tbuckley/cabot-search huggingface dataset:
P10.16.A FULLY AUTOMATED APPROACH TO PREDICT THE VISUAL OUTCOME AFTER PITUITARY ADENOMA SURGERY BASED ON PREOPERATIVE MRI USING DEEP LEARNING
Authors: Y Zhang
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Accurate prediction of the postoperative visual recovery is important to clinical decision-making for pituitary adenoma patients, while still remains a challenge in clinical practice. The purpose of the present study is to predict the visual outcome after pituitary adenoma surgery based on preoperative MRI using a fully automated approach with convolutional neural network (CNN). MATERIAL AND METHODS A total number of 205 qualified pituitary adenoma patients were retrospectively enrolled and subdivided into the recovery cohort (n = 132) and the non-recovery cohort (n = 73), according to results of the visual testing at least six months after endoscopic endonasal transsphenoidal surgery. Based on preoperative T2-weighted images, a fully automated model was built by connecting two CNN models for optic chiasm segmentation and visual outcome prediction, respectively. The optic chiasm automatically segmented by the state-of-the-art nnU-Net architecture were utilized for establishment of the predictive model for visual outcome based on ResNet18. The proposed model was first trained in the development set (n = 163) and then applied in the independent test set (n = 42). Moreover, the test set was further divided into three subsets according to different MR scanners to evaluated the generalizability of our model. RESULTS The CNN model for optic chiasm segmentation achieved an average dice similarity coefficient of 0.831. The predictive model showed feasible performances in predicting the postoperative visual outcome, achieving an accuracy of 0.833 in the test set, with area under the receiver operating characteristic curve of 0.857, sensitivity of 0.815 and specificity of 0.867. Moreover, our model also demonstrated good generalizability, with accuracy of 0.813-0.875 across different MR scanners. CONCLUSION The proposed fully automated model represented the potential to be an accurate and generalizable approach for the prediction of the postoperative visual recovery of pituitary adenoma patients.
P18.04.A APPLICATION OF THE PET RANO 1.0 CRITERIA IN DIFFUSE GLIOMA: RETROSPECTIVE SINGLE CENTER EXPERIENCE
Authors: L Wiegand, E Barci, K J Müller, R Forbrig, M Brendel, M Preusser, S Schönecker, N Thon, P N Harter, L von Baumgarten, N L Albert
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Response evaluation and disease monitoring of gliomas relies on MRI in clinical routine and trials. Recently, novel response criteria utilizing amino acid PET (PET RANO 1.0) have been introduced. This study analyses longitudinal [18F]FET PET data of patients with diffuse glioma and applies the PET RANO 1.0 criteria to describe PET characteristics at baseline, response classes, and changes of individual parameters. MATERIAL AND METHODS In this retrospective single-center study, patients with diffuse glioma and a baseline as well as at least one follow-up [18F]FET PET scan were identified. PET analyses were performed according to the PET RANO 1.0 criteria and included the assessment of maximal and mean target-to-background ratios (TBRmax, TBRmean), PET volume, changes of these values between scans, and the presence of either measurable or no / non-measurable disease. Follow-up scans were classified as PET-based progressive disease (PET-PD), stable disease (PET-SD), partial response (PET-PR), or complete response (PET-CR) according to PET RANO 1.0. RESULTS A total of 475 scans in 148 patients were evaluated with a total of 228 treatment lines, defined as a baseline scan plus a series of one to four follow-up evaluations either with or without treatment. Overall, 164/228 baseline scans had measurable disease and 64/228 had non-measurable or no measurable disease. In the treatment lines, 4% of patients had PET-CR as best response, 23% had PET-PR, 37% had PET-SD, and 36% had PET-PD. PET-PD was determined based on significant volume changes and/or the occurrence of new lesions in the majority of cases (&amp;gt;90%), while significant increases of uptake intensity were found in 30% of cases. A sole increase of uptake intensity as determinant for PET-PD was only found in 8% of cases. PET-PR was determined based on volume reductions in 82% of cases (25% in combination with decreasing uptake intensity) and by a sole reduction of uptake intensity in 18% of cases. Treatment lines of glioblastoma had PET-PD as a best response in 56% of cases, while astrocytomas and oligodendrogliomas only had PET-PD in 44% and 35% of cases, respectively. CONCLUSION This study demonstrates that significant volume changes seem to be the major determinant for treatment response according to the PET RANO 1.0 criteria and are often accompanied by changes of uptake intensity, while sole uptake intensity changes determine response classes only in a subset of patients. Best responses in treatment lines classified with the new criteria varied based on tumor type with IDH-wildtype glioblastoma showing higher rates of PET-PD in comparison with IDH-mutant gliomas. In the future, response assessment from PET RANO 1.0 should be correlated with the MRI-based RANO 2.0 criteria, as well as the clinical outcome of patients.
P17.22.B SILMET TRIAL: A RANDOMIZED, PLACEBO-CONTROLLED STUDY TO EVALUATE THE STAT3 INHIBITOR SILIBININ IN PREVENTING INTRACRANIAL RECURRENCE AFTER COMPLETE RESECTION OF A SINGLE BRAIN METASTASIS FROM NON-SMALL-CELL LUNG CANCER (NSCLC) OR BREAST CANCER
Authors: A Pellerino, A Pace, F Angileri, M Caffo, M Gatti, E Benicelli, L Bertero, A Ricci, L Mangherini, D Garbossa, N Priego, J Bosch-Barrera, M Valiente, R Rudà, R Soffietti
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND A subpopulation of reactive astrocytes (RAs) with activated signal transducer and activator of transcription 3 (STAT3) signalling in peritumoral tissue of brain metastases (BM) has been shown to favor a pro-metastatic microenvironment. High-pSTAT3 expression in RAs of BM has been correlated with a shorter intracranial progression-free survival (i-PFS) as compared with low-pSTAT3 BM. Pharmacological inhibition of the STAT3 pathway with silibinin has been suggested to be active in preliminary cohort of patients with BM. PATIENTS AND METHODS A new “prevention” trial has been initiated in June 2023 to investigate the efficacy of silibinin in comparison to placebo (PCB) to prevent a secondary intracranial relapse in a multicentric cohort of patients with gross-total resected BM from NSCLC and breast cancer. Inclusion criteria are as follows: histologically confirmed BM from NSCLC or BC; single BM who underwent a complete resection; systemic disease not requiring a change of antineoplastic therapy; pSTAT3 presence in RAs of peritumoral tissue confirmed by central assessment; ≥ 18 - 70 years of age; KPS ≥ 70. The primary endpoint is to demonstrate a superiority of silibinin in prolonging time to local recurrence as compared to PCB. The secondary endpoints are time to distant recurrence of BM in the brain, i-PFS, overall PFS (intracranial and/or systemic), overall survival, tolerability, quality of life. Collection of blood and CSF samples for the analysis of STAT3 downstream pathways is an exploratory objective. The sample size (70 patients) was calculated by assuming a median time to local recurrence of BM of 7.5 months for PCB (control arm) according to Mahajan [1] and ≥15 months for silibinin arm. Clinical trial information: NCT05689619 [1] Mahajan A et al. Post-operative stereotactic radiosurgery versus observation for completely resected brain metastases: a single-centre, randomised, controlled, phase 3 trial. Lancet Oncol. 2017
P18.13.A DE-NOVO PURINE METABOLISM CAN BE TARGETED SAFELY IN GLIOBLASTOMA TREATMENT TO OVERCOME CHEMORADIATION RESISTANCE: AN INTERIM RESULT OF PHASE 0/1 CLINICAL TRIAL
Authors: Y Umemura, N Clarke, W Al-Holou, A L Elaimy, A Scott, D Leung, M Kim, S Ferris, J Thomas, J Heth, M Schipper, K Suresh, T Lawrence, D Wahl
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Mycophenolate mofetil (MMF) is a commonly used oral immunosuppressant, which exerts its effect by its antimetabolite mechanism. Contrary to normal brain preferring to salvage purines, which is resource-efficient, glioblastoma tumor cells prefer to make new purine via de-novo purine pathway. The de-novo purine metabolism can be disrupted using MMF which inhibits IMPDH, a key enzyme in this pathway. There are pre-clinical evidence of MMF improving radiation and temozolomide efficacy in glioblastoma mouse models, which led to this first-in-human phase 0/1 trial (NCT04477200) to assess the tolerability of MMF with chemoradiation in glioblastoma, MPA accumulation, and purine synthesis inhibition in tumor. MATERIAL AND METHODS In the phase 0 study, eight recurrent glioblastoma patients received MMF at doses ranging 500-2000mg BID for one-week before planned surgery. The tissues were analyzed using mass spectrometry for drug accumulation and purine synthesis inhibition. In the phase 1 study, adult patients were given MMF starting at 1000mg PO BID, with the possible dose ranging 500-2000 PO BID using TITE-CRM. Nineteen recurrent glioblastoma patients (target N=30) received MMF one-week prior to and concurrently with re-irradiation (40.5 Gy). Thirty newly diagnosed glioblastoma patients received MMF one-week prior to and concurrently with chemoradiation, followed by MMF one-day before and during 5 days of each adjuvant temozolomide cycles. RESULTS Both enhancing and non-enhancing tumor from phase 0 subjects yielded &amp;gt;1µM active drug metabolite, and the GTP/IMP ratio was decreased by 75% in enhancing tumor in MMF-treated patients compared to untreated controls (p=0.009), indicating effective target engagement and inhibition of purine synthesis. In the Phase 1 study, no dose limiting toxicities (DLTs) have been observed at the interim analysis at MMF 1000-1500mg BID combined with chemoradiation. At 2000mg BID, there was no DLT combined with temozolomide alone, however, there were four DLTs noted (hemiparesis, cognitive disturbance, fatigue, thrombocytopenia) when combined with radiotherapy and temozolomide together, though all were reversible. Interim median overall survival in recurrent phase 1 is 15.6 months, and not reached yet in newly diagnosed phase 1. CONCLUSION MMF combined with chemoradiation has been reasonably well tolerated in glioblastoma patients with promising evidence of brain tumor target engagement and drug accumulation in glioblastoma. This study yielded the recommended phase 2 dose of MMF 1500mg BID and will provide preliminary efficacy estimate for a randomized phase 2/3 trial.
P20.09.A CLINICAL, PATHOLOGICAL AND MOLECULAR DISEASE CHARACTERISTICS OF DIFFUSE HEMISPHERIC GLIOMA, H3 G34-MUTANT
Authors: E Le Rhun, A Bink, J Felsberg, D Gramatzki, S Brandner, J K Benhamida, A Wick, J C Tonn, M Mohme, G Tabatabai, D Capper, M Snuderl, E Razis, M Ronellenfitsch, N Neidert, H Ng, U Pohl, T A Bale, S Quach, D Rieger, U Schüller, K Drüschler, E Healy, M Graham, S M L Paine, V Medici, P Sievers, D Schrimpf, W Wick, F Sahm, G Reifenberger, A von Deimling, M Weller
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Diffuse hemispheric glioma, histone 3 (H3) G34-mutant, is a pediatric-type diffuse high-grade glioma newly defined in the World Health Organization (WHO) classification of central nervous system tumors 2021. Here we sought to define the prognostic roles of clinical, neuroimaging, pathological and molecular features of these tumors. MATERIAL AND METHODS We retrospectively assembled a cohort of 114 patients with diffuse hemispheric glioma, H3 G34-mutant and profiled the imaging presentation and the molecular landscape of their tumors. RESULTS Compared with glioblastoma, H3 G34-mutant tumors exhibited less avid contrast enhancement, less necrosis and less edema on magnetic resonance imaging (MRI). Comprehensive analyses of mutational and DNA copy number profiles revealed recurrent mutations in TP53 and ATRX, homozygous deletions of CDKN2A/B, and amplifications of PDGFRA, EGFR, CCND2 and MYCN. MGMT promoter methylation was detected in 79 tumors (75%). Median survival was 21.5 months (95% CI 15.3-27.7) and 8 patients (7.0%) survived for ≥ 5 years. Female sex, gross total resection, and MGMT promoter methylation were prognostic factors on univariate analysis. Among pathological and radiological features, presence of microvascular proliferation and absence of pial invasion were prognostic factors on univariate analyses. CONCLUSION This study refines the clinical and molecular landscape of H3 G34-mutant diffuse hemispheric gliomas. Dedicated trials for this novel tumor type are urgently needed.
P02.25.A TUMOR MICROENVIRONMENT (TME) VIS-À-VIS ANTI-VASCULAR TREATMENT IN GLIOBLASTOMA
Authors: Z Chen, H Cai, X Ni
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Glioblastoma (GBM) the most malignant primary central nerves system tumor, usually failed to postoperative treatment since tumor resistance to treatment. Most of Studies for anti-cancer resistance focus on tumor cell its self. Actually, tumor tissue is composed of tumor cells and surrounding matrix components. The components in tumor microenvironment (TME) work in coordination with each other to promote cancer initiation, progression, metastasis, and treatment resistance. Previously, we have found vasculogenic mimicry (VM), a vessel-like structure formed by highly invasive tumor cells, may contribute to anti-vascular resistance. Since TME includes non-cellular components such as extracellular matrix(ECM)and tumor-associated vasculature, as well as various cellular components such as activated tumor-associated fibroblasts, mesenchymal cells, tumor associated macrophages (TAMs), and pericytes. We further invested TME relating to anti-vascular resistance. MATERIAL AND METHODS First, we examined tenascin-c (TNC) expression, an extracellular protein, and correlated with VM formation in glioma cell lines as well as clinical samples. Since TNC is composed of 2 domains (EGF-like and fibronectin III), we further examined function of these domains affecting on VM formation in glioma cell lines. Second, we examined association of TAMs with angiogenesis in GBM, and further search possible molecular mechanism. RESULTS The expression of TNC increased with the WHO grade of glioma, and the most abundant in GBM, which correspondence to existence of VM structure. Knockdown TNC expression resulted significant reducing the ability of VM formation. Treatment of exogenous TNC protein can enhance the ability of VM formation of glioma cells. The over expression of the EGF-like domain or the full-length TNC in glioma cells revealed significant enhancing VM formation ability. In contrast, over expression of the fibronectin III domain of TNC did not alter VM formation. Furthermore, over expression of the EGF-like domain of TNC or full-length TNC in glioma cells increased the phosphorylation levels of downstream signaling pathways of EGFR. When checked TAMs, we revealed that PTEN deficient GBM may secrete abundant Gal-9, and recruit plenty of TAMs. TAMs may secrete vascular endothelial growth factor A (VEGFA) stimulating angiogenesis and and supporting glioma growth. Moreover, α-lactose through down-regulating VEGFA expression, inhibited glioma angiogenesis. CONCLUSION Our findings by searching tumor microenvironment of glioma, may suggest novel antivascularization strategies through TNC (an extracellular protein in ECM) and TAMs.
P13.12.B POST-PROGRESSION SURVIVAL FOLLOWING FOCAL RE-IRRADIATION WITH 20 GY IN 5 FRACTIONS IN PROGRESSIVE CNS WHO GRADE 3 ASTROCYTOMA AND GLIOBLASTOMA - A MONOCENTRIC RETROSPECTIVE ANALYSIS
Authors: E Hoffmann, M Linnenschmidt, F Behling, M Renovanz, P Bombach, B Bender, J Schittenhelm, R Bodensohn, G Tabatabai, F Eckert, F Paulsen, K Niyazi
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Despite multimodal treatment (resection, radiation therapy, alkylating chemotherapy and/or tumor-treating fields), the treatment of progressive CNS WHO Grade 3 astrocytoma and glioblastoma remains challenging. Re-irradiation (Re-RT) might be considered in the course of the disease. Optimal fractionation/dose prescription schedules are still under investigation, underlining a gap in clinical data in this regard. Here, we retrospectively analyzed post-progression survival (PPS) and progression-free survival (PFS) in a single center cohort. MATERIAL AND METHODS Patients receiving Re-RT with 20 Gy in 5 fractions (4 Gy per fraction; corresponding to 35 Gy in an equivalent dose normalized to 2 Gy (EQD2)) upon progression of recurrent astrocytoma glioblastoma or grade 3 astrocytoma (12/2020-12/2022) were included. Planning target volume for Re-RT was gross tumor volume = (T1 with contrast) + 5 mm. Clinical endpoints included PPS, PFS since start of Re-RT, therapy in case of further progression, bevacizumab therapy, MGMT promotor methylation (MGMT meth), and IDH status. RESULTS To date, 40 patients were analyzed (27 male); median age 62.25 a, range 31-83 a; 34 GBM IDHwt, 6 other), 15 of who showed MGMT meth (24 w/o MGMT meth, 1 not determined). Primary therapy was 60 Gy with concomitant temozolomide (TMZ), TMZ + lomustine, or study medication in 30, 54.0 Gy + adjuvant TMZ in 3, and 40.05 Gy + TMZ in 7 patients. Patients received heterogenous systemic therapies and 0-3 treatment lines prior to Re-RT (median 1 prior treatment modality). Re-RT was considered in localized non-resectable progression. Median time between first line therapy and first progression was 10.8 months and between first line therapy and Re-RT 16.7 months, respectively. Seven patients received an integrated boost of up to 30 Gy. Median PFS was 2.6 months (range &amp;lt;1-10.4 months); with 7,6 months PPS (range &amp;lt;1 - 22.4 months). 19 patients (47.5%) received bevacizumab during further course of the disease. Following Re-RT, 16 patients (40%) received further tumor-directed therapy. CONCLUSION This is a heterogenous single-center cohort. PFS after Re-RT was 2.6 months, and PPS was 7.6 months, respectively, published data reporting 6-12 months PPS after re-irradiation (EQD2 ranging between 48-60 Gy) despite a comparatively low and conservative cumulative dose of 20 Gy (35 Gy EQD2). Treatment time was only 5 days. Thus, re-irradiation with 4 Gy x 5 could be an option in a palliative setting and could be included in interdisciplinary treatment discussions for progressive CNS WHO grade 3 astrocytoma and glioblastoma.
P26.03.B AN INTERNATIONAL ACCELERATOR PROGRAMME FOR NOVEL BRAIN TUMOUR THERAPIES
Authors: C K Aitken, N Huskens, K Bushby, K Noble, P Hamerlik, D Kobayashi, R Mathew, J McCall, R Plummer, R Rahman, J Lopez
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Developing a comprehensive translational programme for brain tumours involves navigating numerous challenges, including robustness of preclinical studies, clinical trial design, safety, understanding and addressing regulatory requirements, and commercialisation. Recognising the difficulty of this journey, the Brain Tumour Research Novel Therapeutics Accelerator (BTR-NTA) was launched in 2023. The BTR-NTA is an accelerator programme providing independent expert guidance to de-risk drug or device development through systematic evaluation. The international, multidisciplinary BTR-NTA Committee spans expertise across the entire therapeutic development pipeline. Supported by Brain Tumour Research, the BTR-NTA programme is free for academic groups and available for a nominal meeting contribution fee for industry applicants. MATERIAL AND METHODS Researchers at any stage of therapeutic development may apply to BTR-NTA. Accepted applicants proceed as follows: 1. Applicants outline their current and prospective data and findings. The proposal and all supporting materials are covered under a confidentiality agreement that protects applicants’ intellectual property; 2. Proposals are reviewed by the BTR-NTA Committee; 3. Applicants and BTR-NTA Committee meet in-person to constructively evaluate the work; and 4. Applicants receive a comprehensive report with feedback on strengths, identification of potential risks, and guidance on next steps. The BTR-NTA Committee dedicates time for in-person meetings with each applicant, and extensive time pre- and post-meeting. RESULTS Since the launch of the BTR-NTA in 2023,13 international research groups have applied to the programme and three therapeutic applications have been advanced to the in-person review by the BTR-NTA Committee. Of the applicants who provided feedback on the BTR-NTA programme, all intended to adjust or refine their future work based on the BTR-NTA Committee’s input and the average rating of the programme’s helpfulness was 9.5 out of 10. CONCLUSION BTR-NTA reviews will continue to take place bi-annually, with capacity to provide support for up to four research groups per review. The ultimate goal of the BTR-NTA is to help researchers with a potential therapy for brain tumours navigate the development journey and reach the clinic in an efficient way. This programme will support development of novel therapies to improve outcomes for patients with brain tumours.
P02.24.B THE IMPACT OF THE IDH1 R132H MUTATION ON MMP2 METHYLATION, EXPRESSION AND INVASION IN EXPERIMENTAL GLIOMAS AND HUMAN GBMS
Authors: A M Lenkiewicz, A Ibragimova, M Ghosh, P Szadkowska, A Ellert-Miklaszewska, S Baluszek, K Jacek, M Castro, B Kaminska
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Glioblastoma (GBM) is a highly diffusive tumor which restricts the efficacy of surgical resection and facilitates tumor recurrence. Matrix metalloproteinase 2 (MMP2) is the extracellular matrix protease that is activated by MMP14 expressed by microglia and plays a central role in tissue remodeling and tumor progression. The R132H mutation in isocitrate dehydrogenase 1 (IDH1R132H) is commonly observed in gliomas, results in hypermethylator phenotype and in GBMs is associated with better survival. The impacts of IDH1R132H on the tumor microenvironment of mIDH1/mATRX/mTP53 gliomas remains unexplored. MATERIAL AND METHODS We employed unique mouse glioma models which mimic human GBM pathology, coupled with high-dimensional technologies (CITEseq and spatial transcriptomics) to analyze and visualize the immune landscape in different gliomas. Additionally, we performed gelatin zymography, qPCR, wound healing assays, and DNA methylation qPCR techniques to validate the obtained results. MMP-2 expression/methylation was studied in the glioma TCGA dataset. RESULTS The expression and activity of Mmp2 were different in experimental gliomas with different IDH1 status. Spatial transcriptomics demonstrated that Mmp2 expression is localized within the IDH1 wild-type tumors and absent in IDH1 mutated ones. Gelatin zymography showed the presence of Mmp2 activity in extracts from IDH1 wild-type tumors. Methylation of Mmp2 gene promoter was increased and resulted in decreased Mmp2 expression in IDH1 mutated gliomas. The IDH1 wild-type gliomas showed more diffuse growth patterns (tumors were stained with Nestin antibody) whereas IDH1 mutant gliomas showed more constrained growth patterns. In the TCGA glioma dataset, methylation of the MMP2 gene promoter was increased which was associated with decreased MMP2 expression in IDH1 mutated gliomas. CONCLUSION We found that the IDH1 mutation results in hypermethylation of the Mmp2 gene promoter, leading to decreased Mmp2 expression and Mmp2 activity in experimental gliomas and human GBMs. Reduced Mmp2 activity and decreased tumor invasion result in more restricted tumor growth, which may facilitate resection, and radiotherapy, thereby improving patient survival. Studies were supported by National Science Center Poland grant 2020/39/B/NZ4/02683 (BK) and PASIFIC Call 1 PAS (MG).