tbuckley/cabot-search huggingface dataset:
NIMG-13. CHANGES IN CORTICAL ARCHITECTURE ASSOCIATED WITH GLIOBLASTOMA ASSOCIATED EPILEPSY
Authors: Anam Anzak, Bernardo Crespo Pimentel, Lorenzo Caciagli, Silvia Marino, Britta Wandschneider
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Emerging evidence suggests both local hyper-excitability promoting epilepsy, and synaptic and paracrine mediated integration of Glioblastoma into brain-wide neural networks. In this study we sought clinical evidence of disease progression, and concurrent radiological evidence of differences in remote cortical architecture, in Glioblastoma patients with and without epilepsy. METHODS 55 patients with biopsy-confirmed Glioblastoma, mean-age 59.4yrs±10.9yrs, were studied. 23 patients had a diagnosis of Glioblastoma-related epilepsy on presentation. We compared clinical markers of disease progression in individuals with and without epilepsy. Further, we explored differences in cortical architecture between both groups. Utilising pre-operative T1-weighted, contrast-enhanced MRI scans (n=45), we performed vertex-wise measurements of cortical thickness (CT) and cortical surface area (CSA) using the Virtual Brain Grafting Toolbox and FreeSurfer v.7.0. Radiologically-identifiable tumour and oedema was masked and excluded from analysis. Scans with right-hemispheric tumours were flipped to the left. Linear mixed-effects models were applied to pre-processed imaging-data. RESULTS Individuals with epilepsy had shorter progression-free survival (median 4.2 months) than those without seizures (9.3 months, p&amp;lt;0.05) with gold-standard treatment. No significant difference between lesion volumes (tumour and oedema) existed between the two groups (unpaired t-test, p&amp;gt;0.05). Controlling for age and tumour location, significant increases (p&amp;lt;0.01) in CT and CSA were observed in patients with Glioblastoma-related epilepsy in lesion-ipsilateral supramarginal gyrus, superior parietal lobule, precuneus/cuneus and temporal lobe compared to those without epilepsy. Interestingly, significant (p&amp;lt;0.05) increases in CT in lesion-contralateral supramarginal gyrus were additionally observed in those with epilepsy compared to those without. CONCLUSIONS Glioblastoma-related epilepsy was associated with poorer survival outcomes and changes in remote cortical architecture. Implicated regions form part of the default mode network, which has previously been identified as a crucial hub for epilepsy. Biological underpinnings of cortical network alterations, and their possible role in promoting not only hyper-excitability but also Glioblastoma progression, require correlation with histopathological characteristics and validation in larger study cohorts.
CTNI-20. ADDRESSING SKIN ADVERSE EVENTS (AES) DURING MIRDAMETINIB TREATMENT IN PATIENTS WITH NEUROFIBROMATOSIS TYPE 1-ASSOCIATED PLEXIFORM NEUROFIBROMAS (NF1-PN): GUIDANCE FROM A MULTIDISCIPLINARY GROUP OF EXPERTS ON THE MANAGEMENT OF MEK INHIBITOR-ASSOCIATED SKIN AES
Authors: Angela Hirbe, Milan Anadkat, Christina Boull, Christopher Moertel, Molly Nickerson, Michael Weber, Dusica Babovic-Vuksanovic, Timothy Gershon
Journal: Neuro-Oncology (2024)

Abstract ReNeu (NCT03962543) is a trial of the investigational, oral, selective MEK1/2 inhibitor (MEKi) mirdametinib in adults (≥18 years) and children (2-17 years) with NF1-PN. Skin adverse events (AEs) were common in ReNeu, and some discontinuations were noted with low-grade AEs. A multidisciplinary team retrospectively reviewed skincare practices at one high-enrolling site (n=12) with no discontinuations due to skin AEs; these were incorporated into ReNeu trial recommendations and recently updated. The purpose was to prevent/manage skin AEs and maintain protocol treatment adherence. MEKi skin AEs vary by pubertal status, therefore recommendations also vary by pubertal status. All patients were counseled to adopt hygienic skincare practices, including bathing daily, and using mild cleansers and hypoallergenic skin moisturizers (cream or ointment-based emollient; minimum BID) to prevent dry skin. Prepubescent patients were advised to incorporate diluted bleach baths (3-4 times/week) when initiating mirdametinib or after rash development. Treatments recommended for mild-to-severe dermatitis were hydrocortisone cream (2.5% BID) on face/skinfold areas and triamcinolone ointment (0.1% BID) on trunk/extremities. Treatments for mild acneiform eruptions included topical clindamycin lotion (1.0% BID) until resolution, with optional hydrocortisone cream (2.5% BID). For moderate-to-severe acneiform eruptions, cephalexin (20 mg/kg/day divided BID, max 500 mg, ≤6 weeks), amoxicillin (25 mg/kg/day divided BID, max 875 mg, ≤6 weeks), or oral fluconazole (20 mg/kg/day, max 100 mg, 5 days then once weekly for 3 months) were suggested. Postpubescent patients were advised to initiate topical 1.0% clindamycin lotion and oral doxycycline or minocycline (50-mg daily, 3 months) with mirdametinib initiation. Patients with subsequent mild-to-severe acneiform eruptions were advised to apply hydrocortisone cream (2.5% BID) or triamcinolone ointment (0.1% BID). Referral to a dermatologist was suggested for all patients with uncontrolled dermatitis, worsening acneiform eruptions, or infection. Proactive skincare practices appeared effective at this site, but prospective validation is necessary before making clinical recommendations.
BIOM-36. DETECTION OF CIRCULATING TUMOR DNA (CTDNA) IN CEREBROSPINAL FLUID (CSF) IN PATIENTS WITH GLIOBLASTOMA TREATED IN PHASE I CLINICAL TRIAL
Authors: Marie Porte, Kristi Beshiri, Kaissa Ouali, Sophie Postel-Vinay, Christophe Massard, Yohann Loriot, Stéphane Champiat, Antoine Hollebecque, Cristina Smolenschi, Madona Sakkal, Anas Gazzah, Rastilav Bahleda, Jean-Marie Michot, Thomas Hueso, Aurore Jeanson, Etienne Rouleau, Ludovic Lacroix, Capucine Baldini
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND As circulating tumor DNA (ctDNA) has been shown to be a source of tumor-specific biomarkers, liquid biopsy has emerged as a novel noninvasive tool in diagnosis, disease monitoring and treatment selection in several solid tumors. However, its use in brain tumors remains challenging because ctDNA is commonly not detected in blood. Thus, CSF (cerebrospinal fluid) has emerged as a potential source of ctDNA in the context of brain tumors. PATIENTS AND METHODS We prospectively evaluated the detection of ctDNA in CSF (CSF-ctDNA) +/- blood of patients with pre-treated MTAP-deleted glioblastoma, currently treated in a phase I clinical trial evaluating PRMT5 inhibitors. We did CSF samples at C2D15 and at progression, after patient’s oral and written consent. CSF was collected by lumbar puncture and analyzed with a panel of 35 genes including IDH1-2, TERT promoter and EGFR. Blood was collected, synchronously with CSF, by peripheral veinous punction and analyzed with the Foundation One Liquid CDx panel. RESULTS Between January and April 2024, five patients were included. All of them undergone initial surgical resection and received at least one previous systemic treatment associated with radiotherapy. At least one somatic mutation was identified in each patient, including EGFR amplification in 2/5 patients (40%). CSF was not available at baseline. One patient provided CSF only at progression. Four patients provided CSF at C2D15 on treatment, and among them, one patient was also collected at progression. At data cut-off, one patient was still on treatment. We identified a detectable level of CSF-ctDNA in only one patient with occipital tumor localization, with detection of EGFR amplification known at diagnosis. Synchronous blood analysis showed only clonal hematopoiesis variants. CONCLUSION We showed in this small cohort of patients that detection of CSF-ctDNA is technically feasible. The type of panel used might be optimized for this population especially to monitor patients as a potential surrogate biomarker for treatment response.
TMIC-17. TARGETING THE FLUIDIC FORCE-SENSING MECHANISM TO TREAT BRAIN TUMOR METASTASIS
Authors: Xi Huang
Journal: Neuro-Oncology (2024)

Abstract Biofluid flow generates fluid shear stress (FSS), a mechanical force widely present in tissue microenvironment. How brain tumor growth alters the conduit of biofluid, thereby impacting FSS-regulated cancer progression is unknown. Medulloblastoma (MB) is the most common malignant brain tumor in children. Dissemination of MB cells into the cerebrospinal fluid (CSF) initiates metastasis within the central nervous system. By simulating CSF dynamics based on magnetic resonance imaging of MB patients, we discovered that FSS is elevated at the cervicomedullary junction. Strikingly, we found that MB-relevant FSS promotes metastasis along mouse spinal cords. Mechanistically, FSS induces metastatic cell behaviours, including weakened cell-substrate adhesion, increased motility, cell clustering, and plasma membrane localization of glucose transporter 1 (GLUT1) to enhance glucose uptake. FSS is perceived by mechanosensitive ion channel PIEZO2, which drives actomyosin contractility-dependent GLUT1 recruitment at the plasma membrane. Genetic targeting of PIEZO2 or pharmacologic inhibition of GLUT1 mitigates metastasis. Collectively, these findings define a targetable FSS-activated mechano-metastatic cascade for the treatment of MB metastasis.
RADT-22. EFFICACY AND SAFETY OF CYBERKNIFE STEREOTACTIC RADIOSURGERY FOR OCCIPITAL CONDYLE METASTASIS
Authors: David Park, Ahed Kattaa, Steven Chang
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Occipital condyle metastasis (OCM) is a rare condition characterized by severe occipital pain and neurological symptoms due to lower cranial nerve deficits, stemming from its anatomical location. Despite the widespread use of stereotactic radiosurgery (SRS) for cranial metastases, its specific impact on OCM remains underexplored. OBJECTIVE This study evaluates the efficacy and safety of CyberKnife SRS in treating OCM, focusing on symptom control and local tumor control. METHOD We retrospectively analyzed cases of OCM treated with SRS at our institute from 2012 to 2023, evaluating patient demographics, presenting symptoms, treatment parameters, and outcomes. Key measures included occipital pain, dysfunctions of cranial nerves IX, X, and XII, and local tumor control. RESULTS Eighteen patients (10 females) with a median age of 64 years (range: 40-79) were treated. Common presentations included occipital pain (44%) and lower cranial nerve deficits (28%). The median target volume was 6.95 cc (range: 0.95-72.7), and the median margin dose was 20 Gy (range: 16-40). The median follow-up period was 7 months (range: 1-44). Notably, only one patient experienced tumor recurrence and subsequently died from primary cancer progression five months after treatment. SRS achieved a 93.8% local tumor control rate over three years, with a median overall survival of 13 months. Among those presenting with symptoms, 87.5% reported pain relief, and 80% observed improvements in cranial nerve function. The only patient without clinical symptom improvement also had tumor recurrence. CONCLUSION CyberKnife SRS is a promising treatment for OCM, offering significant pain relief and improvement in neurological symptoms with excellent local control rates. This non-invasive therapy provides a valuable alternative to surgery, potentially enhancing the quality of life for patients with limited treatment options due to this challenging condition.
DNAR-05. VALIDATING THE ERK5 PROTAC OS11 AS A POTENTIAL NOVEL THERAPEUTIC IN<i>EX VIVO</i> GLIOMA STEM CELL MODELS OF INTRATUMOURAL HETEROGENEITY AND RESIDUAL DISEASE
Authors: Nikita Lad, Callum G Jones, Katie N Myers, Connor L McGarrity-Cottrell, Katherine G Finegan, Ola Rominiyi, Spencer J Collis
Journal: Neuro-Oncology (2024)

Abstract Glioblastoma is a grade IV brain tumour with poor survival rates of 15 months post-diagnosis, and 5-year survival rates of 10%. Limited progress over the past 40 years to improve the current treatment regimen of surgery and chemo-/radio-therapy are mainly due to tumour heterogeneity that drive resistance mechanisms. The persistence of glioma stem-like cells (GSCs) sub-populations, particularly within post-surgical residual tumour tissue. ERK5 is an emerging oncology drug target that we previously highlighted as a potential target for combined therapy with temozolomide (TMZ) in glioblastoma due to heightened ERK5 expression, which is associated with poor survival. This current project aims to expand on our previous findings by establishing whether targeting ERK5 can sensitise glioblastoma cells to TMZ using primary derived ex vivo GSC models of intratumor heterogeneity and residual disease. Primary GSC models were derived from patients at the Royal Hallamshire Hospital. The PROTAC OS11 (CRUK &amp; University of Manchester) was used to degrade ERK5. DNA damage and cell survival were evaluated following treatment of TMZ alone and in combination with OS11. Consistent with our findings in established glioma cell lines, OS11 was able to robustly degrade ERK5 in a 3D GSC model for at least 72hrs. Combining OS11 and TMZ in GSCs led to a significant increase in DNA damage, with MGMT negative cells exhibiting a greater increase in DNA damage compared to MGMT positive cells. However, unlike our previous findings in established cell lines, this did not lead to reduced cell survival in combination with TMZ. These findings further support the preclinical use of ex vivo models that better represent intratumoural heterogeneity and post-surgical GCS niches. Overall, these data highlight the value of preclinical validation in more clinically relevant models to identify the best possible novel therapeutic approaches to pursue further towards clinical delivery.
BIOS-05. PEPTIDE-BASED VACCINES VERSUS DENDRITIC CELL-BASED VACCINE THERAPIES FOR PATIENTS WITH GLIOBLASTOMA: A NETWORK META-ANALYSIS OF CONTROLLED CLINICAL TRIALS
Authors: Vinay Suresh, Mainak Bardhan, Debankur Dey, Archit Goel, Adeeb Ali Mohammad, Suhrud Panchawagh, Vivek Podder, Yazmin Odia, Zhijian Chen
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Glioblastoma (GBM) is the most prevalent primary CNS malignancy in adults, often with a bleak prognosis. Reports suggest the efficacy of dendritic cell vaccines (DCV) and peptide vaccines in extending overall survival (OS). We aimed to compare their efficacy using network meta-analysis (NMA). METHODS We systematically searched PubMed, Cochrane database, SCOPUS, and Clinicaltrials.gov up to February 2024 for controlled trials on DCV or peptide vaccines for GBM. NMA was conducted using the frequentist approach to obtain direct and indirect comparisons of each vaccine. Pairwise analyses were performed using the inverse variance method, comparing each vaccine’s efficacy. PEPvIII-KLH and Rindopepimut were merged into “Peptide-based vaccines” [PEP], and standard of care (SOC) and (Placebo + SOC) were merged. Primary outcome: hazard ratio (HR) of overall survival with 95% confidence intervals. RESULTS Analysis included 5 studies with 451 patients (vaccine arm) and 445 controls, with SOC/[Placebo + SOC] as reference. Common effects model showed DCV + SOC significantly reduced the HR to 0.3385 [0.1753; 0.6539], while the peptide-based vaccine + SOC reduced the HR to 0.8276 [0.6960; 0.9840]. In the random effects model, DCV + SOC had an HR of 0.3132 [0.0839; 1.1688], and the peptide-based vaccine + SOC had an HR of 0.3888 [0.1383; 1.0928]. Heterogeneity: tau^2 = 0.6473, tau = 0.8045, I^2 = 77.7% [39.5%; 91.8%]. In a pairwise meta-analysis comparing the DCV+SOC and SOC/[Placebo + SOC] consisting of 2 trials, the common and random effects models both estimated an HR of 0.3385 [0.1753; 0.6539, I^2 = 0.0%]. Comparing the PEP+SOC and SOC/[Placebo + SOC] based on 3 trials, the common effect model estimated an HR of 0.8276 [0.6960; 0.9840], while the random effects model estimated an HR of 0.3874 [0.1360; 1.1039, I^2 = 84.4%]. CONCLUSION Based on current evidence, DCV vaccines perform better than peptide-based vaccines in reducing mortality in GBM patients. Further trials are required to validate their efficacies.
CNSC-41. DABRAFENIB AND TRAMETINIB AS A PROMISING TREATMENT OPTION FOR PEDIATRIC POPULATION WITH LOW-GRADE GLIOMAS THAT HAVE BRAF V600E MUTATION:A BREAKTHROUGH IN THE FIELD OF NEURO- ONCOLOGY
Authors: Zaib Un Nisa Mughal, Tagwa Kalool Fadlalla Ahmad, Abdul Haseeb, Muhammad Ashir Shafique, Ola Elhadi Abbas Ahmdon, Abdulhadi Mohamed Ahmed Mahgoub
Journal: Neuro-Oncology (2024)

Abstract Two-thirds of all pediatric malignant central nervous tumors, including high-grade (glioblastoma, anaplastic astrocytoma) and low-grade (ganglioglioma, pilocytic astrocytoma) carcinomas, are gliomas. Low-grade glioma(LGG) exhibits genetic alterations caused by the BRAF kinase mutation, such as replacing glutamic acid (E) in place of valine (V) at the 600 positions, known as the V600E point mutation. Pediatric low-grade gliomas (PLGGs) also comprise around one-third of juvenile brain tumors and are the most frequent central nervous system tumors. Patients were randomized 2:1 to dabrafenib plus trametinib (D+T) or carboplatin plus vincristine (C+V). Where possible, complete surgical removal is the mainstay of treatment for progressing or symptomatic PLGG.Radiation therapy has historically been used to treat PLGG in both up-front and salvage scenarios. To delay or avoid the necessity for radiation therapy in young children with advancing or incompletely resected PLGG, chemotherapy was created in 1980. On March 16, 2023, the Food and Drug Administration approved the use of trametinib (Mekinist, Novartis) with dabrafenib (Tafinlar, Novartis) in pediatric patients suffering from low-grade glioma (LGG) who require systemic therapy and are at least one year old. Nevertheless, early-stage clinical trials have produced encouraging results that may revolutionize the treatment of LGG in the near future.
CSIG-01. DECREASING EXPRESSION OF TRAF PROTEINS WITH INCREASING MALIGNANCY WITH LOWEST EXPRESSION IN IDH-WILDTYP GLIOBLASTOMA
Authors: Marco Timmer, Saskia Kuhl, Roland Goldbrunner
Journal: Neuro-Oncology (2024)

Abstract The tumor necrosis factor receptor-associated factors (TRAF) are cytoplasmatic adapter proteins that can interact directly with the intracellular domains of cell surface receptors, such as the TNF receptor superfamily. TRAFs are thus involved in cellular processes like proliferation or apoptosis. Seven members are known; all expressed in the cytosol of various cell and tissue types. Increased levels of TRAF4 in GBM tissue are related to cell proliferation and migration. About 25 % of grade I meningioma show mutations in TRAF7, which are associated with a lower risk of malignant transformation. Therefore expression patterns of all seven TRAF members are evaluated in different glioma grades. Following tumor samples were obtained during neurosurgery and shock frozen in liquid nitrogen: peritumoral tissue, astrocytoma and oligodendroglioma (G2, G3) and glioblastoma (primary and recurrent). Transcription rate of TRAF1-7 was measured via qPCR. Correlation of TRAF expression level and patient overall survival was evaluated using TCGA datasets of the TCGA-LGG” and “TCGA-GBM” projects. With the exception of TRAF5, a decreased mRNA level with increasing malignancy could be found for all TRAFs (TRAF1 p=n.s.; TRAF2 p=0.0026; TRAF3 p&amp;lt;0.0001; TRAF4 p=0.0021; TRAF6 p&amp;lt;0.0001; TRAF7 p&amp;lt;0.0001). IDHwt glioblastoma showed significant lower expression level compared to IDHmut glioblstoma in all TRAFs except for TRAF1 (TRAF2 p&amp;lt;0.0001; TRAF3 p=0.0346; TRAF4 p&amp;lt;0.0001; TRAF6 p=0.0447; TRAF7 p=0.0081). TRAF5 again showed a reverse effect (p=0.0065). Correlation of TRAF expression level in low grade glioma and patient survival revealed longer overall survival with low TRAF1,2,4 and TRAF5 expression (p&amp;lt;0.0001, p= 0.0178, p=0.0307, p&amp;lt;0.0001). No difference in survival rate in high grade glioma could be found.
NCOG-17. THE COMBAT PROJECT - CORE POST OPERATIVE MORBIDITY SET FOR PAEDIATRIC BRAIN TUMOURS
Authors: Sandhya Trichinopoly Krishna, Conor Mallucci, Barry Pizer, Carrol Gamble, Nicola Harman, Michael Jenkinson
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Brain tumours are associated with high morbidity both from the tumour and the medical and surgical interventions used to treat them. Post operative morbidity reporting following surgery for paediatric brain tumours is poor due to the lack of a common language when reporting harms. One solution is to develop a core outcome set to stipulate the minimum post operative adverse outcomes that should be reported. The COMBAT (Core Post Operative Morbidity Set for Paediatric Brain Tumours) Project will develop a core outcome set that can be applied to post operative paediatric brain tumour patients to harmonise how adverse outcomes are measured and reported, enabling comparison between different trials, studies and clinical services. We aim to generate interest in The COMBAT Project and invite participation in the project from healthcare professionals and researchers experienced in paediatric neuro-oncology for the consensus process. METHODS AND ANALYSIS We will engage with national and international stakeholders including patients and their carers, healthcare professionals and researchers. A systematic review will identify harms reported in post operative paediatric brain tumour patients and how they are measured. Qualitative interviews with patients and carers will identify any harms of importance to them. A Delphi survey will be created from the harms identified. A consensus meeting will be held to finalise the core outcome set. The final core outcome set will be published and disseminated to encourage uptake. DISCUSSION There is a clear need for a common language to harmonise measurement and reporting of harms following surgery for paediatric brain tumour patients. This project will define post operative adverse outcomes that are of critical importance to key stakeholders. It will be used to standardise surgical morbidity outcome measurement and reporting in trials, studies and clinical practice and will inform future research in this field.