tbuckley/cabot-search huggingface dataset:
P14.18.A POSTERIOR CRANIAL FOSSA RECONSTRUCTION TECHNIQUE TO REDUCE POSTOPERATIVE PSEUDOMENINGOCELE IN PEDIATRIC PATIENTS OF POSTERIOR FOSSA TUMOR SURGERY WITH SUBOCCIPITAL MIDLINE APPROACH
Authors: M Tang, Y Chen
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Pediatric patients undergoing tumor resection through a suboccipital midline approach carry a high risk of pseudomeningocele and cerebrospinal fluid (CSF) leakage. We describe our experience of eliminating the dead space introduced by the original surgical incision compared to traditional methods to reduce this risk. MATERIAL AND METHODS The data of children who underwent tumor resection with a suboccipital midline approach were retrospectively analyzed. The patients were divided into a traditional group and an improved group according to whether the new technique proposed in this study was used. Complications such as pseudomeningocele, meningitis, and hydrocephalus during hospitalization and follow-up were retrospectively analyzed. Univariate and multivariate logistic regression analyses were used to explore the relationship between the use of new technology and postoperative complications. All patients were followed up regularly for 2 weeks, 1 month, and 3 months after surgery. RESULTS Our retrospective study identified 111 eligible pediatric patients who underwent tumor resection with a suboccipital midline approach and showed that postoperative complications were lower in the improved group than in the traditional group (39.1% vs 55.4%). This difference is particularly marked in the case of PMC (10.9% vs 27.7%, OR 0.26, p = 0.027). The use of new technology was a protective factor for postoperative PMC, while the use of new technology did not significantly lower the occurrence rate of meningitis and postoperative hydrocephalus. The pathological type of tumor may be related to the occurrence of postoperative PMC, but there was no significant statistical difference (p=0.083). CONCLUSION Compared with traditional surgery, eliminating the dead space caused by the primary surgical incision is a simple and feasible technique, which can reduce the incidence of pseudomeningocele.
P26.06.B EVALUATION OF THE ANTITUMOR EFFECT OF A CHEMOTHERAPY-LOADED DEVICE FOR THE TREATMENT OF PRIMARY BRAIN TUMORS
Authors: L Déry, G Charest, B Guérin, M Akbari, D Fortin
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Glioblastoma (GBM) is the most frequent and aggressive primary brain tumor in adults. It is characterized by its infiltration of the brain parenchyma, making complete surgical resection impossible. It is also resistant to radio-chemotherapy. Tumor recurrence is therefore inevitable, and median survival is just over 14 months. The location of these tumors also means that they are protected from chemotherapy by the presence of the blood-brain barrier (BBB). Currently available treatments are inadequate and do not provide optimal tumor control. We believe that treatment localized directly at the tumor site will eliminate a greater number of infiltrating tumor cells while significantly reducing systemic toxicity. MATERIAL AND METHODS For this project, we are collaborating with a team specializing in bioengineering, who have produced a biomaterial enabling the gradual release of various agents. Our aim is to use this biomaterial to deliver chemotherapeutic agents to the tumor site through the surgical cavity. We evaluated the antitumor potential of biomaterial loaded with different chemotherapies. Cell-based assays were carried out using glial tumor cells in the presence of the biomaterial containing chemotherapeutics. Cell viability readings were taken at different times to observe the antitumor effect of the selected neoplastic agents. A survival study was realized with the Fischer F98 rat model, which underwent partial tumor resection followed by injection of biomaterial containing chemotherapy. Histological studies of brains and resected tissues were carried out to assess the effect of the biomaterial on the brain environment. RESULTS In vitro assays showed a strong cytotoxic effect against glial tumor cells at 24h, 48h and 72h of biomaterial-drug incubation. The combination of two chemotherapeutic agents showed the best cytotoxic effect on glial tumor cells. We also performed a partial tumor resection and insertion of the chemotherapy-loaded biomaterial into the surgical cavity of the F98 glioma bearing rat. Similar to in vitro studies, the combination of two antineoplastic agents shows a significant improvement in animal survival. CONCLUSION In conclusion, the in vitro and in vivo results of this study show that the combination of chemotherapy has the greatest antitumor effect. We hope that these exciting results will lead to the development of a new treatment for patients with glioblastoma and potentially other diseases where complete tumor resection is impossible. SUPPORT/ DISCLOSER Funding was provided by donations and scholarships: La rose des vents, Fondation du Centre Hospitalier Universitaire de Sherbrooke (CHUS), Centre de recherche du CHUS (CRCHUS), Centre d’imagerie moléculaire de Sherbrooke (CIMS) and Centre d’excellence en Neurosciences de l’Université de Sherbrooke (CNS). All authors declare that they have no competing financial interests.
P13.11.A OUTCOMES FOLLOWING CYBERKNIFE FOR VESTIBULAR SCHWANNOMA: THE ST. BARTHOLOMEW’S HOSPITAL EXPERIENCE
Authors: P Christodoulou, T Hill, P de Luna, D Parasekevopoulos, G McFeely, C Dean, S Bowles, J Cook, H Rozati, P N Plowman, K Burton, S Rashed, J Pollock, A Shoakazemi, R Lewis
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Vestibular schwannomata (VS) represent &amp;lt;10% of brain tumours. Treatment strategies are surveillance, surgical resection, stereotactic radiosurgery (SRS) or fractionated stereotactic radiotherapy (SRT). Since 2019 SRS/SRT has been delivered with CyberKnife (CK) at Barts. After analysis of dosimetry and verification, the GTV to PTV margin was reduced from 1mm to 0mm, and dose prescribed to the 50% isodose for a single fraction, or 65% if fractionated, with the aim of maintaining tumour control rates whilst sparing additional toxicity. PRV to OARs remained 1mm in both groups. MATERIAL AND METHODS patients were treated with 1mm GTV to PTV expansion (Group 1) and the remaining 57 patients were treated without additional PTV margin (Group 2). Post-treatment imaging and clinic letters were reviewed to assess rates of tumour control and reported adverse events. Results of reducing the PTV margin were compared with previous practice and against the International Stereotactic Radiosurgery Society (ISRS) guidelines. Median follow-up was 32.5 months, range 9 - 56 months. RESULTS All patients in group 1 were treated with 21Gy in 3 fractions. 16 patients in Group 2 (24%) were treated with a single 12Gy fraction. The median dose was 21Gy in 3 fractions, with no patients treated over more than 5 fractions. Change in PTV prescription did not affect tumour control rate. At the point of reporting, tumour control was achieved in 64/66 patients. 1 patient from group 1 proceeded to microsurgical resection at 3 months. The second patient, from group 2, declined surgery and continues with close surveillance. The majority of patients experienced no side effects (38 patients). The most common acute toxicity was headache (33% in group 1 vs 26% group 2), reduced hearing (33% vs 16%) and facial/trigeminal nerve deficit (11% vs 9%). Of those who experienced acute toxicity, for 17 patients (45%) it persisted for greater than 12 weeks, equally distributed between facial/trigeminal nerve deficits, reduced hearing or dizziness. Persistent toxicity was more common in Group 1 (55% vs 21%). 2 patients required V-P shunt insertion after treatment (one from group 1 and one from group 2). CONCLUSION Given the limitations of our small retrospective analysis it appears that CK is an effective and safe treatment for VS. Our rate of tumour control is comparable to international standards with improved rates of hearing preservation (79% vs 67%). Our data suggest reduced treatment margin does not have an impact on tumour control but is associated with reduced toxicity. The toxicity rates in group 2 are consistent with expected toxicity from published data. Long-term follow-up is required to further evaluate tumour control and late effects.
P19.10.A POST-OPERATIVE HYPOFRACTIONATED RADIOSURGERY FOR INTERMEDIATE RISK MENINGIOMA
Authors: D Ghosh, R Conger, A Choudhury, M P Nguyen, I Sethi, J Viner, N Oberheim Bush, R A Morshed, E Goldschmidt, S E Braunstein, D R Raleigh, W C Chen
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Conventional post-operative radiotherapy (RT) after resection of intermediate risk meningioma requires daily outpatient treatment for 6 weeks or more, which impose logistic and financial burdens on patients and the healthcare system. Although shortened course hypofractionated radiosurgery (hypoSRS) over 3 to 5 days has been applied for intact WHO grade 1 or imaging-defined meningiomas, no studies report on post-operative hypoSRS targeting the resection cavity after gross total resection (GTR) of intermediate risk meningiomas. To address this limitation in treatment for patients with the most common primary intracranial tumor, this retrospective case series investigated preliminary safety and efficacy data for patients undergoing hypoSRS after GTR of intermediate risk meningiomas. MATERIAL AND METHODS Seven patients (median age 62.2, interquartile range [IQR] 53.9-71.2, 57.1% female) who underwent GTR of intermediate risk meningioma, defined as primary WHO grade 2 (5 of 7, 71.4%), recurrent WHO grade 1 (1 of 7, 14.3%), or WHO grade 1 with a high risk molecular feature (1 of 7, 14.3%, BAP1 deletion), followed by post-operative hypoSRS, were identified. Meningiomas had a median of 4 mitoses/10 hpf (IQR 3-5) and MIB1 labeling index of 6.5% (IQR 4-8.5%) and were located at the convexity (4 of 7, 57.1%) or parasagittal regions (2 of 7, 28.6%). An institutional targeted DNA sequencing panel was performed on 4 of 7 meningiomas (57.1%). Of these, 3 were intermediate molecular risk (integrated grade 2) and 1 was high molecular risk (integrated grade 3). The hypoSRS target was comprised of at-risk dura and the resection bed without any expansion into brain parenchyma. RESULTS Patients were treated with a median dose of 30Gy in 5 daily fractions (range 25-30Gy, prescribed to a median 87% [IQR 68-89%] isodose line) to a median target volume of 13.6cc (range 7.4-49.9). Four patients were treated with linear accelerator based hypoSRS and 3 with frameless Gamma Knife Icon. Median volume of brain receiving at least 24Gy (V24Gy) was 7.8cc (IQR 3.0-18.0). At a median of 2.4 years of follow up (IQR 1.0-3.7), there were no recurrences, no occurrences of radionecrosis, and no CTCAEv5 G3+ toxicities. CONCLUSION As an alternative to 6 weeks of conventional post-operative RT, this case series suggests that hypoSRS is a safe and convenient treatment for patients with favorable anatomy after resection of intermediate risk meningioma. Larger studies with longer follow up are needed, and a future prospective trial of this approach is planned.
P06.09.B RATIONAL DRUG COMBINATIONS TARGETING FAK AND MEK OVERCOMES TUMOUR HETEROGENEITY IN GLIOBLASTOMA
Authors: M Furqan, R Elliott, P Nagle, A Loftus, R Masalmeh, A Munro, C Drake, J Dawson, V Brunton, M Frame, N Carragher
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Glioblastoma (GBM) presents a formidable clinical challenge with limited treatment options and poor outcomes. Despite efforts, the standard therapy has not improved for almost two decades. The heterogeneity of GBM, driven by multiple intracellular signalling pathways, complicates treatment response and contributes to drug resistance. Recent advancements in targeted combination therapy, such as dabrafenib and trametinib, offer promise for specific GBM subgroups, but identifying effective drug combinations remains challenging. Integrin mediated signalling, particularly through Focal Adhesion Kinase (FAK), plays a crucial role in GBM pathogenesis and invasion. While targeting FAK shows promise, identifying synergistic combinations is essential. Our study employs a chemogenomic screening approach to identify FAK targeted drug combinations in glioblastoma. MATERIAL AND METHODS Glioblastoma cells were cultured and subjected to chemogenomic screening to identify synergistic drug combinations with FAK depletion. Cell viability was assessed using the Alamar Blue assay, while morphological changes were observed using high content imaging. Synergies in drug combinations were determined using the SynergyFinder online tool. Molecular mechanism was elucidated through Reverse Phase Protein Array and western blots, with statistical analysis determining significance. Finally, in vivo efficacy was evaluated in an orthotopic transplantation model. RESULTS Using a CRISPR engineered model, we identified synergistic drug combinations with FAK loss, notably MEK inhibitors. Combining FAK inhibitors with MEK inhibitors showed potent synergy, validated by target engagement assays. Across a diverse panel of patient derived GBM stem cells, this combination inhibited spheroid growth and invasion. RPPA profiling elucidated their molecular effects. In vivo, the combination significantly reduced tumour volume. These results highlight a promising therapeutic strategy for glioblastoma. CONCLUSION In conclusion, our study reveals promising synergies with MEK inhibitors, notably trametinib, across diverse GBM models. This approach also highlights the potential of combination therapy to address the complex challenges of GBM treatment.
P17.25.B TARGETING AURKA-MEDIATED NOTCH SIGNALLING IN HER2+ BREAST CANCER BRAIN METASTASIS WITH ALISERTIB
Authors: A Powell, S Preković, S Cocchiglia, P Jagušt, A D Hill, W Zwart, L Young, D Varešlija
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Breast cancer brain metastasis (BCBM), occurring in 10-38% of patients, notably affects those with HER2-positive and triple-negative subtypes, representing a significant clinical challenge. The molecular subtype of the originating tumor significantly impacts the likelihood and progression of BCBM, with HER2 positive and triple-negative breast cancer (TNBC) carrying the bigger risk. Critically, brain metastases manifest distinct genomic and phenotypic characteristics compared to their primary tumours. The lack of comprehensive understanding of these factors contributes to the scarcity of effective treatments for BCBM. MATERIAL AND METHODS This study leveraged the distinct genomic and phenotypic characteristics of BCBM through RNA sequencing (N=63) and DNA whole exome sequencing (N=39) of patient-matched primary and brain metastatic samples, identifying AURKA as a clinically actionable target. High-throughput drug screen was carried out in five BCBM cell lines using AURKA pathway inhibitors. Investigation of AURKA in a BCBM context was carried out in both in vitro and ex vivo assays utilizing both AURKA-specific inhibitor, Alisertib, and siRNA-mediated knockdown of AURKA. RESULTS Amplifications in AURKA were identified in this BCBM patient cohort and high AURKA mRNA expression was associated with poor overall survival and survival post brain metastasis. Genetic and pharmacological inhibition of AURKA, using both siRNA and Alisertib, exhibited significant anti-tumor effects in various BCBM models, including cell lines, mammospheres, patient-derived organoids, and brain organotypic cultures, with pronounced efficacy in HER2-positive BCBM models. Furthermore, AURKA was found to modulate Notch signaling in HER2+ve BCBM, implicated in promoting therapeutic resistance and stemness, with the co-activator MAML1 essential for this process. AURKAhigh/MAML1high tumours were associated with poorer survival outcomes. CONCLUSION These results suggest AURKA as a critical vulnerability in BCBM, offering new avenues for treatment strategies targeting both its kinase-dependent and -independent functions to potentially improve patient outcomes.
P24.04.A PATIENT AND PUBLIC INVOLVEMENT IN A NEURO-ONCOLOGICAL RESEARCH PROJECT
Authors: S Nordentoft, R Guldager, T Mathiesen, H Pappot, K Piil
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Development and implementation of an intervention targeting a specific population can be significantly enhanced through the integration of Patient and Public involvement (PPI). The aim of this study is to apply PPI in the process of developing a supportive group intervention for caregivers to patients diagnosed with a glioblastoma. MATERIAL AND METHODS Establishment of a national PPI panel including current or bereaved caregivers to patients diagnosed with a glioblastoma was recruited through the Danish Brain Tumor Association (Hjernetumorforeningen). Terms of reference for the panel have been established, describing purpose, terms, and meeting format. Online Team meetings and a face-to-face co-creative workshop with the panel was conducted in corporation with the Danish Knowledge Center for User Involvement in Health Care. Next step, the level and value of caregiver involvement will be measured by using the Patient Engagement in Research Scale (PEIRS-22), to gain knowledge on how meaningful the caregivers experienced their engagement in the research process. RESULTS A national panel of current and bereaved caregivers (n=10) was engaged in the PPI-process and provided valuable knowledge to the development of the intervention. Ongoing online Team meetings were held every second month with the panel, video-recorded, and subsequently transcribed. This process aimed to identify themes within the topics discussed with the panel and to ensure inclusion of the caregivers’ insight and needs in the design of the intervention. The purpose of the workshop was to target the further development of the intervention and to gain more structure in the design. Creating a collaborative PPI-process with the panel included thorough preparation for each meeting with a pre-distributed agenda. Preparing the caregivers for the topics to be discussed, ensured to gain the requested information, and meanwhile creating an open and inviting forum were important element of the process. CONCLUSION PPI in current co-creating process was a time consuming yet valuable process, where caregivers’ experiences and perspectives were addressed in the design and development of a supportive group intervention.
P02.14.B INCREASED PRE-OPERATIVE MEAN PLATELET VOLUME (MPV) IS ASSOCIATED WITH GLIOBLASTOMA IDH-WTOVERALL SURVIVAL, PRELIMINARY DATA FROM 167 PATIENTS
Authors: S Snider, P De Domenico, F Roncelli, A Bisoglio, M Braga, A Ghelfi, L R Barzaghi, C Mura, P Mortini, F Gagliardi
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND In recent years, there has been a growing interest in exploring the potential contribution of hemostasis and platelet activation in GBM biology. This study aims to address the association between pre-operative coagulation profile (PT ratio, aPTT ratio), overall platelets’ count (PC), and the mean platelet volume (MPV) with tumoral characteristics and overall survival in GBM IDH-wt patients. MATERIAL AND METHODS A total of 167 adult patients undergoing maximal safe resection of newly diagnosed glioblastoma WHO grade 4 IDH-wt were included. The variables of interest (MPV, PT ratio, and aPTT ratio) were dichotomized at the median, while the overall PC was split up using the central distribution (10th to 90th percentile). Analyses were conducted to explore the single contributions of these parameters in building a predictive model of overall survival (OS) in these patients. Results: The mean baseline MPV correlated to increasing age (r=0.18, p=0.01), the overall FLAIR tumoral volume (r=0.17, p=0.02), and lesional contrast-enhanced (T1-CE) volume (r=0.19, p=0.01). The median OS in the whole cohort of GBM patients was 14.4 months (95% CI: 12.9-17.6). Patients with MPV &amp;gt; 10.3 10-15L had a median OS of 13.4 months (95% CI: 10.6-17.6) compared to 14.5 months (95% CI: 13.4-20.6) in patients with MPV &amp;lt;= 10.3 10-15L, p = 0.028. Similarly, shorter OS was recorded in patients with PT ratio &amp;gt; 1.01 (p=0.006), and PC out-of-range 165-300 109/L (p=0.026). A subgroup analysis of patients &amp;gt; 65 years confirmed baseline MPV &amp;gt; 10.3 10-15L was associated with shorter OS (9.4 months, 95% CI: 8.1-13.4) compared to 13.3 months (95% CI: 11.3-32.3, p = 0.026). Baseline increased MPV showed an independent predictive role for poor survival (HR: 1.29, 95% CI 1.01-1.66, p=0.04) in multivariate analysis accounting for age, gender, pre-operative performance status, and tumoral molecular and radiological characteristics, whereas PC within central range had a protective role (HR: 0.47, 95% CI 0.26-0.88, p=0.01). CONCLUSION This study highlights an intriguing association between tumoral burden and systemic hemostasis activation in GBM IDH-wt patients. Increased MPV and deranged PC outside the central range were independent in predicting shorter OS, which was even more prominent among older patients.
P18.26.A IMPROVED OUTCOME PREDICTION AND GRADING OF THE NOVEL TUMOUR TYPE GLIOMATOSIS CEREBRI-LIKE GLIOMA, IDH-WILDTYPE (GCLG, IDH-WT)
Authors: M Münzberg, A Muench, I Divé, K Wenger-Alakmeh, M Forster, F Costa, C Dehais, F Bielle, P Kuzman, W C Mueller, V Umathum, T Acker, R Beschorner, L von Baumgarten, P N Harter, C Thomas, M Misch, D Capper, A K Wefers, J E Neumann, U Schüller, M Czabanka, J P Steinbach, K H Plate, S Brandner, L Schweizer
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Based on a cohort of 16 patients, we recently described a novel tumour type of IDH-wildtype glioma in adult patients, characterised by a gliomatosis cerebri-like growth pattern, frequent TERT promoter mutations, and a distinct epigenetic profile (GCLG, IDH-wildtype; DKFZ brain tumour classifier: adult-type high grade glioma, subtype F, HGG-F). MATERIAL AND METHODS We now compiled a larger, multicentric series of 63 patients and conducted an in-depth morphological, molecular and clinical characterisation. RESULTS The series consisted of 43 male and 15 female (NA = 5) patients. Median age was 65 years (range 17-88 years). In the initial series, none of the cases demonstrated vascular proliferation or necrosis; in contrast, 6/50 cases in this extended cohort (12%) showed histological features of malignancy (i.e. vascular proliferation and/or necrosis). In addition, 40% demonstrated molecular features of high-grade gliomas (i.e., CDKN2A/B homozygous deletion, chr.+7/-10, high-level amplifications of EGFR, CDK4, PDGFRA). Progression-free and overall survival in GCLG with and without histological and/or molecular signs of malignancy were significantly different (p&amp;lt;0.001). GCLG lacking signs of malignancy (n = 24) demonstrated an intermediate outcome comparable to IDH-mutant astrocytoma (PFS 58 vs. 54 months; OS 73 vs. 89 months) and may be assigned a CNS WHO grade 3 in the future. GCLG with malignant features (n = 14) demonstrated a clinical outcome similar to glioblastoma, IDH-wildtype, corresponding to CNS WHO grade 4 (PFS 11 vs 9 months; OS 16 vs 14 months). In four patients, we were able to compare tumour tissue from the initial and recurrent resection (median interval: 28 months, range: 11-69 months). Two tumours appeared unchanged upon recurrence, whereas two tumours with flat CNV profile and low-grade morphology subsequently acquired a homozygous CDKN2A/B deletion, microvascular proliferation and necrosis compatible with a malignant transformation during the disease course. Only 6/48 (12.5%) tumours had a MGMT promoter hypermethylation. CONCLUSION GCLG represents a novel IDH-wildtype glioma type in elderly patients with a distinct disease dynamic compared to glioblastoma, IDH-wildtype, and often extensive involvement of multiple brain regions (gliomatosis pattern at initial diagnosis in 50% of cases). We suggest a classification as either CNS grade 3 or CNS grade 4. Given the potentially large radiation field and unmethylated MGMT promoter in many cases, the optimal therapeutic strategies for GCLG with and without malignant features remain to be determined in the future.