bluuebunny/crossref_metadata_2025_split huggingface dataset:
CNSC-37. THE ASSOCIATION BETWEEN THE NUMBER OF HIGH-DOSE METHOTREXATE CYCLES AND LONGER REMISSION PERIODS IN PATIENTS WITH PRIMARY CENTRAL NERVOUS SYSTEM LYMPHOMA: A RETROSPECTIVE REVIEW
Authors: Nahm Joshua , Sinha Mousumi , Schumann Eva Highberg , Vu Mia , Ware Cornelius , Hsu Sigmund , Zhu Jay-Jiguang 
Published: November 2023

Abstract
Representing 3-4% of newly diagnosed central nervous system tumors, primary central nervous system lymphomas (PCNSL) are rare, extra-nodal non-Hodgkin lymphomas with an overall survival (OS) of 91.9 months. Though patients can achieve a complete response (CR) after first-line therapy, PCNSL typically recurs within two years. Standard treatment involves high-dose methotrexate (HD-MTX)-based polychemotherapy, but the ideal number of HD-MTX cycles that achieves and maintains a CR is unclear. To address this question, we conducted a retrospective review of PCNSL patients. The primary outcome was median OS. Secondary outcomes included the OS of recurrent PCNSL patients (rOS), number of HD-MTX cycles before the first recurrence or CR, and adverse events (AE). Survival analysis was performed using the Kaplan-Meier estimate. Forty-one patients (23 males; median age: 66) were identified. The median OS is 114 months (95% CI 44.9, NA). Twenty-nine patients achieved CR after first-line therapy with a median of five cycles. Eleven patients experienced PCNSL recurrence (rPCNSL), with five patients previously achieving a CR. The median rOS before the first recurrence was 60.4 months (95% CI 6.3, NA). The median number of cycles of HD-MTX before recurrence was three cycles, and the cumulative total of HD-MTX was five cycles. Among the 24 patients without recurrence and with CR, the median OS was not reached, but the median number of HD-MTX cycles before CR was six cycles and cumulatively was six cycles. Complete results of AEs will be updated at the meeting, but they currently include grade III hypokalemia (45.8%), grade III anemia (45.8%), and grade III acute kidney injury (25.0%). Despite the limitations of a retrospective review, our findings suggest that a higher number of HD-MTX cycles is associated with prolonged duration of remission. Future studies are warranted to determine an ideal number of HD-MTX to maintain remission state in PCNSL patients.
CNSC-44. BIOLOGICAL PATTERN DISCOVERY IN GLIOBLASTOMA
Authors: Ayyadhury Shamini , Sachamitr Patty , Kushida Michelle , Park Nicole , Coutinho Fiona , Whitley Owen , Prinos Panagiotis , Arrowsmith Cheryl , Dirks Peter , Pugh Trevor , Bader Gary 
Published: November 2023

Abstract
Glioblastoma(GBM - IDH wildtype) is an adult glioma, showing abysmal prognosis. Sequencing technologies show us the existence of a neurodevelopmental frame-work, upon which heterogeneous molecular patterns are overlaid. The tumor's functional capacity is the net result of extrinsic+intrinsic molecular factors interacting with each other. These factors affect how cells communicate and organize themselves into complex functional architectures that support their evolution, survival and resistance. Understanding the phenotypic significance of a tumor's architecture, will allow us to understand these processes and compute complex patterns in GBM that are "biologically-relevant". First, we showed, as a proof-of-concept, that "biologically-relevant" signatures are imprinted within the spatial organization of cells using spatial pixel analysis. We used a phase-contrast image dataset of glioblastoma stem cells grown in culture, imaged 4-12hrly, over 12-16 days. We applied 29 hand-engineered pixel features per image, deriving spatial pixel signatures for each of our 17’601 phase-contrast images. Using different computational analytical methods and gene expression from matched bulk RNA datasets, we showed that spatial pixel patterning follows biologically relevant phenotypes. We found samples of images with high PC2 scores had higher mesenchymal/microglia scores, as compared to samples of images with low PC2 scores, which showed higher neurodevelopmental signatures. In addition, we found that mathematical algorithms describing entropy, homogeneity, contrast and complexity were clearly enriched in specific biological groups. Hence, our study showed that the organizational/architectural patterns of biological entities show preservation of fundamental organizational principles. Building upon the above data (which is currently a manuscript under preparation), we will apply these principles towards pattern discovery of GBM tissues at multiple architectural hierarchies (i.e subcellular, cellular, stroma) using different GBM models, imaging and spatial transcriptomics. If structure equates to function, understanding GBM architecture will have important applications in surgical tool developments and understanding relevant mechanistic patterns in GBM.
STEM-03. TARGETING ANDROGEN SIGNALING IN GLIOBLASTOMA
Authors: Mason Sofia , Chung Sylvia , Juan Beatriz Perez San , Sim Hao-Wen , Dear Rachel , Day Bryan , Holst Jeff , Chaffer Christine 
Published: November 2023

Abstract

BACKGROUND
Glioblastoma is a lethal brain cancer. Androgen receptor (AR) transcript levels and protein expression are upregulated in glioblastoma compared to normal brain. AR signaling has a role in cancer stem cell function in various cancers. Stem cell activity and cancer cell plasticity represent a key resistance mechanism in glioblastoma. Thus, potent brain-penetrant anti-androgen therapies have the potential to improve treatment outcomes in glioblastoma.

METHODS
Clinical samples and patient derived xenografts were assessed for AR expression by immunohistochemistry. Cytoplasmic AR+ and AR- glioblastoma patient-derived xenografts maintained under stem cell conditions were tested in vitro for their response to anti-androgen therapies (abiraterone, enzalutamide and seviteronel). Stem cell function was assessed using a tumoursphere assay. Changes in plasticity markers, including ZEB1, were measured with immunofluorescence.

RESULTS
~55% of people with glioblastoma have detectable cytoplasmic AR based on immunohistochemistry. AR-positive patient-derived glioma stem cell line RN1 was inhibited by low concentrations of anti-androgen agents, with seviteronel having the lowest half maximal inhibitory concentration (IC50) (at 96 hours: enzalutamide 52µM, abiraterone 12µM, seviteronel 7µM). AR-negative line WK1 was also inhibited though with higher IC50s (at 96 hours: enzalutamide 63µM, seviteronel 21µM). Conventional cell lines U87 and U251 were also inhibited by anti-androgen monotherapy. Tumoursphere assays demonstrated that anti-androgen agents inhibit the tumour-forming ability of cells, with seviteronel and abiraterone showing more inhibition than enzalutamide. Immunofluorescence analysis showed downregulation of plasticity marker ZEB1 with anti-androgen treatment (normalised mean fluorescent intensity: abiraterone 0.84, enzalutamide 0.91, seviteronel 0.74).

CONCLUSIONS
Glioblastoma is a devastating disease, lacking effective or targeted treatments. Targeting AR with repurposed anti-androgen drugs may be a promising therapeutic strategy, with the potential to abrogate treatment resistance. We are now evaluating these anti-androgen regimens in animal experiments, which will provide a more replicative microenvironment and confirm blood-brain barrier penetrance.
CCRG-02. DEVELOPMENTALLY PARTITIONED PROLIFERATIVE COMPARTMENTS IN GLIOBLASTOMA
Authors: Plaisier Christopher , O'Connor Samantha , Arora Sonali , Petrecca Kevin , Patel Anoop , Paddison Patrick 
Published: November 2023

Abstract
It is now well established from single-cell RNA-seq studies that glioblastoma (GBM) tumors are complex, maligned neuro-developmental ecosystems harboring diverse tumor cell types. Neoplastic cells can resemble astrocytes, neural progenitors, oligodendrocyte progenitor cells, mesenchymal cells, and radial glial cells that contribute to tumor growth and homeostasis in specific ways. However, GBM single-cell data sets have failed to produce general models for transitions in and out of specific developmental and proliferative states in tumors. One reason is that human GBM tumors do not neatly resolve into developmental hierarchies. Here we focused on modeling GBM tumor cellular heterogeneity by defining "proliferative compartments" in single-cell transcriptomic data derived from primary tumors and early passage tumorsphere cultures. Previously, we observed that each tumor cell entering S-phase has a unique developmental signature that can be leveraged to define broader partitioned proliferative compartments (PPCs) with distinct developmental gene expression and genomic alteration patterns. Thus, we extracted the S-phase cells from a tumor, defined the proliferative compartments in that tumor using de novo clustering, determined the marker genes for each compartment, and defined the broader PPCs across tumors by de novo clustering based on similarity in marker genes. From a cohort of six tumors we observed eight broader PPCs and found that tumors can contain as many as five PPCs or as few as two. Because tumor growth and recurrence both require cell proliferation, we propose that patient-specific PPCs represent the engines of GBM progression.
CSIG-13. DIELECTRIC PROPERTIES OF INTRACRANIAL TUMORS – ROLE OF MYELIN CONTENT
Authors: Proescholdt Martin , Haj Amer , Schebesch Karl-Michael , Riemenschneider Markus , Baborie Atik , Schmidt Nils-Ole 
Published: November 2023

Abstract

INTRODUCTION
Recently, tumor treating fields (TTFields) were established for the treatment of newly diagnosed glioblastoma (GBM). One of the most crucial parameters defining the treatment efficacy of TTFields is the electric field intensity, which depends on the dielectric properties of the tumor tissue. In this study we determined the dieclectric properties of brain tumors by analyzing resected tissue. In GBM patients, histological analysis for cellularity, vascularization and myelin content was performed. In addition, sensitivity analyses for specific parameters were conducted.

METHODS
A cohort of 130 patients with tumors of different histology and malignancy grade have been recruited. Tissue samples were placed into a cylindrical cell with a known diameter. The impedance was recorded at frequencies 20Hz-1MHz. The measured impedance was translated into dielectric properties (conductivity and relative permittivity) based on the parallel plate model. Myelin, which is the most powerful electric isolator in the brain, was assessed in GBM samples by luxol fast blue staining, and quantified in a three-tier scale. To assess the impact of tissue conditions on the measurements, probes were warmed to 35 degree Celsius, dehydrated or irrigated with 0.9% saline solution.

RESULTS
We found significant differences between the conductivity of different types of tumors with meningiomas showing the lowest and GBM tissue exhibiting the highest conductivity values. GBM samples with very high median conductivity values displayed a consistently lower myelin content. In addition, GBM patients with particularly high conductivity had a significantly shorter overall survival (log rank analysis, p = 0.024). While tissue temperature had no detectable effects on the dielectric properties in GBM, saline irrigation tissue hydration significantly affected the results.

CONCLUSION
The dielectric properties of intracranial tumors depend on histological class and malignancy grade. GBM patients with high conductivity values showed a significantly poorer prognosis, indicating this parameter as potential marker for TTF efficacy.
CSIG-22. CAMKIIΓ INTERACTS WITH HIF-1Α IN AN OXYGEN-INDEPENDENT MANNER TO DRIVE PLASTICITY IN GLIOBLASTOMA
Authors: Ventarapragada Divya , McManus Graysen , Zhou Weidong , Park Cheol , Buechler Killian , Stepniak Amelia , Miska Jason , Ahmed Atique 
Published: November 2023

Abstract
Glioblastoma (GBM) is a highly aggressive brain tumor that demonstrates treatment resistance. Hypoxia-inducible factor 1-alpha (HIF-1α) plays a crucial role in GBM progression and recurrence. While HIF-1α overexpression is correlated with poor GBM survival, clinical inhibitors have shown limited efficacy due to compensatory pathways that are not well understood. In previous studies, we discovered GBM upregulates HIF-1α after temozolomide (TMZ) through an unknown mechanism independent of physiological hypoxia. We demonstrated HIF-1α but not HIF-2α knockdown reduces the stem-like properties of GBM and enhances their sensitivity to TMZ therapy in vitro and in vivo. To elucidate the mechanism of TMZ-induced HIF-1α stabilization, we performed co-immunoprecipitation of HIF-1α followed by mass spectrometry analysis (IP-MS). Our findings revealed 99 binding partners that were significantly and uniquely upregulated after TMZ treatment compared to GBM cells cultured under normal oxygen tension (20% O2), hypoxia (1% O2), or DMSO. Among these interactions, we focused on the HIF-1α-CAMKIIγ axis for further investigation based on pathway enrichment, patient survival data, and co-expression analysis in the TCGA_GBM dataset. Co-immunoprecipitation experiments confirmed enhanced binding between HIF-1α and CAMKIIγ in different GBM patient-derived xenograft (PDX) lines while this interaction was significantly reduced in normal astrocytes. Knockdown of CAMKIIγ inhibited the transcriptional activity of HIF-1α, increased its protein turnover, and improved TMZ sensitivity compared to control cells following TMZ treatment. Additionally, the expression of stem-cell markers and neurosphere formation, which are associated with GBM aggressiveness, were attenuated in hypoxia and TMZ conditions when CAMKIIγ was absent. Our data demonstrated that the HIF-1α-CAMKIIγ axis is critical for TMZ-induction of HIF signaling and cellular plasticity.
CSIG-28. R17 INDUCES A PRO-ONCOGENIC PROTEIN HYPERPHOSPHORYLATION PROGRAM IN CUSHING’S DISEASE
Authors: Asuzu David , Mullaney Dustin , Nwokoye Diana , Stoica Stefan , Bhatt Shyama , Mandal Debjani , Maric Dragan , Elkahloun Abdel , Sisay Bayu , Tatsi Christina , Nieman Lynette , Chittiboina Prashant 
Published: November 2023

Abstract

OBJECTIVES
to investigate molecular drivers of CD.

METHODS
We performed single-nucleus assays for transposase-accessible chromatin (snATACseq) and single-nucleus RNAseq (snRNAseq) in 4 CD adenomas including two adenoma-normal pairs. To assess proteins bound to the R17 promoter, we performed reverse chromatin immunoprecipitation (rChIP) using CRISPR dCas9-3XFLAG-Biotin and R17 promoter gRNAs followed by mass spectrometry (LC-MS). Mechanistic studies were performed in murine corticotroph cells (mCort) stably overexpressing R17 versus GFP. Using LC-MS, we quantified total and phospho-peptides from human CD adenomas versus adjacent normal pituitary glands (n = 3/group) and from mCort-R17 versus mCort-GFP cells (n = 5/group).

RESULTS
We found increase in R17 chromatin accessibility and gene expression in CD versus normal corticotrophs. rChIP identified R17 promoter enrichment of SUB1 and histone variant H1.4 indicating active remodeling. In CD specimens and in mCort-R17 cells, PP2A targets EGFR and ERK were hyperphosphorylated. LC-MS identified 30 peptides differentially phosphorylated in both CD adenomas and mCort-R17 cells. mCort-R17 cells demonstrated accelerated cell cycle progression with increased proliferation (P &lt; 0.001). In mCort-R17 cells, the PP2A agonist Fingolimod partially rescued AKT phosphorylation and induced apoptosis.

CONCLUSIONS
R17 is activated in CD due to upstream chromatin remodeling events. Aberrant R17 signaling leads to protein hyperphosphorylation and cell cycle acceleration, which is partially reversible by the PP2A agonist Fingolimod. Fingolimod may represent a novel therapeutic option for patients with CD.
RADT-02. WHOLE-BRAIN RADIATION THERAPY WITH SIMULTANEOUS INTEGRATED BOOST VERSUS STEREOTACTIC RADIOTHERAPY FOR THE TREATMENT OF BRAIN METASTASIS FROM NON-SMALL CELL LUNG CANCER
Authors: Ziwei Wu , Lixia Lu , Yuanyuan Chen , Ming Chen 
Published: November 2023

Abstract

OBJECTIVE
To compare whole-brain radiotherapy with a simultaneous integrated boost (WBRT-SIB) to stereotactic radiotherapy (SRT) in treating non-small cell lung cancer (NSCLC) patients with brain metastases (BMs).

METHODS
Between April 2013 and June 2021, NSCLC patients receiving WBRT-SIB or SRT for 1-10 BMs were reviewed. Propensity score matching was carried out without replacement using a ratio of 1 WBRT-SIB: 1 SRT patient and a caliper width of 0.03 to yield sufficient power and homogeneity between treatment groups. Intracranial progression-free survival (iPFS), overall survival (OS), the cumulative incidence of local tumor progression, and intracranial distant tumor progression were compared between groups. Toxicities were assessed utilizing the National Cancer Institute Common Terminology Criteria for Adverse Events Version 5.0 (CTCAE 5.0).

RESULTS
A cohort of 181 patients with was included in this study. After propensity score matching, there were 37 patients in the WBRT-SIB and the SRT group, respectively. The WBRT-SIB group had a significantly longer median iPFS than the SRT group (10.8 months vs. 6.5 months, p = 0.018). The median OS (p = 0.861) and the cumulative incidence of local tumor progression (p = 0.437) were similar between the two groups. WBRT-SIB was associated with reduced intracranial distant tumor progression (p = 0.043). No toxicities higher than grade 3 were observed in both groups. KPS score was an independent prognostic factor of OS (HR 0.459, p = 0.032).

CONCLUSIONS
Compared to SRT, the iPFS of NSCLC patients with BMs was prolonged after WBRT-SIB, mainly related to better control of distant intracranial tumors. WBRT-SIB is safe and can be an alternative option for patients with BMs. We also found that the KPS score is an independent prognostic factor of OS.
RADT-13. A BIOLOGIC EQUIVALENT DOSE COMPARISON BETWEEN RADIOSURGERY AND COLLAGEN TILE BRACHYTHERAPY FOR POST-OPERATIVE TREATMENT OF A BRAIN METASTASIS RESECTION CAVITY
Authors: Turner Adam , Garcia Michael 
Published: November 2023

Abstract

INTRODUCTION
Recurrence of a previously irradiated brain metastasis represents a challenging clinical scenario. Repeat radiosurgery results in sub-optimal local control (LC). Two independently published prospective cohort studies demonstrated durable LC in this setting with collagen tile brachytherapy (CTBT), a novel Cesium-131 carrier. Here we compare biologically equivalent dosimetric parameters of CTBT to radiosurgery to understand dose metrics that may underlie durable LC from CTBT.

METHODS
A patient was selected from the multi-institutional prospective CTBT registry (NCT04427384) with a brain metastasis resection cavity near brainstem. Planning was performed for radiosurgery (30Gy in 5 fractions, BED of 48Gy) and CTBT (Cs-131, activity of 3.5U). To directly compare dosimetric parameters between radiosurgery and CTBT, biologic equivalent doses (BED) were calculated for brainstem(α/β of 3, BED3) and oncologically at-risk tissue(α/β of 10, BED10). TG101 brainstem dose-constraints were referenced, and respective BED were calculated.

RESULTS
The resection cavity was 4mm away from brainstem and contained 7 CTBT tiles (28 Cs131 seeds). Gradient index (GI) (24Gy BED10 volume/48Gy BED10 volume) was 3.8 for radiosurgery and 2.2 for CTBT. Conformality index (CI) (48Gy BED10 volume/CTV volume) was 1.2 for radiosurgery and 2.6 for CTBT. BED10 to 90% of the cavity wall (2mm rim around the resection cavity) was 49.6Gy for radiosurgery and 92.6Gy for CTBT. BED3 dose limit goals (max dose 31Gy in 5 fractions, BED3 95.1Gy and threshold dose 23Gy in 5 fractions, BED3 of 58.3Gy to 0.5cc) were met for both radiosurgery and CTBT.

CONCLUSION
BED comparisons demonstrate that CTBT leads to higher CI, lower GI, and higher dose to the cavity wall than radiosurgery while meeting BED3 dose limit goals to an adjacent organ at risk. These dose characteristics might underlie durable LC seen in the recurrent brain metastasis setting, though larger scale analyses are being performed with with clinical outcomes on NCT04427384.
RADT-14. ROLE OF CHEMOTHERAPY AFTER RADIATION THERAPY FOR GYNECOLOGIC METASTASES TO THE BRAIN
Authors: Chen Eric , Aquino-Michaels Todd , Batra Sadhvi , Lochner Riley , Rizzo Anthony , Chapman Graham , Kyasaram Ravi , Harris Eleanor , Hodges Tiffany , Ferguson Lindsay , Choi Serah 
Published: November 2023

Abstract

BACKGROUND
Brain metastasis from gynecologic malignancy is rare, and the optimal treatment is undetermined.

METHODS
Retrospective data was collected at a single institution from 2001-2021 on 66 patients with brain metastasis from gynecologic malignancy who underwent brain radiation therapy (RT). Kaplan-Meier survival analyses, long-rank tests, and a multivariate proportional hazards model were performed.

RESULTS
Median overall survival (OS) and intracranial progression-free survival (PFS) were 4.3 and 3.6 months, respectively. 25 (38%) patients started chemotherapy after RT in a median 32.5 days (IQR 12-53). Compared to those who did not start chemotherapy after RT, those who did had a longer median OS (9.8 vs 2.6 months, p &lt; 0.01) and PFS (5.0 vs 2.5 months, p = 0.01). On univariate analysis, factors associated with worse survival included &gt;10 brain metastases (p = 0.09), leptomeningeal involvement (p &lt; 0.01), presence of extracranial disease (p = 0.01), no receipt of surgery (p = 0.05), receipt of whole brain RT (p &lt; 0.01), and no receipt of chemotherapy after RT (p &lt; 0.01). On multivariate analysis including above factors and age-adjusted Charlson Comorbidity Index, only receipt of chemotherapy after RT was significantly associated with improved survival (HR 0.32, CI 0.16-0.64). The most common chemotherapy was platinum-based agents in 10 (40%) patients, with no difference in survival (p = 0.74) between those treated with platinum-based versus other agents. More patients who started chemotherapy after RT compared to those who didn’t had ovarian cancer (56 vs 22%, p = 0.02), underwent surgery (52 vs 29%, p = 0.07), and underwent stereotactic radiosurgery (SRS) (64 vs 27%, p &lt; 0.01). For patients who did vs did not receive chemotherapy after SRS, median OS was 11.3 vs 4.3 months (p = 0.01), and after WBRT 4.5 vs 2.2 months (p = 0.10).

CONCLUSION
Patients treated with chemotherapy after SRS in this population may have improved outcomes, though prognosis remains poor.