bluuebunny/crossref_metadata_2025_split huggingface dataset:
OS06.6.A Real-World Pattern of Care Study on Glioblastoma in the Austrian Population. Final results from 2014-2020
Authors: Oberndorfer S , Woehrer A , Borkovec M , Marosi C , Payer F , Urbanic-Purkart T , Nowosielski M , Iglseder S , Stockhammer G , Kleindienst W , Florea C , Hager A , Tinchon A , Stultschnig M , Surboeck B , Pichler J , Leibetseder A , Weiss S , Hutterer M , Seebrecht L , Roetzer T , Hainfellner A , Hainfellner J 
Published: September 2022

Abstract

Background
The Austrian ABTR-SANO Glioblastoma Registry is the first population-based assessment of patterns of care for patients with Glioblastoma across Austrian healthcare institutions. The primary aim is to assess the real world effectiveness of administered therapies.

Material and Methods
Clinical data are collected via a common web-based IT platform “ABTR-SANO Net” since 2014. The database and the ongoing evaluation of clinical parameters, as well as interims analysis are provided in cooperation with a review board. First Outcome analysis, including patients from 2014-2020, was performed at the end of 2021.

Results
Eleven centers across Austria are involved, and the data of 1416 patients (m/f ratio: 1,35, median age: 66 years) were recently analyzed in detail. Age, extent of resection, as well as ECOG was associated with improved survival. Methylated MGMT Status also showed a moderate survival benefit. Patients with re-resection and re-radiation also exhibited improved survival, which however may be attributed to a selection bias.Second line treatment manly comprised of antiangiogenic treatment, followed by alkylated agents, re-radiation and re-surgery. Median overall survival of all patients was 344 days and clearly age dependent (best for &lt;50 years, worse for&gt;80 years).

Conclusion
This is the first population based outcome analysis of Glioblastoma in Austria. Results regarding prognostic markers and outcome are mostly comparable with international data. Robust population based data are important in order to monitor quality of health care, and to match the data with results from clinical studies.
OS06.7.A Underlying mechanisms of verbal fluency in glioma patients: language or executive functioning?
Authors: Collée E , Van den Berg E , Visch-Brink E , Dirven C , Vincent A , Satoer D 
Published: September 2022

Abstract
Background Glioma patients often suffer from cognitive deficits, such as in language and executive functioning (EF). A sensitive test to identify these deficits is verbal fluency (VF). In VF, participants are asked to generate as many unique words within a given semantic category (category fluency - CF) or starting with a given letter (letter fluency - LF) within one minute. While both language and EF play a role in VF, the relative contribution of both domains remains unclear. We aim to retrospectively investigate performance on VF and, for the first time, on Non-Verbal Fluency (NVF), requiring to connect 5 points in different patterns within three minutes. Additionally, we aim to explore the influence of language and EF on VF performance in glioma patients.
Materials and Methods 69 adults with gliomas in eloquent areas underwent a comprehensive neuropsychological test-battery at 1-2 months before surgery (T1) and 3 (T2) and 12 months (T3) after surgery. The protocol consisted of VF (CF: animals, professions, LF: D-A-T/K-O-M), language tests (Repetition (Akense Afasie Test), Token Test, Boston Naming Test) and EF tests (Five Point Test, Trail Making Test, Stroop Colour-Word Test, Wisconsin Modified Card Sorting Task). VF and NVF performance were compared 1) to healthy population using one sample t-tests/Wilcoxon rank-tests (all patients), and 2) between T1, T2, and T3 with paired sample t-tests/Wilcoxon rank-tests (31 patients). Linear regression analyses were conducted to investigate the predictive value of language and EF on VF for all patients.
Results Preoperatively, patients were impaired on all VF tasks. Especially CF profession performance was more prone to deterioration after surgery at T2 and T3. In contrast, NVF was intact and even improved after surgery (T1-T3, T2-T3). NVF (p = .032, EF) was a predictor for CF animals while the Token Test (p = .023, language) was a predictor for CF professions. Both NVF (p = .032, EF) and the Token Test (p = .004, language) were predictors for LF.
Conclusion First, glioma patients were preoperatively impaired in VF but were preserved in NVF, as is in line with the literature. Secondly, CF professions appeared to be particularly sensitive to detect long-term postoperative decline. Thirdly, the main result of this study is that both language and EF mechanisms appeared to be responsible for VF performance in glioma patients. These findings are useful for interpreting VF impairment in glioma patients and for therapeutic interventions, suggesting a combination of language and EF training materials.
OS09.5.A The experience of interval scans for adults living with primary malignant brain tumours
Authors: Rudkin S , Booth T C , Absolom K , Latchford G , Short S C , Boele F W 
Published: September 2022

Abstract

Background
People living with primary malignant brain tumours (PMBT) face a complex and unpredictable illness. Throughout the disease course they undergo various treatments and follow-up with regular interval scanning. There are potential costs and benefits to interval scanning, however there is no high-quality evidence to suggest interval scanning is beneficial or whether scans alter outcomes of importance for people living with PMBTs. Yet, interval scanning may exacerbate issues such as uncertainty and anxiety - which impacts on patient quality of life. The aim of this study was to gain an in-depth understanding of how adults living with PMBTs experience and cope with interval scanning.

Material and Methods
Twelve patients with a diagnosis of PMBT (glioblastoma n=10; astrocytoma grade 3 n=1; solitary fibrous tumour of the dura grade 3 n=1) under the neuro-oncology teams at Leeds Teaching Hospital NHS Trust and King's College Hospital NHS Foundation Trust took part in the study. They were interviewed remotely about their experiences of interval scans, following a semi-structured interview guide. An abbreviated version of a constructionist grounded theory approach was used to analyse data.

Results
Five main themes were generated from the data: ‘Living with a PMBT’, ‘Interval scanning: the difficult times’, ‘MRI scan: accepting the discomfort’, ‘Waiting for results: coping with the uncertainty’ and ‘Results: providing some certainty in uncertainty’. Although most participants found interval scans uncomfortable, they accepted that they were something that they had to do and were using various coping methods to get through the MRI scan. All participants said that the wait between their scan and results was the most difficult part. Despite the difficulties they experienced, all participants said that they would prefer to have interval scans than wait for a change in their symptoms. Most of the time, scans provided relief, gave participants some certainty in an uncertain situation, and a short-term sense of control over their lives.

Conclusion
The present study shows that interval scanning is important and highly valued by patients living with PMBT. Although interval scans are anxiety provoking, they appear to help people living with PMBT cope with the uncertainty of their diagnosis.
OS09.6.A Factors predicting mood disorders, health related quality of life and sexual disturbances in adults with glioma: a retrospective study
Authors: Leonetti A , Puglisi G , Rossi M , Conti Nibali M , Sciortino T , Gay L , Vigano' L , Fornia L , Cerri G , Bello L 
Published: September 2022

Abstract

Background
It is not clear whether Mood Disorders (MD) and poor Health Related Quality of Life (HRQoL) in glioma patients correlate with clinical and histomolecular features of the tumor or with secondary symptoms associated with treatment. This study assessed the prevalence of MD and decline in HRQoL (with a specific interest in sexuality) in glioma patients, identifying the clinical, imaging and treatment factors associated with these variables.

Material and Methods
260 glioma patients (190 lower grade) were evaluated. Patients were prospectively followed-up from admission to 12 months after surgery, for MD and HRQoL assessment. 115 were asked to fill a questionnaire for sexual life investigation. Clinical, imaging, histomolecular features as well as cognitive functions were evaluated. Variables associated with MD,low HRQoL and sexual life impairment were identified by bivariate analysis.

Results
Factors associated with MD and low HRQoL were different in LGGs and HGGs over the course of the disease. In LGGs the effect of adjuvant treatments was prominent in determining the prevalence of MD and poor HRQoL from the third month after surgery onward. In HGGs, MD and poor HRQoL were associated with older age. In both, cognitive deficits were associated with MD. 42% of patients showed dissatisfaction for their sexual life and decrease of sexual intercourses, which were linked to a reduction of libido (22%), astenia (39%), pharmacological therapy (23%), and self-image insecurity(22%). Patients undergoing adjuvant treatments showed a lower sexual satisfaction.

Conclusion
Overall the data suggest that worsened quality of life, Incidence of Mood disorder and worsening in sexual life affect a relevant amount of patients affected by glioma. Lack of recovery from functional deficits (language, attentive/executive and motor deficits) and adjuvant therapies (expecially radiotherapy) play a crucial role in determining the emergence of Mood Disorders, low HRQoL and worsened sexual life.
OS10.4.A A macrophage-based drug delivery platform for glioma treatment
Authors: Sun M , Bialasek M , Rygiel T , Król M , Weller M , Weiss T 
Published: September 2022

Abstract

Background
There is an urgent need for more effective treatment strategies against gliomas. At present, even though various drugs have potent anti-tumor activity in vitro, their application in vivo is limited by ineffective delivery and systemic toxicity. Therefore, novel strategies are needed to deliver these drugs effectively and safely to the tumor site. Here, we developed an adoptive transfer strategy against malignant brain tumors utilizing macrophages that are loaded with ferritin-protein cages containing drugs or other proteins and transfer these nanocarriers to cancer cells in vitro and in vivo.

Material and Methods
Live-time imaging, microscopy and flow cytometry were utilized to investigate the transfer of ferritin cages from loaded macrophages to human or mouse glioma cells. Co-cultures of glioma cells and macrophages loaded with ferritin-drug cages were used to study the anti-glioma activity in vitro and orthotopic immunocompetent mouse glioma models were used to study the anti-glioma activity in vivo. Affinity purification-mass spectrometry (AP-MS) was used to elucidate the mechanisms of transfer by characterizing the interactome of ferritin cages within macrophages and cancer cells.

Results
We observed a high transfer efficiency of ferritin-cages from loaded macrophages into human and mouse glioma cells in vitro in co-culture assays and confirmed the transfer from macrophages to glioma cells also in vivo upon intravenous or intratumoral treatment of GL-261 or CT-2A glioma-bearing mice. To study the anti-glioma activity with therapeutically active payloads, we loaded murine/human macrophages with ferritin cages carrying cytotoxic payloads. Co-culture of these loaded macrophages with murine or human glioma cells in vitro revealed a time- and concentration-dependent cytotoxicity to glioma cells. In vivo, intravenous or intratumoral administration of ferritin-drug protein cages was tolerated without toxicities and conferred a survival benefit in two orthotopic murine glioma models (GL-261 and CT-2A). Interactome studies of ferritin-cage-binding proteins revealed phagocytic and cytoskeleton re-arrangement pathways to be involved in uptake and transfer of ferritin-cages from macrophages to glioma cells.

Conclusion
This ‘Trojan Horse’ approach constitutes a promising platform to deliver cytotoxic drugs effectively and safely to gliomas and provides a rationale for clinical translation.
OS10.5.A Modeling immunocompetent tumor microenvironment in glioblastoma patient-derived orthotopic xenografts
Authors: Moreno-Sanchez P M , Oudin A , Yabo Y A , Klein E , Baus V , Poli A , Michelucci A , Niclou S P , Golebiewska A 
Published: September 2022

Abstract

Background
To date, glioblastoma (GBM) remains a fatal disease, with a median overall survival of roughly over a year. There is a crucial need of new treatment options, yet most clinical trials have failed partly due to the lack of predictive preclinical model systems. Currently, most patient-derived preclinical models suffer from the reduction or absence of immune system components, which represents a bottleneck for adequate immunotherapy testing. Humanized mice offer new opportunities here, since they rebuild an adaptive human immune system in a NSG mouse. Derivation of glioblastoma patient-derived orthotopic xenografts (PDOXs) in humanized mice appears thus as a promising tool for testing new treatment strategies targeting the tumor microenvironment (TME).

Material and Methods
We derived PDOXs through intracranial implantation of GBM primary organoids in different immunocompromised mouse strains (Nude, NOD/SCID, NSG). To introduce back the adaptive human immune system, GBM PDOXs were further derived in human CD34+ hematopoietic stem cell-engrafted NSG (HU-CD34+) mice. We applied single-cell RNA-sequencing, multicolor flow cytometry, immunohistochemical analyses and functional studies to examine the heterogeneous TME in a cohort of GBM PDOX models. We further interrogated the contribution and crosstalk between the human and mouse components constituting the brain TME in HU-CD34+ PDOXs.

Results
We show that glioma PDOXs can be derived in mice of different background including Nude, NOD-SCID, NSG and HU-CD34+ mice. Mouse-derived TME created in PDOX models contains tumor-associated macrophages (TAMs) known as major immuno-suppressive components of human GBM tumors. We further show that PDOXs derived in HU-CD34+ NSG mice present human CD45+ immune cells in the bone marrow and blood. Interestingly, we detect an influx of human immune cells in tumors developed in the mouse brain, which interact with the brain-derived immunosuppressive TME of mouse origin.

Conclusion
We here provide a thorough characterization of the heterogeneous brain TME created in GBM PDOX models. We show that human GBM can instruct mouse-derived brain cells towards immune-suppressive TME. The missing adaptive immune component can be introduced by derivation of GBM PDOXs in humanized mice. Such immunocompetent in vivo models will be important for testing novel therapies targeting different immune components in GBM.
OS10.6.A What is the initial cell in the subventricular zone for human glioblastoma genesis?
Authors: Yoon S , Choi R , Cho S , Kim H , Lee J , Kim E , Chang J , Kim S , Kim H , Lee J , Kang S 
Published: September 2022

Abstract

Background
We all have a fundamental question about why glioblastoma (GBM) develops. In order to find the answer to this fundamental question, if you find out what the first cell is, you will get closer to the answer. GBM arises from the subventricular zone (SVZ). GBM is one of the most devastating tumour of human brain as the most optimal treatment barely prolongs the survival, and it does not cure the disease. As the majority of GBM tissues show copy number variations (CNV) of co-altered chromosomal 7 gain and 10 loss, we hypothesized the origin cell (Oc) of SVZ may be traced back with these markers. The cellular identity of the Oc is still unknown and it is different from the tumour-derived progenitor-like cells. We aimed to define these cells from the SVZ that have a potential to get activated into GBM.

Material and Methods
We compared bulk RNA sequencing (RNAseq) data of IDHwt GBM tumor tissue (n=122), tumor free SVZ from GBM patients (n=40), tumor-free control SVZ of non-glial tumor (n=9). Pared single nucleus RNAseq (snRNAseq) or single cell RNAseq (scRNAseq) samples of tumor free SVZ (n=11) and GBM tumor (n=8), were done to see cell specific CNVs. We developed genetically engineered mouse models for GBM genesis introducing three driver mutations (TP53, PTEN, and EGFRviii) into SVZ to isolate mouse Oc (mOc) and mouse cancer cells (mCc). The biological characteristics of separated mOc and mCc were compared. Bulk RNAseq and scRNAseq were performed on these cells (mOc, mCc), and their cellular state was compared with the human gene set.

Results
In this work, we found two types of the Oc in the RNA sequencing of 60 human tumour free-SVZ samples. Furthermore, single-cell level analysis revealed that two Oc types in SVZ harbor ongoing patterns of CNV co-alterations from Oc1 to Oc2, and finally to GBM. The Oc1 type cells contained the CNV signature of Oc2 ancestor with neural progenitor cell (NPC) signature. Oc2 type cells expressed a high level of EGFR than other cells with astrocyte-like cell signature. Both of these cells expressed oligodendrocyte progenitor cell (OPC)-like signatures in the SVZ. We validated the human-based findings by using the P53/PTEN/EGFR-mutant mouse model with EGFR/tdTomato overexpression and P53/PTEN knockout in the SVZ cells. As a result, non-tumourigenic and highly motile Oc-like cell-states are found in the mouse models, supporting the firework-like migration pattern from the SVZ.

Conclusion
Our results demonstrate how members of Oc preoccupy the SVZ, known as the stem cell niche and give rise to the tumour. We anticipate that a new therapy may emerge by targeting the Oc in the SVZ.
OS10.7.A Activation of the CCR8-ACP5 axis by human microglia/macrophage derived CCL18 promotes glioma growth
Authors: Huang Y , Motta E , Nanvuma C , Yuan Y , Kuhrt L , Xia P , Lubas M , Zhu S , Schnauss M , Hu F , Zhang H , Lei T , Synowitz M , Flüh C , Kettenmann H 
Published: September 2022

Abstract

Background
Glioblastoma multiforme is a highly malignant primary brain tumor with an average survival of 14 months and very limited therapeutic options. Glioma associated microglia and macrophages (GAMs) foster tumor growth by releasing several cytokines, which have only partly been identified. Here, we studied the chemokine (C-C motif) ligand 18 (CCL18), a chemokine which is only expressed in human, but not rodent GAMs, in a novel ex-vivo brain slice model including transplantation of human induced pluripotent stem cells (iPSC) derived human microglia (iMGL) and human glioma cells in to murine brain slices, which had been depleted of intrinsic murine microglia before.

Material and Methods
After establishing the humanized ex-vivo brain slice model, we performed immunohistochemical analysis (IHC) of growth and invasiveness, qrtPCR on glioma cells isolated by magnetic-activated cell sorting (MACS), functional assays measuring invasiveness, proliferation, migration and colony formation of glioma cells in vitro and in slice experiments. Corresponding studies on tumor growth and invasiveness were performed after treatment with a CCL18 neutralizing antibody, a CCR8 neutralizing antibodies and knockdown of CCR8, ACP5 (Acid Phosphatase 5) and PITPNM3 with small interfering RNA (siRNA) and short hairpin RNA (shRNA). QrtPCR, IHC and Westernblot analysis were performed on primary glioma specimens. We also conducted bioinformatic analyses, based on the TCGA GBM, GLIOVIS and GEPIA databases.

Results
We observed that CCL18 was highly expressed in GAMs, whereas CCR8 was only expressed in glioma cells. We identified the chemokine (C-C motif) receptor 8 (CCR8) as a functional receptor for CCL18 and ACP5 as an important down-stream signaling component in glioma cells. Activation of the CCL18/CCR8/ACP5 signaling pathway in human glioblastoma was associated with enhanced tumor growth and invasiveness.

Conclusion
GAMs derived CCL18 promoted glioma growth by activation of the CCR8/ACP5 axis in human glioma cells and therefore is a potential therapeutic target.
P01.02.B Case Report: Disruption of Resting-State Networks and Cognitive Deficits After Whole Brain Irradiation for Singular Brain Metastasis
Authors: Kocher M , Jockwitz C , Lerche C , Sabel M , Lohmann P , Stoffels G , Filss C , Motthagy F M , Ruge M I , Fink G R , Shah N J , Galldiks N , Caspers S , Langen K 
Published: September 2022

Abstract

Background
Long-term survivors of whole brain radiation (WBRT) are at significant risk for developing cognitive deficits, but knowledge about the underlying pathophysiological mechanisms is limited. Therefore, we here report a rare case with a singular brain metastasis treated by resection and WBRT that survived for more than 10 years where we investigated the integrity of brain networks using resting-state functional MRI.

Material and Methods
A female patient with a left frontal non-small cell lung cancer (NSCLC) brain metastasis had resection and postoperative WBRT (30.0 in 3.0Gy fractions) and stayed free from brain metastasis recurrence for a follow-up period of 11 years. Structural magnetic resonance imaging (MRI) and amino acid [O-(2-[18F]fluoroethyl)-L-tyrosine] positron emission tomography (FET PET) were repeatedly acquired. At the last follow up, neurocognitive functions and resting-state functional connectivity (RSFC) using resting-state fMRI were assessed. Within-network and inter-network connectivity of seven resting-state networks were computed from a connectivity matrix. All measures were compared to a matched group of 10 female healthy subjects.

Results
At the 11-year follow-up, T2/FLAIR MR images of the patient showed extended regions of hyper-intensities covering mainly the white matter of the bilateral dorsal frontal and parietal lobes while sparing most of the temporal lobes. Compared to the healthy subjects, the patient performed significantly worse in all cognitive domains that included executive functions, attention and processing speed, while verbal working memory, verbal episodic memory, and visual working memory were left mostly unaffected. The connectivity matrix showed a heavily disturbed pattern with a widely distributed, scattered loss of RSFC. The within-network RSFC revealed a significant loss of connectivity within all seven networks where the dorsal attention and fronto-parietal
control networks were affected most severely. The inter-network RSFC was significantly reduced for the visual, somato-motor, and dorsal and ventral attention networks.

Conclusion
As demonstrated here in a patient with a metastatic NSCLC and long-term survival, WBRT may lead to extended white matter damage and cause severe disruption of the RSFC in multiple resting state networks. In consequence, executive functioning which is assumed to depend on the interaction of several networks may be severely impaired following WBRT apart from the well-recognized deficits in memory function.