bluuebunny/crossref_metadata_2025_split huggingface dataset:
P11.67.B Tumor centrality is associated with a declining overall survival in irradiated diffuse glioma
Authors: van der Boog A T J , David S , Nagtegaal S H J , Bruil D E , Cialdella F , Snijders T , Robe P A J , Verhoeff J J C 
Published: September 2022

Abstract

Background
For diffuse glioma, tumor location is an important factor that influences symptomatology, treatment strategy and, ultimately, survival. Our previous research showed an association between overall survival (OS) and local involvement in eloquent gray and white matter areas in the left hemisphere. Also, involvement of central anatomical structures, such as midline corpus callosum, seem to relate to poorer survival rates, when predefined categories of survival groups (&gt;6 months, 6-24, 24&lt; months) are established. In this study, we investigated OS in relation to centrality of the tumor and its microstructural environment defined as the Clinical Target Volume (CTV) in diffuse glioma treated with radiotherapy in a data-driven fashion.

Material and Methods
We retrospectively included 273 adult patients with histologically proven diffuse glioma who received first radiotherapy between November 2014 and July 2020 at University Medical Center Utrecht. CTV was spatially normalized to stereotaxic MNI152 space and its center of gravity (CoG) was subsequently calculated. Then, the distance between CoG of CTV to the center of the MNI brain was measured in millimeters (mm) for every tumor. A multivariable Cox-regression model included the distance between CoG of CTV and center of MNI brain, age, sex, total intracranial volume (TIV), Karnofsky Performance Status (KPS), WHO grade and extent of resection.

Results
During follow-up, 183 patients (67%) deceased and median OS of the population was 13.7 months (range 0.03 - 65.25) from start of radiotherapy. CoG of CTV to center of brain distance had a significantly inverse association with OS in a multivariable Cox-regression model (P &lt; 0.001) with a hazard ratio 0.97 [95% Confidence Interval: 0.95-0.98] per mm.

Conclusion
In line with literature, centrality of diffuse glioma was associated with a poor survival in irradiated diffuse glioma. In fact, this association was linear, showing a better OS the greater the distance between center of CTV and center of MNI brain after correcting for known prognostic factors such as WHO grade, KPS and extent of resection. Tumor centrality is not a biomarker of involvement in specific eloquent brain regions in and of itself, but a poorer OS in these areas might indicate a proximity to large bulk of commissural white matter tracts and tumor progression along these tracts. Structures of the memory circuit like the fornix and cingulum are also centrally located. Damage to these areas are highly associated with cognitive decline in the memory domain, which is independently related to decreased survival in diffuse glioma patients. Another factor could be tumor involvement of the subventricular zone along the walls of caudate and the lateral ventricles, in which we previously showed that is also associated with worsened survival.
P11.69.B IDH1/2wildtype gliomas grade 2 and 3 with molecular glioblastoma-like profile have a distinct course of epilepsy compared toIDH1/2wildtype glioblastomas
Authors: van Opijnen M P , Tesileanu C M S , Dirven L , van der Meer P B , Wijnenga M M J , Vincent A J P E , Broekman M L D , Dubbink H J , Kros J M , van Duinen S G , Smits M , French P J , van den Bent M J , Taphoorn M J B , Koekkoek J A F 
Published: September 2022

Abstract

Background
IDH1/2 wildtype (IDHwt) glioma WHO grade 2 and 3 patients with pTERT mutation and/or EGFR amplification and/or +7/−10 chromosome gain/loss have a similar overall survival time as IDHwt glioblastoma patients, and are both considered glioblastoma IDHwt according to the WHO 2021 classification. However, differences in seizure onset have been observed. This study aimed to compare the course of epilepsy in the two glioblastoma subtypes.

Material and Methods
We analyzed epilepsy data of an existing cohort including IDHwt histologically lower-grade glioma WHO grade 2 and 3 with molecular glioblastoma-like profile (IDHwt hLGG) and IDHwt glioblastoma patients. Primary outcome was the incidence proportion of epilepsy during the disease course. Major secondary outcomes included onset of epilepsy, number of seizure days and antiepileptic drug (AED) polytherapy.

Results
Out of 254 patients, 78% (50/64) IDHwt hLGG and 68% (129/190) IDHwt glioblastoma patients developed epilepsy during the disease course (p=0.121). Epilepsy onset before histopathological diagnosis occurred more frequently in IDHwt hLGG compared to IDHwt glioblastoma patients (90% versus 60%, p&lt;0.001), with a significantly longer median time to diagnosis (3.5 versus 1.3 months, p&lt;0.001). Median total seizure days was also longer for IDHwt hLGG patients (7.0 versus 3.0, p=0.005), and they received more often AED polytherapy (32% versus 17%, p=0.028).

Conclusion
Although the incidence proportion of epilepsy during the entire disease course is similar, IDHwt hLGG patients show a significantly higher incidence of epilepsy before diagnosis and a significantly longer median time between first seizure and diagnosis compared to IDHwt glioblastoma patients, indicating a distinct clinical course.
P11.75.B Survival benefit of radiotherapy and surgery in patients with lung cancer brain metastases with poor prognosis factors
Authors: Liang L , Wang Z , Duan H , Lu J , Jiang X , Hu H , Li C , Yu C , Zhong S , Cui R , Guo X , He Z , Chen L , Mou Y 
Published: September 2022

Abstract

Background
Radiotherapy and surgery are the standard treatments for lung cancer brain metastases (BMs). However, limitted studies focused on the treatments for patients with lung cancer BMs with poor prognosis factors. The purpose of this study was to investigate the effects of radiotherapy and surgery in patients with lung cancer BMs with poor prognosis factors, providing reference for clinical strategies.

Material and Methods
We analyzed retrospectively 714 patients with lung cancer BMs. A 1:1 propensity score matching (PSM) was performed to balance potential confounders. Analyses of overall survival (OS) and risk factors for OS were assessed by log-rank test and Cox proportional hazard model.

Results
Age ≥65 years, Karnofsky Performance Scale (KPS) score ≤70, anaplastic large-cell lymphoma kinase (ALK)/epidermal growth factor receptor (EGFR) wild type, extracranial metastases, non-surgery and non-radiotherapy led to poor prognosis. Patients were stratified according to these factors. Radiotherapy and surgery showed no survival benefit in patients with aged ≥65 years or pretreatment KPS score ≤70 before and after PSM. Before PSM, whole brain radiotherapy (WBRT) improved the OS and predicted good prognosis in patients with ALK/EGFR wild type or extracranial metastases. WBRT also predicted good prognosis in patients with non-surgery. Stereotactic radiosurgery (SRS) improved the OS and predicted good prognosis in patients with ALK/EGFR wild type or non-surgery. WBRT plus SRS improved the OS and predicted good prognosis in patients with extracranial metastases or non-surgery. WBRT plus SRS also predicted good prognosis in patients with ALK/EGFR wild type. Surgery improved the OS and predicted good prognosis in patients with non-radiotherapy. After PSM, SRS improved the OS and predicted good prognosis in patients with non-surgery. WBRT plus SRS improved the OS and predicted good prognosis in patients with non-surgery or extracranial metastases. WBRT plus SRS also predicted good prognosis in patients with ALK/EGFR wild type. Surgery improved the OS of patients with non-radiotherapy. We defined that the treatment would provide significant survival benefit if it both prolonged the OS and predicted good prognosis. Meanwhile, the results after PSM were more convincing than the results before PSM.

Conclusion
Radiotherapy has significant survival benefit in patients with lung cancer BMs with poor prognosis factors, including patients with ALK/EGFR wild type or extracranial metastases or non-surgery. Surgery only has significant survival benefit in patients with non-radiotherapy.
P12.02.A Landscape of surfaceome and endocytome in human glioma is divergent and depends on cellular spatial organization
Authors: Governa V , Talbot H , Gonçalves de Oliveira K , Cerezo-Magaña M , Bång-Rudenstam A , Forsberg-Nilsson K , Malmström J , Bengzon J , Welinder C , Belting M 
Published: September 2022

Abstract

Background
Cell-surface proteins have a key role in drug development, and tumor cell-surface proteins integrated with the plasma membrane (tumor surfaceome, TS) have attracted considerable attention as targets for immunotherapies in cancer. Checkpoint inhibitor blocking antibodies, antibody drug conjugates (ADCs), and CAR-T cells are all directed at the TS. However, a remaining challenge is the lack of strategies to comprehensively map potential TS target antigens for the design of more rational, individualized treatments. Of particular relevance, ADC and other intracellular drug delivery strategies rely on targets that functionally engage in endocytic internalization.

Material and Methods
With the aim to address these challenges and to provide insight into the complexity of the TS, we have developed a versatile technology for TS mapping (TS-MAP). As proof-of-concept, we focused on primary brain tumors that remain among the most aggressive forms of cancer, and for which attempts to conquer the most common variant, glioblastoma (GBM) have failed so far. TS-MAP is compatible with primary 3D cultures and intact patient glioma tumors with preserved tissue architecture, and specifically identifies proteins capable of endocytosis as tractable targets for ADCs and other modalities requiring toxic payload internalization. Moreover, we have curated a TS classifier (SURFME) for categorization of bona fide membrane proteins.

Results
We show how cellular spatial organization (2D vs. 3D) fundamentally transforms the surfaceome and endocytome in glioma with general implications for target screening approaches. The TS-MAP platform was further applied to profile the surfaceome and endocytome landscape in a cohort of freshly resected patient gliomas. We found a highly diverse TS repertoire between patient tumors, not directly associated with grade and histology, which highlights the need for individualized approaches.

Conclusions
The TS-MAP platform and SURFME classifier should be widely applicable to a variety of brain tumors. Our findings in GBM provide new layers of understanding fundamental to the future development of immunotherapy strategies, as well as new procedures for proteomics-based target identification aimed at a better understanding of how to harness the TS for personalized immunotherapy. Our results reflect the oncogenetic multiclonality and transcriptional diversity of gliomas, which warrants future studies that elucidate how the oncogenetic profile and spatial organization synergize to shape the full complexity of the tumor microenvironment.
P12.09.B Extracellular vesicle derived-miR-146a increases melanoma brain metastasis progression via Notch signalling pathway dysregulation
Authors: Rigg E K , Wang J , Xue Z , Lunavat T , Hoang T , Parajuli H , Han M , Liu G , Bjerkvig R , Nazarov P , Nicot N , Kreis S , Wurth C , Miletic H , Sundstrøm T , Li X , Thorsen F 
Published: September 2022

Abstract

Background
Melanoma has the highest tropism of any cancer to metastasize to the brain, and 40% of late-stage patients develop brain metastasis. Invasion, survival, and progression of tumors is dependent on the support of the surrounding microenvironment; therefore, modulation of neighboring cells is a key factor in metastasis. Extracellular vesicles (EVs) are important in cell-to-cell signalling, shuttling proteins, RNA and DNA to alter the surroundings into a favorable tumor microenvironment. Our aims were to investigate the role of melanoma brain metastasis (MBM) derived EVs in MBM development to find possible contributing mechanisms to cancer progression for eventual therapeutic targeting.

Material and Methods
MBM-EVs isolated via sequential ultracentrifugation were injected into mice as a pre-treatment prior to intracardial injection of MBM cells. EVs were co-cultured with normal human astrocytes (NHA) to investigate phenotypic changes. MiRNA sequencing was performed on EVs collected from MBM cells and compared to NHA and melanocytes to determine a candidate miRNA for targeting. In situ hybridization was utilized to evaluate the level of miRNA in clinical patient MBM samples. Functional in vivo validation was performed by injecting miRNA knockout MBM cells into mice. Sequencing of NHA in the presence or absence of target miRNA mimic was used to determine downstream targets.

Results
Mice primed with EVs had a significant increase in MBM tumor burden, compared to non-primed mice. Co-culture with MBM-EVs resulted in NHA activation in vitro, with increased proliferation, invasion, cytokine production, and upregulation of GFAP. MiR-146a was highly upregulated in MBM EVs, and miR-146a mimics activated NHA. Patient samples had a significant increase in miR-146a expression, compared to healthy brain controls. MiR-146a knockdown in MBM mice models reduced MBM burden and prolonged animal survival. Sequencing of NHA determined NUMB, an inhibitor of the Notch signalling pathway, as a target of miR-146a. Numb and other downstream Notch proteins expression was significantly altered in NHA in the presence of both MBM-EVs and miR-146a.

Conclusion
In conclusion, EVs are important regulators of MBM and establish tumor-supporting reactive astrocytes by delivery of miR-146a. MiR-146a alters Notch signalling in astrocytes via inhibition of the tumor suppressor gene NUMB. Elevated miR-146a levels in patients suggests a potential clinical intervention is possible via miR-146a targeting.
P12.13.B Investigating the tumor - immune cell crosstalk inex vivo glioblastoma models
Authors: Rezaeipour M , Klein E , Dording C , Niclou S P , Golebiewska A 
Published: September 2022

Abstract

Background
Immunotherapy is a promising therapeutic approach to fight cancer by activating the immune system. Multiple immune-based strategies are under development that aim at recruiting or re-activating cellular components of the immune system. While immunotherapies have recently revolutionized cancer therapy, they have shown so far little therapeutic success in glioblastoma patients. To enhance the efficacy of novel strategies, we need to better understand the immunogenic status of glioblastoma cells and their cross-talk with immune cells in different microenvironmental niches.

Material and Methods
We assessed expression of molecules related to antigen processing and presentation as well as immune checkpoints in patient tumor databases as well as in a series of glioblastoma patient-derived organoids, 3D stem-like cultures and adherent cell lines under varying microenvironmental conditions (varying oxygen levels, inflammation). We further established an allogenic co-culture protocol for glioblastoma organoids with immune cells isolated from HLA matched donor blood, allowing for the functional assessment of the crosstalk between tumor and immune cells.

Results
Analysis of a large cohort of patient tumors and patient-derived glioblastoma preclinical models shows inter-patient heterogeneity at the level of components of major histocompatibility complex (MHC)-MHC-II, immune checkpoints. Glioblastoma cells in general express MHC-I machinery, albeit at different levels. MHC-II and immune checkpoints are variably expressed across glioblastoma cells. Different tumor microenvironment conditions, including hypoxia and interferon-γ, impact the expression of immune-related molecules. Upon co-culture, HLA-matched donor-derived T cells integrate well into the core of glioblastoma tumor organoids and display reciprocal crosstalk with tumor cells.

Conclusion
Assessing antigen presentation and immune cell responses at the functional level are key to improve patient-specific responses to immunotherapies. Advanced glioblastoma organoids incorporating the immune compartment appear as clinically-relevant models for ex vivo efficacy studies.
P14.05.B Plasma-EV based liquid biopsy for precision medicine in the treatment of glioblastoma
Authors: Faletti S , Zaccheroni E , Osti D , Del Bene M , DiMeco F , Pelicci G 
Published: September 2022

Abstract

Background
Glioblastoma (GBM) is a devastating and protean brain tumor. Diagnosis and molecular characterization rely on magnetic resonance imaging and brain biopsy which are challenged by low specificity/sensitivity and surgical risks. This hampers the longitudinal monitoring of patients with GBM, whose molecular dynamism ideally requires to refine the therapeutic plan in different disease stages. Extracellular vesicles (EVs) shed by GBM act as a reservoir of circulating biomarkers and can be easily collected through a blood sample, placing the rational to exploit them as a platform for liquid biopsy in GBM.

Material and Methods
We isolated EVs from 2ml of pre-operative platelet-free plasma by Size Exclusion Chromatography (SEC). EVs are characterized by (i) immunoblot and Fluorescent-Activated Cell Sorter (FACS) for the presence of EV markers; (ii) TEM for morphology and size; (iii) Nanoparticle Tracking Analysis (NTA) for size and concentration; (iv) RNAseq and ddPCR for EV-associated nucleic acid profiling.

Results
SEC allowed to define EV-enriched fractions expressing the EV-markers CD9, CD81, Flotillin1, lacking the non-EV marker Calnexin and depleted of the majority of plasma contaminants. EV quantification by NTA confirmed their enrichment in the plasma from GBM patients. EV-RNA length (&lt; 200nt) and total yield (1-10ng among different samples) allowed a successful RNAseq library preparation for downstream identification of splicing isoforms, translocations, fused mRNAs, and expression level of GBM-specific transcripts. The ddPCR-based analysis of mutations and copy number alterations proved the ability of cell-derived EV-DNA to recapitulate the alterations of the parental cells. Although the yield of plasma-EV-DNA is low (around 1ng), this paves the way to optimize the isolation/analysis of plasma EV-DNA to permit tumor profiling.

Conclusion
Plasma-EV based liquid biopsy could implement the personalisation of GBM care for every timepoint of the disease course. Increased plasma-EV concentration is an effective biomarker for GBM presence and its measurement well suits with the clinical routine. EV-RNA/DNA mirror the genomic profile of parental tumor and their analysis could allow the identification of actionable molecular aberrations and the monitoring of GBM mutability during follow-up. Thus, the multilayered analysis of plasma-EV concentration and cargo could enable GBM early diagnosis and to monitor therapy response and the whole tumor evolution.
P15.07.A Predicting sites of local tumour progression - what should be our imaging biomarker?
Authors: Mayrand R C , Wei Y , Li C , Perry Mayrand R , Wan Y , Simon N , Sinha R , Sravanam S , Price S J 
Published: September 2022

Abstract

Background
Glioblastoma is the most aggressive primary brain tumour diagnosed in adults. Despite intensive treatment of maximal safe resection and chemoradiotherapy, the prognosis remains grim due to invasive tumour cells. Current treatment and standard imaging methods are highly limited in terms of managing these invasive cells as they are often located outside the area of surgical resection and are generally resistant to chemoradiation. DTI appears to be a promising tool for imaging tumour cell invasion and predicting the site of recurrence especially when decomposed into its anisotropic (q) and isotropic (p) components. The aim of this study is to investigate the sensitivity of imaging biomarkers as predictors of recurrence.

Material and Methods
All pre-op and recurrence sequences were co-registered to the pre-op post-contrast T1-weighted images as reference. Co-registration of images was performed using FSL and ANTs. The ROIs for 49 patients with a primary diagnosis of GBM were segmented using 3DSlicer. Each voxel was assigned to one of four status: true negative, false negative, true positive and false positive. Sensitivity and specificity between the pre-op ROIs and the progression region were calculated using FSL. The significance of the differences in sensitivity and specificity between the ROIs was computed in MATLAB.

Results
The sensitivity for the contrast enhancing region was 48.77 ± 26.13 (Mean ± SD) and 62.40 ± 23.07 (Mean ± SD). The abnormal q alone has a significantly greater sensitivity than the contrast enhancing region (t = -2.7327, df = 96, p-value = 0.0075). The sensitivity for the ROI of combined contrast enhancement and abnormal q was 65.86 ± 23.29 (Mean ± SD). There is an even more significant increase in sensitivity when the contrast enhancing ROI is combined with abnormal q region (t = -3.4133, df = 96, p-value = 9.4123e-04) compared to when it is alone. There was no statistical difference in the specificities of the different ROIs.

Conclusion
Current surgical and radiation volumes focus solely on pre-op contrast enhancement. However, these results suggest that combining the abnormal q with the standard contrast enhancing region is a more sensitive predictor of tumour recurrence than contrast enhancement alone, while still retaining high specificity. The higher sensitivity is an indicator of correct identification of tumour recurrence while the high specificity correctly identifies normal brain, or non-recurrent regions. These results are currently being prospectively assessed in a multi-centre study (PRaM-GBM).