bluuebunny/crossref_metadata_2025_split huggingface dataset:
NCMP-23. EVALUATION OF IMMUNOTHERAPY EFFECTS IN CANCER PATIENTS ON EPILEPTIFORM ACTIVITY
Authors: Wong Kaela , Thakur Ayush , Zuidema Elizabeth , Avila Edward , Chen Xi , Lai George , Mao David 
Published: November 2023

Abstract

BACKGROUND/OBJECTIVE
Immune checkpoint inhibitors are associated with increased risk of autoimmune neurologic conditions, both in the peripheral and central nervous system. Increased activation of the immune system can lower seizure threshold, potentially increasing a patient’s risk of seizures. We hypothesize that patients treated with immune checkpoint inhibitors have a higher rate of seizures.

METHODS
We retrospectively reviewed 465 cancer patients undergoing electroencephalography (EEG) monitoring performed at Memorial Sloan Kettering Cancer Center from January 2022 to March 2023. Data was gathered from an EEG RedCap database containing patient demographic and seizure data. Patients were separated based on whether they had received immune checkpoint inhibitors (+ICI) prior to seizure occurrence or were never exposed to immune checkpoint inhibitors (-ICI) and had a seizure. Patient cancer type and presence of brain lesions (primary or metastases) were also reviewed.

RESULTS
Out of 465 patients, 109 received immune checkpoint inhibitors (+ICI) during their treatment. Seven of those patients were reported to have had at least one seizure (7/109, 6.42%) following treatment with ICI. The remaining 356 patients did not undergo immune checkpoint inhibitor treatment (-ICI), of which 30 were reported to have had at least one seizure (30/356, 8.43%). Of the +ICI patients who were experiencing seizures, 5 of them had brain lesions; 4 had primary brain tumors and 1 had brain metastases. Of –ICI patients, 21 patients had brain lesions; 15 had primary brain tumors and 6 had brain metastases.

DISCUSSION
Although immune checkpoint therapy may lead to increased activation of the immune system, our data did not reveal a higher incidence of seizures. Limitations to our study include its retrospective design, low number of patients, and low overall number of seizures captured on EEG.
NCMP-26. PANCEREBELLITIS ASSOCIATED WITH CISPLATIN THERAPY IN A PATIENT WITH OROPHARYNGEAL/ NASOPHARYNGEAL SQUAMOUS CELL CARCINOMA
Authors: Li Yi , Abualia Mohammad , Drappatz Jan , Mantica Megan 
Published: November 2023

Abstract
Cisplatin, a platinum-based drug, is one of the oldest and most widely used chemotherapeutic agents. It exerts its anti-tumor effect by forming DNA inter-strand and intra-strand cross-links, resulting in lesions that eventually activate apoptotic pathways. Cisplatin remains widely used for the treatment of several solid tumors, though this is often limited by its toxicity which can affect many organ systems, including nephrotoxicity, hepatotoxicity, ototoxicity, and neurotoxicity. A dose-dependent peripheral sensory neuropathy is the most reported cisplatin-induced neurotoxicity. Central nervous system (CNS) toxicity is less common, likely due to the large molecular size of cisplatin preventing its passage through the blood-brain barrier (BBB). There have been reports of cognitive impairment, posterior reversible encephalopathy syndrome, and optic neuritis associated with cisplatin. We present a case of a 38-year-old patient who was treated with concurrent cisplatin and radiation therapy for oropharyngeal/nasopharyngeal squamous cell carcinoma, and around a month after the end of therapy, was found to have imaging findings concerning for pancerebellitis. Extensive workup into infectious causes of cerebellitis was negative. Although there are no reports in the literature of cerebellitis due to cisplatin, it could be the culprit in this case. Animal studies have shown cerebellar dysfunction occurring in the setting of cisplatin exposure. Moreover, it is thought that the drug can reach the CNS if there is a disruption of the BBB, this is supported by the fact that CNS toxicity is more seen in patients who have primary CNS neoplasia, CNS metastatic disease, radiation exposure to the head, among other mechanisms that could potentially disrupt the BBB. Thus, it is important to consider CNS adverse effects, including cerebellitis, in patients receiving cisplatin, especially among those with a potentially compromised BBB.
NCOG-36. IMPACT OF COLLAGEN TILE BRACHYTHERAPY AS TREATMENT FOR RECURRENT GLIOBLASTOMAS ON FUNCTIONAL STATUS AND QUALITY OF LIFE
Authors: Garcia Michael , Brachman David , Lee Stuart , Peach Matthew Sean , Wanebo John , Smith Kris , Chen Clark , Kotecha Rupesh , Ahluwalia Manmeet , Hanft Simon , Nowlan Adam , McCracken David , Floyd John , Shah Mitesh , Richardson Angela , Patel Toral , Pham Huong , Ryan Robert , Wasilewski Andrea , Shen Colette , Robin Adam , Ranjan Tulika , Bojanowski-Hoang Kimberly , DiNapoli Vincent , Chamoun Roukoz , Choutka Ondrej , Mercado Catherine , Haydon Devon , Leng Lewis , Rodriguez Analiz , Deb Nimisha , Patel Akash , Piccioni David , Campbell Lisa , Patel Sita , Hall Angela 
Published: November 2023

Abstract

BACKGROUND
Recurrent glioblastoma is an aggressive disease with dismal prognosis despite advances in standard therapy, making the maintenance of functional status and quality of life (QOL) in patients an important endpoint during treatment. Here, we report functional status (KPS) and QOL metrics (LASA and FACT-Br) at 6-months post-treatment for recurrent glioblastoma patients treated with maximal safe resection followed by intraoperative placement of collagen tile brachytherapy with Cesium-131 (Surgically Targeted Radiation Therapy or STaRT), a novel brachytherapy carrier.

OBJECTIVE
To assess the impact of STaRT on KPS and QOL among patients with recurrent glioblastoma (rGBM) at 6-months post-treatment.

METHODS
Patients were treated between 10/2020 and 05/2023 as part of a multi-institutional registry study (NCT#04427384). KPS was used to measure functional status. Linear Analog Self-Assessment (LASA) and Functional Assessment of Cancer Therapy – Brain (FACT-Br) were used to measure QOL. All assessments were collected at pre-surgery, and 1,3, and 6-months post-treatment.

RESULTS
57 rGBM patients were treated on the Registry between 10/2020 and 05/2023. Of the 57 participants, 47 participants remain in the study, with 21 participants reaching the 6-month time point (5 exits, 5 deaths). Median age was 60 years (range 28-81). Methylguanine methyltransferase (MGMT) promoter was methylated in 17.5%, unmethylated in 38.5%, and unknown in 44%. Gross total resection was achieved in 72% of participants. Median KPS was 80% (range 40%-100%) at screening versus 70% (range 40%-90%) at 6 months post-treatment. Median LASA was 37 (range 8-50) at pre-surgery versus 34 (range 5-48) at 6-months post-treatment. Minimally important differences (MID) were noted between pre-surgery (136.9 ± 29.5) and 6-months post-treatment (112.5 ± 35.7) for the FACT-Br Total Score.

CONCLUSION
This interim data analysis supports further investigation of STaRT as a treatment for recurrent glioblastomas as a means of providing stable functional status and quality of life.
NCOG-40. PATTERNS OF PROGRESSION IN PATIENTS WITH NEWLY DIAGNOSED PRIMARY CENTRAL NERVOUS SYSTEM LYMPHOMA FOLLOWING TREATMENT WITH HIGH-DOSE METHOTREXATE
Authors: Cappelli Louis , Newman Jennifer , Sharif Muhammad , Kayne Allison , Epperla Narendranath , Elguindy Ahmed , Palmer Joshua , Alnahhas Iyad , Shi Wenyin 
Published: November 2023

Abstract

INTRODUCTION
Primary central nervous system lymphoma (PCNSL) is a rare form of non-Hodgkin's lymphoma that primarily affects the brain. Recurrence of PCNSL within the central nervous system is common, but patterns of intracranial recurrence following induction chemotherapy have not been extensively studied. This study aims to elucidate the patterns of recurrence and progression in PCNSL.

METHODS
Adult patients from two institutions with newly diagnosed PCNSL that received HD-MTX based chemotherapy from 2011-2023 were included. Patient charts and diagnostic imaging were retrospectively reviewed. The pattern of recurrence/progression was reviewed by comparing the initial diagnostic MRI to the first recurrence MRI (T1 post-contrast and FLAIR sequence). Distant recurrences were defined as separate lesions from the previous primary enhancing lesion, located outside the initial FLAIR abnormality observed on imaging. Local recurrences were characterized as new lesions overlapping with the primary enhancing lesion/FLAIR abnormality.

RESULTS
25 patients were identified to have been diagnosed with PCNSL and progressed through initial definitive treatment with HD-MTX based chemotherapy. 2/25 received initial management with radiation therapy. Median age at diagnosis was 66 years. The median time to progression was 18.1 months (Range; 0.9-70). Twelve of the 25 patients had a complete response to initial systemic therapy, 6 had a partial response, and 7 patients had disease progression through chemotherapy. Eleven of the 25 patients were found to have multifocal disease at diagnosis. 13/25 (52%) patients had distant recurrence only, 5/25(20%) had only local recurrence, and 7/25 (28%) displayed both local and distant recurrence pattern.

CONCLUSION
In this retrospective review, for patients diagnosed with PCNSL who are able to undergo HD-MTX we identified that the majority of disease recurrence is outside or distant to the primary disease site vs locally (80% vs 20%). Such findings should be verified with a larger cohort and can help direct further consolidation strategies.
NCOG-41. REAL WORLD EXPERIENCE WITH TTFIELDS WITH EMPHASIS ON THERAPY COMPLIANCE
Authors: Jelgersma Claudius , Akkas Gülsüm , Alsolivany Joan , Wasilewski David , Gastl Bastian , Vajkoczy Peter , Misch Martin , Kaul David , Bullinger Lars , Onken Julia 
Published: November 2023

Abstract
Tumor Treating Fields (TTF) therapy has emerged as a significant adjunctive component in the treatment of high-grade tumors following its validation in the EF-14 trial in 2017. The incorporation of TTF therapy, alongside cyclic temozolomide (TMZ) therapy, has demonstrated enhanced outcomes in terms of PFS and OS when the useage exceeds 18 hours per day (75% compliance rate). Post-hoc analysis of the EF-14 trial has demonstrated that compliance rates exceeding 90% are associated with an additional benefit. Given the cost-intensive nature and significant constraints associated with the therapy, our objective is to generate real-world data on compliance through a retrospective analysis at a high-throughput academic center. Between June 2015 and February 2022, a total of 115 patients were prescribed TTFields as pa rt of their treatment for high-grade glioma. Mean age was 50y and mean preoperative Karnofsky Index 80-90. The average duration of therapy was 8 months. The majority of patients (74%) initiated therapy concurrently with 1st-line treatment, while only 25% managed to start concomitant to the first cycle of temozolomide. 16.7% started TTFields in the 2nd-line and 9.3% in the 3rd-line setting. Thirteen patients discontinued TTFields treatment within the first 3 months and were consequently excluded from further compliance analysis. Across the study cohort, the median compliance rate was 72% (SD 22%), with an average of 41 days of breaks observed. Compliance was highest during the first 3 cycles, with rates of 79%, 73%, and 72%, respectively. Linear regression analysis did not identify any predictors of compliance, including age at surgery, timing of therapy, duration of therapy, gender, and preoperative Karnofsky Index. These findings highlight the importance of monitoring and promoting adherence to TTFields therapy to maximize its potential benefits in the management of high-grade gliomas. Further strategies are warranted to expedite the start of therapy and improve long-term compliance.
EXTH-09. GM-CSF AND IL-7 FUSION CYTOKINE ENGINEERED TUMOR VACCINE GENERATES LONG-TERMTH-17 MEMORY CELLS AND INCREASES OVERALL SURVIVAL IN AGED SYNGENEIC MOUSE MODELS OF GLIOBLASTOMA
Authors: Shireman Jack , Gonugunta Nikita , Pattnaik Akshita , Zhao Lei , Wang Xiaohu , Galipeau Jacques , Dey Mahua 
Published: November 2023

Abstract
Age-related immune dysfunctions, such as decreased T-cell output, are closely related to pathologies like cancers and lack of vaccine efficacy among the elderly. Engineered fusokine, GIFT-7, a fusion of IL-7 and GM-CSF, can reverse aging-related lymphoid organ atrophy. We generated a GIFT-7 fusokine tumor vaccine and employed it in aged syngeneic mouse models of glioblastoma, and found that peripheral vaccination with GIFT-7TVax resulted in thymic regeneration and generated durable long-term anti-tumor immunity specifically in aged mice. Global cytokine analysis showed increased pro-inflammatory cytokines including IL-1b in the vaccinated group that resulted in hyperactivation of dendritic cells. In addition, GIFT-7 vaccination resulted in increased T-cell trafficking to the brain and robust Th-17 long-term effector memory T-cell formation. TCR-seq analysis showed increased productive frequency among detected rearrangements within the vaccinated group. Overall, our data demonstrate that aging immune system can be therapeutically augmented to generate lasting anti-tumor immunity.
EXTH-10. QUAD-DM1: A HIGHLY POTENT DRUG CONJUGATE FOR BREAST CANCER AND BREAST CANCER BRAIN METASTASIS TREATMENT
Authors: Debinski Waldemar , Fink Kaitlin N , Rossmeisl John , Mott Ryan T , Herpai Denise 
Published: November 2023

Abstract
Triple-negative breast cancer (TNBC) remains an unmet need in medicine. Previously, we and others found that interleukin 13 receptor alpha 2 (IL-13RA2), EphA2, EphA3 and EphB2 receptors are over-expressed in almost all patients with glioblastoma (GBM). We performed a first-of-a-kind Phase I clinical trial in dogs with spontaneous gliomas using a cocktail of cytotoxins targeting IL-13RA2 and EphA2 receptor. The majority of dogs experienced &gt;50% of tumor regression; four dogs exhibited &gt;92% tumor shrinkage and several dogs became long-term survivors. Next, we pursued the novel idea of targeting four tumor-associated receptors, instead of two, with one pharmaceutical compound. To this end, we produced a multivalent ligand, termed QUAD. More recently, we found that a conjugate of QUAD with emtansine (DM1), a microtubule-disrupting agent, demonstrated a specific killing potency on GBM cells, in low picomolar range. Unexpectedly, we observed that human breast cancer cells are also highly responsive to this drug candidate. We thus examined the presence of the four receptors in breast cancer cells and tissue micro-arrays, including involved lymph nodes, and in paired primary tumor - brain metastases, spanning two molecular subtypes of breast cancer: TNBC and HER2+. We found that the four targeted receptors are expressed in almost all breast cancer and related metastases to brain specimens, based on the expression levels for the genes and the gene products. Furthermore, the breast cancer cell lines like HC1806, MDA-MB-468, MDA-MB-231, BT549, and the breast metastatic cell line MDA-MB-231-BRM cells are killed at up to picomolar concentrations of QUAD-DM1. MDA-MB-231 tumors growing in mammary pads of athymic mice responded significantly to QUAD-DM1 given intravenously; QUAD recognizes murine receptors similarly to human. Thus, QUAD-DM1 is a novel type of a multivalent drug conjugate for the treatment of breast cancer and its brain metastases, which is applicable, but not exclusively, to TNBC.
EXTH-20. A MOUSE MODEL REVEALS VULNERABILITY OF IDH1-MUTATED GLIOMA TO FERROPTOSIS
Authors: Mela Angeliki , Dovas Athanassios , Mahajan Aayushi , Humala Nelson , Nguyen Trang , Kanangat Smriti , Upadhyayula Pavan , Sprinzen Lisa , Argenziano Michael , Huang Dennis , Guo Jia , Casaccia Patrizia , Siegelin Markus , Stockwell Brent , Bruce Jeffrey , Canoll Peter 
Published: November 2023

Abstract
The molecular classification of gliomas is currently based on the presence of IDH1 mutation, which is associated with better prognosis and longer survival. The hallmark of the IDH1 mutation is the production of D-2-Hydroxyglutarate with subsequent effects that are not fully understood. Ferroptosis, an iron-dependent mechanism of non-apoptotic cell death, is mostly triggered through blocking system Xc- or suppressing the antioxidant enzyme glutathione peroxidase 4 (GPX-4). In this study, we generated a mouse model of glioma harboring the IDH1(R132H) mutation in heterozygous condition, in combination with p53-deletion induced by the expression of PDGFA. We show that IDH1(R132H)-expressing mice survive longer compared to their wild-type counterparts, while histological analysis reveals characteristics of low-grade diffuse gliomas. We generated cell lines from primary tumors and analyzed their metabolic profile and response to mitochondrial stress and Ferroptosis. We treated them in vitro with RSL3, a GPX-4 inhibitor, alone or in combination with Cysteine and Methionine restriction. We show that IDH1(R132H)-expressing cells are far more sensitive to Ferroptosis in vitro. Finally, we show that convection-enhanced delivery of RSL3 in combination with dietary Cysteine and Methionine restriction in vivo, significantly prolongs survival of the IDH1(R132H)-expressing mice. Our findings suggest that Ferroptosis provides promising therapeutic potential worth exploring further and our mouse model could be used to test the efficacy of different treatments for IDH1(R132H) gliomas.
EXTH-23. EFFECT OF EVOGLIPTIN AND TEMOZOLOMIDE COMBINATION THERAPY FOR THE TREATMENT OF GLIOBLASTOMA, IN VITRO AND IN VIVO
Authors: Yang Seung Ho , Lee Keun Soo , Lee Jung Eun 
Published: November 2023

Abstract
A recent study showed that high dipeptidyl-peptidase IV (DPP4) expression affects glioma progression. The purpose of this study is to investigate the synergistic effect of a DDP4 inhibitor, evogliptin and temzolomide (TMZ) combination therapy for glioblastoma (GBM) in vitro and in vivo. U87, U252, and A172 cells were treated with 50, 250, and 500 uM TMZ or with 5, 10, and 20 mM evogliptin for 24, 48 and 72 hrs. For in vivo experiment, GBM xenograft models were used. Three groups (n=5 mice) were treated with TMZ(15mg/kg/day), evogliptin (2mg/25g/day), and combination of TMZ and evogliptin via i.p. injection for 4 weeks. For evaluating the relevant mechanism, Affymetrix miRNA arrays are used. The MTT assay revealed that the combination treatment had higher cytotoxicity against U87, U251, and A172 cells than the monotherapy had after 48 and 72-hr treatment. mRNA DDP4 levels were much more decreased after combination administration. The median survival of each group was 43.6, 55.2, 53.2, 65.2, and 71.3 days in the control, evogliptin, TMZ, the first combination therapy with low-dose evogliptin (2mg/25g/day) and TMZ, and the second combination therapy with high-dose evogliptin (10mg/25g/day) and TMZ, respectively. In Affymetrix miRNA arrays, miR-1246, miR-149-3p, miR-3148, miR-4440, miR-4484, miR-4535, miR-6126, miR-6780b-5p, and miR-7110-5p were increased after evogliptin treatment. miR-149-5p, miR-23a-5p, miR-3195, miR-4330, miR-4497, miR-4669, miR-671-3p, and miR-744-5p were decreased. miR-4440 and miR-6780b-5p were also increased following combination therapy. In the TCGA dataset, the survival of glioma patients with low DPP4 expression is longer than that in patients with high DPP4. A DDP4 inhibitor, evoglipin regulates miRNA in GBM cell lines. The combination of evogliptin and TMZ had a moderate effect on the treatment of GBM in vitro and in vivo. miR-4440 and miR-6780b-5p could be associated with inhibiting the proliferation of GBM cells by targeting DPP4.
EXTH-28. ISOCITRATE DEHYDROGENASE MUTATIONS PREDICT SENSITIVITY TO HISTONE DEACETYLASE INHIBITION AND ENHANCED HISTONE ACETYLATION DYNAMICS ONLY IN THE CONTEXT OF GLIOMA
Authors: Sears Thomas , Drumm Michael , Wang Wenxia , Horbinski Craig 
Published: November 2023

Abstract
Isocitrate dehydrogenase 1/2 mutations (IDHmut) define a subtype of glioma with profound epigenetic dysregulation through genomic hypermethylation. IDHmut gliomas are incurable and fatal, demonstrating new treatments are needed. These mutations are common in other solid tumors, including chondrosarcoma (CS) and intrahepatic cholangiocarcinoma (ICC). Histone deacetylase (HDAC) enzymes compose a class of epigenetic drug targets utilized clinically to treat cancer, but their potential against IDHmut gliomas has not been extensively studied. We previously showed that IDHmut glioma cultures exhibit pronounced sensitivity to the effects mediated by the FDA-approved HDAC inhibitor (HDACi) panobinostat. Here, we integrate proliferation and cytoxicity data to show that this effect is unique to gliomas. In the context of histone H3 acetylation (H3KAc), panobinostat increased H3KAc, on average, by 7.6-fold and 30.5-fold in IDHwt and IDHmut glioma cultures, respectively (p&lt; 0.001). This difference in HDACi-mediated H3KAc based on IDH status was not significant for CS and ICC. IDHmut gliomas are more sensitive two other FDA-approved HDACis: belinostat and vorinostat. RNA-Seq analysis showed that panobinostat more greatly affected gene expression in IDHmut glioma cells, particularly in the context of gene downregulation. Similarly, H3KAc ChIP-Seq showed a decrease in promoter histone acetylation moreso in IDHmut glioma cultures treated with panobinostat: there is an average loss of 1,236 and 14,759 H3KAc peaks at gene promoters in IDHwt and IDHmut cultures, respectively. This suggests that IDHmut gliomas exhibit enhanced histone acetylation dynamics in response to HDACi. Furthermore, using a PDX glioma model, we show that only mice engrafted with IDHmut glioma exhibit a significant survival increase in response to the HDACi belinostat: median survival was extended by 14 days in IDHmut glioma-bearing mice (p= 0.01), whereas belinostat extended median survival by 4 days in IDHwt glioma-bearing mice (p= 0.11). These results suggest that HDACi may be an effective in treating IDHmut gliomas.