bluuebunny/crossref_metadata_2025_split huggingface dataset:
CTNI-55. INITIAL TEMOZOLOMIDE MONOTHERAPY WITHOUT RADIOTHERAPY MIGHT BE OF LIMITED BENEFIT IN THE TREATMENT OF ASTROCYTOMA, IDH-MUTANT, CNS WHO GRADE 2 AND 3
Authors: Weller Jonathan , Katzendobler Sophie , Blobner Jens , Thiele Frederic , Becker Hannes , Quach Stefanie , Egensperger Rupert , Niyazi Maximilian , Suchorska Bogdana , Thon Niklas , Weller Michael , Tonn Joerg-Christian 
Published: November 2022

Abstract

QUESTION
The role of temozolomide chemotherapy alone in isocitrate dehydrogenase (IDH)-mutant astrocytomas has not been conclusively determined. Recent studies have linked temozolomide therapy with induction of hypermutation and poor clinical course in some IDH-mutant gliomas.

METHODS
In this retrospective, single-center study, 183 patients with astrocytoma, IDH-mutant, CNS WHO grade 2 or 3 diagnosed between 2003 and 2019 were included. Patients initially monitored by means of a wait-and-scan strategy, or treated with radiotherapy alone, or receiving temozolomide alone, after histological sampling through biopsy or tumor resection, were studied. Progression-free and overall survival was analysed. A matched-pair analysis accounting for post-surgical tumor volume was conducted.

RESULTS
Initial T2 tumor volume and WHO grade were associated with survival in univariate analyses (p &lt; 0.01). The proportion of WHO grade 2 gliomas was highest in the wait-and-scan cohort (p &lt; 0.01). Tumor volumes were largest in the temozolomide cohort (p &lt; 0.01). Radiotherapy was associated with longer progression-free survival than temozolomide (6.2 vs 3.4 years, p = 0.02) and wait-and-scan strategies (6.2 vs 4 years, p = 0.03). Patients treated with radiotherapy showed longer overall survival than patients treated with temozolomide (14.4 vs 10.7 years, p = 0.02). Survival was longer in patients initially monitored by means of a wait-and-scan strategy than in patients treated with temozolomide (not reached vs 10.7 years, p &lt; 0.0001). The same association was seen in a subgroup analysis of WHO grade 2 astrocytomas (p = 0.02) and by trend in a matched pair analysis (p = 0.09).

CONCLUSION
The results suggest superiority for progression-free survival of radiotherapy alone over temozolomide alone or wait-and-scan strategies and for overall survival of radiotherapy alone and wait-and-scan therapies over temozolomide in IDH-mutant WHO grade 2 and 3. Recent study results indicating that temozolomide might compromise prognosis in some patients with IDH-mutant gliomas might be supported by our data.
CTNI-61. CLINICAL EFFICACY AND PREDICTIVE BIOMARKERS OF ONC201 IN H3K27M-MUTANT DIFFUSE MIDLINE GLIOMA
Authors: Kawakibi Abed Rahman , Tarapore Rohinton , Gardner Sharon , Chi Andrew , Kurz Sylvia , Wen Patrick Y , Arrillaga-Romany Isabel , Batchelor Tracy , Butowski Nicholas , Sumrall Ashley , Shonka Nicole , Harrison Rebecca , DeGroot John , Mehta Minesh , Odia Yazmin , Hall Matthew , Daghistani Doured , Cloughesy Timothy , Ellingson Benjamin , Kim Michelle , Umemura Yoshie , Garton Hugh , Franson Andrea , Schwartz Jonathan , Li Sunjong , Cartaxo Rodrigo , Ravi Karthik , Cantor Evan , Cummings Jessica , Paul Alyssa , Walling Dustin , Dun Matthew , Cain Jason , Li Jiang , Filbin Mariella , Zhao Lili , Kumar-Sinha Chandan , Mody Rajen , Chinnaiyan Arul , Kurokawa Ryo , Pratt Drew , Venneti Sriram , Grill Jacques , Kline Cassie , Mueller Sabine , Resnick Adam C , Nazarian Javad , Waszak Sebastian , Allen Joshua E , Koschmann Carl 
Published: November 2022

Abstract
Patients with H3K27M-mutated diffuse midline glioma (DMG) have no proven effective therapies beyond radiation. ONC201, a DRD2 antagonist and mitochondrial ClpP agonist, has shown promise in this population. Clinical and genetic variables associated with ONC201 response in H3K27M-mutant DMG continue to be investigated. A combined clinical and genetic study evaluated patients with H3K27M-DMG treated with single-agent ONC201 at the established phase 2 dose. Clinical outcomes of patients treated on two recently completed multi-site clinical studies (NCT03416530 and NCT03134131, n = 75) were compared with historical control data from patients with confirmed H3K27M-DMG (n = 391 total, n = 119 recurrent). Patients treated with ONC201 monotherapy following initial radiation, but prior to recurrence, demonstrated a median overall survival (OS) of 25.6 months from diagnosis and recurrent patients demonstrated a median OS of 16.2 months from recurrence, both of these more than doubling historical outcomes. Using a Cox model to correct for age, gender and tumor location, OS of ONC201-treated patients with H3K27M-mutant tumors remained significantly better than non-ONC201-treated historical controls (p = 0.0001). A survival and radiographic analysis based on tumor location, revealed stronger responses in thalamic patients. In patients with thalamic tumors treated after initial radiation (n = 16), median OS was not reached with median follow up of 22.1 months (historical control median OS of 12.5 months, n = 83, p = 0.0001). Significant correlations were found between baseline cerebral blood flow (CBF) on perfusion imaging and OS (Pearson’s r = 0.75, p = 0.003) and between nrCBF and PFS (r = 0.77, p = 0.002). Baseline tumor sequencing from treated patients (n = 20) demonstrates EGFR mutation (n = 3) and high EGFR expression as a marker of resistance and improved response in tumors with MAPK-pathway alterations (n = 5). In conclusion, ONC201 demonstrates unprecedented clinical and radiographic efficacy in H3K27M-mutant DMG with outcomes enriched in patients with thalamic tumors, treatment prior to recurrence, MAPK-pathway alterations, and patients with relatively high CBF.
CTNI-62. LONG-TERM EFFICACY AND SAFETY OF LAROTRECTINIB IN PATIENTS WITH TROPOMYOSIN RECEPTOR KINASE (TRK) FUSION PRIMARY CENTRAL NERVOUS SYSTEM (CNS) TUMORS
Authors: Perreault Sébastien , Drilon Alexander , Lassen Ulrik N , Geoerger Birgit , Nysom Karsten , Øra Ingrid , Gavrilovic Igor T , Norenberg Ricarda , Bernard-Gauthier Vadim , De La Cuesta Esther , Laetsch Theodore W , Doz François , Van Tilburg Cornelis M 
Published: November 2022

Abstract

BACKGROUND
Larotrectinib is a highly selective TRK inhibitor that demonstrated an objective response rate (ORR) of 30% and a 24-week disease control rate (DCR) of 73% across 33 evaluable adult and pediatric patients with TRK fusion primary CNS tumors, as of July 2020 (Doz et al, Neuro Oncol 2021). We report updated data on an expanded dataset.

METHODS
Patients with TRK fusion primary CNS tumors in two clinical trials (NCT02637687, NCT02576431) were included. Responses were investigator-assessed.

RESULTS
As of July 2021, 38 patients with TRK fusion primary CNS tumors (median age, 10.8 [range 1.3–79.0] years) were identified: high-grade glioma (HGG; n = 23), low-grade glioma (LGG; n = 9), and other (n = 6). Sixteen (42%) patients had ≥ 2 prior systemic therapies. ORR for 37 evaluable patients was 30% (95% confidence interval [CI] 16–47): three complete responses, eight partial responses, 21 stable disease (16 patients ≥ 24 weeks), and five progressive disease. For pediatric patients (n = 28), the ORR was 39% (95% CI 22–59). For pediatric patients with HGG and LGG, ORRs were 43% (95% CI 18–71) and 38% (95% CI 9–76), respectively. ORRs for patients with 0, 1, 2, and ≥ 3 prior therapies were 33%, 20%, 38%, and 38%, respectively. Median time to response was 1.9 months. The 24-week DCR was 73% (95% CI 56–86). Median duration of response (DoR) was not reached; 12-month DoR rate was 64%. Median progression-free survival was 16.5 months (95% CI 6.7–not estimable). Median overall survival (OS) was not reached; 24-month OS rate was 65%. Treatment duration ranged from 0.1+ to 38.7+ months. Treatment-related adverse events (TRAEs) were mostly Grade 1–2. No patients discontinued treatment due to TRAEs.

CONCLUSION
Larotrectinib demonstrated a high DCR, rapid and durable responses, and a manageable safety profile in patients with TRK fusion primary CNS tumors.
DNAR-03. TARGETING POLY (ADP-RIBOSE) SIGNALING TO INDUCE LETHAL DNA DAMAGE IN IDH MUTANT GLIOMA
Authors: Kitagawa Yosuke , Wakimoto Hiroaki , Melamed Lisa , Nasser Ali , Miller Julie , Cahill Daniel 
Published: November 2022

Abstract
Isocitrate dehydrogenase (IDH) 1 or 2 mutant gliomas have unique metabolic characteristics and DNA damage response. Radiotherapy and chemotherapy has been proven to be an effective treatment for IDH mutant gliomas. A key mediator of DNA damage response, Poly(ADP-ribose) (PAR) is regulated by opposing enzymes, poly(ADP-ribose) polymerases (PARPs) that synthesizes PAR through enzymatic polymerization of nicotinamide adenine dinucleotide (NAD), and poly(ADP-ribose) glycohydrolase (PARG) that breaks down and recycles PAR. We recently demonstrated that combining PARG inhibitor (PARGi) and Temozolomide (TMZ) in IDH mutant cells drove an imbalanced sequestration of NAD into PAR, resulting in metabolic lethality through NAD depletion. Here, we sought to characterize the effect of combining PARGi and radiation. Isogenic pairs of IDH1-mutant glioma cells, alongside multiple IDH mutant patient-derived glioma cells, were treated with TMZ, radiation, PARPi, PARGi, and combination thereof. In contrast to PARPi which can have a “trapping” effect, PARGi monotherapy displayed no significant difference between IDH mutant and wild-type isogenic cells. However, we found a substantial augmentation of radiation cytoxicity when combined with PARGi, that was genotype-specific in IDH mutant glioma models, mirroring that seen with PARPi and radiation (Wang et al, Science Advances 2020). Unlike TMZ+PARGi, NAD was not depleted with PARGi and radiation. Conversely, the cytotoxic effect was partially reversed with either PARPi or IDH inhibitor, indicative of a key contribution of PAR mediated DNA damage signaling in the IDH mutant context. Therefore, these results support a model of converging vulnerabilities in IDH mutant cells, with PAR-mediated DNA repair mechanisms independent from NAD metabolism.In summary, this study demonstrates that the combination of PARGi and radiation regulates DNA repair pathways with cytoxicity specific to IDH mutant gliomas. Targeting PAR can potentially be a promising treatment for clinical translation in IDH mutant gliomas, minimizing the radiation effect to surrounding normal cells.
DNAR-11. CHARACTERIZING THE GENOMIC CONSEQUENCES OF G-QUADRUPLEX STABILIZATION IN ATRX-DEFICIENT HIGH-GRADE GLIOMA
Authors: Dharmaiah Sharvari , Chen Brandon , Malgulwar Prit Benny , Tadimeti Vasudev , Farooqi Ahsan , Huse Jason 
Published: November 2022

Abstract
α-thalassaemia/mental retardation X-linked (ATRX) mutations are a critical molecular marker for high-grade glioma (HGG). These mutations lead to accumulations of abnormal DNA secondary G-quadruplex (G4) structures, thereby inducing replication stress and DNA damage. As G4s arise at GC-rich regions (i.e., pericentromeric and telomeric regions), ATRX-deficiency alters genome-wide accessibility of chromatin and causes transcriptional dysregulation. However, the genomic consequences of this in the context of ATRX-deficiency are poorly understood. Our goal is to target ATRX deficiency through G4 stabilizers, a class of novel small molecule compounds that selectively bind to and stabilize G4s. Using a combination of functional experiments such as cell viability, western blot, flow cytometry, RNA-sequencing (RNA-seq), and immunofluorescence (IF), we evaluated the mechanisms that drive selective lethality upon G4 stabilization. Patient-derived glioma stem cells (GSCs) were treated with either vehicle (DMSO) or varying doses of CX-5461 (G4 stabilizer, Senhwa Biosciences). Excitingly, ATRX-deficient GSCs demonstrate dose-dependent enhanced sensitivity to G4 stabilization, compared to ATRX-intact and vehicle controls. Cell viability assays confirmed the specificity of CX-5461 in comparison to other commercially used G4 stabilizers. G4 stabilization activated p53-independent apoptosis and exhibited G2/M arrest in ATRX-deficient GSCs and, interestingly, upregulated expression of both ATR and ATM pathways, indicating enhanced replication stress and DNA damage, respectively. IF staining confirmed enhanced induction of replication stress and DNA damage markers 53BP1 and gH2AX. Our preliminary findings suggest that ATR and ATM activation leads to Cyclin D1 degradation and inhibition of transcription factor NF-κB, thereby driving apoptosis. In fact, RNA-seq analyses revealed positive enrichment of apoptosis, DNA repair, and NF-κB pathways and negative enrichment of the G2/M checkpoint in ATRX-deficient GSCs treated with CX-5461. Our work defines mechanisms of action and efficacy of a novel therapeutic strategy for pre-clinical ATRX-deficient HGG models, with strong implications for other ATRX-deficient cancers and potential translation into clinical practice.
DDEL-06. HEAT-ACTIVATED DOXORUBICIN UPTAKE FACILITATED BY LASER INTERSTITIAL THERMAL THERAPY
Authors: Athukuri Prazwal , Moreno Karina , Yang Yuhui , McDonald Malcolm , Lee Sungho , Latha Khatri , Marisetty Anantha , Rao Ganesh 
Published: November 2022

Abstract
Although surgery has been shown to provide a survival benefit in patients with glioblastoma multiforme (GBM), tumor location and geometry may restrict maximal resection. Additionally, the margin of resection cavity contains infiltrating tumor cells that result in recurrence and therapy resistance. Laser interstitial thermal therapy (LITT) is a treatment modality that uses thermal energy to destroy tumor cells. LITT is useful for tumors that are not appropriate for conventional surgical resection. Our laboratory has developed a LITT model to study LITT in a genetically engineered mouse model of GBM. The combination of heat activated nanoparticles and LITT represents an opportunity to target the infiltrating tumor margin, extending the treatment penumbra. We hypothesized that heat-activated liposomes containing doxorubicin (ThermoDox, Celsion) would demonstrate infiltration into the brain parenchyma after treatment with LITT. We treated tumor-bearing mice with LITT or sham (laser fiber implanted but not activated) after either ThermoDox (5mg/kg) or PBS infusion, 30 minutes before performing LITT or sham treatment. We euthanized these mice 1 hour after LITT or sham treatment, harvested brains, and performed immunofluorescence to identify doxorubicin in parenchymal cells. Doxorubicin was identified in 100% of mice treated with LITT following ThermoDox administration which is in contrast with groups treated with LITT and PBS, sham and ThermoDox, and sham and PBS. Here, we show that heat-activated nanoparticles are disrupted through hyperthermia followed by the release of doxorubicin only in the presence of hyperthermia, which paves way for the clinical use of ThermoDox as adjunct chemotherapy following LITT in treatment-resistant GBM treatment.
DDEL-10. ULTRASOUND-ENHANCED DRUG DELIVERY IN HUMANS ALTERS ENDOTHELIAL PHENOTYPE AND PERTURBS THE ULTRASTRUCTURE OF THE BLOOD BRAIN BARRIER
Authors: Gould Andrew , Korobova Farida , Arrieta Victor , Amidei Christina , Canney Michael , Chen Li , Stupp Roger , Sonabend Adam M 
Published: November 2022

Abstract
The use of low-intensity pulsed ultrasound with concomitant injection of microbubbles (LIPU/MB) achieves local and reversible opening the blood-brain barrier (BBB), enhancing the delivery of systemically administered drugs to the brain parenchyma. Electron microscopic studies conducted in animals proposed that LIPU/MB enhances paracellular diffusion across the cerebral vasculature, by disrupting tight junction proteins between endothelial cells, as well as enhancement of caveolar transcytosis. The effects of LIPU/MB on the ultrastructure of the human BBB and cerebral endothelial phenotype have not been systematically investigated. Here we report a first in-human electron microscopic study, examining endothelial phenotype and BBB ultrastructure in the peri-tumoral brain of humans after undergoing LIPU/MB-enhanced drug delivery. Non-eloquent peritumoral brain was biopsied at different time points (4-63 minutes) following an intraoperative LIPU/MB procedure in three patients who underwent a surgical resection of recurrent glioblastoma through a phase I clinical trial [NCT04528680]. Transmission electron microscopy was used to examine cross sections of the microvasculature and associated components of the BBB. We observed a significant (P = 0.0397) time-dependent decrease in the frequency of endothelial caveolae immediately after sonication compared to non-sonicated control vessels, which resolved within 1 hour of treatment. We also observed a time-dependent increase in membrane-bound vacuoles in the endothelial cytoplasm following sonication (P = 0.0002, one-way ANOVA). Sonicated blood vessels occasionally showed swollen astrocytes, convoluted luminal protections, and lightening of otherwise dense tight junction proteins, not frequently observed in non-sonicated biopsies from the same patients. Our study shows that LIPU/MB changes the endothelial phenotype within the cerebral vasculature, and suggests the accumulation of vacuoles in endothelial cells after BBB opening.
DDEL-14. SYSTEMIC THERAPY USE FOR THE TREATMENT OF MENINGIOMA: A SYSTEMATIC REVIEW
Authors: Taleb Khalid , Laucis Anna 
Published: November 2022

Abstract

INTRODUCTION
Meningiomas are the most common primary central nervous system tumor. Many studies have investigated systemic therapy agents for treating meningiomas, but no study has systematically evaluated the various agents used while comparing outcomes. The goal of this study was to investigate the recent systemic therapy agents used to treat meningioma tumors and to compare relevant clinical outcomes such as progression-free survival and overall survival in patients with meningioma tumors receiving systemic therapy agents as part of their care.Materials and

METHODS
A systematic literature review was performed to investigate systemic therapy agents used to treat meningioma tumors. The PubMed database was used for this review and articles published from 7/4/2011 to 7/4/2021 were evaluated. The exclusion criteria included the following: animal and cell line studies, case reports, review articles, articles in a foreign language (other than English), as well as articles not related to meningioma or to systemic therapy agents.

RESULTS
163 articles were initially evaluated. After excluding 152 articles using the exclusion criteria for our study, a total of 11 articles exploring 14 different systemic therapy agents were ultimately included and compared, mainly focusing on the two clinical outcomes of progression-free survival and overall survival. The study findings suggest that Bevacizumab may have the most promising results for reducing peri-tumoral edema and extending progression-free survival, with the highest observed progression-free survival at six months of 86% compared to lower progression-free survival for other systemic therapy agents.

CONCLUSION
This systematic review study evaluated systemic therapy agents used to treat meningioma tumors. Bevacizumab was found to have the most promising results overall. However, further studies are now needed to evaluate the efficacy and possible side effects of Bevacizumab amongst a larger population of patients with different meningioma tumor grades, locations, and treatment responses.
DDDR-09. TARGETED DYSREGULATION OF SPHINGOLIPID RHEOSTAT BALANCE IN IDH1MUT GLIOMAS TRIGGERS PRO-APOPTOTIC METABOLIC AND SIGNALING ACTIVITY
Authors: Dowdy Tyrone , Yamasaki Tomohiro , Li Aiguo , Zhang Lumin , Zaibaq Faris , Lita Adrian , Gilbert Mark , Larion Mioara 
Published: November 2022

Abstract

BACKGROUND
IDHwt gliomas exhibit sphingolipid rheostat balance that permits tumors to evade apoptosis by elevating the sphingosine-1-phosphate (S1P)-to-ceramide ratio. Overexpression of sphingosine kinase (SPHK) and consequent accumulation of S1P contribute to progression, chemoresistance, migration, and metastasis in malignant glioblastoma (GBM). We discovered that IDH1mut gliomas present a characteristic sphingolipid rheostat in which pro-apoptotic ceramides and sphingosines are elevated over oncopotent S1P. This characteristic involves inherent silencing of the SPHK2; obliging spheroids to rely on SPHK1 exclusively. We postulated that targeting this unique metabolic vulnerability would abrogate the growth-promoting and anti-apoptotic effects of S1P.

METHODS
IDH1mut glioma cell lines (TS603, BT142 & NCH1681) and empty vector-induced normal human astrocytes (NHAEV) were cultured and treated with a combination of SPHK1 inhibitor, N,N-dimethylsphingosine and C17-sphingosine to dysregulate sphingolipid rheostat. Biostatic response (i.e., IC50) was measured via spectrophotometric assay. Metabolic and signaling mechanisms were investigated by LC-MS lipidomic and RNA sequencing analysis. Mechanism of apoptosis was determined via western-blotting.

RESULTS
Following combination treatment, a global increase in ceramides, sphingosines, and their derivatives over S1P was detected in the sphingolipid rheostat. A decline in growth-promoting MAPK signaling enzymes and elevation of enzymes indicative of mitochondria-driven apoptosis occurred. Elevation of TNFα-related regulatory enzymes (NR1H3, MYLIP, INSIG, ABCA1) negatively impacted cholesterol homeostasis along with catalytic enzymes involved in cholesterol (and isoprenoid) biosynthesis. The effective concentration against IDH1mut spheroids was not cytotoxic to NHA spheroids.

CONCLUSION
The combination treatment potentiated a pro-apoptotic shift in sphingolipidome and revealed a novel mechanism of drug action involving concomitant global attenuation of cholesterol metabolism. While previous studies reported that decreasing cholesterol in gliomas compromises viability and induces apoptosis a link between cholesterol and sphingolipid metabolism remains unknown. Our data demonstrated that targeting sphingolipid rheostat triggers a cascade of pro-apoptotic signaling and metabolic activity that lower the threshold for apoptosis in IDHmut gliomas.
DDDR-12. THE ROLE OF CASEIN KINASE 1 EPSILON IN TEMOZOLOMIDE SENSITIVITY IN GLIOBLASTOMA STEM CELLS
Authors: Bilton Shawna , Sheng Zhi 
Published: November 2022

Abstract

A major hurdle in effectively treating glioblastoma is the resistance to current chemotherapy temozolomide (TMZ), exhibited intrinsically in glioblastoma stem cells (GSCs). GSCs are a population of tumor cells that are self-renewing, highly resilient and capable of forming genetically heterogeneous and difficult-to-treat tumors. Therefore, overcoming TMZ resistance holds significant promise in the treatment of glioblastoma. Casein kinase 1 ε (CK1ε) has been identified as a stem cell factor that is important for GSCs to self-renew. However, whether CK1ε confers TMZ resistance in GSCs remains elusive.

METHODS
To test the role of CK1ε in the chemoresistance of GSCs, we treated GSC adherent cell lines with TMZ, CK1ε inhibitor IC261, and a combination of TMZ plus IC261. Cell viability was assessed with MTS viability assay or CellTiter-Blue viability assay.

RESULTS
Cell viability was significantly decreased in GSCs treated with 0.8μM IC261 combined with 100μM TMZ as compared to cells treated with either 0.8μM IC261 or 100μM TMZ alone (p &lt; 0.05). We assessed synergistic drug effects using the Bliss independence model to yield Excess Over Bliss (EOB) scores. EOB &gt; 0% indicates a synergistic effect; EOB = 0% indicates additive effect; and EOB &lt; 0% indicates antagonistic effect. Cells treated with 0.8μM IC261 together with 100μM TMZ yielded EOB of &gt; 0%.

CONCLUSIONS
Previous work has identified CK1ε as an important stem cell factor in the survival GSCs, but there lacked studies testing the role of CK1ε in TMZ chemoresistance in vitro. We demonstrate synergistic inhibition of cell viability in GSCs treated with CK1ε inhibitor IC261 in combination with TMZ. Based on these results, CK1ε is suggested to play an important role in the chemoresistance of GSCs to TMZ.