bluuebunny/crossref_metadata_2025_split huggingface dataset:
JS04.6.A The landscape of tumor cell states and spatial organization in H3-K27M mutant diffuse midline glioma across age and location
Authors: Liu I , Jiang L , Samuelsson E , Marco Salas S , Hack O , Jeong D , Shaw M , Englinger B , LaBelle J , Ernst K , Palova H , Pokorna P , Sterba J , Slaby O , Geyeregger R , Jones D , Koschmann C , Svedlund J , Resnick A , Diaz A , Haberler C , Czech T , Slavc I , Cotter J , Ligon K , Alexandrescu S , Yung W , Arrillaga-Romany I , Suva M , Beck A , Gojo J , Monje M , Nilsson M , Filbin M 
Published: September 2022

Abstract

Background
Histone 3 lysine27-to-methionine mutations (H3-K27M) frequently occur in childhood diffuse midline gliomas (DMGs) of the pons, thalamus and spinal cord, presumed to be driven by the specific spatiotemporal context of these midline locations during postnatal development. While most common in the pons and at mid-childhood ages, the same oncohistone mutation is recurrently detected in adult DMGs and throughout different midline regions. The potential heterogeneity of tumors at different ages and in different anatomical locations of the midline are vastly understudied.

Material and Methods
Through dissecting the transcriptomic, epigenomic and spatial architectures of a comprehensive cohort of patient H3-K27M DMGs - spanning the age range from 2-68 years and locations from spinal cord to thalamus - at single cell resolution, we delineate how age- and location-dependent contexts shape glioma cell-intrinsic and -extrinsic features in light of the shared driver mutation.

Results
We identify that oligodendrocyte precursor (OPC)-like cells constitute the stem-like compartment in H3-K27M DMGs across all clinico-anatomical groups, however, depending on location, display varying levels of maturity resembling less differentiated pre-OPCs or more mature OPCs further differentiated along the oligodendroglial lineage. We further demonstrate increased mesenchymal cell states in adult tumors, which we link to age-related differences in glioma-associated immune cell compartments. We for the first time resolve the spatial organization of H3-K27M DMG cell types in intact patient tissues, identifying a local niche of the oligodendroglial lineage.

Conclusion
Our study provides a powerful resource for rational modeling and therapeutic frameworks taking into account determinants of age and location in this lethal glioma group.
OS02.7.A The role of epilepsy in elderly patients with Glioblastoma: An Austrian multicenter analysis
Authors: Demetz M , Hecker C , Krigers A , Kerschbaumer J , Pöppe J , Geiger P , Spinello A , Griessenauer C J , Thomé C , Schwartz C , Freyschlag C F 
Published: September 2022

Abstract

Background
Higher age is a significant predictor of poor outcome in glioblastoma multiforme (GBM) patients. Thus, acquisition of a better understanding of additional prognostic factors in these often-frail patients is of utmost importance. Epileptic seizures correlate with improved overall survival (OS) in low-grade gliomas; however, the impact of epilepsy in GBM patients on outcome parameters is poorly defined. Furthermore, persisting epilepsy significantly influences the patients’ quality of life (QoL). This study aims at specifically evaluating the impact of epilepsy in elderly GBM patients.

Material and Methods
Two Austrian academic neurosurgical centers retrospectively analyzed all elderly (≥65 years) GBM patients with de-novo tumors, who underwent tumor resections between 09/2006 and 07/2021. Epidemiological, histopathological and survival data were gained from patients’ electronic charts and screened for presence of epilepsy preoperatively or during follow-up.

Results
391 patients (55% males, 45% females) with a median age at surgery of 73 years (Interquartile Range (IqR) 68.5-77.5) were analyzed. The mean predicted OS was recorded to be 12.4 months (CI95% 10.9-14.0). Median preoperative Modified Rankin Scale (mRS) was 2 (IqR 1-3), and median preoperative Karnofsky performance score was 80 (IqR 60-90). Mean follow-up was 10.4 months (CI95% 9.1-11.6) in our cohort. 95/391 patients (24%) suffered from preoperative epilepsy. 17 (18%) patients still suffered from epilepsy after tumor resection with eight patients who developed new postoperative seizures, and four patients (1.0%) showed a worsening of already preoperatively diagnosed seizures. Major surgery-associated neurological complications included new motor deficits in 29 (7%) and new aphasia in 16 (4%) patients. Logistic regression showed, patients with seizures had significantly lower mRS (OR=0.735 [CI95% 0.563 0.961], p=0.032) and less frequently occipital tumor location (OR=0.347 [CI95% 0.152-0.791], p=0.018). Postoperative epilepsy resulted in significantly prolonged hospitalization after the surgery (OR=2.622[CI95% 1.496-3.979], p=0.009). Survival did not correlate with preoperative epilepsy (p&gt;0.05). However, Cox regression revealed that multifocal tumor location (HR=1.777 [CI95% 1.197-2.639], p=0.025) as well as thalamic involvement (HR=11.121 [CI95% 3.431-36,046], p=0.030) negatively influenced OS. Furthermore, surgery-associated complications shortened OS significantly (HR=1.945 [CI95% 1,296-2,916], p=0.025).

Conclusion
Even though epilepsy was not found to directly impact survival in elderly GBM patients, we found that surgery led to epilepsy freedom in a significant proportion of our patient cohort, thereby potentially leading to improved QoL. Greatest focus should be set on avoiding any surgery-associated deficits, since these severely influence the OS.
OS05.4.A Single-cell characterization of human GBM reveals regional differences in tumor-infiltrating leukocyte activation
Authors: Schmassmann P , Roux J , Dettling S , Hogan S , Herter S , Bacac M , Shekarian T , Martins T A , Ritz M , Hutter G 
Published: September 2022

Abstract

Background
Clinical trials of systemic T cell checkpoint blockade in GBM patients showed only disappointing results. This may be attributed in part to the immunosuppressive components of the GBM immune tumor microenvironment (iTME). Therefore, major efforts have been undertaken to describe the GBM iTME on a single cell level. However, human data on the composition of the iTME in different tumor regions (contrast enhancing tumor center versus peripheral infiltration zone) remain scarce.

Material and Methods
Here, we performed high-depth single-cell RNA sequencing (scRNA-seq) on patient-matched biopsies from tumor center and the peripheral infiltration zone of five primary GBM patients. Additionally, peripheral blood mononuclear cells (PBMC) of the same patients were included in the analysis to explore the transcriptional changes occurring during tumor infiltration of circulating immune cells. Main findings of the transcriptional analysis were confirmed by flow cytometry.

Results
Through analysis of &gt; 45’000 cells, we revealed a distinct regional transcriptional profile of microglia (MG) and monocyte-derived macrophages (MdM), a non-reactive/exhausted MG subcluster in the GBM iTME and an impaired interferon-response signature in the tumor-peripheral cytotoxic cell compartment. Comparing CD8+ T cells from the tumor periphery to PBMC-derived CD8+ T cells of the same patient revealed CX3CR1high and CX3CR1int CD8+ T cells with effector and memory phenotype, respectively, enriched in the PBMC but lacking in the tumor periphery. Tumor peripheral CD8+ T cells shared features with tissue-resident memory CD8+ T cells with exhausted effector functions.

Conclusion
Our analysis provides a large-scale dissection of GBM-associated cell types complemented by patient-matched PBMCs, serving as a high dimensional reference map of the human GBM iTME.
OS09.7.A Experiences and unmet needs of grade 2-4 glioma patients and (health care) professionals regarding (return to) work: the BrainWork study
Authors: Zegers A , Coenen P , Heeren A , Takke N , Ardon H , Compter A , Dona D , Kouwenhoven M , Schagen S , de Vos F , Duijts S 
Published: September 2022

Abstract

Background
In the Netherlands, 1,200 persons are annually diagnosed with a glioma, of whom many are of working age. Studies regarding cancer and work often exclude primary brain tumour patients, due to specific problems these patients may experience. Hence, the aim was to explore the experiences and unmet needs regarding return to work, work retention, or work discontinuation of both grade 2-4 glioma patients, and involved (health care) professionals.

Material and Methods
Individual semi-structured interviews were held with grade 2-4 glioma patients as well as health care and occupational professionals involved in (the care for) glioma patients. Grade 2-4 glioma patients were eligible to participate if they were of working age and had an employment contract at time of diagnosis. Recruitment of patients was performed via three hospitals and via social media. The professionals were recruited via the network of researchers linked to BrainWork. Interviews were transcribed verbatim, and thematically analysed using ATLAS.ti9.

Results
Nineteen glioma patients participated in this study (68% male, mean age 45 (SD 11), 58% grade 2, 16% grade 3, 26% grade 4). The main themes identified were: 1) impact of glioma-specific consequences on work ability, 2) communicating about an invisible, progressive illness at work: discrepancies in perceptions, 3) working with a brain tumour: looking at possibilities, and 4) navigating offers of (work-related) support. Sixteen professionals were interviewed (e.g., clinical neuro-oncologist, insurance physician) with an average experience of fifteen years. Four key themes were identified: (1) distilling the right approach: generic or specific vocational rehabilitation?; (2) work adjustments are common, but information deficiency causes delay; (3) opinions about work ability are diverse and influenced by glioma-specific characteristics; and (4) need for attention and tailored recommendations regarding glioma and work.

Conclusions
Working is possible for glioma patients although they encounter glioma-specific problems, and commonly need work adjustments. These adjustments should be communicated early, to prevent employer-employee conflicts. A specific reintegration plan, including a neuropsychological assessment and a glioma-tailored rehabilitation program, is considered the most adequate approach. Open communication between the patient and the (work) environment in general is necessary to abate discrepancies in perception. Communication between health care professionals and occupational professionals should be improved to diminish differences in opinions about the work ability of glioma patients. Finally, more attention and more tailored recommendations regarding glioma and work are necessary.
P01.01.A Lesion-Function Analysis from Multimodal Imaging and Normative Brain Atlases for Prediction of Cognitive Deficits in Glioma Patients
Authors: Kocher M , Jockwitz C , Lohmann P , Stoffels G , Filss C , Motthagy F M , Ruge M I , Weiss Lucas C , Goldbrunner R , Shah N J , Fink G R , Galldiks N , Langen K , Caspers S 
Published: September 2022

Abstract

Background
Cognitive deficits are common in glioma patients following multimodality therapy, but the relative impact of different types and locations of treatment-related brain damage and recurrent tumors on cognition is not well understood.

Material and Methods
In 121 WHO Grade III/IV glioma patients, structural MRI, O-(2-[18F]fluoroethyl)-L-tyrosine FET-PET, and neuropsychological testing were performed at a median interval of 14 months (range, 1-214 months) after therapy initiation. Resection cavities, T1-enhancing lesions, T2/FLAIR hyperintensities, and FET-PET positive tumor sites were semiautomatically segmented and elastically registered to a normative, resting state (RS) fMRI-based functional cortical network atlas and to the JHU atlas of white matter (WM) tracts, and their influence on cognitive test scores relative to a cohort of matched healthy subjects was assessed.

Results
T2/FLAIR hyperintensities presumably caused by radiation therapy covered more extensive brain areas than the other lesion types and significantly impaired cognitive performance in many domains when affecting left-hemispheric RS-nodes and WM-tracts as opposed to brain tissue damage caused by resection or recurrent tumors. Verbal episodic memory proved to be especially vulnerable to T2/FLAIR abnormalities affecting the nodes and tracts of the left temporal lobe.

Conclusion
In order to improve radiotherapy planning, publicly available brain atlases, in conjunction with elastic registration techniques, should be used, similar to neuronavigation in neurosurgery.
P01.06.B Interim results from CAR-Study B: An ongoing randomized trial on the effect of SRS or WBRT on cognitive performance in patients with 11-20 brain metastases
Authors: Schimmel W C M , Verhaak E , Hanssens P E J , Kavelaars X M , Mulder J , Kaptein M C , Sitskoorn M M , Gehring K 
Published: September 2022

Abstract

Background
Both stereotactic radiosurgery (SRS) and whole brain radiation therapy (WBRT) have proven to be effective treatments for multiple brain metastases (BM) with similar overall survival. Cognition and Radiation (CAR) Study B is a randomized trial on the effect of Gamma Knife radiosurgery (GKRS) or WBRT on cognitive performance in patients with 11-20 BM. The primary and secondary aim of this interim analysis were to check whether Bayesian stopping rules for cognitive failure were met, and to compare cognitive changes after treatment respectively, for the first 45 patients enrolled.

Material and Methods
Patients with 11-20 newly diagnosed BM on a triple-dose contrast-enhanced MRI-scan, expected survival &gt;3 months and Karnofsky Performance Status (KPS) ≥70, were stratified by age, histology, total BM volume, systemic treatment, KPS, and baseline Hopkins Verbal Learning total recall (HVLT-R TR) score, and randomized 1:1 (minimization) to GKRS or WBRT. Neuropsychological tests were administered before (T0) treatment (n=21 vs n=20), and at 3 (T3; n=16 vs n=14) and 6 (T6; n=9 vs n=9) months thereafter. A decline of ≥5 points in HVLT-R TR score was considered a cognitive failure. The trial would be halted if the posterior probability for a higher cognitive failure rate in one group versus the other was &gt;0·975 at T3 or T6 according to the employed beta (2.09,2.91) prior (prior mean of 42%), based on the average failure rates at 4 months reported by Chang et al. (2009). Between-group differences in changes of test performances over 6 months were analyzed using mixed ANOVAs. Proportions of cognitive changes (T0-T6) at the individual level based on reliable change indices correcting for practice effects, were determined.

Results
HVLT-R TR failure rates in the GKRS versus WBRT group were 31% versus 29% at T3, and 0% versus 33% at T6. The observed failure rates after WBRT at T3 and T6 were lower than the average failure rates of Chang et al. (2009). Posterior probabilities were 0·451 at T3 and 0·918 at T6. Over 6 months, changes in performance on tests of immediate (p=·003) and delayed recall (p=·024), and information processing speed (p=·003) were significantly different between groups (large effect sizes), with significant declines after WBRT, but not after GKRS. Over 6 months, at the individual patient level, there were no declines in performances across all tests in the GKRS group (n=8) while performances declined in 4 out of 8 patients in the WBRT group.

Conclusion
The stopping rules were not met since the posterior probabilities did not cross the threshold. Other preliminary findings in this small sample suggest that cognitive decline, both at group and individual level, is more pronounced after WBRT compared to GKRS. Accrual is continued (NCT02953717; ZonMw 842003006).
P01.10.B The relation between executive functioning and MEG multilayer network centrality in glioma patients
Authors: van Lingen M R , Breedt L C , Hillebrand A , Klein M , Kouwenhoven M C M , Reijneveld J C , De Witt Hamer P C , Zimmermann M L M , Santos F A N , Douw L 
Published: September 2022

Abstract

Background
Many patients with glioma suffer from deficits in executive functioning (EF), regardless of tumor location and size. While some patients experience improving EF after tumor resection, others deteriorate over time. This variability in cognitive trajectories is still poorly understood, but neuroscientific approaches that view the brain as a network may bear correlative and predictive value in this respect. Particularly integrative network connectivity of the fronto-parietal network are crucial for EF, but studies so far have only investigated isolated neural frequency bands of interest. Here, we synergize fronto-parietal network connectivity across frequency bands and test its explanatory power for EF at diagnosis and 1 year after tumor resection.

Material and Methods
Patients with diffuse glioma (n=37) underwent neuropsychological assessments, including three tests for EF, and resting-state magnetoencephalography (MEG) at both time points. Patients’ EF performance was standardized to z-scores using validated norm scores, adjusting for age, sex and education. MEG was source-reconstructed using patients’ MRI in combination with a beamformer approach and time series were filtered into six classical frequency bands. Band-specific functional connectivity between 78 cortical regions was estimated, after which an interconnected multilayer, multi-frequency network was created per patient. Multilayer centrality was then calculated as a measure of integrative network connectivity per region, and averaged over all fronto-parietal network regions to yield a single value reflecting integrative, multi-frequency network connectivity per patient at each time point.

Results
At diagnosis, eight patients had z-scores &lt;-1.5, indicating clinically relevant cognitive deficits. Preoperatively, poorer performance on the Concept Shifting Task was associated with lower multilayer centrality (p=.017), while improving performance on this task from diagnosis to 1 year after resection was associated with an increase in multilayer centrality (p=.022). Multilayer centrality at diagnosis did not significantly predict EF at follow-up.

Conclusion
Our results establish a significant relationship between poorer and decreasing EF with lower and decreasing multilayer, multi-frequency integrative connectivity of the fronto-parietal network in glioma patients. Studies with larger and more homogeneous samples may further explore the relevance of this multilayer approach in understanding and particularly predicting postoperative decline in EF in these patients, as our sample was characterized by large heterogeneity in cognitively relevant patient and tumor characteristics.
P02.08.A The relations of focal and total DNA methylation in gliomas
Authors: Majchrzak-Celińska A , Naskret-Barciszewska M , Giel-Pietraszuk M , Nowak W , Śron P , Barciszewska A 
Published: September 2022

Abstract

Background
The role of epigenetic events in gliomagenesis is undoubtful. However, the role of specific pathological events is not so clear. It was shown that loss in total DNA methylation correlates with higher tumor malignancy and oxidative DNA damage. But promoter methylation of many genes was reported to be significant for gliomas’ malignancy and predictive for the treatment outcome. In carcinogenesis in general global DNA hypomethylation and focal hypermethylation coexist. The aim of our project was to evaluate the correlation between total DNA methylation and promoter methylation of selected genes.

Material and Methods
We analysed glioma tissues from 60 patients. For total DNA methylation analysis we used the radiolabelling method with TLC separation of nucleotides and content estimation with phosphoimager. For promoter methylation analysis we have chosen: MGMT (O-6-Methylguanine-DNA Methyltransferase), MPG (DNA-3-methyladenine glycosylase), GJA1 (Gap junction alpha-1 protein / connexin 43). The promoter methylation level was evaluated with the methylation-sensitive high-resolution melting (MS-HRM) method.

Results
Total DNA methylation was reversely correlated with brain tumor grade, confirming that 5-methylcytosine loss is important step in gliomagenesis. From 3 genes only MPG promoter methylation showed clear low reverse correlation with tumor grade. Promoter methylation in GJA1 show low correlation with both, MGMT and MPG, but there was no link between MGMT and MPG. IDHwt presence was significantly correlated with higher tumor grade. Promoter methylations in MPG and GJA1 were better correlated with IDH status than in MGMT.

Conclusion
There is a clear correlation between total DNA methylation and tumor malignancy. Gene promoter methylation is not highly correlated with total DNA methylation and shows low significance in selected cases. Promoter methylation showed clear correlation with tumor grade only in MPG case. That suggests diverse mechanisms steering DNA methylation in general and local changes. It also shows that total DNA methylation is best predictor of tumor grade.
P03.02.B Vestibular side effects following robotic guided stereotactic radiosurgery of vestibular schwannoma
Authors: Rueß D , Pöhlmann L , Jünger S , Kocher M , Ruge M 
Published: September 2022

Abstract

Background
New-onset vestibular disorders (VD), such as dizziness and imbalance, are common side effects after stereotactic radiosurgery (SRS) for vestibular schwannomas (VS). Although these symptoms can severely affect the daily life of VS patients, there are limited data available providing prognostic information on the risk of developing VD after SRS.

Material and Methods
We included patients who received Cyberknife® SRS for newly diagnosed unilateral VS between 2012 and 2015. The incidence of vestibular disorders before and after treatment was recorded and correlated with tumor, patient, and treatment characteristics.

Results
We identified 71 patients with a median age of 58 years (range: 21-82) and a median follow-up of 66 months (range: 3-105). Tumor volume before treatment was 1.5 cm3 ± 1.4 (range: 0.1-8.6). A mean marginal dose of 12.9 Gy ± 0.3 (range: 12-14) was administered, and all studied patients remained free of tumor recurrence. Forty-one (58%) of the patients had VD prior to SRS. Of the remaining 30 patients who did not have VD before treatment, 16 (53%) developed new VD (vertigo, n=4; balance disorders, n=8; mixture of VD, n=4). The median time to onset of symptoms was 6 months (range: 2-36). In most patients (n=11, 69%), the new symptoms completely resolved within a median time of 21 months (range: 1-63). In multivariate analysis, neither tumor volume (p=0.7), age (p=0.06), nor radiation dose (p=0.16) were significantly associated with the occurrence of VD.

Conclusion
In this cohort, about half of the patients develop new onset of transient VD after SRS. The incidence of VD after SRS was found to be independent from usual tumor-, patient- and treatment-related factors. Therefore, a detailed analysis of the dose exposure to the structures of the vestibular apparatus is recommended.