tbuckley/cabot-search huggingface dataset:
OS07.3.A DYNAMIC METABOLIC SHIFTS RESHAPE GLIOBLASTOMA: IMPACTS ON SPATIAL STRUCTURE AND IMMUNE RESPONSE
Authors: N Conrad, J Benotmane, G Villa, O Schnell, D Heiland, J Kueckelhaus
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND The structured layers of the human neocortex stand in sharp contrast to the disordered arrangement found in malignant CNS tumors. Glioblastoma (GBM), with its diverse characteristics, presents formidable hurdles in both research and treatment, as successful approaches demand a uniform biological understanding. In this study, we capitalize on recent advances in spatial biology, employing integrated spatially resolved transcriptomics and metabolomics to identify the factors driving the unique architectural changes observed in GBM. MATERIAL AND METHODS We performed spatial metabolomics (MALDI) and transcriptomics (Visium n=43 and MERFISH n=25) of glioblastoma patients. Computational analysis was performed with the SPATA2 R package. RESULTS We found that most spatially recurrent pattern in glioblastoma emerge in a gradient-like organization,particularly influenced by proximity to areas of necrosis and hypoxia. Samples without hypoxic regions demonstrated less spatial organization. Metabolomic and transcriptomic profiling revealed enhanced responses to hypoxia coupled with reduced cell proliferation and elevated expression indicative of the S-phase in cell division in regions near necrosis. The vicinity to hypoxic areas appeared to be associated with increased chromosomal alterations as well as extracellular matrix remodeling and epithelial-to-mesenchymal transition, implying that the invasive capabilities of GBM cells originate from these hypoxic niches. By further integrating spatially resolved TCR-sequencing, we identified that hypoxic gradients drive defined T cell response with higher likelihood of T cell dysfunction within a distance of 235 μm (sd: 132 μm) to hypoxia. This suggests that the presence of necrosis, hypoxia, and hypoxia associated metabolites could serve as potential predictive markers for T-cell behavior and exhaustion in glioblastoma. CONCLUSION Our investigation provides a comprehensive examination of the impact of two common environments in glioblastoma: necrosis and hypoxia. We demonstrate that the intricate structure of glioblastoma is not merely shaped by genetic chance and random events. Rather, it is substantially molded by spatial proximity to critical elements such as necrosis and hypoxia. This understanding contributes to an advancing framework aimed at unraveling the complex biology of glioblastoma.
P23.06.A LONG-TERM OUTCOMES OF RADIOTHERAPY FOR SKULL BASE AND NECK PARAGANGLIOMAS
Authors: M Alonso Becerra, A Lucas Calduch, M Macià Garau, N Garcia Exposito, A Lozano Borbalas, G Plans Ahicart, A Rosselló Gómez, A Fernández Coello, N Vidal Sarro, I Modolell Farré, I Sancho Kolster, C Majós Torró, A Pons Escoda, M Simó Parra, R Velasco Farga, P Cifré Serra, J Bruna Escuer, A Álvarez Renuncio, Y Lin, L Martínez Ávila, M Moretti, M Ruiz Domínguez, L Martín González, C Balcells Quintana
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Management of skull base and neck paragangliomas remains controversial, with treatment options including observation, surgery, embolism, and radiotherapy, either alone or in combination, depending on tumor size and patient comorbidities. Surgical interventions, including embolism, can risk complications involving lower cranial nerves and bleeding, which is a significant downside for benign tumors. Radiotherapy has been described as a feasible option for growing or symptomatic unresectable paragangliomas, providing both local control and minimal side effects. MATERIAL AND METHODS A retrospective analysis was conducted on patients undergoing radiotherapy, with or without previous approaches, at our institution. RESULTS From January 2009 to December 2022, 19 patients with skull base and neck paragangliomas underwent radiotherapy. Median age at treatment was 61 years (range 39-85), being 79% male and 21% female. Eight patients (42%) had been previously treated with surgery (4 patients) or embolization (4 patients). The rest of the patients (58%) were treated only with radiotherapy. Most paragangliomas were jugular (57%), while the remaining were tympanic (16%), jugulotympanic (16%), and carotideal (2%). Depending on the volume of treatment, two modalities of radiotherapy were decided. Most patients (84%, 16 patients) were treated with fractionated stereotactic radiotherapy (FSRT) (50 Gy in 25 fractions), with a median Planning Target Volume (PTV) of 43.1 cm3 (range 4.2 - 157.7). The other group (16 %, 3 patients) received radiosurgery (single dose of 15 Gy), with a median PTV of 1.1 cm3 (range 0.87 - 1.53). Clinical and radiologic outcomes were assessed over a median follow-up of 61 months (range 8-155). Two patients were lost from follow-up. No late toxicities were observed. Symptom relief was achieved in all cases, at least partially. There was no clinical worsening related to radiotherapy at long term follow up. Radiologically, local control was obtained in 94.7% of patients: all lesions remained stable, with no significant shrinkage, except for one paraganglioma treated with FSRT that progressed. CONCLUSION Paragangliomas can be successfully treated with radiotherapy, with a high local control probability at long term follow-up, with low acute toxicity and without worsening of previous symptoms.
P20.04.A ATYPICAL TERATOID/RHABDOID TUMOR ARISING FROM THE THIRD VENTRICLE IN YOUNG ADULT
Authors: J Hwang, C Lee, S Yoon, K Park, S Park
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Atypical teratoid/rhabdoid tumor (AT/RT) Is a high-grade CNS malignancy predominantly seen in infants and children. AT/RTs occur throughout the neuraxis but have high predilection for midline structure such as pineal gland and brainstem. Suprasellar location is rare and pure third ventricular AT/RT is exceptional. We report a case of AT/RT in a young adult with third ventricle origin. This is the second documented case of adult third ventricle AT/RT. MATERIAL AND METHODS A 24-year-old male presented with two-week-long dizziness and diplopia. Magnetic resonance imaging (MRI) of the brain showed a heterogeneously enhancing large lesion in the third ventricle with isointense on T1WI and T2WI. Supratentorial ventricular space was enlarged with Evan’s ration of 33%. He underwent anterior transcallosal transchoroidal approach with gross tumor resection. RESULTS Postoperative course was uneventful with no hormonal deficiency. CSF diversion was not needed. Histopathological examination revealed AT/RT, WHO grade 4, with loss of SMARCB1 (INI 1) protein. H3 mutation was not found. He later underwent cranio-spinal irradiation with local booster followed by high dose chemotherapy (carboplatin, thiotepa and etoposide) with autologous stem cell transplantation. No recurrence was found on follow-up MRI at 10 months after operation. CONCLUSION AT/RT is a rare primary CNS tumor but their incidence among adults is being increased. We report a case of young adult AT/RT with very rare third ventricle location. AT/RT maybe considered as a differential diagnosis for suprasellar-third ventricle lesion in young adults.
JS08.6.A SYNTHETIC [18F]FET-PET GENERATION AND HOTSPOT PREDICTION VIA PREOPERATIVE MRI OF GLIOMA LACKING RADIOGRAPHIC HIGH-GRADE CHARACTERISTICS
Authors: E Suero Molina, M Tabassum, G Azemi, Z Özdemir, A Valls Chavarria, W Roll, C Thomas, C Russo, S Liu, W Stummer, A Di Ieva
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Lack of availability of amino acid Positron Emission Tomography (PET) in many regions limits comprehensive therapeutic decision-making for patients with gliomas without typical high-grade imaging features. To address this gap, we evaluated a novel generative artificial intelligence (AI) approach for creating synthetic [18F]FET-PET and predicting high [18F]FET-uptake from multimodal magnetic resonance imaging (MRI). MATERIAL AND METHODS Our approach involves training a deep learning (DL)-based model to segment tumors in preoperative MRI and extracting radiomic features using the pyradiomics package and classification with a Random Forest classifier. To generate [18F]FET-PET images, we employed a Generative Adversarial Network (GAN) framework and utilized a split-input fusion module for processing different MRI modalities through feature extraction, concatenation, and self-attention. We employed four principal metrics for quality assessment: Peak Signal-to-Noise Ratio (PSNR), Structural Similarity Index (SSIM), Root Mean Square Error (RMSE), and Visual Information Fidelity (VIF). RESULTS We included MRI and PET images from 215 studies for the hotspot classification task and 211 studies for the synthetic PET generation task. The top-performing radiomic features achieved 80% accuracy for hotspot prediction. Of all the [18F]FET-PET scans generated synthetically, 90% were classified as clinically useful by senior physicians. PSNR analysis indicated high signal fidelity with a peak at 40 dB, while SSIM values showed substantial structural congruence. RMSE analysis demonstrated lower values below 5.6, indicating a robust congruence of the synthetic PET. Complementing these findings, VIF scores mostly ranged between 0.6 to 0.7, reflecting a high level of visual information fidelity and affirming that the synthetic PET images retain the critical informational content required for clinical assessment and diagnosis. CONCLUSION For the first time, we demonstrate that predicting high [18F]FET-uptake and generating synthetic PET images out of multimodal MRI in LGG and HGG is feasible. Furthermore, we can predict higher [18F]FET-uptake with high accuracy. Advanced MRI modalities and other generative AI models will be used to improve the algorithm further in future studies.
P20.01.B A MONO-INSTITUTIONAL RETROSPECTIVE ANALYSIS OF MENINGEAL SOLITARY FIBROUS TUMOR/ HEMANGIOPERICYTOMA: CLASSIFICATION AND GRADING SCHEMES CORRELATION WITH OUTCOME
Authors: V Redaelli, M Patanè, V Pinzi, M Del Bene, P Gaviani, A Botturi, G Simonetti, C Calatozzolo, A Silvani, B Pollo, G Marucci
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND The aim of the present study was to enrol a large mono-institutional cohort of patients affected by meningeal solitary fibrous tumor (SFT)/hemangiopericytoma (HPC), collecting all available clinical features and information about treatments and outcomes, in order to: - classify this population according to the 2021 WHO CNS Classification and comparing that with the previous 2016 WHO Classification; - better characterize and analyse the prognostic significance of clinical and pathological variables; - identify patients with high risk of recurrence and metastases, to improve the management of these neoplasms, with benefits also for health service MATERIAL AND METHODS This retrospective study included 77 patients with histopathologically proven SFT/HPC. Reclassification according to the 2021 and 2016 WHO guidelines was done. Progression-free survival (PFS) and Overall Survival (OS) were evaluated for all patients. RESULTS The median follow-up period was 105 months. The median PFS and OS were 106 and 154 months, respectively. Correlating OS of patients to WHO grading we observed that all Grade 1 patients according to the 2016 WHO Classification are all still alive, while only 57% of patients with Grade 1 according to the 2021 WHO Classification are alive. At the same time, only 18% of patients with Grade 1 according to the 2016 WHO Classification relapsed, while 50% of patients with Grade 1 according to the 2021 WHO Classification relapsed. These differences resulted statistically significant (p&amp;lt;0.05). Regarding Grades 2 and 3 cases, the differences between the WHO Classifications did not reach the level of significance. CONCLUSION In conclusion, the 2016 WHO Classification of SFT/HPC demonstrated a greater ability to discriminate aggressive from more indolent cases, in comparison to the 2021 WHO Classification.
Efficacy, safety and tolerability of GSK3858279, an anti-CCL17 monoclonal antibody and analgesic, in healthy volunteers and patients with knee osteoarthritis pain: a phase I, randomised, double-blind, placebo-controlled, proof-of-mechanism and proof-of-concept study
Authors: Jagtar Singh Nijjar, Katharine Abbott-Banner, Yolanda Alvarez, Nicola Aston, Damon Bass, Jane H Bentley, Joanne Ellis, Christian Ellson, Edward C Emery, Maria Feeney, Disala Fernando, David Inman, Rejbinder Kaur, Louise K Modis, Sam Munoz Vicente, Catherine Muya, Kiran Nistala, Eirini Panoilia, Riju Ray, Sarah Siederer, Julia E Smith, Lucinda Weir, Nicolas Wisniacki
Journal: Annals of the Rheumatic Diseases (2024)

The objective of this study was to evaluate efficacy, safety and tolerability of the first-in-class, anti-CCL17 monoclonal antibody, GSK3858279, in treating knee osteoarthritis (OA) pain.
P13.17.A THE EFFECTS OF RADIOTHERAPY ON GREY AND WHITE MATTER VOLUME IN THE BRAINS OF PATIENTS WITH HEAD AND NECK CANCER
Authors: C W J van der Weijden, K Wickborn, M C A Kramer, A M Buunk, J M Spikman, J A Langendijk, T W H van Zon-Meijer, E F J de Vries, A van der Hoorn
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Patients with head-and neck-cancer (HNC) often receive radiotherapy as part of their treatment. Due to the tumour location, exposure of the brain to irradiation is inevitable, but the brain is not confounded by effects of having an intracranial brain tumour. Detailed knowledge of radiotherapy-induced effects on the brain can help to improve treatment planning by optimizing radiation doses and avoiding critical brain structures, thereby reducing the risk of neurotoxicity while effectively treating the tumour and thus improving quality of life. As T1w MRI allows the quantification of grey matter and white matter volumes, it can be used as proxies to assess tissue alterations. Therefore, this study aims to evaluate whether changes in grey and/or white matter volume could be detected in patients with HNC treated with radiotherapy. MATERIAL AND METHODS Patients with HNC that received radiotherapy (&amp;gt;50 Gy) as part of their regular treatment were subjected to T1w (MP2RAGE) MRI at the start of radiotherapy and at the end of radiotherapy (0-14 days). Differences in grey and white matter volume of various brain regions in the posterior fossa, inferior temporal lobe, and medial temporal lobe (total 24 ROIs) between start and end of radiotherapy was determined. These brain regions were chosen, as they are closest to the tumour location. Differences in brain volumes were correlated to the radiation dose using Spearman correlations. RESULTS So far, 9 of 40 patients have been enrolled. They had a mean age of 50±15 years. Two were female and 7 male and 2 received photon radiotherapy and 7 proton radiotherapy. From evaluated brain regions, grey matter volume of the right middle and inferior temporal gyrus was significantly lower (p=0.043) after radiotherapy (8.39±0.87 mL) than before radiotherapy (8.87±1.01 mL). For other regions, no significant differences were observed. Only non-significant increases in white matter ROI volumes between start and end of radiotherapy were observed. Differences in brain region volumes between start and end of radiotherapy were not significantly correlated with the radiation dose, neither for grey matter (-0.30±0.30 ρ) for white matter (0.19±0.30 ρ). CONCLUSION With an inclusion of 9 out of 40 subjects, we mainly found non-significant changes in grey and white matter volumes after radiotherapy in HNC patients, although reductions in temporal grey matter reached significance. More inclusions are necessary to reach proper power and to determine whether changes in brain volumes can be used for early detection radiotherapy induced brain alterations and if they correlate with radiotherapy dose. FUNDING This study is supported by a VENI grant to Anouk van der Hoorn (no: 09150161910041).
JS03.6.A TUMOR ASSOCIATED MACROPHAGE DERIVED EXOSOMES MODULATE IMMUNOTHERAPEUTIC SENSITIVITY OF SHH MEDULLOBLASTOMA BY TARGETING M6A MODIFIED FOXD1
Authors: Q Chang, Y Liu
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Medulloblastoma (MB) is the most common malignant brain tumor in children. The infiltration of tumor-associated macrophages (TAMs) in tumor microenvironment (TME) is correlated with the poor prognosis in SHH subtype of MB patients. Epigenetic alterations on RNA m6A modification were identified in this tumor. However, it remains unclear whether the TAMs infiltration in TME was correlated with the m6A modification status during tumor progression. METHODS The expression of m6A modification-related proteins and TAMs specific marker were assessed by immunohistochemistry in 40 SHH MB primary tumors. Methylated RNA immunoprecipitation sequencing (MeRIP-seq) and transcriptomic RNA sequencing (RNA-seq) were used to screen target genes affected by TAM-derived exosomes in SHH MB cells. Mechanisms of m6A-modification on target gene (FOXD1) were demonstrated by WB, qPCR, RNA half-life time and RNA immunoprecipitation assays. Combination treatment with AAV2/9-shFOXD1 and PD-1 inhibitors were performed in the NeuroD2: SmoA1 mouse model. RESULTS We reported for the first time that significant infiltration of TAMs was associated with decreased expression of METTL14 in primary SHH MBs. Exosomal microRNAs (miR-320e, miR-196b-5p, and miR-628-5p) released by TAMs targeted to the 3’-UTR (3’ Untranslated Region) of METTL14 in MB cells, promoting the gene’s degradation and consequently downregulating the overall m6A level in SHH MB. MeRIP-seq and RNA-seq analyses screened out Forkhead box D1 (FOXD1) as the target gene upregulated by TAMs-derived exosomes through m6A modification in MB cells, which was correlated with poor prognosis in SHH MB patients. Further experiments in vitro verified YTHDF2 can recognize m6A-modified FOXD1 and promote its mRNA degradation. Knockdown of FOXD1 in SHH MB cells significantly promoted the release of the CD8+T cell recruiting chemokines CXCL10/11. Treatment with AAV2/9-shFOXD1 significantly enhanced the anti-tumor effect of PD-1 inhibitor in NeuroD2: SmoA1 SHH MB mice. CONCLUSION Our study revealed the m6A modification status of SHH MBs influenced by TAMs derived exosomal miRNAs. FOXD1 promoted the malignant progression of SHH MB through m6A modification. Increased immunotherapeutic sensitivity of the combination treatment with FOXD1 knockdown and anti-PD-1 blockade in vivo shed lights on a novel therapeutic strategy of SHH MB.
P10.10.B CLASSIFYING LOWER-GRADE GLIOMA SUBTYPES WITH 3D WHOLE-BRAIN MRI SCANS AND DEEP LEARNING: A NON-INVASIVE AND INTERPRETABLE APPROACH
Authors: B Iadarola, F Sforazzini, L Luchetti, M Leoncini, M Battaglini, R D’Aurizio
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Patient management with lower-grade glioma (LGG) requires tumour sampling to identify IDH mutation and 1p19q codeletion status, which are pivotal for subtype classification and subsequent therapy. The use of MRI has been investigated so far by radiomics which focuses on features extracted from 2D images of the tumour region only. Deep Learning (DL) algorithms, and in particular Neural Networks (NN), proved to be effective in improving the detection of cancers from diverse imaging data, often through tumour segmentation masking. We aimed to develop a DL-based framework to streamline the LGG molecular-based subtypes classification from the whole-brain 3D MRI scans and, subsequently, to extract a fine map of the brain regions which resulted relevant for the classification. MATERIAL AND METHODS Pre-operative MRI scans (T2-FLAIR, T1gad) and molecular information (IDH mutation, 1p19q codeletion status) of 82 LGG patients were collected from the TCIA and TCGA datasets. 56 “IDH-mutant astrocytomas” and 26 “IDH-mutant 1p19q codeleted oligodendrogliomas” were split into class-balanced training (65) and test (17) sets. A computational framework was developed to preprocess the MRIs, train and optimize different DL models through hyperparameters fine-tuning and to automatically detect the best-performing one. We explored a total of 162 configurations, using single and multiple MRI modalities within two residual NN and calculated the attention maps using guided back-propagation. RESULTS In the test set we obtained a balanced accuracy of 92% and a F1-weighted score of 89% in differentiating IDH-mutant astrocytomas (sensitivity=0.83) from IDH-mutant 1p19q codeleted oligodendrogliomas (sensitivity=1). The generated attention maps confirmed that features extracted from the perilesional regions positively influenced the classification of the tumour subtypes, especially of astrocytomas (100% of cases); on the contrary, the widely used tumoral region was scarcely considered in the classification of this subtype (10%), having an impact only in oligodendrogliomas (60%). Interestingly, contralateral and other distant-from-the-tumour areas were relevant in the classification of both subtypes (40%), with a focus on distant-from-the-tumour areas in oligodendrogliomas (60%). CONCLUSION 3D whole-brain scans coupled with optimized DL-based approach showed to be a non-invasive and promising alternative in classifying LGG molecular-based subtypes, providing a more exploratory insight in the subject-level discrimination of brain regions differently associated with IDH mutation and 1p19q codeletion status. Further validations are needed to prove the efficacy of the proposed method in supporting the clinical decision-making.