bluuebunny/crossref_metadata_2025_split huggingface dataset:
P10.16.B ATR INHIBITION ENHANCES CELL DEATH AND INDUCES IMMUNE-RELATED GENE EXPRESSION IN COMBINATION WITH STANDARD TREATMENT IN PATIENT-DERIVED GLIOBLASTOMA CELLS
Authors: Lozinski M , Bowden N , Graves M , Fay M , Day B , Stringer B , Tooney P 
Published: September 2023

Abstract

BACKGROUND
Patients with glioblastoma are confronted with a high likelihood of recurrence and poor prognosis despite an aggressive treatment-regime involving surgery followed by radiation therapy (RT) and temozolomide (TMZ). RT and TMZ cause extensive DNA damage and replication stress, thus activating tumour cell death pathways. Upregulation of the DNA repair mechanisms significantly reduces effective treatment response and contributes to poor patient outcomes. We investigated the effect of inhibiting ATM- and Rad3-Related protein (ATR), a crucial sensor of replication stress and initiator of cell cycle arrest in tumour cells, using the potent and selective ATR inhibitor, gartisertib.

MATERIAL AND METHODS
Twelve patient-derived glioblastoma cell lines were grown as monolayer cultures in serum-free media and treated with TMZ, RT and/or gartisertib. Cell viability of treated cells was assessed after a 7-day incubation using the MTT method, while cell confluence, apoptosis and cell death were examined using the Incucyte S3 Live-Cell Analysis System (Sartorius, Germany). Gene expression of glioblastoma cell lines treated with TMZ+RT and/or gartisertib was assessed 4-days post-treatment.

RESULTS
As a single agent, gartisertib potently reduced glioblastoma cell viability, while 8-fold less potent in human astrocyte cells. Glioblastoma cell lines with mutated DNA damage response-related genes were more sensitive to gartisertib treatment. Live-cell imaging of glioblastoma cells treated with gartisertib (1 µM) plus TMZ (35µM) and RT (2Gy) showed a significant increase in cell death and apoptosis compared to gartisertib or TMZ+RT alone. ATR inhibition by gartisertib strongly synergised with TMZ, while moderately synergising with RT in reducing glioblastoma cell growth. Gartisertib, alone and in combination with TMZ+RT, increased gene expression in pro-inflammatory cytokines, antigen presentation, and pattern recognition pathways while decreasing genes involved in hypoxia and epithelial-mesenchymal transition pathways.

CONCLUSION
These data suggest the potential for ATR inhibition as an effective chemo- and radiosensitiser in glioblastoma tumours. Whether the change in gene expression induced by ATR inhibition reduces hypoxia within or provokes an immunogenic response directed at glioblastoma tumours, requires further investigation.
P10.20.B POSTOPERATIVE ISCHEMIA CAUSED BY MICROSURGICAL RESECTION PROMOTES PRONEURAL-TO-MESENCHYMAL TRANSITION IN GLIOBLASTOMA
Authors: Ballestín A , Pichol-Thievend C , Bourmeau G , Blanchard B , Pettiwala A , Reveilles J , Leboucher S , Anezo O , Seano G 
Published: September 2023

Abstract

BACKGROUND
Four glioblastoma (GB) cellular states drive the intratumoral heterogeneity of this lethal primary brain tumor and are influenced by genetics, the tumor microenvironment (TME), and response to treatment. The impact of microsurgical resection on the TME and plasticity of GB cells is unknown. Postoperative cerebral ischemic events have been described after these surgical resections, altering the proper distribution of subsequent chemo-radiotherapy treatment. Despite the aggressive standard of care, 90% of patients experience recurrence a few months after treatment and it usually begins with the regrowth of highly invasive cells that spread from the peritumoral brain resection zone. Therefore, the objective of this study was to perform morphological and transcriptomic phenotyping of residual tumor cells and TME after microsurgical resection.

MATERIAL AND METHODS
The GFP-transduced syngeneic GB IDH-wildtype cell lines CT2A and GL261 were orthotopically implanted in C57Bl6j mice brains. We developed a refined microsurgical resection protocol for GB in a size-matched study by carefully following the same surgical steps performed in patients. Mice were randomly divided into four groups: control (prior to surgery) and 1, 3, and 7 days post-surgery. Tumor tissues were harvested for time-resolved bulk and single-cell RNA sequencing as well as immunohistochemistry (IHC) studies.

RESULTS
According to our time-resolved transcriptomic and IHC analyses, microsurgical resection induced pronounced proneural-to-mesenchymal transition (PMT), chromatin remodeling, and stimulation of hypoxia-driven pathways in residual GB cells after surgery. Moreover, single-cell RNA-seq of post-resection tumors allowed us to observe significant changes in the TME relative to the immune response and vascular function in line with ischemia exposure.

CONCLUSION
The impact of microsurgical resection has important consequences on the phenotypic landscape of GB tumor cells and TME, which is characterized by a transient ischemic TME that induces PMT in GB cells. In addition, we developed a refined microsurgical resection model that can be useful in a wide variety of preclinical studies. Support/Disclosure: This study was supported by the Institut National du Cancer (INCa; 1154 INCa-2020-1-PLBIO-01-ICR-1) and by the Marie Skłodowska-Curie Postdoctoral Fellowship under the European Union’s programme Horizon2020 (HORIZON-MSCA-2021-PF-01, GlioSurg, Grant agreement ID: 101061921).
P10.30.B COMBINATION TREATMENT WITH ERIBULIN AND TTFIELDS INDUCES APOPTOSIS AND G2/M CELL CYCLE ARREST IN HUMAN GLIOBLASTOMA CELLS
Authors: Goett H , Schön C , Beusker P , Uhl E , Stein M 
Published: September 2023

Abstract

BACKGROUND
TTFields has emerged to a first line treatment in newly diagnosed glioblastoma (GBM) patients. Several preclinical studies showed that the alternating electric fields inhibit proliferation and survival of human glioblastoma cells by disruption of the spindle apparatus and impairment of mitotic segregation. Eribulin is an antimitotic drug, that is currently used in the third line treatment of breast cancer. As it is also able to inhibit the pro-mitotic function of TERT, which is mutated in 80% of human glioblastoma, the drug was also shown to have a radiosensitizing and antiproliferative effect on human glioblastoma and ovarian cancer cell lines. This study aims to evaluate the effect of the combination of Eribulin and TTFields on the survival and cell cycle of glioblastoma cells.

MATERIAL AND METHODS
U87, A172 and four patient derived glioblastoma cell lines were cultured and plated to 80% confluence. Cells were then treated with TTFields at a frequency of 200kHz for 24 hours and/or received the ED50 and 0.5-fold ED50 of Eribulin. Controls remained untreated respectively. After 24 hours cells were harvested and counted by automatic cell count. Survival and cell cycle status were evaluated by FACS analysis.

RESULTS
The rate of early apoptotic cells was 82.28% in the group treated with TTFields and Eribulin. With TTFields treatment only 50.99% and with Eribulin alone 14.38% of cells were in an early apoptotic state. Untreated control cells had an apoptosis rate of 4.25%. The combination of TTFields and Eribulin was significantly more effective than the single treatment modalities (p&gt;0.05). Treatment with TTFields increased the rate of cells an G2/M status. This effect was even stronger in the group with combination treatment.

CONCLUSION
Combination treatment of the antimitotic drug Eribulin with TTFields is able to improve the inhibitory effect of the drugs on cell survival. Furthermore the combination therapy effects the cell cycle of glioblastoma cells inducing G2/M arrest. Future preclinical studies should focus on the antimitotic effect and the influence of the treatment on genome integrity for a more detailed insight into the mechanisms of action.
P11.03.A DOES REGULAR SURVEILLANCE IMAGING IMPROVE SURVIVAL IN GLIOBLASTOMA? RESULTS FROM A NATIONAL, MULTI-CENTRE COHORT STUDY (INTERVAL-GB)
Authors: Gillespie C S , Bligh E R , Poon M T C , Solomou G , Gough M , Islim A I , Millward C P , Rominiyi O , Zakaria R , Price S J , Watts C , Camp S , Booth T , Thompson G , Mills S J , Waldman A , Brennan P , Jenkinson M D ,   British Neurosurgical Trainee Research Collaborative, Neurology and Neurosurgery Interest Group, INTERVAL-GB Collaborative
Published: September 2023

Abstract

BACKGROUND
Glioblastoma is the most common malignant primary brain tumour in adults and is usually incurable. Post-operative magnetic resonance imaging (MRI) is used to assess extent of resection, and subsequent follow-up MRI is used to monitor response to treatment and to detect progression. The benefit of regular, scheduled follow-up MRI on patient management and outcomes is unclear.

MATERIAL AND METHODS
In this multi-centre, retrospective observational cohort study we included patients with a histopathologically confirmed glioblastoma, operated between August 31, 2018 and February 1, 2019 who received any adjuvant oncological treatment. Follow-up MRI schedules, indications, and clinical outcomes were collected. The primary objective was to investigate the follow-up MRI surveillance practice after surgery for glioblastoma and assess compliance with recommendations from the National Institute for Health and Care Excellence (NICE) (Post-operative scan &lt;72 hrs, MRI every 3-6 months). The secondary objectives were to determine indications for MRI scans and the association on overall survival (OS) and progression-free survival (PFS).

RESULTS
754 patients, with a median age of 63 years (range: 21-84) from 26 neuro-oncology centres were included. Most patients had post-operative MRI within 72 hours of surgery (88.1%, N=407/462). The median number of subsequent follow-up MRI was 1 (Interquartile range 0-4). 28.1% of patients had follow-up MRI in accordance with NICE recommendations (N=212/754). Patients in this group were more likely to receive second-line chemotherapy (28.6% vs 19.5%, P=0.009). The median follow-up period was 10.5 months (IQR 5.3-19.4 months). Median overall survival was 15.1 months (95% CI 12.9-17.3) in the scheduled MRI group and 9.1 months (95% CI 7.8-10.4) in the non-compliant group. On multivariable cox regression analysis, regular, scheduled MRI was independently associated with longer overall survival (HR 1.67, 95% CI 1.33-2.10, P&lt;0.001), but not PFS (HR 1.20, 95% CI 0.98-1.47, P=0.074). Patients with progression first detected on scheduled imaging had a significantly longer OS (18.4 vs 15.6 months, P=0.013) and PFS (9.9 months vs 7.9 months, P=0.041).

CONCLUSION
Following regular scheduled surveillance follow-up MRI for glioblastoma is associated with longer overall survival. Prospective trials are needed to determine whether regular or symptom-directed MRI influences survival outcomes and quality of life.
P11.14.B PROGNOSTIC ASSOCIATIONS OF STEROID USE IN GLIOBLASTOMA: A POPULATION-BASED STUDY
Authors: Abdel Moneim Y , Weller M , Gramatzki D 
Published: September 2023

Abstract

BACKGROUND
Steroids are widely used in brain tumor patients to control symptoms related to tumor and cerebral edema. A possible detrimental effect of steroid treatment on prognosis in glioblastoma patients has been proposed. Whether this represents only a negative patient selection due to the potential confounding factor of steroid treatment or whether glucocorticoid use per se causes a worse prognosis remains a matter of debate.

MATERIAL AND METHODS
We reviewed retrospective data of 225 patients diagnosed with isocitrate dehydrogenase (IDH)-wildtype glioblastoma from 2010 to 2014 in the Canton of Zurich, Switzerland. We assessed clinical data and the use of steroids at different time points. Survival data were analyzed with the Kaplan-Meier method, and corrections for known prognostic or predictive factors were performed with Cox regression analyses. Correlations were determined with Spearman’s correlation coefficient.

RESULTS
Most patients (N=203, 95%) received steroids at least once in the first year after diagnosis, the majority (N=153, 69%) in the perioperative setting (defined at the time of hospitalisation for the surgery plus/minus seven days), and 94 patients (62%) in the first three months. Steroid use at three months after surgery was associated with with steroid treatment at six months, too (p&lt;0.01). The latter was associated with inferior overall survival after correction for known prognostic factors (p=0.006).

CONCLUSION
Use of steroids at six months after diagnosis was associated with inferior survival in glioblastoma even when controlling for confounding factors. The precise mode of action of steroids in this setting remains to be identified, but cytoprotective effects of tumor cells versus radiotherapy and chemotherapy as well as decreased immune function of the host are potential mechanisms.
P11.16.B THE MAYO CLINIC MULTIDISCIPLINARY NF2 CLINIC EXPERIENCE OF BEVACIZUMAB IN NEUROFIBROMATOSIS TYPE 2-RELATED SCHWANNOMATOSIS PATIENTS WITH VESTIBULAR SCHWANNOMAS
Authors: Webb M J , Webb L M , Van Gompel J J , Link M J , Neff B A , Carlson M L , Driscoll C W , Ruff M W , Anderson K A , Neth B J , Kizilbash S H , Uhm J H , Lane J I , Benson J C , Blezek D J , Mehta P M , Bathla G , Sener U T 
Published: September 2023

Abstract

BACKGROUND
Neurofibromatosis type 2-related schwannomatosis (NF2) is an autosomal dominant tumor-predisposition syndrome characterized by bilateral vestibular schwannomas (VS) as well as other nervous system tumors. Management decisions for NF2-related VS are typically predicated on tumor size, associated symptoms, patient age, and comorbidities. Observation, surgical resection, and stereotactic radiosurgery can be viable options. In patients with VS associated with NF2, vascular endothelial growth factor A (VEGF-A) inhibitor, bevacizumab, is a systemic treatment option. In this single institution study, we review our clinical experience in patients with NF2 who received bevacizumab for VS and evaluate the effect of bevacizumab treatment on VS growth and symptom progression.

MATERIAL AND METHODS
This is a retrospective analysis of patients seen at the Mayo Clinic Rochester Multidisciplinary NF2 Clinic. Three-dimensional volumetric data for VS were measured using manual segmentation with Visage PACS software under the direct supervision of a board-certified neuroradiologist.

RESULTS
Out of 76 patients with NF2 evaluated in the past 3 years, we identified 19 that received treatment with bevacizumab. Median age of NF2 diagnosis was 19 years (range 0.5-61) with a median NF2 phenotype severity score of 2 (range 1-3). Thirteen of these patients have discontinued bevacizumab, accounting for a median duration of 12.2 months (range 3.3-88 months) of bevacizumab treatment. Bevacizumab was discontinued due to hypertension (n=5), proteinuria and renal dysfunction (n=3), tumor progression (n=2), fatigue or other intolerance (n=2), or non-compliance (n=1). The remaining 6 patients are currently receiving bevacizumab treatment for a median duration of 9.4 months as of March 2023 (range 3.7-48.3 months). Fifteen patients had brain MRI data available to evaluate VS change during bevacizumab treatment, with partial response observed in 5 patients, stable disease in 8, and progression in 2. Ten of the 13 patients who stopped bevacizumab had MRI data to evaluate VS change following treatment termination. Within 6 months of bevacizumab discontinuation, 6 patients had rebound growth of their VS between 21-95% from their previous tumor volume, while 4 did not. Three patients with rebound growth went on to have surgery or irradiation for VS management.

CONCLUSION
Our single institution experience confirms that bevacizumab can slow progression of VS and symptoms associated with VS growth. However, we note that there is the potential for rapid VS growth following bevacizumab discontinuation, for which we propose heightened surveillance imaging and symptom monitoring for at least 6 months upon stopping anti-VEGF therapy.
P11.19.A MACROPHAGES-BASED IMMUNOTHERAPY OF SOLID TUMORS MICROENVIRONMENT: THE TEM-GBM STUDY (NCT03866109)
Authors: Eoli M , Gentner B , Anghileri E , Farina F , Capotondo A , D'Alessandris G , Di Meco F , Ferla V , Franzin A , Ferroli P , Gagliardi F , Legnani F , Mazzoleni S , Mortini P , Olivi A , Pallini R , Saini M , Snider S , Naldini L , Russo C , Ciceri F , Finocchiaro G 
Published: September 2023

Abstract

BACKGROUND
We have developed an HSC-based platform to switch from pro-tumor to anti-tumor bone-marrow derived tumor-infiltrating macrophages. Specifically, Temferon cell therapy delivers IFN-a into the tumor microenvironment (TME) in a targeted manner via Tie-2 expressing monocytes, with transcriptional and post-transcriptional controls mediated by miRNA target sequences.

MATERIAL AND METHODS
TEM-GBM is an open-label, Phase 1/2a dose-escalation study evaluating the safety and efficacy of Temferon in up to 27 newly diagnosed, unmethylated MGMT glioblastoma (GBM) patients. Twenty-four patients are assigned to 8 cohorts and will receive a single increasing dose of Temferon, 3 additional patients will be further enrolled to confirm the safety profile of the chosen Temferon dose to be tested in a broader group of patients (Phase 2). Patients are followed up to 2 years after treatment with Temferon. Here we report the analysis on the biological activity of Temferon on patients who underwent a second surgery intervention.

RESULTS
As of 31st March 2023, 6 out of 19 Temferon treated patients underwent a second surgical intervention; of these, 4 belonged to low dose cohorts (C1-C2) and 2 to high dose cohorts (C4-C5). The second surgery occurred at a median of 11 months after 1st surgery (range 7-17 months). Where enough fresh material was collected to enrich for CD45+ cells within the tumor, a 3% to 5% of gene-marked tumor infiltrate was found (2/2 specimens) suggesting that Temferon-derived cells homed to the TME. To verify if the local delivery of IFN-a by TEMs was able to upregulate the Interferon Stimulated Genes (ISGs) in tumor tissue, the transcripts for IFIT1, IRF7, OAS1a genes were evaluated by RT-PCR in formalin-fixed paraffin sections obtained at first and second surgery. The analysis was performed on eighteen (18) 1st surgery samples (from C1 to C6), and on six (6) 2nd surgery specimens. At 1st surgery, transcripts were detected in 17 out of 17 specimens (one sample excluded since housekeeping genes did not amplify) and most of the patients showed a relatively low quantity of ISGs expression. The comparison of the overall ISGs expression at first surgery and second surgery highlighted the activation of IFN-responsive genes at second surgery suggesting the occurrence of the local delivery within the TME of biologically active IFN-a.

CONCLUSION
The results provide initial evidence of Temferon’s potential to modulate the TME of GBM patients.
P11.31.B LEPTOMENINGEAL SPREAD AFTER POSTOPERATIVE STEREOTACTIC RADIOTHERAPY FOR BRAIN METASTASES
Authors: Hakstege M P , Kiderlen M , Crouzen J , Hagenbeek R , Wiggenraad R , Nandoe Tewari R , Kerkhof M , Vos M , van der Voort van Zyp N , Mast M , Petoukhova A , Broekman M , Zindler J 
Published: September 2023

Abstract

BACKGROUND
Stereotactic radiotherapy (SRT) is the preferred treatment after surgical resection of brain metastases to improve local tumour control compared to observation. Some recent studies suggest that leptomeningeal metastases (LMM) occur more often after postoperative SRT compared to primary SRT with brain metastases in situ. This may be caused by tumour cells spillage during surgery. The aim of this study was to determine the incidence of LMM after postoperative SRT of brain metastases in our institution.

MATERIAL AND METHODS
All patients treated with postoperative SRT for brain metastases in our hospital between 2015 and 2020 were included in this retrospective analysis. LMM was diagnosed by a neuro-radiologist (RH) on a cerebral MRI. LMM, overall survival, and time to local recurrence (LR) were estimated from date of SRT, using the Kaplan-Meier method.

RESULTS
In total, 53 patients with 84 brain metastases were included in the analysis. Median age at SRT was 58 years (range 45 - 75 years). Median survival in this cohort was 16 months (IQR 9 - 26 months). Eight of 53 patients (15%) developed LMM at a median of 9 months after SRT. Using Kaplan-Meyer analysis, the incidence of LMM at 1 and 2 years was 15% and 19%, respectively. Twelve patients (23%) of 53 experienced LR at a median of 9 months. The 1 and 2-year actuarial incidence was 14% and 35%, respectively.

CONCLUSION
In our cohort, the incidence of LMM after postoperative SRT for brain metastases is comparable to other studies. Studies are needed to determine whether the incidence of LMM after postoperative SRT can be reduced.
P11.32.A GLIOBLASTOMA NOMOGRAM: PREDICTING THE LOCATION OF FIRST PROGRESSION AFTER LONG-COURSE CHEMORADIOTHERAPY BASED ON A NATIONAL COHORT
Authors: Clarke A M , Lukacova S , Dahlrot R H , Haslund C A , Muhic A , Bibby B M , Trip A K 
Published: September 2023

Abstract

BACKGROUND
Glioblastoma (GBM) is known for its high local failure rate, as well as its migration, leading to these possible locations of disease progression:
1. Local-only; lesion of progression is connected to the initial tumour location
2. Non-local; lesion of progression is not connected to the initial tumour location
3. Combined; both local-only and non-local progression lesions are present
An upfront prediction of progression location could potentially be used to select patients for differential treatment strategies. The aim of this retrospective national study was therefore to predict location of first progression using clinical variables.

MATERIAL AND METHODS
All adults with newly diagnosed GBM between 2014-2019 who started long-course (chemo)radiotherapy were included, if they had a radiotherapy-planning MRI made. The MRI of first progression was identified by retrospective review following RANO-criteria, and used to assess the location of contrast-enhancing progression. Median time to progression (TTP) and survival beyond progression were estimated using the Kaplan-Meier method (log rank test for comparison). To predict location of progression in subgroups of patients, we used a multivariable multinomial model (age, biological sex, performance status, tumour location & focality & laterality, MGMT-methylation status, and extent of surgery).

RESULTS
We included 940 patients (MGMT methylated n=376, unmethylated n=483, not reported n=81), of whom 760 had radiographic progression. Of those, progression location was local-only in 69%, non-local in 16%, and combined in 15%. Median (95% CI) TTP in months was shortest in the combined group (8.4, 7.3-9.4), followed by the local-only (9.2, 8.5-9.8) and non-local (13.9, 12.3-15.6) (p-value &lt;.001). Survival beyond progression in months was shortest in the combined group (5.0, 3.8-6.2), followed by the non-local (6.0, 4.4-7.6) and local-only (9.0, 8.3-9.7) (p-value &lt;.001). When comparing patients with MGMT-methylated and unmethylated tumours, the probability (95%CI) of local-only progression was .67 (.62-.73) vs. .73 (.69-.78), non-local was .21 (.17-.26) vs. .11 (.08-.14), and combined was .12 (.08-.15) vs. .16 (.12-.19). In the multivariable model, the probability (95%CI) of local-only progression varied from .49 (.29-.69) to .86 (.74-.97), of non-local from .04 (.00-.09) to .34 (.15-.53), and of combined from .05 (.01-.10) to .34 (.07-.60) between respective subgroups.

CONCLUSION
Location of progression was associated with time to progression and survival beyond progression. In our study population it was feasible to identify subgroups of patients with a high chance of local-only progression, who may potentially benefit most from radiation dose-escalation. Both patients with MGMT-methylated and unmethylated tumours had the highest chance for first progression located at the initial tumour site only.