bluuebunny/crossref_metadata_2025_split huggingface dataset:
P01.07.A HUB-RELATED GRAPH METRICS AS MARKER FOR COGNITIVE OUTCOMES IN ADULT GLIOMA SURVIVORS AFTER MULTIMODAL THERAPY
Authors: De Roeck L , Blommaert J , Sunaert S , Dupont P , Clement P , De Vleeschouwer S , Sleurs C , Lambrecht M 
Published: September 2023

Abstract

BACKGROUND
Although cognitive impairment is a serious and prevalent long-term side effect in adult glioma survivors after therapy, predictive imaging-based markers remain inconsistent to date. Structural brain network topology could be altered by both the tumor and its’ treatment through reorganization of hubs (i.e. highly interconnected nodes). Here, we explored the role of nodal hub-related graph metrics in higher cognitive functioning.

MATERIAL AND METHODS
48 WHO grade 2-3 adult glioma survivors (&gt;1 year post-therapy) and 42 matched controls, underwent a cognitive assessment, covering five cognitive domains. Cognitive scores were transformed into w-scores, corrected for age and education. In addition, weighted nodal graph metrics were calculated based on diffusion weighted imaging, using multi-shell multi-tissue constrained spherical deconvolution and anatomically-constrained tractography. Hubs (hub score≥2) were calculated based on 4 nodal metrics, in which the 20% nodes with highest nodal strength and betweenness centrality, and lowest clustering coefficient and characteristic path length received 1 point (score 0-4). Significant differences in nodal graph metrics between patients and controls, and hubs versus non-hubs were tested in a repeated measures ANOVA, using Bonferroni correction for multiple testing. Significant group differences in nodal graph metrics were correlated to cognitive scores per domain.

RESULTS
In healthy controls 12/78 nodes were defined as hubs, i.e. the bilateral postcentral, precentral, superior frontal, parietofrontal, superior parietal gyri, thalamus and putamen. In glioma survivors, the left superior-parietal region and left putamen had a significantly lower likelihood of being a hub (p&lt;.001). These specific areas showed assortativity to be positively correlated with attention, language and executive function (r(90)&gt;.51, p&lt;.001) and characteristic path length to be negatively correlated with all cognitive domains (r(90)&gt;.51, p&lt;.001). Nodal metrics of clustering coefficient, characteristic path length, local efficiency and assortativity were significantly different between groups in both hub and non-hub regions (both p&lt;.001). Except for betweenness centrality, all nodal metrics strongly correlated with cognitive outcomes, occurring more often in hubs (33-50%) than intermediate hubs (10-33%) or non-hubs (4-12%).

CONCLUSION
Reorganization of hubs in the brain network is frequently observed in this cohort of glioma survivors compared to healthy controls. Hub connectivity seems to be important in cognitive functioning, more than for non-hub regions. Therefore, structural nodal hub-related graph metrics might be important to consider in predicting cognitive outcomes in glioma survivors.
P01.11.A MECHANISMS OF LANGUAGE PLASTICITY IN PATIENTS HARBORING LEFT HEMISPHERE GLIOMAS
Authors: Tate M , Ramsey M , Saxena M 
Published: September 2023

Abstract

BACKGROUND
Infiltrating gliomas are slow growing intrinsic brain lesions that have been shown to induce functional reorganization, although the mechanisms by which this occurs are not well understood. The present study examines glioma-induced neuroplasticity of language networks to investigate this phenomenon.

MATERIAL AND METHODS
117 patients’ fMRI scans were analyzed from patients harboring gliomas whom completed 1-5 fMRI language tasks. Data was analyzed via two methods: cluster-based and cortical/subcortical mask-based. Right hemisphere gliomas (RHG) (n=40) were first analyzed to establish a reliable control group by determining statistically significant voxels across all five language tasks (LT), yielding a core conserved network. The language network induced by left hemisphere gliomas (LHG) (n=77) was then directly compared to the RHG language network to examine language plasticity.

RESULTS
LHG induced global reorganization of the canonical language network, including preserved homologous and novel left hemisphere (LH) and right hemisphere (RH) activation clusters. In each of the five LT, the LHG group showed activation of fewer total suprathreshold voxels in both the cluster (3 fewer clusters and 38,892 fewer active voxels/task) and mask-based (8 fewer active masks/task and 91,965 fewer active voxels/task) analyses while having a higher peak intensity (5.4 total increase in zmax) within the activated clusters. In addition, a generalized pattern of increased RH recruitment was seen in LHG patients, with 87% (137/157) of non-zero masks shifting their laterality index (LI) to the right hemisphere. These data suggest that the reorganized LHG-induced language network functions through less nodes along with a rightward shift of language lateralization. In addition, a subgroup analysis of frontal (n=16) and temporal (n=32) LHG revealed that frontal tumors promote increased RH activation relative to temporal tumors, with 94% (32/34) of non-zero masks shifting their LI to the RH compared to 68% (23/34), respectively. Frontal tumors also preferentially recruit the contralateral (RH) frontal lobe and ipsilateral (LH) temporal lobe, while temporal gliomas preferentially recruit the ipsilateral frontal lobe.

CONCLUSION
Infiltrating tumors within the left hemisphere promote language plasticity via consolidation of the classical LH language network along with recruitment of previously silent, novel language areas in the right and left hemispheres. This improved understanding of patterns of language plasticity may aid in more accurate pre-surgical risk stratification and counseling, therapeutic targeting for post-surgical recovery, and intelligent “pre-habilitation” strategies to maximize neuroplasticity prior to tumor resection.
P02.14.B SPATIAL TRANSCRIPTOMIC ARCHITECTURE OF TUMOURS OF THE PERIPHERAL NERVOUS SYSTEM
Authors: Heiland P , Menstell J A , Schnell O , Beck J , Bremer J , Heiland D 
Published: September 2023

Abstract

BACKGROUND
Studies into the genetics of peripheral nerve tumors have been focused on their association with known gene mutations and syndromes as well as on the tumor microenvironment of malignant peripheral nerve sheath tumors. Still, not many advances have been made into clarifying the structure and diverse pathophysiology of these tumors. Here we present spatially resolved transcriptomic profiling of benign and malignant entities and describe the topographical architecture of the neoplastic and microenvironmental diversity.

MATERIAL AND METHODS
We employed spatially resolved transcriptomics using the 10X Visium technology from paraffine embedded specimens. We included hybrid peripheral nerve sheath tumors (HPNSTs) plexiform neurofibromas and malignant peripheral nerve sheath tumors (MPNST). Computational analysis was employed by the SPATA2 toolbox. Transcriptomic niches were identified by graph-based spatial clustering. Correlation of histomorphological features and transcriptomic programs was performed by a co-expression network-based analysis.

RESULTS
We identified hub genes associated with neurofibroma and schwannoma histopathology across primary pathologies and discovered that neurofibroma regions of HPNSTs exhibited unique transcriptional programs marked by a significant higher local accumulation of bone-derived macrophages and lymphoid cells compared to primary neurofibromas. A novel marker, Apolipoprotein D (APOD), was found to accurately identify neurofibroma subregions in HPNSTs, which was confirmed by immunostaining in a control cohort. In MPNSTs, we observed a high grade of inter- and intrapatient heterogeneity driven by unique transcriptional niches and genetic variability. Subsequent pathway analysis revealed distinct oncogenic signaling driver across regional niches along with variance in immune infiltration. Our findings highlight the disbalance between histological annotation and actual tumor cell abundance in MPNSTs indicated by inferred copy number alterations.

CONCLUSION
Our integrated analysis pipeline revealed distinct transcriptional signatures and cellular interactions within benign PNSTs, including neurofibromas and hybrid peripheral nerve sheath tumors (HPNSTs) and sought to expose the tumor heterogeneity of MPNST and identify various cancer niches. Our study underscores the potential of spatially resolved transcriptomics as a powerful tool for advancing our understanding of PNST biology, and ultimately improving diagnosis, prognosis, and treatment strategies.
P02.17.A FEATURES OF METABOLIC PSEUDO-PROGRESSION VISUALIZATION OF GRADE 3-4 GLIOMAS AFTER COMBINATION THERAPY. CORRELATION WITH MRI
Authors: Smirnova A , Gromova E , Plakhotina N , Anishkin M , Smirnova A 
Published: September 2023

Abstract

BACKGROUND
Follow-ap assessment of post-therapeutic changes in gliomas of 3-4 raids revealed the phenomen of metabolic pseudoprogression. This feature was manifested in a transistor increase in the capture of the radiopharmaceutical. This "anomaly" requires study for a correct differential diagnosis between progression and pseudoprogression

MATERIAL AND METHODS
For the period from 2019 to 2023, 27 patients aged 24-72 years (average age 55 years) with the phenomena of metabolic pseudoprogression of 3-4 grades gliomas after combination therapy participated in the study. The studies were carried out using PET-CT and 1.5T, 3.0T MR scanners using T2, T2 flair, T13D before and after contrast, T2* perfusion. Postprocessing was carried out using a workstation SINGO.VIA using technological processes: neuro3d, MM oncology, MR neurology.

RESULTS
It was found that in all cases of transient increase in radiopharmaceuticals capture after radiotherapy in terms from 9 months to 36 months, the values of radiopharmaceuticals accumulation were determined in the range of 1.8-3.5 and were they were divided into two groups according to MRI data: group A (n=17) with structural changes, group B (n=10) with a stable MR pattern. According to MRI data in group A, there was an increase in the pathological zone, these changes involved white matter with more pronounced changes in the periventricular regions. In group B, the changes concerned gray matter. In addition, changes in group B were accompanied by manifestations of vasculopathy of the SMART type (Stroke-Like Migraine Attacks After Radiation Therapy). In subsequent observations, these changes in both groups were reduced, both according to PET and MRI

CONCLUSION
A temporary increase in the values of the capture of radiopharmaceuticals after combination therapy for high grade gliomas can be determined both in the white and gray matter of the brain. This may correspond to the manifestations of a post-radiation reaction. Compared with the MRI data, there is a difference in morphological manifestations at the level of gray and white matter, which is probably due to their different radioresistance. These newly discovered factors may be of key importance for further treatment of patients
P02.18.B INTEGRATIVE OMICS ANALYSIS OF IDH1 MUTANT GLIOMA PATIENTS REVEALS ALTERATIONS IN BUTYRATE METABOLISM
Authors: Fritah S , Cano-Galiano A , Toth R , Hau A , Martinez-Garcia E , Allega M , Sumpton D , Fack F , Dieterle M , Adiamah M , Gobin M , Nicot N , Muller A , Kaoma T , Lesur A , Mittelbronn M , van Dyck E , Prasad Bekal M , Esquenazi Y , Hiller K , Sakariassen P , Miletic H , Dittmar G , Nazarov P , Tardito S , Lund-Johansen M , Bjerkvig R , Golebiewska A , Niclou S 
Published: September 2023

Abstract

BACKGROUND
Mutations in isocitrate dehydrogenase (IDH) 1 or 2 define glioma classification and determine the biology of these tumors. Although IDH is an essential enzyme in the cellular metabolism, powerful genome-wide analyses focus mostly at the genetic and epigenetic levels, while differences between distinct glioma entities at the proteomics, metabolomics, and functional levels are still poorly understood. Here, we provide an integrative multi-omics analysis of glioma patients to reveal metabolomic vulnerabilities of gliomas stratified by IDH mutation.

MATERIAL AND METHODS
We performed a multi-omics analysis of two cohorts of glioma patients (n=28) stratified based on IDH mutation status. Molecular assessment included LC-MS analysis, EPIC DNA methylation arrays, RNA-seq/HTA array-based transcriptomics and label-free quantitative proteomics. In 13 patients 13C-glucose was injected prior to surgery and tumor and adjacent brain tissue was collected. Gut microbial profiling using 16S ribosomal RNA (rRNA) sequencing was performed in a separate cohort of 128 glioma patients and 24 healthy individuals. Additional validation was performed in isogenic glioma stem-like cultures with CRISPR knock-in of IDH mutation.

RESULTS
We show that several molecular layers collectively contribute to biological differences between IDH mutant and wild-type gliomas, with strongest differences observed at the DNA methylation level. IDH mutant gliomas present specific molecular features linked to tumor metabolism. We confirm previous findings on 2-HG, cysteine and de novo glutathione synthesis pathways, which are specifically altered in IDH mutant gliomas. We further identify butyrate metabolism as a novel pathway highly active in IDH mutant gliomas. Butyrate is a bacterial metabolite with multiple systemic effects that is normally synthesized in the gut. This is supported by our gut microbiota metagenomics analysis of glioma patients. Yet the detection of enzymes associated with butyrate metabolism in tumor tissue and cell lines suggests a differential/enhanced metabolic rewiring of the butyrate signaling in IDH mutant gliomas

CONCLUSION
Our data shows the importance of multiple molecular layers in shaping specific features of IDH mutant gliomas. We unravel an activated butyrate metabolism in IDH mutant gliomas that may underly a novel gut-brain axis in glioma patients.
P02.26.B METABOLIC PLASTICITY IN GLIOBLASTOMA TUMOR-INITIATING CELL AND RESISTANCE TO LSD1-DIRECTED THERAPY
Authors: Marotta G , Costanza B , Osti D , Faletti S , Zaccheroni E , Richichi C , Del Bene M , Pelicci G 
Published: September 2023

Abstract

BACKGROUND
Glioblastoma (GBM), the most common primary brain tumor in adults, remains incurable despite multimodal therapy. There is a pressing unmet medical need for new therapeutic strategies, especially because patients experience only short-term benefit after primary treatment and the vast majority inevitably relapse. Adaptation to harsh microenvironmental conditions, including nutrient deprivation, proteostasis perturbation, hypoxia and drug treatment, induce molecular and metabolic changes in glioblastoma that lead to the acquisition of a tolerance to stress and resistance to drug. In this context, we demonstrated that Lysine-specific histone demethylase 1 (LSD1) is a regulator of tumor-initiating cell (TICs) survival, adaptation and recovery from stress. LSD1 pharmacological inhibition with a specific and brain penetrant inhibitor (LSD1i) induces a maladaptive integrated stress response (ISR) which leads to the death of TICs exposed to ER stress or nutrient deficiency.

MATERIAL AND METHODS
Given the high GBM heterogeneity, we analyzed different patient-derived TICs grown in vitro as sphere and characterized for their genetic landscape and in vitro/in vivo stem cell-like features. We applied mechanistically different strategies, including biological, metabolic and pharmacological approaches, as well as transcriptomic and proteomic profiling. Zebrafish and GBM xenografts have been exploited as in vivo models.

RESULTS
LSD1i treatment induces physical and functional rearrangements of mitochondria, culminating into their enhanced bioenergetic activity and ATP production that predispose to cell death. Interestingly, only a subset of patient-derived TICs benefits from LSD1i therapy. These samples are largely dependent on glycolysis and, upon LSD1i administration, they are unable to further enhance it when mitochondrial energy production is inhibited. The samples resistant to LSD1i maintain their cellular behavior unaltered even upon prolonged treatment. They display reduced susceptibility to the stressful cues represented by either LSD1i and the known ER stressors Thapsigargin and Tunicamycin, by efficiently restoring energy homeostasis and properly activating the Activating Transcription Factor 4 (ATF4)-dependent ISR. Remarkably, LSD1i resistant samples display metabolic flexibility and switch between glycolytic and oxidative metabolism to ensure their survival.

CONCLUSION
The identification of specific metabolic vulnerabilities could offer unique opportunities for therapeutic intervention: the selective LSD1i vulnerability relies on the preferential dependence on glycolysis, while the great metabolic plasticity of LSD1i resistant TICs coordinates changes that favor their adaptation to stressful microenvironments and therapeutic insults.
P04.01.B MEK INHIBITORS IN PEDIATRIC RECURRENT SYMPTOMATIC UNRESECTABLE LOW-GRADE GLIOMAS HARBORING MAPK ALTERATION: A SINGLE CENTER EXPERIENCE
Authors: Fonte C , Castelli B , Tellini M , Guidi M , Giunti L , Di Nicola M , Buccoliero A , Caporalini C , Giordano F , Mussa F , Genitori L , Sardi I 
Published: September 2023

Abstract

BACKGROUND
Treatment of inoperable, recurrent, progressive pediatric low-grade gliomas (pLGGs) remains controversial. Recent studies focused on aberrant activation of the mitogen-activated protein kinase (MAPK) pathway, due to gain of function mutations in RAS or BRAF genes or loss or inactivation of NF1. Selumetinib and trametinib, orally bioavailable and selective MEK1/MEK2 inhibitors (MEKi), act on MAPK pathway. In April 2020 the US Food and Drug Administration and in June 2021 the European Medicines Agency approved selumetinib for inoperable plexiform neurofibromas in Neurofibromatosis type 1 (NF1). We evaluated MEKi efficacy and safety in pLLGs harboring MAPK alteration.

MATERIAL AND METHODS
From July 2021 to February 2023 eight patients (5 females, 3 males, median age 8 years, range 4-18) were admitted to our hospital for symptomatic, recurrent, inoperable pLGGs (location: 3 hypothalamic-optic chiasm region, 2 posterior fossa, 1 temporo-mesial, 1 quadrigeminal plate, 1 diffuse leptomeningeal; MAPK alteration: 3 NF1 inactivation, 4 KIAA1549/BRAF gene fusion, 1 RNF130/BRAF fusion). MEKi were administered (6 selumetinib, 2 trametinib) after disease progression for failure of previous treatments (6 partial resection, 7 multiple chemotherapies, 2 radiotherapy). MRI assessment was performed every 4 months and radiological response was defined in accordance with RAPNO criteria.

RESULTS
At first evaluation, 3/8 patients (37,5%) showed a partial radiological response (-64,96% mean volume reduction, range 52,61%-77,19%) and 4/8 (50%) stable disease (0-41.67% volume decrease). Disease progression was observed in a patient heavily pretreated for acute leukemia. One patient with leptomeningeal spreading showed progressive disease at second evaluation. Median time to progression has not yet been reached. Six of 8 patients experienced at least one toxicity. The most frequent toxicities reported were mucocutaneus disorders (rash, mucositis, eczema). Three patients presented creatine phosphokinase (CPK) increase (one grade 2 with rapid normalization after therapy discontinuation). All patients on trametinib had to reduce treatment dose (for skin toxicity or increasing blood pressure).

CONCLUSION
MEKi, selumetinib and trametinib, represent promising strategies in children with recurrent/progressive LGGs harboring MAPK alterations. In our small series, the treatment was effective and well tolerable in patients with localized disease and without other risk factors. The most common toxicities were CPK elevation and rash. Further studies are needed to identify patients who may benefit most from MEKi treatment and to establish whether such treatments are superior to chemotherapy in front line setting for MAPK altered pLGGs.
P06.10.A CAR-ENGINEERED PRIMARY NK CELLS SHOW PROMISING EFFECTS AS TARGETED THERAPY AGAINST EGFR-POSITIVE GLIOBLASTOMA
Authors: Roller B , Reindl L M , Strassheimer F , Ludmirski G , Elleringmann P , Kiefer A , Röder J , Steinbach J P , Wels W S , Ullrich E , Burger M C 
Published: September 2023

Abstract

BACKGROUND
Glioblastoma (GB) is the most frequent primary brain tumor and despite intensive treatment regimens including surgery, radiotherapy, and chemotherapy, it is still characterized by a dismal prognosis. Immunotherapies such as T cells or natural killer cells (NK) that carry tumor-specific chimeric antigen receptors (CAR) hold promise for the development of more effective treatment strategies. CAR-engineered derivatives of the human NK cell line NK-92 targeting EGFR or EGFRvIII showed potent antitumor activity against glioblastoma cell lines in vitro and in vivo. Nevertheless, NK-92 has some limitations compared to primary NK cells, such as the required irradiation prior to application in humans.

MATERIAL AND METHODS
To overcome this limitation, we evaluated the suitability of peripheral blood derived human primary NK cells (pNK) as carriers for a CAR targeting the common GB antigen epidermal growth factor receptor (EGFR) and the tumor-specific EGFR variant EGFRvIII. pNK cells from healthy donors were transduced with a lentiviral vector encoding the cetuximab-derived 225.28.z CAR (CAR-pNK) which recognizes an epitope common to both receptors. Specific tumor cell lysis by the CAR-pNK cells was then investigated in FACS-based cytotoxicity assays with GB cells expressing EGFR, EGFRvIII, or both target antigens. In addition, we tested in vivo feasibility of the CAR-pNK cells by single time intravenous injection in a subcutanous LNT-229/EGFRvIII glioblastoma xenograft model.

RESULTS
In comparison to non-transduced pNK cells, CAR-pNK cells displayed enhanced lysis of LNT-229 GB cells expressing EGFR and EGFRvIII. Likewise, markedly increased cytotoxicity of CAR-pNK was observed against GB cell lines such as SKMG-3 and BS153 with intrinsic EGFR gene amplification or expression of EGFRvIII, respectively. Furthermore, in a subcutaneous LNT-229/EGFRvIII glioblastoma xenograft model we observed delayed tumor growth after a single intravenous injection of CAR-pNK cells.

CONCLUSION
In summary, these results demonstrate promising efficacy of primary CAR-NK cells targeting EGFR and EGFRvIII both in vitro and in vivo. In ongoing work we are evaluating CAR-pNK cells in an orthotopic LNT-229 glioblastoma xenograft mouse model, which may provide the basis to translate this approach to early clinical testing.