tbuckley/cabot-search huggingface dataset:
P11.01.A ACROMEGALY’S EFFECT ON COGNITIVE FUNCTIONS IN PATIENTS WITH PITUITARY ADENOMA
Authors: A Bala, A Olejnik, T Dziedzic, P Kunert
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Acromegaly is a condition caused by pituitary adenomas, which results in increased growth hormone (GH) secretion. For a long time, the main concern in acromegalic patients was on the physical symptoms and problems, which frequently overshadowed the possible neuropsychological outcomes. As a result, the impact of GH overproduction on cognitive functioning is still unclear. The study aimed to evaluate the association between acromegaly and cognitive performance among individuals with pituitary tumors. MATERIAL AND METHODS The study included 24 patients with pituitary tumors secreting GH (age: 42.9±11.7; years of education: 12.8±3.6) and a control group of 24 demographically matched healthy participants. The study excluded participants who had a history of neurological or psychiatric illnesses, substantial visual field abnormalities, or were taking chronic medication for another illness. Subjects were tested with a comprehensive battery of neuropsychological tests, assessing memory (California Verbal Learning Test - CVLT, Rey-Osterrieth Complex Figure (ROCF) - recall, Digit Span from WAIS-R), attention (Color Trails Test, Visual Elevator from TEA), verbal fluency (semantic and phonemic), naming (Boston Naming Test), visuospatial functions (Rey-Osterrieth Complex Figure - copy, Block Design from WAIS-R), and executive functions (Tower of London - ToL, Stroop Test). To avoid the influence of medication intake, patients with adenoma underwent cognitive evaluations at the start of their medical therapy. RESULTS The study found significant differences in functioning between patients and healthy individuals, specifically in verbal (delayed recall in CVLT: p &amp;lt; 0.01) and visual (ROCF: p &amp;lt; 0.01) memory, attention (Visual Elevator from TEA: p &amp;lt; 0.05), executive functions (ToL extra moves: p &amp;lt; 0.05), and working memory (Digit Span backwards: p &amp;lt; 0.05). There were no significant differences in naming, verbal fluency, or visuospatial skills. Larger tumors were correlated with greater deficiencies of attention (Visual Elevator from TEA: r = -0.6, p &amp;lt; 0.05) and verbal memory (delayed recall in CVLT: r = -0.4, p &amp;lt; 0.05). However, there were no associations between test outcomes and GH levels. CONCLUSION Overproduction of GH can have an impact on cognitive processes such as memory, attention, and executive functioning. Hence, the neuropsychological evaluation should be considered the gold standard in the diagnostic process of this group of patients.
P02.23.A SPATIAL PROFILING OF THE MYELOID COMPARTMENT IN MENINGIOMA REVEALS DISTINCT PHENOTYPIC HETEROGENEITY ACROSS METHYLATION CLASSES
Authors: D Calafato, Y Tang, G Rukhovich, B Patel, A Suwala, F Sahm, M Gerstung, F Hartmann
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Recent advances in neuro-oncology highlighted the meninges as an important immunological hub at the crossroads between systemic immunity and the central nervous system. Meningiomas are predominantly benign tumors arising from meningeal cells. However, about 20% are high-grade cases, commonly refractory to standard treatment, showing high recurrence rates. Methylation-based classification has crucially improved meningioma patient stratification. However, the biological processes that govern differences between these classes remain unknown. Here, we investigate the role of differential immune infiltration, cellular communities, and their spatial organization. In light of previously found differential immune infiltration across methylation classes, this study aims to spatially resolve the role of myeloid cells and study their influence on tumor progression and recurrence. MATERIAL AND METHODS We deployed multiplexed ion beam imagining and spatial transcriptomics on a retrospective cohort with extensive clinical annotations. Analyzing single-cell transcriptomic data of a subset of patients (n=22), we delineated the expression of gene and protein markers that were used to design an antibody panel comprising 41 targets for cell-type identification, phenotypic and metabolic characterization at the protein level. Additionally, we curated a targeted gene panel for spatial transcriptomics to perform granular spatial analysis. An integration of histological, spatial transcriptomic, and protein layers provides a comprehensive multi-omics approach to studying spatial cellular interactions. RESULTS Transcriptional programs and cell populations observed in single-nuclei data were captured in the spatial context revealing differences in the myeloid compartment across meningioma methylation classes. In specific classes, myeloid cells constitute a significant part of the tumor bulk warranting further investigation into their phenotypic differences. Accordingly, our analyses revealed a distinct phenotypic macrophage landscape along disease progression. Furthermore, spatial profiling of the metabolic regulome displayed distinct niche formation within perivascular and tumor compartments. CONCLUSION In this study we confirm that macrophages undergo a phenotypic switch from more tolerogenic in low-grade to inflammatory in high-grade cases of meningioma. Correspondingly, specific phenotypic and metabolic features of myeloid and tumor cells contribute to tumor progressions. Considering the limited targeted therapy options and poor responses to immunotherapy in meningioma patients, we hope that our spatial multi-omics analysis may reveal recurrent infiltration patterns of phenotypically distinct cell types that could be informative of biological processes and predictive of disease outcome.
P02.20.A NICHE-DEPENDENT MODES OF IMMUNE CELL TRAFFICKING IN GLIOBLASTOMA OFFER TARGETS FOR NOVEL IMMUNOTHERAPIES
Authors: R Sankowski, A Dalmau Gasull, M Prinz
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Glioblastoma trigger systemic immune responses, resulting in elevated white blood cell counts and elevated temperatures, as the body attempts to combat tumor cells. However, glioblastoma reprograms immune cells to evade immune-mediated destruction and promote tumor growth. While targeted immunotherapies have shown promise in some cancers like melanoma, they have not been efficacious for malignant brain tumors, leading to significant societal costs due to high morbidity and mortality rates. MATERIAL AND METHODS Understanding immune cell trafficking is crucial for developing effective immunotherapies. We conducted spatially resolved single-cell analyses to investigate immune cell entry into glioblastoma. Integrating these data with multi-omic sequencing analyses of anatomically dissected specimens from glioblastoma-affected human brain border regions and tumor cores revealed distinct paths of immune cell trafficking into glioblastoma. RESULTS One path involves an ordered entry of mononuclear cells through the subarachnoid and perivascular spaces, guided by chemotactic cues. Cells in these regions display markers of immune activation, suggesting immune priming. Another path occurs at sites of vascular leakage due to hypoxia and necrosis, where a mix of mononuclear cells and neutrophils accumulate. These cells exhibit immunosuppressive transcriptomic programs, regulated by the phagocytosis-inducing transcription factor MITF and downstream metabolic changes controlled by PPAR-gamma. Ongoing analyses aim to identify pharmacological agents that can modulate immune cell reprogramming at hypoxic niches. CONCLUSION In summary, we have identified distinct modes of immune cell trafficking in glioblastoma. Chemotaxis-mediated trafficking via the brain border regions appears to prime immune cells, while entry at hypoxic niches is associated with immune suppression. Pharmacological agents shielding immune cells from immunosuppressive molecular cues in the tumor microenvironment show promise for glioblastoma immunotherapy.
P11.04.A FAILURE TO PREDICT FUNCTION FROM STRUCTURE IN GLIOMA PATIENTS: LESSONS FROM TRANSLATING NEUROSCIENCE METHODS TO A CLINICAL POPULATION
Authors: L Smolders, W De Baene, R van der Hofstad, L Florack, G Rutten
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Predicting function from structure is central to optimizing the onco-functional balance in neurosurgical planning: if we can predict changes in function due to changes in structure, we may be able to predict the functional outcomes of surgery. In recent years, this challenge has been formulated in terms of predicting Functional Connectivity (FC) from Structural Connectivity (SC), both derived from advanced MRI. Several recent studies claim high individual-level accuracy in predicting FC from SC on healthy subjects. We investigated whether these approaches could be extended to the prediction of FC from SC in glioma patients. MATERIAL AND METHODS Three recent studies with promising results were considered for adaptation. To ensure correct implementation, we reproduced their methods on 1000 healthy subjects of the Human Connectome Project (HCP), a data set used in all three studies. We also retrospectively included 242 glioma patients from the Elisabeth-TweeSteden hospital (Tilburg, The Netherlands) to investigate if the studies’ methods could be translated to this population. SC was derived from tractography on diffusion-weighted MRI, while FC was derived from resting-state functional MRI. Performance was calculated as the average individual-level correlation between FC predicted from SC and FC derived from fMRI, and assessed with 10-fold cross-validation, using 90% of the data for training and 10% for validation. To compare performance on the two different data sets in a meaningful way, we constructed a baseline predictor that calculates the group average fMRI-derived FC of the training set and uses this single matrix as predictor for the validation set. RESULTS We replicated the prediction performance of 0.71 reported by the first of the three studies using HCP data. On the glioma patient data, we achieved a performance of 0.43. However, we found that for both data sets, the group average predictor outperformed the prediction model presented by the study, achieving a performance of 0.84 and 0.56 respectively. Subsequently, we found that the group average predictor matched the prediction performance reported by the other two studies. CONCLUSION None of the three studies improved upon the basic group average predictor, indicating that none of the predictive models represent a meaningful individual mapping from SC to FC. We consider it likely that the construction of SC or FC is currently not accurate enough at individual level to capture meaningful variation in individuals, either due to excessive noise in resting-state fMRI or due to inadequate accuracy in individual-level parcellations. In conclusion, a failure of promising methods to work on clinical populations may not be caused by population-specific difficulties, but by subtle problems with the methods themselves, only revealed upon careful scrutiny of the implications of the presented quantitative results.
P16.11.B UTILITY OF DNA METHYLATION PROFILING AGAINST UNRESOLVED PEDIATRIC HIGH-GRADE BRAIN TUMOR IN ROUTINE DIAGNOSTICS
Authors: Y Hou, J Zhu, Q Yu, J Wu, J Zhao, Y Cao
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Recent advances in genetics and epigenetics research have underscored the heterogeneity of pediatric brain tumors, characterized by overlapping morphological and molecular features across various tumor types. This complexity presents substantial challenges for precision diagnosis in routine diagnostics. In this study, we collected a cohort of pediatric high-grade brain tumors that remain unresolved after next-generation sequencing (NGS). Our goal is try to refine diagnosis by DNA methylation profiling, thereby evaluating the utility of this new diagnostic tool against unresolved and challenging cases in standard clinical practice. METHODS In this retrospective analysis, we selected 10 cases from local pathology archives based on the following criteria: (1) age at diagnosis&amp;lt; 18 years; (2) brain tumor with high-grade evidence; (3) NGS was employed but failed to provide a definitive diagnosis or not aligned to WHO CNS tumor classification. All cases were subjected to the Illumina Infinium MethylationEPIC v2.0 BeadChip, DNA methylation profiling was conducted by using an customized pipeline alongside the DKFZ brain tumor classifier. NGS was previously done by utilizing a DNA-panel targeting over 500 genes associated with tumor-related genetic variations. The collection of tumor samples and clinical data was processed in accordance with standards approved by the local ethical committees. RESULT All cases were supratentorial high-grade tumors, aged 1 to 16 years (n=10). Utilizing DNA methylation profiling, definitive diagnoses were established in 60% of cases: two cases of embryonal tumor with multilayered rosettes (ETMR), one pediatric diffuse high-grade glioma MYCN subtype, one pleomorphic xanthoastrocytoma (PXA), one medulloblastoma non-WNT/non-SHH subgroup 7, and one alveolar rhabdomyosarcoma. The remaining cases (n=4) neither yielded convincing calibrated scores from the DKFZ brain tumor classifier (v12.8) nor provided valuable insights from methylation based t-SNE clustering or copy-number profiling analysis. These 4 cases includes: a pediatric high grade glioma (pHGG) harboring CDK12, DICER1, JAK3, NF1, NTRK2, RB1 and SPEN mutation; a pHGG harboring PIK3CA, NF1 and TP53 mutation; a malignant embryonal tumor in the pineal gland harboring ATRX, BCL2, BLM, CYSLTER2, GPR101, HIF1A and SHOC2 mutation; and a malignant embryonal tumor with TERT, SMARCA4 mutation and EML4-ALK fusion. CONCLUSION In confronting the diagnostic complexities of pediatric high-grade brain tumors, DNA methylation profiling may provide more critical evidence that can address and unravel intricate clinical diagnostic challenges. SUPPORT/DISCLOSURE This research was supported by Natural Science Foundation of Chongqing (No.CSTB2023NSCQ-BHX0105).
P20.20.B SINGLE-CENTER EXPERIENCE IN THE MANAGEMENT OF ADULT MEDULLOBLASTOMAS: A RETROSPECTIVE ANALYSIS
Authors: S Kamer, E Karaman, M Acar, Y Anacak
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Medulloblastoma is a type of brain tumor that is less common in adults than in children. The standard treatment involves surgically removing as much of it as possible, followed by radiation therapy and chemotherapy. However, because this type of tumor is rare in adults, there is limited information available about its clinical characteristics and prognostic factors. This study aims to investigate the clinical features and treatment outcomes of adult patients who received postoperative radiotherapy for medulloblastoma at a single tertiary center. MATERIAL AND METHODS Patients aged 18 or above with a pathologic confirmation of medulloblastoma diagnosis who received postoperative craniospinal irradiation (CSI) at our institution between 2000-2021, was included in the study. Radiotherapy was administered with 3D conformal technique initially to whole cranium and spinal axis to 36Gy, followed by 18Gy boost to posterior fossa or tumor bed with 1.8Gy per fraction. Clinical characteristics, prognostic factors and survival outcomes were obtained from follow-up visits and electronic health records. RESULTS 31 cases (median age:28 (19-44)) were analyzed, of which 54.8% were male. The pathologic diagnoses comprised of 51.6% for desmoplastic/nodular histology, 41.6% classical histology and 6.4% anaplastic histology. 25 cases were at non-metastatic stage according to Chang Classification. Total tumor resection (residual disease &amp;lt;1.5cm2) was achieved in 83.9% cases. Twenty-one cases (67.7%) were categorized as standard risk, while ten were classified as high-risk group. Median treatment time was 47 days (38-71) and time between surgery and radiotherapy was 44 days (14-110). Median follow-up time was 91 months. Overall, 70.4% of patients were alive and no evidence of disease while 8 of patients were deceased. Six deaths were due to disease progression, one to traumatic intracranial hemorrhage, and the cause of death for one patient could not be obtained. 5 and 10-year overall survival was found to be 89.4% and 71.9%, respectively. Sex, histopathologic subtype, risk group were not found to be statistically significant prognostic factors, whereas a prolonged duration between surgery and radiotherapy (&amp;gt; 6 weeks) correlated adversely with prognosis (p: 0.025). Relapse-free survival was estimated to be 71.8% and 68.2% for 5- and 10-years, respectively. Nine recurrences occurred, all being in primary site with two also recurred in spinal axis. Seven cases received surgery, five received chemotherapy and five cases received radiotherapy as a salvage treatment. Five of nine patients were deceased due to disease progression after salvage treatment. CONCLUSION Adult patients with medulloblastoma have a better prognosis compared to pediatric patients. Craniospinal irradiation is a crucial part of local treatment. Extended follow-up is needed to monitor for recurrence and toxicity.
P13.02.A A CLINICALLY RELEVANT IN VIVO MODEL RECAPITULATES THE LATE EFFECTS OF RADIOTHERAPY IN CHILDHOOD MEDULLOBLASTOMA SURVIVORS
Authors: T Egnuni, J Castle, G Shaw, D Weller, E Fielder, M Singh, R Skinner, T von Zglinicki, S Clifford, S Miwa, D Hicks, S C Short
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Medulloblastoma (MB) is the most common malignant brain tumour in children, with a 5-year survival rate of up to 80%. However, survival is often accompanied by debilitating late-effects that occur as a result of the cranial-radiotherapy. Survivors typically experience increased frailty, reduced physical functioning and impaired neurocognitive functioning. Here, we describe a clinically relevant in vivo model that recapitulates age-equivalent MB radiotherapy dose, and the resulting late-effect profile with potential for future intervention studies. MATERIAL AND METHODS Thirty-six male C57BL/6J juvenile mice at 35 postnatal days (PND) were randomly allocated into 3 equal groups (G1-G3). G1 mice received sham treatment; G2 mice received 10 fractions of 3Gy whole brain cranial-radiotherapy (CRT; human-equivalent of 37.5Gy EQD2) and G3 mice received CRT with 3x 3Gy of posterior fossa boost (PFB) in addition (48.75Gy EQD2). The Small Animal Radiation Research Platform (SARRP) was used to deliver radiation using a 10mm x 10mm collimator with gantry running from - 60° to 60°. Frailty, physical functioning and neurocognitive impairment were longitudinally assessed using frailty index (FI), grip strength test, rotarod test, Y-maze and Barnes maze up to PND394. RESULTS No mice died from acute radiation toxicity and there was no significant difference in either survival or body weight loss among all treatment groups. There was no significant difference between G2 and G3 mice in most of the assessments, suggesting receipt of PFB caused no additional deficits. Assessment of frailty showed significantly higher FI in mice that received CRT at PND97 (p=0.001), PND130 (p=0.0001), PND191 (p=0.007) and PND233 (p=0.002) compared to the sham group. CRT treated mice had significantly reduced grip strength at PND233 (p=0.006; grip strength test) and poor body balance and co-ordination at PND172 (p=0.003; rotarod). Assessment of working memory using the Y-maze showed a significant memory deficit in CRT group at PND266 compared to sham treated group (p=0.009). Barnes-maze short-term memory (STM) and long-term memory (LTM) assessment at 24 hours and 7 days after training, respectively, showed significantly decreased LTM (p=0.029) but not STM (p=0.392) in CRT treated group compared to sham treated mice. CONCLUSION Our in vivo model showed that juvenile mice tolerated high doses of CRT. We demonstrated increased frailty, physical and neurocognitive impairments that coincides with the late-effect profile observed in CRT treated childhood MB survivors. Importantly, this clinically relevant in vivo model provides a baseline model for the future appraisal of interventions to alleviate the late-effects experienced by childhood MB survivors.
P01.08.A HYOXIA-INDUCED EXPRESSION OF ARHGAP FAMILY MEMBERS PROMOTES GLIOBLASTOMA DISSEMINATION
Authors: P Vaughn-Beaucaire, L Muller, S Prior, S Lawler, A Bruning-Richardson
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND The Rho GTPase activating proteins (ARHGAPs) perform vital roles in the regulation of the Rho GTPases with direct effect on cellular plasticity and cell migration/invasion. We recently reported on the role of five ARHGAPs, identified by a microarray screen, in morphological plasticity in established and patient-derived Glioblastoma (GBM) cell lines and associated clinical relevance in terms of tumour recurrence after treatment. We established that the ARHGAPs either promoted or targeted cell migration/invasion by allowing cells to undergo morphological changes in preparation for dissemination. We also showed that co-expression of two ARHGAPs, 12 and 29, is associated with reduced time to recurrence after initial treatment in patients. ARHGAP activity has been also reported in metastatic cancers including breast and colorectal cancer highlighting the biological relevance of these, as yet understudied, proteins. MATERIAL AND METHODS Here, we explored the GBM microenvironment and the effect of hypoxia on ARHGAP expression and localisation in glioma cell lines. RESULTS Using immunocytological and in vitro migration and invasion assays we were able to ascertain that ARHGAP4, 12, 22, 25 and 29 acquired subcellular distributions different to those recorded under normoxia and expression also decreased or increased under hypoxia. We also found that the effect of the migrastatic inhibitor 6-bromo-indirubin-3′-oxime (BIO) targeting GSK-3 signalling was potentiated when cells were challenged with the drug under hypoxic conditions. CONCLUSION Our results confirm our initial findings of biological relevance of the ARHGAPs in cellular activities and highlight important roles for the ARHGAPs for promoting migratory/invasive activity and behaviour in GBM cells. We also conclude that migrastatic inhibitors will exert enhanced activity on GBM cells under hypoxic conditions making them excellent candidates for complement treatment with cytotoxic drugs or radiotherapy for an improved management of GBM.