bluuebunny/crossref_metadata_2025_split huggingface dataset:
P12.07.B Getting to the core of microglia versus bone marrow-derived macrophages in glioblastoma
Authors: Woolf Z R , Smith A , Swanson M E V , Scotter E L , Schweder P , Correia J , Park T I , Dragunow M 
Published: September 2022

Abstract

Background
Microglia and bone marrow-derived macrophages (BMDMs) are two ontogenetically distinct myeloid populations present within glioblastoma that can comprise 30-50% of the tumour mass. Historically, these cell types have been conflated and studied as a single population of ‘tumour-associated macrophages’. Recent advances in single-cell omics have allowed population delineation, suggesting microglia and BMDMs may play different roles within the tumour and subsequently differentially affect tumour progression. Despite building evidence for the unique functions of these cells within glioblastoma, the inherent heterogeneity of the tumour landscape has complicated such studies. Indeed, macrophages exist as phenotypically and functionally diverse populations that are polarised in a context-dependent manner. Hence, to understand the differences between microglia and BMDMs within glioblastoma, both ontogeny and spatial location must be considered.

Material and Methods
To elucidate the functional roles of microglia and BMDMs across the tumour landscape, a publicly available RNAseq dataset was utilised to classify myeloid cells into four populations based on spatial location and ontogeny. These were tumour core BMDMs and microglia, or tumour periphery BMDMs and microglia. Differential gene analysis was then performed to identify significant differentially expressed genes (DEGs) between classified myeloid populations. Tumour core DEGs were then compared against the Ivy Glioblastoma Atlas to define their expression across anatomical tumour regions. Finally, myeloid DEGs were validated at the protein level on human glioblastoma tissue through immunohistochemistry.

Results
Microglia and BMDMs showed different spatial distributions across the tumour landscape and displayed distinct functional expression profiles. Microglia held a more chemotactic and pro-inflammatory profile, whereas BMDMs held a more pro-tumoural profile. However, a comparison of microglia between the tumour core and periphery revealed that tumour microglia upregulate many pro-tumoural genes, including multiple genes that have previously been defined as ‘BMDM-enriched’. Moreover, we found myeloid DEGs identified within the tumour core cluster to distinct spatial tumour regions such as the vascular or hypoxic niche. Immunohistochemical staining reflected these spatial expression profiles, identifying a distinct population of phagocytic macrophages within the hypoxic niche.

Conclusion
Although microglia and BMDMs represent two ontogenetically distinct myeloid populations within glioblastoma, both cell types can adopt similar functional expression profiles within the tumour core, particularly within tumour niches. This indicates that myeloid cell function is strongly influenced by the tumour microenvironment, rather than ontogeny alone.
P12.10.A Supratentorial glioblastoma with spinal metastasis: a case report with molecular profiling
Authors: Jancalek R , Hendrych M , Solar P , Hermanova M , Slaby O 
Published: September 2022

Abstract

Background
Glioblastoma (GBM) is regarded as an aggressive brain tumor that rarely develops extracranial metastases. Despite well-investigated molecular alterations in GBM, there is a limited understanding of these associated with the metastatic potential of GBM.

Material and Methods
We present a case report of a 43-year-old woman with frontal GBM IDH-wildtype, who underwent gross-total resection followed by chemoradiation. Five months after surgery, the patient was diagnosed with an intraspinal GBM metastasis. Next-generation sequencing analysis of both primary and metastatic GBM tissues was performed using the Illumina TruSight Tumor 170 assay.

Results
The number of single nucleotide variants observed in the metastatic sample was more than 2-times higher. Mutations in TP53, PTEN, and RB1 found in the primary and metastatic tissue samples are indicative of the mesenchymal GBM subtype. Among others, in the metastatic sample, there were detected two inactivating mutations (Arg1026Ile, Trp1831Ter) in the NF1 gene, two novel NOTCH3 variants of unknown significance predicted to be damaging (Pro1505Thr, Cys1099Tyr), one novel ARID1A variant of unknown significance (Arg1046Ser), and one gene fusion of unknown significance EIF2B5-KIF5B.

Conclusion
Based on the literature evidence, the inactivation of NF1, NOTCH3, and ARID1A could explain, at least in part, the acquired invasiveness and metastatic potential in this particular GBM case.
This work was supported by the grant MUNI/A/1408/2021 of the Masaryk University, Brno, Czech Republic, and INTER-EXCELLENCE Programme / INTER-COST project no. LTC20027 of the Ministry of Health, Czech Republic.
P12.11.B The role of miRNAs in glioma in response to hypoxia
Authors: Smith L C , Chakraborty D , Lourdsamy D , McIntyre D , Smith D 
Published: September 2022

Abstract

Background
Hypoxia, low oxygen, is a microenvironment that promotes tumour progression, particularly in gliomas. The regulation of many biological processes are maintained by miRNAs. The hypoxia status of glioma cells effects the regulation of processes by affecting the expression of individual miRNAs.The aims of this study is identifying significant miRNAs that are either under or overexpressed in hypoxia compared to normoxia in glioma cells and further exploring the effect of hypoxia on miR-92a-3p and miR-149-5p in gliomas on the apoptotic and cellular senescence pathways.

Material and Methods
A range of glioma cells were used for screening including primary cell lines: GIN28 and GIN31; low-grade cell lines: LGG19 and LGG24; paediatric cell line: SF188 and commercially available glioblastoma cell line U87. These cells were culture at both 1% (hypoxia) and 20% (normoxia) oxygen levels. Screening of miRNAs was achieved by quantitative polymerase chain reaction (qPCR) using miRNA specific primers. Knockdowns/in were achieved by transfecting with miR-92a-3p and miR-149-5p mimics and inhibitors. Caspase-glo assay was used to assess the effect of hypoxia on apoptosis.

Results
miRNA 92a-3p and miR-149-5p were found to be downregulated and upregulated respectively in primary gliomas cells in hypoxia compared to normoxia. These particular miRNAs are also found to have multiple targets in apoptosis and cellular senescence.

Conclusion
The screening of 90 miRNAs among the different categories of gliomas highlighted multiple miRNAs that were significant in hypoxia compared to normoxia. Using primary cell lines have identified hypoxia-affected miRNAs in glioblastomas. This discovery will increase our knowledge and understanding of the hypoxia effect on miRNAs which may aid and direct targeted therapy to conquer hypoxia in glioblastomas.
P12.14.A The role of onco-metabolite (R2hydroxyglutarate) in the IDH mutant glioblastoma microenvironment
Authors: Ravi V M , Behringer S , Joseph K , Beck J , Schnell O , Heiland D H 
Published: September 2022

Abstract

Background
Recently, we found that the reactive astrocytes in the IDH wild type glioblastoma contribute to anti-tumor immunity and support pro-oncogenic signaling. Here, we characterized the transcriptomic signature of IDH1/2-mutant glioma associated astrocytes and determined a unique inflammatory transformation, profoundly different to astrocytes in IDH wildtype glioma patients due to an onco-metabolite R-2-hydroxyglutarate using Next generation sequencing and human ex-vivo slice model.

Material and Methods
We purified and transcriptionally profiled astrocytes from 9 patients with confirmed IDH1-R132H mutation, by means of RNA-sequencing and the data were analyzed using the established pipelines. We also used spatial transcriptomics to evidently show the spatial distribution of astrocytes in IDH-mutated/wildtype glioma samples. We validated our findings using human organotypic slice model inoculated with IDH-mutant cell line or treated with oncometabolite 2-hydroxy glutarate. Additionally, LC-MS was further used to give us a chart of neurotransmitters due to altered microenvironment.

Results
Our results from RNA sequencing showed a transcriptional transformation of reactive astrocytes within the microenvironment of IDH-mutated tumors compared to wildtype glioma by means of RNA-sequencing of purified astrocytes. And, using our established human neocortical GBM model inoculated with IDH mutant tumor and R-2HG treatment, we showed that we were able to activate inflammatory transcriptional programs in astrocytes, mediated by the presence of microglia. Further, by spatially mapping the transcriptomic profiles of purified microglia, we were able to confirm that microglia also demonstrate inflammatory activation in IDH mutated glioma. This inflammatory astrocyte transformation is associated with a loss of neurotransmitter homeostasis (disrupted levels of glutamate) in the treated sections, as has been previously reported in IDH mutated tumors. Additionally, R-H2G increased neuronal spiking rate in, pointing to potential excitotoxicity.

Conclusion
Our work provides a crucial contribution towards understanding the role of R-2HG in the IDH mutant glioma microenvironment and sheds light on the significant microenvironmental differences to IDH wild-type glioma.
P13.01.A Challenges and Solutions for Establishing a CNS Tumor Registry in Africa
Authors: Fezeu F , Opara C , Djientcheu V , Fonkem E , Samnick S 
Published: September 2022

Abstract

Background
CNS tumor registries (CTR) has evolved to a key tool for data collection, evaluation of diagnostic and treatment of patients suffering from tumors of the central nervous system (tCNS) in the U.S, but CTR in Africa does not yet exist. In comparison to high-income countries (HIC), many low- and middle-income countries (LMIC) do not yet have national or central CNS tumor registries. Furthermore, appropriate diagnostic steps like MRI and pathological analysis are still scarce in many LMIC. Improving the availability of CTR in resource- limited regions could allow better understanding of some specificities of tCNS including incidence, prevalence, mortality and morbidity. However, CTR, MRI and pathological analysis tend to be costly and thus difficult to implement in the LMIC setting.

Material and Methods
A review of the current body of literature on tCNS in Africa was conducted using multiple scientific online data bases. Search terms included ,,CNS tumor registry,” “developing countries,” “low and middle income,” and other related terms as starting point for future initiatives.

Results
It was found that more than 1,3 billion people residing in Africa lack access to a continental CTR. There is no well established standards for reporting tCNS. Most tCNS are still underreported in many countries of Africa. The exact burden of tCNS in Africa is unknown. Although many successful, long-term, initiatives for international neurological and neurosurgical collaborations are published, any CTR of Africa similarly to the Central Brain Tumor Registry of the United States (CBTRUS) is lacking.
Conclusion:
Disparities in access to care for patients suffering from tCNS have been well published but well established solutions are still under investigations. Partnerships between centers in LMIC and HIC are making progress to better understand the burden of disease in LMIC and to create context-specific solutions for practice in the LMIC setting. Collaboration between the World Health Organisation, national centers for disease control in Africa, departments of neuroscience in LMIC and well established registries like the CBTRUS as well as other interested groups could be meaningful strategical steps to be initiated for the establishment of CTR in Africa. A CTR for Africa could lead to better comprehension of tCNS in Africa, thus facilitate prevention, diagnostic, treatment and research.
P15.01.A Metabolic-imaging of human glioblastoma explants: a new precision-medicine model to predict treatment response early
Authors: Morelli M , Lessi F , Di Stefano A , Santonocito O , Gambacciani C , Pieri F , Aquila F , Ferri G , Snuderl M , Mulholland P , Ottaviani D , Aretini P , Pasqualetti F , Franceschi S , Mazzanti C 
Published: September 2022

Abstract

Background
Glioblastoma (GB) is the most severe form of brain cancer, with a 12-15 month median survival. Although cell therapies for GB are on the near horizon, surgical resection, temozolomide (TMZ) and radiotherapy (RT) remain the primary therapeutic options for GB, and no new small-molecule therapies have been introduced in recent years. This therapeutic standstill is partially because preclinical models of GB do not reflect the complexities of GB cell biology. Furthermore, the aggressive progression of GB makes it critical to identify patient-tailored therapeutic strategies early.

Material and Methods
We developed a novel in-vitro 3D glioblastoma explants (GB-EXPs) model derived from patients’ resected tumors maintaining cytoarchitecture seen in the tumors. We then performed metabolic-imaging by fluorescence lifetime imaging microscopy (FLIM) on live GB-EXPs to predict drug response, using TMZ as test drug.

Results
The entire process was successfully completed within 1 week since surgery. A unique drug response sample stratification emerged that was well reflected at the molecular level, highlighting new targets associated with TMZ treatment and identifying a molecular signature associated with survival.

Conclusion
To the best of our knowledge, this is the first time that FLIM-based metabolic imaging is used on live glioblastoma explants to test anti-neoplastic drugs. FLIM-based readouts of drug response in GB explants could accelerate precision treatment of patients with GB and the identification of new anti-GB drugs.
P15.05.A Prediction of response to lomustine-based chemotherapy in glioma patients at relapse using MRI and FET PET
Authors: Wollring M M , Werner J , Bauer E K , Tscherpel C , Lohmann P , Kabbasch C , Goldbrunner R , Fink G R , Langen K J , Galldiks N 
Published: September 2022

Abstract

Background
This study evaluates O-(2-[18F]fluoroethyl)-L-tyrosine (FET) PET and contrast-enhanced MRI for early response assessment in glioma patients at relapse treated with lomustine-based chemotherapy.

Material and Methods
Thirty-seven adult patients with WHO CNS Grade 3 or 4 gliomas at relapse (glioblastoma, 70%; median number of relapses, 1) were retrospectively identified. Besides MRI, serial FET PET scans were performed at baseline and early after chemotherapy initiation (median number of cycles, 2). Mean and maximum tumor-to-brain ratios (TBR), metabolic tumor volumes (MTV), the occurrence of distant hotspots with a mean TBR &gt; 1.6 at follow-up, and dynamic parameters (i.e., time-to-peak and slope) were derived from all FET PET scans. Threshold values of PET parameters were defined using receiver operating characteristic analyses to predict progression-free survival (PFS) of ≥6 months and overall survival (OS) of ≥12 months. MRI response assessment was based on RANO criteria. The predictive value of FET PET parameters and RANO criteria were subsequently evaluated using univariate and multivariate survival estimates.

Results
After treatment initiation, the median follow-up time was 11 months (range, 3-71 months). Maximum TBR and MTV (threshold, ≤0%) and RANO criteria predicted a significantly longer PFS (all P&lt;0.001) and OS (all P&lt;0.03). At follow-up FET PET imaging, the occurrence of new distant hotspots (n≥1) predicted a worse outcome, with significantly shorter PFS (P=0.001) and OS (P&lt;0.001). Dynamic PET parameters did not predict a significantly longer PFS or OS (P&gt;0.05). Multivariate survival analyses revealed that new distant hotspots at follow-up had the highest level of significance to predict non-response (P=0.002; hazard ratio, 5.722), independent of RANO criteria, IDH mutation status, and O6-methylguanine-DNA-methyltransferase promoter methylation.

Conclusion
FET PET seems to be a powerful tool for identifying responders to lomustine-based chemotherapy early after treatment initiation.
P15.08.B Intraoperative confocal laser endomicroscopy of brain tumors - potential and challenges from a neuropathological perspective
Authors: Maragkou T , Quint K , Pollo B , Hewer E 
Published: September 2022

Abstract

Background
Intraoperative consultation, usually in the form of a frozen section, is an integral part of current neuropathology practice. Typical indications include determination of specimen adequacy, intraoperative diagnosis and distinction between tumoral and non-tumoral tissue in diffusely infiltrating gliomas in tumor periphery. The latter is currently limited by the fact that typically not all potential regions of interest can be sampled for frozen sections and the turnaround times of frozen sections usually do not permit multiple repetitive assessments. The commercial availability of a clinical-grade in vivo laser endomicroscope for neurosurgical applications may have the potential to change this and to permit a microscopic analysis in near-real time, which in turn may have a significant impact on resection strategies for brain tumors. In this work, we investigate the potential role of CLE in neurosurgery and the transferability of histological criteria to confocal imaging.

Material and Methods
The potential role of CLE in neurosurgery in comparison to other techniques for intraoperative tumor assessment was determined by analyzing common intraoperative neuropathological workflows and identifying unaddressed opportunities. The transferability of the histological criteria from standard histology to confocal imaging was achieved by analyzing matched image pairs (standard histology and CLE) from several common tumor entities.

Results
We identified the time gap between specimen resection and the availability of the frozen section results as an important application for intraoperative CLE imaging in neurosurgery. Importantly, neuropathologists could assess tissue in near real time in an unlimited number of digital biopsies prior to resection, which adds a potent new tool to the neurosurgical armamentarium. CLE images revealed features similar to already known tissue architecture/morphology seen in standard histology, which correlated well in matched histological images. Unique aspects of individual cells and other surrounding tumor tissue elements were observed in vivo while the CLE probe acquired images throughout its focal-depth range.

Conclusion
Widespread application of CLE may have a major impact on neuropathologists' role in intraoperative diagnosis and bring along both opportunities and challenges. For broad clinical adoption, strategies for histological criteria validation as well as for determination of diagnostic accuracy need to be developed.
P15.09.A Canny edge detection algorithm for quantitative differentiation between diffuse and circumscript glioma growth patterns on MRI
Authors: Thiele F , Weller J , Katzendobler S , Trumm C , Thon N , Tonn J 
Published: September 2022

Abstract

Background
Lower grade gliomas show heterogenous appearance on T2-weighted MRI. Some tumors grow diffusely along axonal structures whereas others distort adjacent brain tissue through local mass effect. The diagnostic, therapeutic and prognostic implication of differential growth patterns on MRI remain unknown and are difficult to assess quantitatively.

Material and Methods
A web-based application allowing for image preprocessing and providing a comprehensive edge detection tool by means of quantifying tumor border delineation on T2-weighted images based on the canny edge detection algorithm was developed. A sigma value between 1 and 100 determined the threshold where tumor borders where not detected by the algorithm anymore, with 1 equating to the lowest threshold and thus detection of all edges contained in the image. Two experienced faculty members assigned sigma values to axial T2 images of a random sample of 20 WHO grade 2 astrocytomas, IDH-mutant and 1p/19q-non-codeleted. The sigma values were then compared with a binary, subjective rating by the same faculty staff according to the perceived predominant growth pattern (diffuse versus circumscript) of each glioma.

Results
When subjectively categorizing tumors binarily (diffuse versus circumscript), there was moderate interrater variability between observers (cohen’s kappa=0.6). Raters agreed in 16 of 20 cases, terming 7 gliomas unanimously diffuse and 9 gliomas circumscript. In 4 cases, the raters opinions diverged. The sigma values differed significantly between diffuse and circumscript tumors in both raters (rater 1, p=0.002; rater 2, p=0.018). For rater 1, the mean sigma difference between diffuse and circumscript tumors was 10.7 and 9.3 for rater 2.

Conclusion
Edge detection algorithms can be efficiently applied on MRI scans and are highly accurate in differentiating diffuse from circumscript gliomas. Objectification demands defining imaging criteria for diffuse and circumscript appearance of lower grade gliomas on MRI.
P15.10.B A multicenter phase 3 trial in progress: diagnostic performance of18F-fluciclovine PET for the detection of recurrent brain metastases after radiation therapy (REVELATE)
Authors: Chao S T , Chaglassian A , Tainer N , Teoh E J 
Published: September 2022

Abstract

Background
Following treatment of brain metastases, which can affect up to 40% of patients with cancer, patients will typically be closely monitored with serial brain magnetic resonance imaging (MRI) owing to the high likelihood of recurrence. The recommended follow-up modalities (CE-T1-weighted and FLAIR/T2-weighted MRI) have poor specificity, meaning that differentiation of true disease from treatment-related changes such as radiation necrosis can be difficult. Recent pilot studies have reported amino acid PET radiopharmaceutical, 18F-fluciclovine, to be potentially useful in discriminating brain tumor recurrence from treatment-related changes. This may potentially help physicians to make confident diagnoses and inform subsequent treatment plans.

Material and Methods
REVELATE (NCT04410133) will evaluate the diagnostic performance of 18F-fluciclovine PET (read with conventional MRI for anatomical reference) for the detection of recurrent brain metastases in patients for whom MRI is equivocal. This multicenter, phase 3, prospective, open-label trial aims to enroll approximately 150 subjects from across 19 US sites with solid tumor brain metastases who have undergone radiation therapy, if they have a lesion considered equivocal on MRI that requires further confirmatory diagnostic procedures (either biopsy/neurosurgical intervention or clinical follow-up). Patients will undergo 18F-fluciclovine PET &lt;42 days after the equivocal MRI and 1-21 days pre-biopsy/neurosurgical intervention. Clinical follow-up will occur for 6m post-18F-fluciclovine PET.

Results
The primary endpoint of REVELATE is the subject-level 18F-fluciclovine negative and positive percent agreement (equivalent to specificity and sensitivity, respectively) for detection of recurrent brain metastases. Further objectives include evaluation of the lesion-level diagnostic performance, inter-reader and intra-reader agreement, and safety evaluations.

Conclusion
This ongoing phase 3 study will provide efficacy and safety data for the use of 18F-fluciclovine for the detection of recurrent brain metastases. Enrolment began in October 2020 and the trial is active but not recruiting at the time of submission.