAs and 44% of patients with GPAs (p=< 0.001). Re-do surgery was required in 2.7% of nGPA cases (via transsphenoidal approach) and 32% of GPA cases; in this GPA subgroup, 22.7% patients required transsphenoidal surgeries while 9.3% patients required transcranial surgeries. Stereotactic radiosurgery in recurrence/progression accounted for 4% of nGPA patients and 22.7% of GPA patients. There were 3 mortalities, all in GPA group. Overall, nGPA group had better postoperative course as compared to GPA group.

CONCLUSION

The frequency of preoperative symptoms in GPAs is more significant and associated with lesser chances of gross total tumor resection, higher rates of recurrence, and worse postoperative course in comparison to nGPAs.
NCOG-46. WHITE MATTER TRACT INVOLVEMENT BY INTRA-AXIAL BRAIN TUMORS; DIAGNOSTIC & THERAPEUTIC IMPLICATIONS
Authors: Bakhshi Saqib Kamran , Quddusi Ayesha , Mahmood Danish , Waqas Muhammad , Shamim Muhammad Shahzad , Mubarak Fatima , Enam Syed Ather
Published: November 2021

Diffusion tensor imaging (DTI) is a relatively recent modality which aids in visualization of WMT and their relation to intracranial lesions. Despite almost two decades since the beginning of its use in tumor resection, there is still dearth of data on its diagnostic and prognostic value from low- and middle-income countries. We aimed to assess the pattern of involvement of white matter tracts (WMT) by intra-axial brain tumors on DTI. Secondary objectives were to evaluate implications of involvement of WMT on surgical resection, and post-operative functional outcome. This was a retrospective study of 77 consecutive patients, who underwent DTI guided surgery for brain tumors. The involvement of WMT by tumors on DTI was assessed by a radiologist (who was blind to the pathology) using the Witwer classification. The pathology was reported by histopathologists using WHO brain tumor classification. Karnofsky Performance Scale (KPS) was used for assessing patients’ neurological status at admission, and at follow-up. Forty-five (58.4%) out of 77 tumors reviewed, caused infiltration of WMT, whereas only 22 (28.6%) tumors caused displacement of WMT (p = 0.040). Among 32 cases of astrocytoma, involvement of WMTs was influenced by the grade of tumor (p = 0.012), as high-grade tumors caused infiltration (19; 59.4%), unlike low grade tumors which commonly caused displacement (2; 50%). Oligodendroglioma caused infiltration/disruption of WMTs in most cases, irrespective of the grade (19 out of 25 cases; 76%). At last follow-up, 27 (35.1%) patients showed improvement in KPS and 14 (18.2%) reported deterioration, while there was no change observed in 36 (46.8%) patients. Infiltration of WMTs was associated with poor functional outcome. We conclude that intra-axial brain tumors mostly cause infiltration of WMTs, particularly high-grade astrocytoma, and oligodendroglioma of any grade. Infiltration of WMTs is associated with poor functional outcome at follow-up.
NCOG-48. LONGITUDINAL ASSESSMENT OF SUBJECTIVE COGNITIVE FUNCTION IN A BRAIN TUMOR SAMPLE: IMPROVED CORRESPONDENCE WITH NEUROPSYCHOLOGICAL PERFORMANCE OVER TIME
Authors: Gardner Melissa , Zarrella Giuliana , Dietrich Jorg , Parsons Michael
Published: November 2021

INTRODUCTION

Estimates of subjective cognitive function (SCF) generally show minimal correlation with objective measures of neurocognitive function (NCF). Our group recently validated a new metric of SCF in neuro-oncology patients, creating the Cognitive Index of the Functional Assessment of Cancer Therapy-Brain (FACT-Br-CI). This study examines whether brain tumor (BT) patients evaluated on more than one occasion show improved relationship between SCF and NCF. We hypothesized that change scores in SCF and NCF across evaluation would be more highly correlated than SCF and NCF at either timepoint.

METHODS

A retrospective study of BT patients who completed two neuropsychological evaluations (baseline, follow-up) was conducted. NCF was measured by the clinical trial battery composite (CTBC), a mean of 6 commonly used neuropsychological test scores. SCF was measured by the FACT-Br-CI. Mood/Anxiety were measured by the Beck scales (BAI/BDI-II). Change over time on each metric was evaluated with paired t-test. Correlational analyses evaluated relationships between NCF, SCF, and mood within and between time points.

RESULTS

Twenty-nine patients (16 female; mean age=54.6y; mean education=15.5y) completed all CTBC measures and FACT-Br-CI, 28 of whom completed and BDI and/or BAI. On group analyses, there were no significant differences between baseline and follow-up on CTBC (t=-.53;p=ns) or FACT-Br-CI (t=-.98;p=ns). Correlations between CTBC and FACT-Br-CI were nonsignificant at baseline (r=.24;p=ns), but significant at follow-up (r=.56;p=0.002). Change scores over time were unrelated (r=-.104;p=ns). Similar to previous studies, the FACT-BR-CI correlated with the BDI-II at baseline (r=-.38;p=0.04) and follow-up (r=-.59;p< 0.001) and with the BAI at follow-up (r=-.44;p=0.02).

CONCLUSION

In this small group of brain tumor patients seen for repeated neuropsychological evaluations, we found that agreement between SCF and NCF was much higher on their second than initial evaluation. These findings suggest that patients may develop enhanced awareness of their cognitive function from an initial evaluation that persists over time.
EXTH-01. SECOND GENERATION OF INDUCED NEURAL STEM CELLS TO MIGRATE AND KILL AS AN ADJUVANT TO RADIOTHERAPY IN NON-SMALL CELL LUNG CANCER METASTASIS
Authors: Mercer-Smith Alison , Thang Morrent , Buckley Andrew , Valdivia Alain , Jiang Wulin , Bell Noah , Kumar Rashmi , Bomba Hunter , Woodell Alex , Luo Daniel , Floyd Scott , Hingtgen Shawn
Published: November 2021

Non-small cell lung cancer (NSCLC) spread to the leptomeninges is devastating with a median survival of only a few months. Radiation is frequently offered for symptomatic relief but alone does not eliminate leptomeningeal metastases (LMM). With no standard-of-care for patients with LMM, new adjuvant therapies are desperately needed in order to combat this disease. Neural stem cells (NSCs) have shown remarkable promise as drug delivery vehicles in the treatment of brain tumors due to their inherent tumoritropic properties. Using a cell sphere culture-based system, we have transdifferentiated fibroblasts into a second-generation induced neural stem cell (hiNeuroS) secreting the cytotoxic protein tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) to allow for the possibility of readily available, autologous cell carriers. Herein, we provide evidence that hiNeuroS-TRAIL cells can migrate to and suppress growth of NSCLC metastases in combination with radiation. In vitro time-lapse motional analysis and in vivo post-mortem tissue analysis showed that hiNeuroS-TRAIL cells migrate to NSCLC tumors. In vitro co-cultures with isobologram analysis suggests that TRAIL and radiation together have a synergistic cytotoxic effect on NSCLC tumors. In an intratumoral injection model of hiNeuroS-TRAIL, mice treated with the combination therapy of hiNeuroS-TRAIL and 2 Gy together had a small fraction of the mean tumor volume (6.4%) of controls (100%) compared to monotherapies (107.3% radiation-only, 46.6% hiNeuroS-TRAIL only). Only combination-treated mice demonstrated a significant extension in survival, which amounted to a 42% extension compared to controls. In the LMM model with ICV-infused therapy, the combination-treated mice showed significantly smaller tumor volumes (2.0%) compared to control (100%) or 2 Gy (54.9%) treated mice. Mice treated with hiNeuroS-TRAIL-only also showed only 4.6% of the tumor volume of control mice. Combination-treated mice and hiNeuroS-TRAIL-treated mice both showed significant improvements in survival (36.6% and 46.3% median extension in survival, respectively compared to controls).
EXTH-02. AAV MEDIATED BRAIN DELIVERY OF AN ADCC-ENHANCED ANTIBODY OBVIATES XENOGRAFT GROWTH IN MOUSE MODELS OF HER2+ BREAST CANCER BRAIN METASTASIS
Authors: Laks Dan , Chen Kenny , Ren Xiaoqin , Shah Ishan , Hameedi Usman , Tocci Jenna , Fiore Timothy , Grant Kyle , Bales Kelly , Samuel Hasson
Published: November 2021

BACKGROUND

HER2+ tumors constitute approximately 20% of breast cancer patients and are characterized by overexpression of the growth factor receptor HER2 (ERBB2), a cell proliferation driver. Effective anti-HER2 therapies confer prolonged patient survival necessitating the need for transformative treatments targeting brain metastases, a major cause of mortality in ~30-50% of HER2+ metastatic breast cancer patients. HER2-directed antibody immunotherapy, while efficacious for peripheral disease, has limited central nervous system exposure (CNS). To overcome these challenges, we transduced CNS cells with a novel AAV vector carrying an anti-HER2 antibody payload.

METHODS

We assessed the biochemical equivalence and functional effectiveness of AAV vector-encoded antibodies using in vitro assays. After selecting promising vector-encoded antibody candidates, a novel, blood-brain barrier penetrant AAV capsid was administered via i.v. dosing to an orthotopic xenograft mouse model of HER2+ brain metastases. Bioluminescent imaging provided a longitudinal measure of brain tumor burden. At study termination, we measured antibody biodistribution in cerebrospinal fluid (CSF), serum, and brain homogenates with AlphaLISA assays.

RESULTS

Using HER2+ breast cancer cell lines, we determined that an antibody-dependent cell cytotoxicity (ADCC) enhanced anti-HER2 antibody was most effective and demonstrated that AAV-vector encoded forms of the antibody performed comparably to recombinant reference antibodies. Following i.v. administration of a HER2 antibody encoding AAV vector, we measured >1 ug/mL of the antibody in CSF. Importantly, AAV-mediated expression of the ADCC-enhanced HER2-directed antibody significantly abrogated tumor growth in orthotopic xenograft models.

CONCLUSIONS

Peripheral administration of an AAV vector was able to transduce brain tissue such that efficacious levels of HER2-directed antibodies were produced. This strategy was successful at preventing tumor growth in our physiologically relevant model of breast cancer brain metastases. Such a treatment modality should be further evaluated in patient derived PDX models to validate translational efficacy for human patients.
EXTH-05. TUMOR TREATING FIELDS IN COMBINATION WITH THE TERT-INHIBITOR ERIBULIN HAVE SYNERGISTIC ANTIPROLIFERATIVE EFFECTS ON HUMAN GLIOBLASTOMA CELLS
Authors: Stein Marco , Beusker Piet , Goett Hanna , Kolodziej Malgorzata , Uhl Eberhard
Published: November 2021

OBJECTIVE

Combination therapy, a treatment modality that combines two or more therapeutic agents, is a cornerstone of cancer therapy. The optimal combination therapy for Tumor Treating Fields (TTFields) in glioblastoma (GBM) treatment is unknown. The aim of our study was to analyze, the effects of the TERT-inhibitor eribulin in combination with TTFields on human GBM cells.

METHODS

Human GBM cells of the established cell lines U87, A172 and U251, and two patient-derived cell lines, were treated with eribulin monotherapy, TTFields monotherapy, or both modalities together. After 72 hours of therapy, cell counts were measured and clonogenic assays were performed. Annexin staining and fluorescence-activated cell scanning (FACS) was used to analyze cell death.

RESULTS

Overall surviving fractions were 39.8±11.0% for eribulin monotherapy, 32.2±23.9% for TTFields monotherapy, and 10.9±9.9% for the combined treatment. Mean observed annexin positive fractions were 11.2±8.2% (control), 28.6±9.7% (eribulin), 34.8±8.1% (TTFields), and 78.1±13.5% (combination), respectively. The mean clonogenic fractions over all cell lines were 25.9±7.8% for eribulin and 46.4±12.9% for TTFields. For the combination therapy, a synergistic effect with a decreased mean of 3.6% clonogenic fractions was observed.

CONCLUSION

Eribulin increases cell death and reduces clonogenicity our experiments. Additionally, a synergistic effect of the combined treatment of TTFields and eribulin synergistic was observed. Eribulin in combination with TTFields could be a new effective therapy for GBM.
EXTH-13. LOCAL DELIVERY OF AN IL-15 SUPERAGONIST USING A REPLICATING RETROVIRUS SIGNIFICANTLY IMPROVES SURVIVAL AND LYMPHOCYTE INFILTRATION IN POORLY IMMUNOGENIC MURINE GLIOBLASTOMA MODELS
Authors: Haddad Alexander , Spatz Jordan , Montoya Megan , Collins Sara , Gill Sabraj , Wang Elaina , Chuntova Polly , Young Jacob , Kasahara Noriyuki , Aghi Manish K
Published: November 2021

Glioblastoma (GBM) leads to severe systemic and local immunosuppression, and immunotherapies have had limited clinical success. Here, we evaluated the treatment efficacy of RLI, a superagonist of T-cell activator IL-15, delivered to tumor cells using a tumor-selective retroviral replicating vector (RRV) in the syngeneic murine SB28 and Tu2449 GBM models, which are both engineered to be poorly immunogenic with low-mutational burden and known resistance to immunotherapy, and hence more accurate biomimetic models of human GBM. RRV-RLI replicated and spread effectively in cultured murine GBM cells with robust production of functional RLI (165.4 ± 5.3 ng/mL). Stereotactic injection of RRV-RLI into pre-established intracerebral SB28 tumors significantly reduced tumor growth on bioluminescent imaging, and increased median survival compared to control mice (55 vs. 19 days, p=0.002), leading to long-term survival in 12% of treated mice. In the Tu2449 model, imaging results showed complete eradication of intracerebral tumors after RRV-RLI treatment, with long-term survival (median not reached) in > 85% of treated mice, compared to a median survival of 12.5 days in control mice (p=0.001). RRV-RLI treated tumors showed significantly increased CD8 T-cell infiltration, without altering immunosuppressive cell populations. Similarly, broad anti-tumor inflammatory changes, including increased expression of genes involved in T-cell activation and killing, were observed in the NanoString nCounter platform using a 770-gene panel representing various immune cell types. Notably, RLI was not detected in the blood of treated mice, and tumor-localized RRV-RLI gene delivery showed no adverse systemic immune effects in either model. In summary, RRV-mediated RLI immunotherapy results in immunostimulatory and pro-inflammatory changes to the tumor microenvironment and achieves a significant survival benefit in two poorly immunogenic syngeneic murine models of GBM. This tumor-localized immunomodulatory gene therapy has the potential to safely reverse the T-cell depleted immunophenotype of GBM.
EXTH-14. PRECLINICAL EVALUATION OF NOVEL CDK4/6 INHIBITOR GLR2007 IN GLIOBLASTOMA MODELS
Authors: Yin Lei , Yao Zhenglin , Wang Yue , Huang Ying-Hui , Mazuranic Michelle , Yin Ang
Published: November 2021

Glioblastoma multiforme (GBM) is characterized by a high frequency of cyclin-dependent kinase (CDK)4 and CDK6 pathway dysregulation. None of the approved CDK4/6 inhibitors are indicated for GBM. Poor blood–brain barrier (BBB) penetration is a potential factor limiting treatment efficacy in GBM. GLR2007 is an investigational CDK4/6 inhibitor with the potential for improved penetration across the BBB. These preclinical studies investigated the anti-tumor efficacy in GBM xenograft models and central nervous system distribution of GLR2007. In vivo evaluation of the anti-tumor efficacy of GLR2007 versus vehicle, abemaciclib, and/or palbociclib was performed in two BALB/c nude mouse GBM xenograft models. Efficacy was expressed as tumor growth inhibition (TGI, change in mean tumor volume from baseline as a percentage of change in vehicle group) or increased survival time. Following 21 days of treatment, TGI in BN2289 subcutaneous xenografts was 39.4% and 56.4% for 25 mg/kg and 50 mg/kg GLR2007 groups, respectively, 34.0% for 25 mg/kg palbociclib, and 24.9% for 25 mg/kg abemaciclib (p < 0.001 in all groups vs vehicle control). In U87-luc orthotopic xenografts, compared with vehicle controls, median survival time was 50.0% (p = 0.0009) longer in the 12.5 mg/kg GLR2007 group, similar to the 150 mg/kg abemaciclib group (54.4%, p = 0.0002), and was 182.6% (p < 0.0001) longer in mice treated with 50 mg/kg GLR2007. Quantitative whole-body autoradiography was used to determine the distribution of [14C]GLR2007 in Sprague Dawley rats following a single oral dose. Total radioactivity levels in the brain exceeded those in plasma by 2.3–4.5-fold from 2–6 h after dosing. These preclinical studies suggest the potential of GLR2007 for the treatment of GBM, supported by evidence that GLR2007 showed numerically greater anti-tumor efficacy than approved CDK4/6 inhibitors palbociclib and abemaciclib in GBM xenograft models, and evidence of substantial central nervous system distribution.
EXTH-21. MECHANISMS OF SYNERGISTIC GROWTH SUPPRESSION BY RADIOTHERAPY AND C-MET INHIBITION IN EXPERIMENTAL GLIOBLASTOMA
Authors: Silginer Manuela , Papa Eleanna , Szabo Emese , Vasella Flavio , Roth Patrick , Weiss Tobias , Weller Michael
Published: November 2021

Glioblastoma remains to be one of the most lethal solid cancers and novel therapies are urgently needed. There is increasing interest in the role of the HGF/MET pathway in the response of glioblastoma to radiotherapy. c-MET-mediated radioresistance may be partially induced via proinvasive and DNA damageresponse pathways and HGF may be involved in the regulation of immune responses. Here, we explored the role of the c-MET pathway in response to radiotherapy and investigated potential modes of action that mediate synergistic effects of MET pathway inhibition and irradiation in syngeneic murine glioma models in vitro and in vivo. Murine glioma cells express HGF and c-MET and respond with c-MET phosphorylation upon exposure to exogenous HGF. In vitro, glioma cell viability and proliferation are not affected by pharmacological or genetic c-MET pathway interference, and the c-MET inhibitor tepotinib fails to sensitize glioma cells to irradiation. Conversely, in vivo c-MET inhibition combined with focal radiotherapy synergistically prolongs survival in two syngeneic orthotopic glioma models compared with either treatment alone. Complementary studies demonstrated that synergy was lost when gliomas were established and treated in immunodeficient mice, and importantly, also when c-MET gene expression was disrupted in the tumor. Thus, synergistic suppression of experimental syngeneic glioma growth by irradiation and c-MET inhibition requires at least two mechanisms, expression of c-MET in the tumor and a functional immune system. In summary, our data suggest clinical evaluation of c-MET pathway inhibition in combination with radiotherapy in human glioblastoma.
EXTH-22. NEOADJUVANT IMMUNOTHERAPY WITH ANTI-PD1 ALTERS THE TUMOR MICROENVIRONMENT POST SURGERY IN A MODEL OF RECURRENT GLIOBLASTOMA
Authors: Hoang-Minh Lan , Doonan Bently , von Roemeling Christina , Yang Changlin , Shin David , Trivedi Vrunda , Karachi Aida , Wang Yu , Mitchell Duane
Published: November 2021

SIGNIFICANCE

New promising clinical trials for glioblastoma are evaluating the efficacy of neoadjuvant immunotherapy in the context of recurrent tumor surgery.

OBJECTIVE

We investigated the effects of neoadjuvant PD1 blockade on the glioma tumor microenvironment in a clinically relevant murine model of recurrent tumor.

RESULTS

Using an orthotopic mouse KR158 resection model of glioblastoma that we have established, we show that neoadjuvant anti-PD1 and surgery enhance animal survival and increase the recruitment of CD8+ and CD4+ T cells at recurrent tumor sites following bulk tumor resection compared to surgery followed by adjuvant immunotherapy. Transcriptome and spatial genomic analyses reveal alterations in immune exhaustion and activation pathway signaling after neoadjuvant anti-PD1treatment when compared with adjuvant anti-PD1-treatment or surgery alone.

CONCLUSIONS

These results provide insights into the effects of neoadjuvant PD1 blockade on the tumor microenvironment and uncover additional treatment targets.
EXTH-27. MOLECULAR CHARACTERIZATION AND PRECLINICAL DEVELOPMENT OF NOVEL SMALL MOLECULE INHIBITOR SPECIFIC FOR WILD-TYPE IDH1 FOR FERROPTOSIS INDUCTION IN GLIOBLASTOMA
Authors: Murnan Kevin , Tommasini-Ghelfi Serena , Hurley Lisa , Dussold Corey , Wahl Daniel , Stegh Alexander
Published: November 2021

Increased de novo synthesis, mobilization and uptake of fatty acids are required to provide sufficient lipids for membrane biogenesis in support of rapid tumor cell division and growth. In addition to their structural roles as components of the plasma membrane, fatty acid-derived lipids regulate ferroptotic cell death, a type of programmed cell death, when oxidized by iron-dependent lipoxygenase enzymes. De novo lipogenesis and the defense against oxidative lipid damage require large amounts of cytosolic NADPH. Our group has recently found that HGG up-regulate wild-type Isocitrate dehydrogenase 1 (referred to hereafter as ‘wt-IDH1high HGG’) to generate large quantities of cytosolic NADPH. RNAi-mediated knockdown of wt-IDH1, alone and in combination with radiation therapy (RT), slows the growth of patient-derived HGG xenografts, while overexpression of wt-IDH1 promotes intracranial HGG growth. Isotope tracer and liquid chromatography-based lipidomic studies indicated that wt-IDH1 supports the de novo biosynthesis of mono-unsaturated fatty acids (MUFAs) and promotes the incorporation of monounsaturated phospholipids into the plasma membrane, while displacing polyunsaturated fatty acid (PUFA) phospholipids. In addition, enhanced NADPH production in wt-IDH1high HGG increases glutathione (GSH) level, reduces reactive oxygen species (ROS), activates the phospholipid peroxidase glutathione peroxidase 4 (GPX4)-driven lipid repair pathway, and dampens the accumulation of PUFA-containing lipid peroxides, known executioners of ferroptosis. To pharmacologically target wt-IDH1,we have used and characterized wt-IDH1i-13, a first-in-class competitive α,β-unsaturated enone (AbbVie). wt-IDH1i-13 potently inhibits wt-IDH1 enzymatic activity, by covalently binding to the NADP+ binding pocket. Our data indicate that wt-IDH1i-13 promotes ferroptosis, which can be rescued by pre-treatment of cells with the peroxyl scavenger and ferroptosis inhibitor ferrostatin. wt-IDH1i-13 is brain-penetrant, and similar to genetic ablation, reduces progression and extends the survival of wt-IDH1high HGG bearing mice, alone and in combination with RT. These studies credential to wt-IDH1i-13 as a novel therapeutic modality for the treatment of wt-IDH1 gliomas.
EXTH-28. NLGN4X TCR TRANSGENIC T CELLS TARGETING EXPERIMENTAL GLIOMAS
Authors: Krämer Christopher , Kilian Michael , Will Rainer , Sanghvi Khwab , Green Edward , Friedrich Mirco , Wick Wolfgang , Platten Michael , Bunse Lukas
Published: November 2021

BACKGROUND

The application of personalized vaccines has shown to be effective in patients with newly diagnosed glioblastoma in phase 1 clinical trials. Responses of CD8 T cells directed against the glioma-associated antigen Neuroligin-4, X-linked (NLGN4X) were reported in multipeptide vaccine trials in patients with glioblastoma. Here, we characterized the functional status of NLGN4X TCR transgenic T cells in vitro and assessed their therapeutic capacity in vivo.

METHODS

TCR encoding sequences were delivered by lentiviral transduction to activated T cells from healthy donors. After confirmation of TCR surface expression T cells were used for a functional in vitro characterization. For in vivo assessment of NLGN4X-specific TCR transgenic T cells, NLGN4X-expressing U87 glioma cells were injected into the flank of NSG MHCI/MHC II knockout mice, which do not develop graft versus host disease. TCR transgenic T cells were injected intravenously on day 11 and day 18 and tumor size was monitored.

RESULTS

TCR transgenic T cells depicted stable surface expression for at least 11 days in vitro after transduction. Thereby, murine TCR beta constant region positive T cells featured a polyfunctional phenotype demonstrated by a significant increase of Interferon-γ and TNF-α and remained reactive to the NLGN4X epitope for at least 7 days. Additionally, NLGN4X TCR transgenic T cells showed significantly increased antigen-specific production of the cytolytic protein granzyme B and elevated levels of perforin. In a novel xenograft mouse model NLGN4X TCR transgenic T cells slowed the tumor growth compared to the initial tumor size until day 25 after tumor inoculation.

DISCUSSION

We demonstrate that NLGN4X TCR transgenic T cells specifically and consistently recognize their corresponding immunogenic sequence and target antigen-overexpressing glioma cells. We present first evidence of in vivo reactivity, while further experiments are required to assess the full therapeutic potential of NLGN4X-TCR-transgenic T cell therapy for glioma patients.
EXTH-32. NOVEL THIORIDAZINE DERIVATES: ANTIPROLIFERATIVE AND APOPTOSIS-INDUCING ACTIVITY ON GLIOBLASTOMA CELLS IN VITRO
Authors: Schwab Stephanie , Sarnow Katharina , Alme Eirin , Goldbrunner Roland , Bjørsvik Hans-René , Bjerkvig Rolf
Published: November 2021

BACKGROUND

Although withdrawn from the market due to cardiotoxicity, we showed that the antipsychotic drug Thioridazine shows chemosensitizing effects in combination with Temozolomide (TMZ) for the treatment of glioblastoma multiforme (GBM). Based on our prior observations, the aim of this study was through medicinal chemistry, to design and synthesize new compounds based on Thioridazines tricyclic structure, and to determine their therapeutic potential.

METHODS

Fourteen compounds were synthesized where variations were made within the tricyclic side chains. The newly synthesized compounds were screened for therapeutic efficacy with or without TMZ using a WST-1 cell viability assay and real-time imaging system (IncuCyte). Tests were performed on both monolayer cell cultures, as well as on glioma stem cell spheroids (GSC). The therapeutic effects were also studied on human astrocytes (NHA) as well as on rat brain organoids (BO). Annexin V/propidium iodide (PI) double staining followed by flow cytometric analysis was performed after 48 hours of treatment.

RESULTS

Following an extensive screening, we identified two novel compounds (EA01 and EA02) that at concentrations of 4 and 9.5 µM showed a strong cytotoxicity on GBM cell lines (U-87 MG p< 0,0001, U251 p< 0,0001, LN18 p= 0,0004) as well as on glioma stem cells (GSC) (P3 p< 0,0001) compared to NHA and BOs respectively. Also, when BOs were confronted with GSC spheres in an invasion assay, a selective cytotoxicity was observed in the GSCs. Mechanistically, we show that both compounds induce apoptosis in GBM cells. Moreover, intravenous delivery of increasing concentrations of EA01 and EA02 revealed no toxicity in animals at concentrations up to 21 mg/kg.

CONCLUSION

We developed two new tricyclic therapeutic compounds that show a strong selective cytotoxicity in GBM cells with limited systemic toxicity in animals. Ongoing studies are investigating the therapeutic potential of EA01 and EA02 in orthotopic xenografts in vivo.