bluuebunny/crossref_metadata_2025_split huggingface dataset:
CNSC-51. PRIMARY INTRACRANIAL ALVEOLAR SOFT PART SARCOMA (PIASPS): A SYSTEMATIC REVIEW OF CASE REPORTS AND CASE SERIES FROM 2000 – 2023
Authors: Qadri Haseeb Mehmood , Bashir Asif 
Published: November 2024

Abstract

BACKGROUND AND OBJECTIVE
Alveolar soft part sarcoma is a rare malignancy of the lower extremities considered to be of unknown cellular origin. Common in young female patients, the ASPS usually has a strong metastatic potential, mostly involving the lungs at the time of presentation. Cases involving the CNS primarily, without any evidence of systemic disease have emerged i.e. the primary intracranial alveolar soft part sarcoma (PIASPS). We aim to determine the clinical manifestations, natural progression and management of primary intracranial alveolar soft part sarcoma.

MATERIALS AND METHODS
After an extensive literature search using PubMed Central and Google Scholar, seven case reports and two case series of 14 patients with PIASPS were retrieved and included using the Preferred Reporting Items for Systemic review and Meta-analyses guidelines, published between 2000 and 2023.

RESULTS
Female preponderance of the neoplasm (57.14%) with an average age of 24.9 years was noted. Headache (36.36%) and papilledema (25%) were the most common presenting complaint and sign, respectively. Brain parenchymal involvement was noted in 71.42% cases, mostly the frontal lobe and left hemisphere. The lesion appeared isointense to hypointense on T1-weighted images and hyperintense on T2-weighted images (66.67%) on MRI. Gross Total Resection was possible in 57.14% lesions. On immunohistochemistry, the tumor cells manifested TFE3 and PAS positivity in 25% and 20% of the cases respectively. An average survival after follow up duration was found to be 31.79 months.

CONCLUSION
Surgery and radiotherapy are the mainstay of treatment of PIASPS, while meningioma an important differential diagnosis. TFE3 fusion product is readily been helpful in diagnosis. Evidence of a primary lesion in the CNS cannot rule out the presence of an occult primary elsewhere in the body. This, along with the slow growing nature of the neoplasm and delayed localized recurrences, require a long-term follow-up.
STEM-03. TARGETING F-ACTIN DYNAMICS OF GLIOBLASTOMAS TO OVERCOME THERAPY RESISTANCE: IMPACTS ON DNA REPAIR AND GLIOMA STEM CELL PHENOTYPE
Authors: Magalhaes Yuli , Forti Fabio 
Published: November 2024

Abstract
Glioblastoma (GBM) is a highly aggressive brain tumor with high recurrence and resistance to therapies. The F-actin cytoskeleton in GBM is related to cell invasion and the glioma stem cell (GSC) phenotype, affecting self-renewal and migration. Our research identifies a novel role for the F-actin pathway in DNA repair, impacting genomic stability and contributing to therapy resistance. Understanding F-actin’s role is crucial for developing targeted strategies to improve GBM treatment outcomes. This study examines the effects of pharmacological F-actin depolymerization on reversing resistance to ionizing radiation (IR) and temozolomide (TMZ) in GBM spheroids. We established resistant sublines of GBM U87-MG cells through IR and TMZ cycles, observing significant resistance increases via MTT assays. Also, resistant cells had enhanced spheroid formation capacity, with higher size and proliferation. Alterations in DNA repair and F-actin pathway were observed, with intensified and disorganized F-actin polymerization and efficient repair in resistant cells. Elevated expression of stemness markers (Nestin, CD133, and CD44) indicated a GSC-like phenotype in resistant cells, corroborated by increased tumorigenicity and de novo spheroid formation. These markers were further enhanced by DNA damage. Treating cells with actin polymerization inhibitors reduced resistance to TMZ and IR, partly due to impaired DNA repair capacity. Additionally, F-actin disassembly affected stemness marker expression, reinforcing the link between cytoskeletal dynamics and the GSC phenotype. Our findings suggest that F-actin dynamic is crucial for resistance in GBM. Targeting F-actin could resensitize recurrent GBM tumours by diminishing DNA repair capabilities and affecting the GSC-like phenotype, offering new therapeutic avenues.
STEM-06. DISTANT ORIGIN OF GLIOBLASTOMA RECURRENCE: NEURAL STEM CELLS IN THE SUBVENTRICULAR ZONE SERVE AS A SOURCE OF TUMOR RECONSTRUCTION AFTER PRIMARY RESECTION
Authors: Li Xue , Kim Hyun Jung , Kim Tae Min , Choi Seung Hong , Lee Soon-Tae , Park Jong Bae , Yoo Jihwan , Chang Jong Hee , Park Chul-Kee , Wu Hong-Gyun , Won Jae-Kyung , Lee Yeonhee , Lee Jeong Ho , Kang Seok-Gu , Lee Joo Ho 
Published: November 2024

Abstract
The recurrence of glioblastoma (GBM) remains unavoidable. Neural stem cells (NSCs) in the subventricular zone (SVZ) are considered a treatment target due to their potential role as the cellular origin of GBM. However, it is not yet confirmed whether GBM recurrence also originates from these cells. We first conducted deep sequencing on paired patient samples, including primary tumors (pT), recurrent tumors (rT), and SVZ tissues. The sequencing results revealed that in 5 out of 9 patients, the rT evolved independently from the SVZ rather than directly from the pT. Based on this, we developed a mouse model to simulate the GBM recurrence process by transforming SVZ NSCs into GFP-labeled cells carrying cancer mutations via electroporation. Following the resection of the tdTomato-labeled pT, we observed that 57.1% of the rT consists of a mixture of GFP- and tdTomato-positive tumor cells. To study the behavior of NSCs, we improved the existing mouse model by removing cortical tissue to simulate the complete resection of the pT. Four weeks post-surgical resection, 64.7% of tumors reconstructed in the resection cavity (RC), driven by the migration of OPC lineage cells. Time-course RNA-seq results indicated that the CXCL12-CXCR4 pathway might be responsible for driving the migration of SVZ NSCs to the RC. Further deconvolution and fluorescence staining analysis confirmed that CXCL12 secreted by endothelial cells around the RC could drive CXCR4-positive NSCs to migrate to the area. Additionally, the CXCR4 antagonist AMD3100 significantly reduced tumor recurrence in mice and extended survival. RNA-seq results from both mouse and human paired tumor samples confirmed that the CXCL12-CXCR4 pathway was enriched in locally recurrent tumor specimens and was correlated with shorter patient survival. In summary, our study provides evidence that GBM recurrence originates from SVZ NSCs. Moreover, we identified the CXCL12-CXCR4 pathway as a potential therapeutic target for GBM recurrence.
CCRG-02. MICRORNA TARGETING LOGIC IN DIRECT NEURONAL REPROGRAMMING OF GLIOBLASTOMA
Authors: Yuan Luorongxin , Cates Kitra , Kim Albert , Yoo Andrew 
Published: November 2024

Abstract
microRNA (miR)-124 is one of the main drivers of mitotic exit during neurogenesis, which is recapitulated in miR-9/9* and -124 (miR-9/9*-124)-mediated direct neuronal reprogramming. In the reprogramming of various cell types, miR-9/9*-124 induce non-neuronal cell fate erasure before activating the neuronal program. Regardless of the different starting transcriptome landscapes, a core gene regulatory network (GRN) is always targeted by miR-9/9*-124, with cell cycle progression as the most significant pathway. We reason that miR-9/9*-124 can induce cell fate erasure in cancerous cells by repressing similar GRNs, using glioblastoma multiforme (GBM) as a paradigm. Mechanistic insights into GBM fate erasure by miR-9/9*-124 while inducing the postmitotic state would facilitate the understanding of GRNs that govern the tumorigenic identity of GBMs and potentially offer novel therapeutic implications. Indeed, miR-9/9*-124 readily induces mitotic exit in patient-derived GBM cell lines, represses GBM cell fates, and promotes neuronal identity over time as assessed by RNA-seq. Mice receiving GBM intracerebral xenografts with miR-9/9*-124 survived significantly longer than those receiving non-specific control miRNA. Global profiling of miRNA targeting activity by AGO2-eCLIP reveals that miR-124 binds to transcripts enriched in G1/S transition and mitogen response. Conversely, miR-506—a miR-124 homolog—despite of sharing identical seed sequences, has significantly less targeting activity and fails to stop cell cycle progression. We are currently dissecting how the difference in the miRNA 3’ sequence renders contrasting biological outcomes. Preliminary data suggests that the length of miRNA alone alters targeting specificity to cell cycle transcripts. However, different permutations of miRNA 3’ sequence, though sufficient to induce mitotic exit, are not all competent to achieve neuronal reprogramming, indicating that mitotic exit and neurogenic activities of miR-124 could be decoupled. We hope that understanding the grammar logic of miRNA targeting would provide deeper insights into how miRNAs can be leveraged to manipulate GBM identity.
CCRG-03. DETECTION OF HETEROGENEOUS CELL CYCLE ALTERATIONS UPON TMZ CHEMOTHERAPY TREATMENT THROUGH ADVANCED MACHINE LEARNING
Authors: Villa Giulia , Kückelhaus Jan , Yabo Yahaya , Schnell Oliver , Delev Daniel , Benotmane Jasim Kada , Heiland Dieter Henrik 
Published: November 2024

Abstract
Glioblastoma (GB), the most aggressive central nervous system tumor, is hallmarked by its frequent relapse under alkylating chemotherapy. GB cells frequently exhibit changes in cell cycle phases during TMZ treatment, with a reduction in the G0-G1 phase and an increase in the S and G2 phases. This indicate both tumor cell re-entry into the cell cycle and a TMZ-induced arrest, contributing to resistance and progression. In this study, we leverage dynamic protein abundance of Ki-67, a proliferation marker peaking during S, G2, and M phases, to analyse cellular responses to TMZ in various cell lines and tissue samples. We designed an image-based machine learning approach for pattern recognition to reconstruct and analyse the cell cycle at the single-cell level. Six primary cell lines were characterized through whole-genome DNA, methylation and RNA sequencing. Functional read-outs were performed with large-scale, time- and concentration-dependent TMZ treatments in cell culture and GB-tissue slice models. Our model successfully reconstructed detailed cell cycle stages, showing that untreated cells were predominantly in the G0-G1 phase. TMZ treatment significantly shifted cells toward the S/G2 phase (p &lt; 0.02) in 3 of 6 cell lines and the pseudo-time reconstruction highlighted dose-dependent cell cycle changes. Cell lines with enhanced stem-like features, defined based on epigenetic and transcriptional data signature, showed no cell cycle changes at high TMZ doses (&gt;150µM), regardless the MGMT promoter methylation status. This heterogeneity in cell cycle response emphasizes the complexity of GB and the need for personalized treatments. Our study provides insights into GB MGMT cell cycle alterations and resistance mechanisms that are independent of MGMT methylation status, a known TMZ response biomarker. Therefore, the observed TMZ-induced cell cycle changes may serve as novel biomarkers for assessing treatment response, paving the way for personalized therapeutic approaches.
CSIG-04. ANTI-TUMOR RESPONSE OF ONCOMAGNETIC MONOTHERAPY IN GLIOBLASTOMA
Authors: Pandey Arvind , Hambarde Shashank , Baskin David , Helekar Santosh 
Published: November 2024

Abstract

BACKGROUND
Glioblastoma (GBM) is the most lethal primary malignant brain tumor with a median survival of 15–20 months. Concurrent temozolomide (TMZ) chemotherapy and radiation (XRT) remain the current standard of care (SOC) treatment for newly diagnosed GBM. The addition of tumor treating fields (TTFs) improves median survival for newly diagnosed GBM from 16 to 20.9 months. This modest improvement underscores the urgent need to identify a new treatment modality as a safe and effective therapy.

PURPOSE
The noninvasive Oncomagnetic device developed in our laboratory selectively kills glioblastoma (GBM) in vitro. We studied the cellular and molecular effects of Oncomagnetic monotherapy (OMT) on GBM cell lines and investigated immune response in a syngeneic mouse model.

RESULTS
OMT significantly reduces cell proliferation and cell survival in vitro. OMT induces persistent ROS primarily by increasing superoxide level in cancer cells and reduces mitochondrial-membrane potential in GBM cells. It also induces DNA damage and arrests cells in G1-phase of the cell cycle. Whole-body Oncomagnetic stimulation caused a substantial retardation of tumor growth and reduction of the contrast-enhanced tumor volume in 9.4T MRI scans. OMT showed significant increase in overall survival in treated mice. We also observed upregulated immune response indicated by RNA sequencing data obtained from OMT-treated GBM cells as well as in treated GBM mouse tumor sections by imaging mass cytometry analysis. The tSNE analysis of various immune clusters suggests significant increase in immune response by activating CD4+, CD8+, murine-macrophages and M1-macrophages located at tumor site in the treated group.

CONCLUSION
The obtained data indicate significant anti-tumor response by inhibiting cancer signaling pathways and an increased immune response. Our findings suggest unique mechanism of action for OMT stimulation and provide a strong rationale for standalone OMT for GBM.
CSIG-09. BEYOND SINGLE AGENTS: EXPLORING THE POTENTIAL OF ABEMACICLIB IN COMBINATION WITH PANOBINOSTAT FOR IMPROVED GLIOMA TREATMENT
Authors: Rao Namratha B , Miller Tracy A , Premkumar Daniel R , Pollack Ian F 
Published: November 2024

Abstract

BACKGROUND
Glioblastoma is the most common primary central nervous system tumour with a median survival of less than 15 months. Addressing the underlying redundant, and converging signaling pathways necessitates the utilization of small molecule inhibitors capable of simultaneous targeting and inhibition. In glioma, the aberrant CDK4/6-Rb pathway dysregulation resulting in disruption of cell cycle checkpoint progression can lead to uncontrolled cell division, a hallmark of cancer. The neuro-pharmacokinetics of abemaciclib, a Cyclin-dependent kinase inhibitor, is being currently investigated in phase 1 clinical trials by National Cancer Institue, [NCT05413304]. The importance of panobinostat as a Histone deacetylase inhibitor and potentiating the effects of various small molecular inhibitors in published literature is paramount. This study is based on investigating ways to overcome resistance by exploring the synergistic cytotoxic effects of abemaciclib in combination with panobinostat in glioma.

METHODS
We investigated the antiproliferative effects of abemaciclib and panobinostat on glioma cells using an MTS cell proliferation assay. Inhibitor combination analysis was done using, SYNERGYFINDER via zip-model. Flow cytometry with Annexin V staining further assessed cell death and apoptosis induced.

RESULTS
The antiproliferative effects of abemaciclib, alone and in combination with panobinostat, in pediatric lines (KNS 42, SJG2), and adult human glioblastoma line, SF188 exhibited lower IC50 as compared to adult high grade glioma lines (LN 18, LNZ 308). Synergy analysis revealed a strong cytotoxic effect in KNS 42 and SF 188 cells treated with the combination. Flow cytometric analysis indicated that the combination therapy induced significant cell death only in a subset of cell lines- KNS 42 and SF 188, suggesting underlying genetic heterogeneity influences treatment response, warranting further mechanistic studies.

CONCLUSION
Combination therapies using abemaciclib and panobinostat, targeting CDK4/6 and histone deacetylation pathways, show promise against aggressive and treatment-resistant gliomas. Further investigation into these combination approaches is crucial to understand resistant mechanisms, optimize efficacy, and establish their clinical efficacy for improving glioma patient outcomes.
CSIG-23. CYTOMEGALOVIRUS-INFECTED HUMAN GLIOBLASTOMA CELL LINES SHOW AN AGGRESSIVE PHENOTYPE ASSOCIATED WITH UPREGULATION OF IL-6/STAT3 AND AKT SIGNALING
Authors: Tajiknia Vida , Mercado Noe , Murphy Eain , lawler Sean 
Published: November 2024

Abstract

BACKGROUND
Cytomegalovirus (CMV) has been implicated in glioblastoma (GBM) pathogenesis by affecting stemness, angiogenesis and immune pathways. Clinical trials targeting CMV in GBM patients have shown some early promise, and CMV seropositivity has been associated with poorer outcomes. However, the underlying mechanisms remain unclear. Here we investigated the effects of CMV infection on critical signaling pathways in GBM (IL6/STAT3, and Akt signaling) based on the hypothesis that CMV may contribute to poorer outcomes in GBM by increasing oncogenic signaling.

MATERIALS AND METHODS
Human U251 and LN229 GBM cell lines were infected with mCherry expressing human CMV TB40 strain at a multiplicity of infection (MOI) of 0.5. We performed basic phenotypic studies in vitro and investigated the status of IL6/STAT3, and Akt signaling by Western blotting.

RESULTS
Both LN229 and U251 cell lines were readily infectable by CMV. Infection of U251 cells was over 90% and in LN229 cells was approximately 60%. Interestingly expression of CMV was sustained over many passages in these cell lines. Infection was also verified by the presence of the CMV pp65 protein assessed by Western blotting. Measurement of cell proliferation indicated faster growth after CMV infection. Interrogation of key pro-oncogenic signaling pathways in GBM revealed a robust upregulation of IL6, as well as phospho(Tyr705)-STAT3 and phospho(Thr308)-Akt. This elevation of pro-oncogenic signaling pathways was observed in both cell lines compared with controls.

CONCLUSIONS
Here we show for the first time that infection of human GBM cell lines with CMV results in a more aggressive phenotype associated with upregulation of IL6/STAT3 signaling as well as a significant increase in phospho-Akt levels. We are currently studying sensitivity to standard therapies and additional molecular changes in these cells. These data support the hypothesis that CMV causes more aggressive disease and that CMV is a relevant therapeutic target in GBM.
RADT-09. CHEMORADIOTHERAPY WITH TEMOZOLOMIDE VS. RADIOTHERAPY ALONE IN PATIENTS WITH IDH WILD-TYPE AND TERT PROMOTER MUTATION HISTOLOGICAL GRADE 2/3 GLIOMAS: A POSTHOC ANALYSIS OF A RANDOMIZED CONTROLLED TRIAL
Authors: Wang Peng , Zhang Jing , Feng Jin , Chen Li , Ren Yin , Deng Kaiwen , Liu Fei , Qiu Xiaoguang , Liu Yanwei 
Published: November 2024

Abstract

PURPOSE
In 2016, we initiated a signal center prospective randomized trial to compare chemoradiotherapy (CRT) with temozolomide (TMZ) to radiotherapy (RT) alone in patients with IDH wild-type and TERT promoter mutation histological grade 2/3 gliomas. This study demonstrated patients who received CRT had a longer median OS than those who received RT alone and found no statistical difference in PFS between the two groups. Now, we recruited more patients in the CRT group to further explore whether there were differences in PFS between patients treated with CRT and RT. Besides, we explored the effect of MGMT promoter (MGMTp) methylation status on OS and PFS in patients receiving CRT therapy in the STUPP schedule.

METHODS
We expanded the scope by enrolling 21 participants in the CRT group and extending the follow-up period. OS and PFS were analyzed using the log-rank test, and high-risk factors were explored through Cox regression analysis.

RESULTS
Patients’ median follow-up is 21.9 months. CRT group has a longer median OS (25.3 vs 17.2 months; P = 0.029, HR = 0.443) and PFS (14.6 vs 8.3 months; P = 0.0008, HR = 0.387) than the RT group. Multivariate analysis identified CRT as a favorable prognostic variable for both OS (P = 0.003) and PFS (P = 0.002). The status of MGMTp methylation did not affect OS (P = 0.560, HR = 1.30) and PFS (P = 0.75, HR = 0.88) in patients with IDH-wt/TERTp-mut receiving TMZ chemotherapy. CRT with TMZ did not significantly increase grade 3 or higher toxicities.

CONCLUSIONS
The long-term results confirmed that the OS and PFS benefits of the RT plus TMZ regimen exceeded those of the RT alone group in patients with IDH-wt/TERTp-mut gliomas.
RADT-17. FRACTIONATED REIRRADIATION OF RECURRENT IDH WILDTYPE GLIOBLASTOMA: HIGHER REIRRADIAITON DOSE AND SAFETY
Authors: LeCompte Michael , Vuppala Neil , Reyes Juan , Page Brandi , Croog Victoria , Huang Ellen , Redmond Kristin , Kleinberg Lawrence 
Published: November 2024

Abstract
The optimal regimen, normal tissue tolerances, and appropriate indications for reirradiation for recurrent glioblastoma (GBM) are uncertain. We evaluate outcomes and toxicity after fractionated reirradiation. Patients with recurrent IDH wildtype GBM after prior standard radiotherapy during 2007-2022 were retrospectively reviewed. All patients initially received conventionally fractionated radiotherapy. Radiation necrosis (RN) was determined by imaging or pathology. Overall survival (OS) was estimated using Kaplan-Meier methodology. Univariate and multivariate Cox proportional hazard models for OS were constructed. Bivariable associations with RN were estimated using fisher exact tests. 99 patients (median age 56 yrs, median KPS 80) were treated with reirradiation (median followup 7.4 mo). Median time between initial and reirradiation was 20 months (range, 2 – 214 mo). Median received dose at reirradiation was 41.4 Gy (30.6 – 60 Gy) to a median planning target volume (PTV) of 183 cc (16 – 825 cc). Median cumulative maximum dose to the optics and brainstem were 54 Gy (4 – 103 Gy) and 76 Gy (5 – 146 Gy), respectively. Median OS was 9 mo (95% CI 6.2 – 10.6 mo). On univariate analysis, time between initial and reirradiation ≥24 mo (HR 0.58, CI 0.36 – 0.94) and reirradiation dose ≥41.4 Gy (HR 0.56, CI 0.35 – 0.88) were associated with longer OS. On multivariate analysis, interval between radiation sessions (HR 0.56, CI 0.34 – 0.91) and higher reirradiation dose (HR 0.55, CI 0.35 – 0.87) remained associated with OS. No cases of radiation injury to the optics or brainstem were reported. 10% of patients experienced RN. Reirradiation dose ≥41.4 Gy, reirradiation PTV ≥200 cc and interval between radiation sessions &lt; 24 mo were not significantly associated with RN. These data support the safety and efficacy of fractionated reirradiation for recurrent GBM including for large tumors. This study suggests that higher reirradiation dose may be feasible, including for large treatment volumes.