tbuckley/cabot-search huggingface dataset:
P26.04.A CASEIN KINASE 2 INHIBITOR, CX-4945, INDUCES APOPTOSIS AND RESTORES BLOOD BRAIN BARRIER HOMEOSTASIS IN A PRECLINICAL MODEL OF GLIOBLASTOMA
Authors: M Caffo, G Casili, A Filippone, V Bova, D Mannino, A Salako, S Scuderi, M Bulzomì, M Campolo, E Esposito
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Glioblastoma multiforme (GBM) is the most common primary malignant tumor of the central nervous system (CNS). Casein kinase 2 (CK2), a serine/threonine kinase, has been reported to have a dual action, regulating cellular processes and acting as an oncogenic promoter of tumor development. Here, we aimed to study the effect of CK2 inhibition by CX-4945 in U87 and hCMEC/D3 cells. MATERIAL AND METHODS U87 cells were treated with CX-4945 (5, 10 and 15 μM) for 24 hrs, while the hCMEC/D3 cell line were first stimulated with lipopolysacharide (LPS) and then treated with CX-4945 (5, 10 and 15 μM). Cytotoxicity tests, Western blot analysis and Immunofluorescence were performed to study the involvement of the different pathways. RESULTS We found that CX-4945 suppressed proliferation, reduced the inflammatory pathway and angiogenesis, oxidative stress, attenuated the activation of neurotrophic factors (NFs), while enhancing the apoptosis pathway. Furthermore, it promoted the restoration tight junctions. CONCLUSION These new insights into CK2 molecular signaling in GBM and blood brain barrier (BBB) demonstrate that CX-4945 may represent a promising approach for future GBM therapy, not only in the tumor microenvironment but also at the BBB.
P18.51.A UNIQUE GENETIC AND EPIGENETIC ALTERATIONS IN GLIOBLASTOMA VERY LONG-TERM SURVIVORS (VLTS): INSIGHTS FROM TWO CLINICAL CASES
Authors: E Anghileri, B Pollo, C Calatozzolo, E Lazzarini, S Patrizi, L Pedace, S Barresi, M Patanè, L Maddaloni, E Lamperti, S Indraccolo, R Paterra, E Miele
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Glioblastoma (GBM) 5-year survival (LTS) and a 10-year survival (VLTS) rate are extremely low, reaching 7% and 4.7% respectively (2020 CBTRUS Statistical Report). The biological mechanisms that drive the prolonged clinical outcomes remain significantly understudied. MATERIAL AND METHODS As part of a recent study on LTS (PMID: 38423245), here we detail two out of the 17 VLTS cases, addressed with extensive molecular analyses. RESULTS Patient AR 10-046 was a 31-year-old female with a left fronto-parietal giant cell GBM (gcGBM), treated with surgery, radiotherapy and chemotherapy. After 6 months from the diagnosis, she recurred and underwent tumor exeresis and adjuvant TMZ, maintaining disease stability for a total of 243 months. According to the v12.5 BTC the tumor was assigned to the methylation subclass pedHGG_RTK1a subtype (score &amp;gt;0.99), frequently associated with Lynch syndrome (LS). Indeed, we detected MSH6 mutation in tumor DNA as well as in peripheral lymphocyte. We detected high Tumor Mutational Burden. Interestingly, the Copy Number Variation (CNV) plots showed chromosome 1q gain and chromosome 13 loss with no other typical GBM alterations.Patient AR 10-037 was a 70-year-old male with left temporal lobe GBM treated with surgery, adjuvant radiotherapy and chemotherapy, achieving a survival of 73 months. Histology was classical GBM. The tumor was assigned to the pedHGG_MYCN subclass with a suboptimal score (0.5). At CNV examination, apart from the canonical chromosome 7 gain and chromosome 10q loss, we observed MDM2 gene amplification and possible rearrangements on chromosome 12 and 18 with the typical aspect of a chromothripsis (CT), confirmed by RNASeq analysis. Our case presented CT on chr12 harboring two putative gene fusions: CPSF6::CPM and PTPRR::RAB3IP never reported in the literature. CONCLUSION We described two cases of VLTS patients with peculiar molecular profile, widening the scenario of clinical and molecular variability that can be found in such patients. Further studies are still needed to identify the biological mechanisms causing such prognosis, with a fundamental contribution from molecular analyses, including DNAm profiling, NGS and RNAseq. FUNDING RRC Italian Ministry of Health
P09.09.A IMAGING CHALLENGES: IMMUNOTHERAPY’S INFLUENCE ON THE DIAGNOSTIC ACCURACY OF AMINO ACID PET IN SUSPECTED PROGRESSIVE BRAIN METASTASES
Authors: L Baumgart, C Delbridge, B Meyer, W Weber, H S Meyer, J Gempt, I Yakushev
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Immunotherapy (IT) has gained increased significance as a systemic therapy option in the management of various types of metastatic cancer, including cases involving brain metastases (BMs). The differential diagnosis of progressive/relapsed BMs and treatment-related changes (TRC) is often based on imaging with amino acid (AA) PET, in addition to standard magnetic resonance imaging (MRI), as this has been established to provide higher diagnostic accuracy. However, diagnostic value of the AA-PET in the context of IT has not been studied so far. In this pilot study we quantified diagnostic accuracy of AA PET in patients with suspected progressive BMs under IT. MATERIAL AND METHODS This retrospective study included patients with suspected progressive/relapsed BMs on MRI after radiotherapy (RT) between 04/2007 - 01/2023. Only patients with AA PET ≤ 4 weeks prior to surgery/biopsy of BMs were selected. AA PET results were compared with histopathological findings and distinctive features were highlighted. RESULTS Out of 29 patients, 7 were treated with IT (IT+ group). Remaining patients (IT- group) were treated with chemotherapy, targeted therapy, a combination of both, or obtained no systemic therapy before PET. The groups did not differ regarding age, gender, initial number of BMs or time interval between PET and last RT. In the IT+ group, 6 patients had malignant melanoma and 1 patient urothelial carcinoma as primary tumor. The IT+ patients obtained ipilimumab, nivolumab, or pembrolizumab, sequentially, or in combination. In the IT+ and IT- group, 7 and 21 PET scans were read as suspicious for progressive/relapsed BMs, respectively. The rate of false-positive findings was 5/7 (71.4%) and 3/21 (14.3%), respectively (chi square test, p=0.008). Histopathological analyses revealed an inflammatory reaction with lymphocytic infiltrates in the examined tissue in the IT+ group. CONCLUSION There is a significantly higher rate of false-positive AA PET findings in patients with BMs who have been treated with IT. This observation may be explained by an immunologically mediated inflammatory reaction. Further immunological analyses of lymphocytic infiltrates could provide more information.In conclusion, until more data are available, caution should be exercised when diagnosing tumor recurrence using AA PET in patients who have previously received IT.
P26.08.B LASER-ASSISTED FABRICATION OF AN IN VITRO 3D-ENGINEERED BLOOD-BRAIN/TUMOR BARRIER MODEL
Authors: N Barin, H E Balcioglu, A Accardo, P French
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Efficient drug delivery to brain tumors is greatly hindered by the blood-brain barrier (BBB). Although different in vitro BBB models have been developed, they do not capture the capillary dimensions, incorporate multiple cell types, feature biomimetic flows, and/or provide sufficient 3D cell-to-cell contact. We aimed to develop a model for the blood-brain/tumor barrier (BBTB) that incorporates these characteristics simultaneously. MATERIALS AND METHODS 3D micro-porous capillary-like structures (µPCs) that mimic the brain capillary dimensions were fabricated using two-photon polymerization (2PP), a 3D light-assisted printing technique that enables precise microscale fabrication. These structures serve as a scaffold for culturing and organizing various BBTB cell types. µPCs are fabricated at the intersection of two channels within a microfluidic slide, facilitating controlled fluid flow inside and outside the µPCs using a pressure-driven pump. Human umbilical vein endothelial cells (HUVECs) and the U87 glioblastoma cell line are utilized. Immunofluorescence staining (using CD31, tubulin, actin, and DAPI) and scanning electron microscopy are performed to assess cell colonization. RESULTS Initially, we cultured endothelial cells on µPCs under static conditions (i.e. without fluid flow). We optimized µPC designs by modifying channel and rod diameters, alignment, and pore sizes to improve structure stability, confocal microscopy visibility, and cell colonization. These experiments resulted in a design that achieved complete endothelial cell coverage. We also confirmed that the µPCs setup allows co-cultures of glioblastoma and endothelial cells. Next, we 3D printed the 2PP-fabricated µPCs within single-channel microfluidic slides that allowed control of internal fluid flow within the µPCs. When endothelial cells were perfused through the µPCs under biomimetic flow rates, after three days of culture, they uniformly covered the surface of µPCs. We also developed a protocol for precise printing of µPCs in 2-channel slides. The first channel enables internal fluid flow within the µPCs, where endothelial cells are cultured via physiological microfluidic flows. The second channel controls the external flow surrounding the µPCs, where astrocytes, pericytes, and glioma cells can be cultured in static conditions. We will use this setup to soon perform co-cultures of endothelial cells, gliomas and pericytes. CONCLUSION We designed a representative model for the BBTB capillaries, using a hybrid approach that combines 2PP and microfluidics. To ensure the BBTB model’s physiological relevance, future assessments will include cellular adherence, cellular spatial distribution, expression of integrity proteins, basal lamina formation, and vessel permeability. This work was partly funded by the Dutch Research Council via the ENW-XS grant N. OCENW.XS23.2.105.
P16.08.B TARGETING MYELOID CELLS IN COMBINATION IMMUNOTHERAPIES FOR PAEDIATRIC MEDULLOBLASTOMA
Authors: Z Abbas, H Hii, J Buck, J Byrne, I Johnson, M Howlett, T Johns, N G Gottardo, R Endersby
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Stagnation in clinical outcomes, as well as severe side-effects of current treatments for high-risk medulloblastoma, have prompted the search for novel therapies. To date, immunotherapies have not demonstrated success in medulloblastoma. Due to the highly aggressive nature of relapsed medulloblastoma, we posit that immunotherapies have the greatest chance of success if applied first-line, alongside conventional therapies. We have previously shown that while conventional therapies deplete adaptive immune cells from the medulloblastoma microenvironment, macrophages persist following treatment. Moreover, medulloblastomas are myeloid dominant tumours and blocking the anti-phagocytic CD47-SIRPa interaction has demonstrated preclinical efficacy as a monotherapy. MATERIAL AND METHODS We tested the combination of anti-CD47 immunotherapy with craniospinal irradiation in patient-derived xenograft models of medulloblastoma and have characterised treatment responses using flow cytometry, RNA sequencing, and immunohistochemistry. RESULTS We found that the combination of anti-CD47 and radiotherapy is remarkably effective in radiosensitive tumours, resulting in long-term tumour-free survival. We found that the combination therapy results in enhanced macrophage infiltration and phagocytic activation in radiosensitive tumours compared to either monotherapy. However, we found this combination to be ineffective in tumours which do not regress in response to irradiation. CONCLUSION Although this combination treatment may not be a one-size-fits-all approach, biomarkers of radiosensitivity may allow for the identification of patients most likely to benefit from this combination.
P11.02.B ASSESSMENT OF PATIENT-REPORTED NEUROLOGICAL DEFICITS THROUGH BRAIN NETWORK DISRUPTIONS ON MRI IN PATIENTS WITH BRAIN METASTASES
Authors: S David, F Cialdella, S H J Nagtegaal, E E van Grinsven, M E P Philippens, J J C Verhoeff
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Patients with brain metastases (BMs) experience a range of neurological deficits, including motor and vision problems. The EORTC BN20 is a validated questionnaire specifically designed to evaluate various aspects of patient-reported neurological health of patients with brain tumors. In the COIMBRA study (NCT05267158), data is prospectively collected pre- and post-radiotherapy (RT) including clinical assessments, imaging, and patient-reported outcomes. This study aims to explore the relationship between BM lesion location, the resulting white matter disruptions (i.e. the disconnectome), and the reported resultant neurological deficits in motor or visual functions. MATERIAL AND METHODS Between April 2019 and April 2023, 216 patients with BMs undergoing stereotactic radiosurgery completed the baseline questionnaire. T1 MRI scans and gross tumor volumes (GTVs) were nonlinearly registered to the MNI152 template using the EasyReg tool. Patient-specific disconnectomes were calculated using BCBtoolkit. Voxelwise correlations between disconnectomes or lesion distributions (GTV) and patient scores on motor or visual deficits from the BN20 questionnaires were tested using robust permutation tests with the PALM toolbox. Multiple comparison related false positives were corrected with family-wise error rate adjustment with significance established at p-val&amp;lt;0.05. RESULTS Significant correlations in an area of 593mm3 were found between reported motor deficits and the presence of lesions in the Precentral and Superior Frontal Gyri and Superior Thalamic Radiation, and broader dysconnectivity in areas including the Corticospinal Tracts (CST) and Precentral Gyrus (PCG), involving a volume of 14726 mm3. For reported visual deficits, significant correlations were identified in the occipital lobe, particularly affecting the Optic Radiations and the occipital cortex regions in both sides with a cluster size of 12876 mm3. No correlations were found between the mere presence of lesions and visual disorder scores. CONCLUSION Disconnectome-driven correlations with deficit scores show a good fit with the well-known anatomy for the motor- and the visual systems. Both motor and visual problems are measured with three simple questions with four rating options from the BN20 questionnaire, which appear sufficient to identify the critical role of network disruptions. White matter disruptions should be considered to fully appreciate the neurological or other impact of BMs, suggesting that further targeted investigations could enhance diagnostic precision and therapeutic interventions for these patients. While these findings are significant, further investigation is needed to determine if more distinct motor-related issues, such as trouble with coordination, or visual disorders like diplopia or field cuts, can be pinpointed to specific brain areas or networks.
P14.16.A IS A LINAC WITH A 5MM MLC WIDTH REALLY A BARRIER TO IMPLEMENTING A HIGH-QUALITY COMPLEX SRS SERVICE?
Authors: C Dean, S Bowles, N MacDougall, J Cook, H Rozati, R Lewis
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Stereotactic Radiosurgery (SRS) for patients with intracranial disease is increasing, especially for smaller and more numerous metastases. In England, Varian HyperArc using a Truebeam linac is nationally commissioned via benchmarking. HyperArc contains SRS-specific optimisation and non-coplanar VMAT delivery and is an attractive option due to its cost effectiveness compared with competing specialised platforms such as Elekta GammaKnife and Accuray CyberKnife. Depsite these benefits, the treatment of small targets or those with highly complex shapes is dominated by specialised platforms with a largely stated reason being perceived concern over delivered dosimetric certainty. This work assesses achievable dosimetric accuracy for complex SRS using Varian HyperArc suing a standard 120-leaf 5mm width MLC. MATERIAL AND METHODS Four patients with small and/or complex PTVs previously treated with CyberKnife at our institution were identified:26 metastases 24Gy/1f (PTV min. volume 0.01cc);5 metastases 24 Gy/1f (PTV min. volume 0.11cc);Pituitary adenoma 25Gy/1f (PTV width min. 5 mm near optics);Acoustic neuroma 21 Gy/3f (PTV width min. 3 mm near cochlea). Patients were re-planned with HyperArc using 4 arcs at 6FFF, emulating the prescription dose spillage (PDS) &amp; modified gradient index (mGI) achieved in the CyberKnife plans. Plans were produced in Eclipse v17.1, calculated using the AAA algorithm (v 17.1.0.1) on a 1mm calculation grid. The plan was then transferred to a CT scan of an in-house water equivalent phantom containing radiochromic EBT3 film in clinically meaningful coronal and sagittal dose planes and re-calculated. All plans were delivered under image guidance and the 2D film dosimetry was compared with the calculated dose from Eclipse using a global 5%/1mm (TH 20%) gamma test using well-established absolute dose film methodology in Sun Nuclear SNC Patient (v 8.2). RESULTS In all cases, HyperArc had very similar plan quality to CyberKnife, with maximum dose gradients between 20-23% of prescription dose per mm beyond the PTV (up to 5.8Gy/mm). Up to 1mm geometric offset was permitted to allow for imaging localization &amp; film registration uncertainty in the analysis. Mean gamma pass rates were 93.3% pre-alignment and 98.5% post-alignment. CONCLUSION The very high gamma pass rates achieved in this novel work illustrate excellent delivered dose accuracy for high-quality SRS plans. The use of a radiochromic film dosimetry allows for the demonstration of such accuracy using a standard Truebeam linac without the use of a high-definition MLC even for the smallest and most complex SRS targets. This work enables us to re-think previously held beliefs around perceived dosimetric limitations of multi-arc VMAT with a 5 mm MLC width for the delivery of high-quality SRS. Removing this barrier could start to bridge the existing gap in worldwide SRS service provision for patients.
P14.19.A PRE-CLINICAL SAFETY AND EFFICACY OF AN INNOVATIVE SURGICALLY IMPLANTABLE MEDICAL DEVICE TO DELIVER ELECTRIC FIELD THERAPY IN GLIOBLASTOMA
Authors: A Narayanan, D Venters, T Olukoga, R Purdy, N Munir, J Zhao, J Treen, C Bullock, R Fu
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Glioblastoma (GBM) is the most common and aggressive primary brain cancer in adults. Current standard of care (SOC) involves maximal surgical resection and adjuvant chemoradiotherapy but clinical outcomes remain poor. Electric field therapy (EFT) is one of few developments in recent decades to demonstrate robust survival benefit in GBM, but is currently only available as an external system. Fully implantable EFT would allow continuous and immediate treatment following surgery thereby maximizing therapeutic efficacy. It would also preserve the quality of life of patients and caregivers. MATERIAL AND METHODS QV Bioelectronics (Manchester, UK) is developing a fully implantable system to deliver EFT in GBM, called GRACE. The first generation includes industry-standard, GBM-targeted electrodes, a custom cranioplasty for skull fixation, and an implantable pulse generator (IPG) to deliver proprietary stimulation regimes. Optimized stimulation regimes were applied to patient-derived 3D GBM cell lines (n=5) and human iPSC-derived neuronal cultures (n=4) to demonstrate treatment efficacy and selectivity. EFT was tested independently and alongside SOC options. Implanted EFT technology has progressed through formative usability and initial large animal studies. In silico modeling of GRACE was conducted to simulate electric field distributions around implanted electrodes and resultant heat dynamics in surrounding brain tissue with continuous device operation. RESULTS Proprietary stimulation regimes demonstrate at least 80% reduction in cancer cell viability across cell lines (L0627 p=0.0005, L160315 p=0.0020) - greater efficacy than currently used regimes described in the literature. Dosing compliance studies demonstrate the importance of continuous stimulation, with 2.7x greater reduction in cancer cell viability with 24hr/day stimulation vs. 18hr/day. Studies of EFT safety with neuronal cultures are underway with estimated completion later in 2024. QV Bioelectronics will also be undertaking further biological replicates with several patient-derived glioma stem cell lines. No gross abnormalities or adverse events related to EFT in pre-clinical health large animal models were noted. Initial in silico results demonstrate that therapeutically effective field strengths can be achieved in clinically relevant target volumes and can rapidly reach safe thermal equilibrium in continuous device operation. CONCLUSION QV Bioelectronics demonstrates novel, highly effective EFT regimes; studies to confirm GBM selectivity are underway. Simulation has demonstrated the feasibility of implantable EFT achieving therapeutic field strengths. Further work will combine optimized current delivery sequencing with MRI-derived GBM patient models to define a framework for clinical electrode trajectory planning.
OS06.3.A EFFECT OF EARLY INTEGRATION OF PALLIATIVE CARE ON THE QUALITY OF LIFE IN GLIOBLASTOMA PATIENTS
Authors: H Golla, C Nettekoven, M Hellmich, C Bausewein, N Thon, G Becker, O Schnell, R Rolke, H Clusmann, L Radbruch, U Herrlinger, H Vatter, M Neukirchen, M Sabel, D Civello, D Müller, T Brumbarova, R Voltz, R Goldbrunner
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND The disease course of glioblastoma (GB) patients is usually characterized by high symptom burden and short median survival (approx. 14 months). Nevertheless, they rarely receive specialized palliative care, especially in the early stage of the disease (early integration of palliative care, EIPC). The “Early Palliative Care for Patients with Glioblastoma” (EPCOG) study therefore aimed at investigating the impact of EIPC on quality of life (QoL) in this cohort of patients. MATERIAL AND METHODS Confirmatory, multicenter, single blinded, randomized, controlled clinical study. Patients with newly diagnosed/recurrent GB were randomly assigned to the control or interventional group. Patients in the interventional arm received proactive specialized palliative care (PC physician and PC social worker) on a monthly basis for 12 months. The control group received standard care. Data were collected by a blinded researcher every three months for 24 months. The primary outcome was QoL assessed by the sum of three subscales (trial outcome index, TOI) of the Functional Assessment of Cancer Therapy for brain tumor (FACT-Br) from baseline to six months of treatment. RESULTS 556 patients were screened for eligibility, 231 patients were included in the study. 109 patients were treated in the intervention and 108 patients in the control group. Groups did not differ significantly in terms of age, gender or first/recurrent diagnosis. 34 patients were still alive after 24 months (intervention group: n=15, control group: n=19). 131 patients died during the study (intervention group: n=71, control group: n=60); without a statistically significant difference between groups. Within the intervention period, the TOI relative to the baseline tended to be better in the intervention group than in the control group, especially after three months. However, the difference was not statistically significant. CONCLUSION This is the first multicenter, randomized, confirmatory clinical trial to investigate the impact of EIPC on GB patients with an observation period long enough to realistically reflect the course of the disease. Despite the very vulnerable patient group, the study was even feasible with a higher number of patients than originally planned. The selected primary outcome parameter (TOI) included physical and functional, but not emotional and social factors, which may play a more important role in assessing QoL of GB patients.