bluuebunny/crossref_metadata_2025_split huggingface dataset:
OS02.4.A Molecular characterization of adult cerebellar glioblastomas identifies distinct prognosis subgroups
Authors: Picart T , Poncet D , Barritault M , Pallud J , Metellus P , Zouaoui S , Bauchet L , Guyotat J , Gabut M , Honnorat J , Ducray F , Meyronet D 
Published: September 2021

Abstract

BACKGROUND
Adult cerebellar glioblastomas (cGBM) are very rare and recent studies have shown that they constitute a heterogeneous group of gliomas. The aim of the present study was to characterize the prevalence and prognostic significance of major driver molecular alterations in a large series of cGBM.

MATERIAL AND METHODS
Adults with histologically proven cGBM diagnosed between 2003 and 2017 were identified from the French brain tumor database and the Club de Neuro-Oncologie of the Société Française de Neurochirurgie. Tumors were reviewed and reclassified according to WHO 2016. Targeted sequencing was performed, including determination of H3F3A, TERTp, IDH1/2, FGFR1, BRAF and EGFR status.

RESULTS
A total of 83 adult patients (median age 57 years) with cGBM (hemispheric n= 47, vermian n=14 or both n=22) were identified. Median overall survival was 10 months. Main molecular alterations observed were TERT promoter, H3F3A K27M, hotspot FGFR1 (N546 and K656), BRAF mutations, EGFR amplification and ATRX loss of expression in 19.2%, 18.8%, 10.9%, 2.6%, 19.5% and 22.7% of patients, respectively. cGBM could be classified into 6 mutually exclusive subgroups associated with age at diagnosis and prognosis: pTERT and/or EGFR amplified tumors (n=22, 26.5%, median age = 62 years, median OS = 4 months), H3K27M-mutant tumors (n=15, 18.1%, median age = 48 years, median OS =8 months), tumors with MAPK pathway activating mutations (FGFR1, BRAF) or occurring in NF1 patients (n=15, 18.1%, median age = 41 years, median OS = 57 months), radiation-induced tumors (n=5, 6%, median age = 47 years, median OS = 5 months), IDH-mutant tumors (n=1) and unclassified tumors (n=25, 30.1%, median age = 63 years, median OS = 17 months). In multivariate analysis, MAPK activating mutations and ATRX loss of expression were independently associated with a better outcome and pTERT/EGFR alterations with a worse outcome.

CONCLUSION
About 18% of tumors diagnosed as cGBM harbor actionable MAPK activating genetic alterations. Targeted sequencing enables to classify these tumors into clinically relevant subgroups.
OS03.3.A Characterization of long-term metabolic changes of irradiated brain metastases using serial dynamic FET PET imaging
Authors: Galldiks N , Stoffels G , Werner J , Bauer E K , Baues C , Celik E , Ruge M I , Fink G R , Langen K , Lohmann P 
Published: September 2021

Abstract

BACKGROUND
In the present study, we characterized the long-term metabolic changes of brain metastases irradiated with stereotactic radiosurgery (SRS) by sequential dynamic PET imaging using the radiolabeled amino acid O-(2-[18F]-fluoroethyl)-L-tyrosine (FET). We hypothesized that this approach is of considerable clinical value to diagnose delayed radiation-induced changes.

MATERIAL AND METHODS
From 2010–2021, we retrospectively identified patients with brain metastases from solid extracranial primary tumors who (i) were treated with SRS with or without concurrent immunotherapy using checkpoint inhibitors, (ii) had equivocal or progressive MRI findings after SRS, and (iii) subsequently underwent at least two additional dynamic FET PET scans during follow-up for long-term evaluation. Mean tumor-to-brain ratios (TBR) and the dynamic FET PET parameter time-to-peak were obtained. Diagnostic performances were calculated using receiver operating characteristic curve analyses. Diagnoses were confirmed histologically or clinicoradiologically.

RESULTS
We identified 36 patients with 98 FET PET scans (median number, 3; range, 2–6). Concurrent to SRS, 8 patients (22%) were treated with checkpoint inhibitors. Following SRS, suspicious MRI findings occurred after a median time of 11 months (range, 2–64 months). Subsequently, FET PET scans were acquired over a median period of 13 months (range, 5–60 months). The overall median follow-up time was 26 months (range, 8–101 months). Twenty-one patients (58%) had delayed radiation-induced changes. TBRs calculated from the last available FET PET scan showed the highest accuracy (92%) to identify delayed radiation-induced changes (threshold, 1.95; P&lt;0.001).

CONCLUSION
FET PET has a high diagnostic accuracy for characterizing the long-term changes of irradiated brain metastases.
OS06.9A Diversity of cellular communication in glioblastoma
Authors: Joseph K , Vollmer L , Ravi V M , Beck J , Hofmann U G , Schnell O , Heiland D H 
Published: September 2021

Abstract

BACKGROUND
Owing to recent advances in understanding of the active functional states exhibited within glioblastoma (GBM), intra-tumoral cellular signaling has moved into focus of neuro-oncological research. In our study, we aim to explore the diversity of transcellular signaling and investigate correlations to transcriptional dynamics and cellular behavior.

MATERIAL AND METHODS
Electrophysiological mapping of primary GBM cultures was performed by planar microelectrodes, in conjunction with calcium imaging in a human neocortical section based GBM model. Exposure to conditions that are physiologically present within the tumor was carried out to identify specific signaling cells of interest and signaling diversity presented as response to specific environmental conditions. Transcriptional dynamics and plasticity were examined by means of scRNA-sequencing with CRISPR based perturbation, spatial transcriptomics and deep long-read RNA-sequencing.

RESULTS
Electrophysiological profiles of primary GBM cell lines revealed highly variable network activity. Despite these different characteristics, all profiled primary cell-lines exhibited characteristics of scale-free networks, confirmed in a human neocortical GBM model. When the GBM was allowed to grow in “in-vivo” like environment, basal activity was significantly increased, owing to interactions with elements within the neural environment. Cellular signaling was directly correlated to changes in the environment, like hypoxia or glutamatergic activation, and total inhibition of electrical signaling was achieved only with a combination of both gap junction and synaptic inhibitors. Using single-cell sequencing and proteomics, we identified several genes related to synaptogenesis that plays a crucial role in network formation and consequently transcellular signaling. CRISPR based perturbation of these genes resulted in alterations in cellular morphology and decreased cellular connectivity, with electrical signaling being significantly attenuated. Single-cell sequencing of perturbed tumor cells in the GBM model revealed a loss of developmental lineages and significant reduction of cellular stress response state.

CONCLUSION
Our findings highlight the role of electrical signaling in glioblastoma. Cellular stressors induce intercellular signaling, leading to transcriptional adaptation suggesting that there exists a highly complex and powerful mechanism for dynamic transcriptional state adaptation.
OS08.4.A Retrospective analysis of in vivo 1H-magnetic resonance spectroscopy based on a machine learning approach enables reliable prediction of IDH mutation in patients with glioma
Authors: Bumes E , Fellner C , Lenz S , Linker R , Weis S , Wendl C , Wimmer S , Hau P , Gronwald W , Hutterer M 
Published: September 2021

Abstract

BACKGROUND
Mutation of isocitrate dehydrogenase (IDH) is not only an important landmark in the development of low-grade gliomas, but also has prognostic significance and is a potential therapeutic target. There is a high need to determinate IDH mutation status at diagnosis and during the course of therapy in a non-invasive and reliable manner. We established a machine learning approach based on a support vector machine to detect IDH mutation status in in vivo standard 1H-magnetic resonance spectroscopy (1H-MRS) at 3T with an accuracy of 88.2%, a sensitivity of 95.5% (95% CI, 77.2–99.9%), and a specificity of 75% (95% CI, 42.85–94.5%) in a prospective monocentric clinical trial. Here, the same method is applied in a retrospective cohort at 1.5T and tested for transferability.

MATERIAL AND METHODS
Validation cohort. The validation cohort comprised 100 patients with glioma for which standard in vivo 1H-MRS spectra had been acquired between 2002 and 2007. Standard single voxel spectroscopy had been measured at 1.5T using a PRESS sequence with a TR of 1500ms and a TE of 30ms. One sample had to be excluded due to non-malignant histology and for 15 samples the IDH mutation status was not available. Therefore, the validation cohort comprised 84 samples, of which 35 were bearing an IDH mutation in immunohistochemistry (sequencing for confirmation is outstanding). Machine learning. To transfer our method to an independent validation cohort our previously established machine learning approach was first trained on all samples of the 3T group. The trained algorithm was then applied to the data of the validation cohort. Here, among other factors the different field strengths, with which the spectra were acquired (3T vs. 1.5T) had to be considered.

RESULTS
27 samples of the validation cohort had to be excluded due to poor spectra quality. Our approach correctly detected IDH mutation status in 47 of 62 patients (75.8%), although the technical conditions were significantly different from our published prospective cohort. 17 of 30 patients bearing an IDH mutation were correctly identified, while 30 of 32 wild type patients were determined successfully.

CONCLUSION
Our approach to detect IDH mutation status has promising application in an unselected retrospective cohort, demonstrating transferability across different technical conditions. Further investigations to improve our technique and an advanced neuropathological processing of the samples are planned.
OS08.5.A Proteomic analysis of meningioma
Authors: Hanemann C O , Dunn J , Akther Y , Ercolano E , Adams C , Banton M , Sharma V , Hilton D 
Published: September 2021

Abstract

BACKGROUND
Meningioma is the most common primary intracranial tumor. Although ~80% are benign some WHO grade I are clinically aggressive. Chemotherapies are ineffective and biomarkers for clinical management are lacking. Approximately 60% sporadic meningiomas harbor mutations in the NF2 gene andutations in TRAF7, KLF4, AKT1, SMO and PIK3CA have been identified in the majority NF2-positive tumors esp lower grade. However, the molecular mechanisms behind meningioma tumourigenesis is still unclear. We aim to identify novel biomarkers and therapeutic targets of meningioma by characterizing the proteomic landscape.

MATERIAL AND METHODS
We analysed grade I, II and III frozen meningioma specimens and three different mutational groups: AKT1/TRAF7, KLF4/TRAF7 and NF2 -/- using LC-MS/MS to analyse global proteins, enriched phosphoproteins and phosphopeptides. Differential expression and functional annotation of proteins was completed using Perseus, IPA® and DAVID. For mutational subtypes quantitative phosphoproteomics was performed using TMT 10plex labeling approach followed by motif analysis using motif-X algorithm. We validated differential expression of proteins and phosphoproteins by Western blot and immunohistochemistry.

RESULTS
We quantified 3888 proteins and 3074 phosphoproteins across all meningioma grades. Bioinformatics analysis revealed commonly upregulated (phospho)proteins to be enriched in Gene Ontology terms associated with RNA metabolism. Validation confirmed significant overexpression of proteins such as EGFR, CKAP4, the nuclear proto-oncogene SET, the splicing factor SF2/ASF as well as total and activated phosphorylated form of the NIMA-related kinase, NEK9, involved in mitotic progression. Hexokinase 2 was overexpressed in higher grades. For the mutation subtypes we have quantified 4162 proteins across all mutational meningioma subgroups. Analysis showed distinct proteomic profiles of mutational subgroups. Comparative analysis showed 10 proteins were commonly significantly upregulated among all mutational subtypes vs. normal meninges. 257 proteins were commonly significantly downregulated and enriched with molecular functions including aldehyde dehydrogenase and oxido-reductase. Mutational subtype-specific analysis identified 162 proteins significantly upregulated in AKT1/TRAF7 vs. remaining sample groups to be enriched in the oxidative phosphorylation pathway. 14 and 7 proteins were commonly significantly upregulated in KLF4/TRAF7 and NF2 -/- mutant meningioma subtypes respectively. Several of these up-regulated proteins including ANNEXIN-3, CRABP2, CLIC3 and Endoglin were verified via WB. Lastly, analyses of 6600 phosphosites predicted regulatory kinases

CONCLUSION
We show extensive proteomic and phospophoproteomics analysis of meningioma and suggest new therapeutic and biomarker candidates.
OS09.4.A Health-related quality of life in low-grade glioma survivors 26 years after diagnosis
Authors: Boele F W , Reijneveld J C , de Witt Hamer P C , van Thuijl H F , Wesseling P , Lagerwaard F J , Taphoorn M J B , Kouwenhoven M C M , Snijders T J , Douw L , Klein M 
Published: September 2021

Abstract

BACKGROUND
Many patients with low-grade gliomas (LGGs) continue to survive for many years, yet little is known about patients’ health-related quality of life (HRQOL) in long-term survivorship. We previously investigated HRQOL in LGG patients diagnosed on average 6 years prior to assessment (T1, N=195) with a follow-up in stable patients on average 12 years after diagnosis (T2, N=65). We present a final follow-up of LGG survivors (T3), now decades after diagnosis.

MATERIAL AND METHODS
We invited patients who participated in our previous assessment (N=65), regardless of disease status. Patients completed questionnaires to assess HRQOL, fatigue, and depressive symptoms: Short Form-36 Health Survey (SF-36), European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire-Brain Tumour Module (EORTC BN20), Checklist Individual Strength (CIS), and the Center for Epidemiological Studies Depression Scale (CES-D). Changes over time (T1-T2-T3) on group level and participant level were assessed.

RESULTS
Of the 65 patients, 18 (27.7%) were deceased, 3 (4.6%) experienced tumour progression to WHO III, 7 (10.8%) declined, and 3 (4.6%) could not be contacted. Thirty-four patients (52.3%) participated. Of these, 2 had missing HRQOL data, with 32 patients included in analysis. Survivors were M=52.0 (sd=11.3) years old and diagnosed M=26.2 (sd=3.7, range 19–35) years prior. On group level, a statistically significant (but not clinically relevant) improvement in mental health (p=0.049), and a clinically relevant (but not statistically significant) decline in emotional role functioning was found. No other group-level changes over time in HRQOL were found. Minimal detectable change in HRQOL scale scores over time was observed in individual participants (28.1% only improvement; 25.0% only decline; 21.9% both improvement and decline) with 25.0% remaining completely stable. At T3, 25.0% of survivors scored above the cut-off for high risk of clinical depression (≥16 CES-D), and 53.1% of survivors classed as severely fatigued (≥35 CIS).

CONCLUSION
In this cohort of LGG survivors, assessed decades after diagnosis and treatment, HRQOL does not appear to be greatly impacted during survivorship. However, depressive symptoms and fatigue remain relatively common. Findings can help inform patients, their families, and clinicians and can serve as a benchmark for treatment trials evaluating interventions that can have very long-term effects.
OS09.6.A Cognition and health-related quality of life in long time survivors of high-grade glioma
Authors: Spoor J K H , Donders-Kamphuis M , Veenstra W S , van Dijk S A , Dirven C M F , Sillevis Smit P A E , van den Bent M J , Leenstra S , Satoer D D 
Published: September 2021

Abstract

BACKGROUND
Although prognosis is poor in high-grade glioma (HGG) patients, some become a long-term survivor (LTS). Health-related quality of life (HRQOL) and cognition are seen as indicators for quality of survival in HGG but data in LTS and their caregivers are scarce. We aim to investigate cognition and HRQOL in LTS with evaluation by their proxies.

MATERIAL AND METHODS
We included LTS with initial HGG-diagnosis between 1999–2014. Cognition was assessed with: Boston Naming Test, shortened Token Test, verbal (Category and Letter) Fluency, Diagnostic Instrument of Mild Aphasia, Hopkins Verbal Learning Test and Trail Making Test (A, B, B/A) and HRQOL with: EORTC Quality of Life Questionnaire (C30) and Brain Cancer Module (BN20). 15 Proxies evaluated patients’ HRQOL with: C30, BN20 and they filled in a burden scale: Caregiver Strain Index (CSI).

RESULTS
21 patients with grade III or IV glioma and 7 years (range 5–20 years) median survival after diagnosis participated. Compared to normative data patients deviated significantly on HVLT (direct recall, delayed recall, recognition true positives), TMT (A, B and B/A), BNT and CF (p&lt;0.05) which was not affected by hemispheric localization (left/right) or tumor grade (III/IV). HVLT delayed recall was significantly worse in patients with &gt;12 years survival compared to patients with &lt;12 years survival. Average QoL rating in patients was 75%, proxy’s evaluation about patients’ QoL was similar. Moderate correlations (p&lt;0.05) were found between impaired scores on TMT and CF and C30 cognition subscale and between impaired scores on CF, HVLT delayed recall and BNT and BN20 language subscale. At individual level only one patient had intact scores on all administered tests. Other patients had mild impairments on 1–5 subtests and severe impairment on 1–8 subtests. Five out of 14 (36%) proxies reported a great level of caregiver strain on CSI.

CONCLUSION
Most LTS suffer from cognitive impairments. Despite worse prognosis and cognitive impairments, at group level patients report relatively intact QoL, which is supported by their proxies. However, at the individual level severity of impairments is variable and high caregiver strain is reported in one-third of the proxies. Objective cognitive functioning was only modestly associated with subjective experience in patients. A patient-tailored approach is recommended to investigate individual impairments and needs for rehabilitation and support for patients and also for their carers.
OS10.4.A The effects of SmartCare on neuro-oncology family caregivers’ distress: a randomized controlled trial
Authors: Boele F W , Weimer J M , Proudfoot J , Marsland A L , Armstrong T S , Given C W , Drappatz J , Donovan H S , Sherwood P R 
Published: September 2021

Abstract

BACKGROUND
Patients with primary malignant brain tumors have high symptom burden and commonly rely on family caregivers for practical and emotional support. This can lead to negative mental and physical consequences for caregivers. We investigated effectiveness of an 8-week nurse-led online needs-based support program (SmartCare©) with and without online self-guided cognitive behavioral therapy (CBT) for depression compared to enhanced care as usual (ECAU) on depressive symptoms, caregiving-specific distress, anxiety, mastery, and burden.

MATERIAL AND METHODS
Family caregivers with depressive symptoms were randomized to three groups: SmartCare© plus/minus self-guided CBT, or ECAU. Primary outcomes (depressive symptoms (CES-D); caregiving-specific distress (Caregiver Needs Screen)) and secondary outcomes (anxiety (POMS-A), caregiver mastery (Caregiver Mastery Scale), and caregiver burden (Caregiver Reactions Assessment)) were assessed online. Intention to treat analyses of covariance corrected for baseline scores were performed for outcomes at four months.

RESULTS
In total, 120 family caregivers participated. Accrual and CBT engagement were lower than expected, therefore intervention groups were combined (n=80) and compared to ECAU (n=40). For depressive symptoms, no statistically significant group differences were found. Caregiving-specific distress decreased in the intervention group compared with ECAU (p=0.01, partial ɳ 2=0.08). Among secondary outcomes, there was a trend towards improvement in mastery for the intervention group compared with ECAU (p=0.08, partial ɳ 2=0.04).

CONCLUSION
SmartCare©, with or without self-guided CBT, reduced caregiving-specific distress with a trend towards improving mastery. SmartCare© has the potential to improve the lives of families coping with a brain tumor diagnosis.
P03.04 Primary CNS lymphoma of the corpus callosum: presentation and neurocognitive prognosis. Study of a monocentric cohort of 27 patients
Authors: Nilles C , Delgadillo D , Martin Duverneuil N , Mokhtari K , Mathon B , Hoang-Xuan K , Duran-Pena A , Morales A , Houillier C 
Published: September 2021

Abstract

BACKGROUND
The corpus callosum (CC) is frequently involved in primary central nervous system lymphomas (PCNSL). The aim of our study was to describe the impact of these lesions on neurocognition of patients presenting with PCNSL of the CC (PCNSL-CC) and their post-therapeutic evolution.

MATERIAL AND METHODS
This is a retrospective single-center study. Patients newly diagnosed at Pitié Salpêtrière Hospital from (1999–2018) were included in this study according to the following criteria: age &gt;18, immunocompetent patient, pathological confirmation (Diffuse Large B cell lymphoma) and CC as main location of the tumor on MRI. Clinical, neuroradiological and neuropsychological data of the patients were collected. In addition, prognostic factors for the neurocognitive outcome of the patients were investigated.

RESULTS
27 patients were included (median age: 67 years, median KPS: 70). At the time of diagnosis, 74% of patients had cognitive impairment and 59% of patients had balance disorders. The cognitive functions most frequently affected were memory and executive functions. Tumor lesions in the CC had a median maximum diameter of 5 cm with a so called “butterfly pattern” in 92% of cases. All patients received a high dose methotrexate based polychemotherapy, including one with radiation therapy, and 67% of patients achieved a complete remission (CR). Median PFS and OS were 33.3 months and 177.9 months respectively. With a median follow-up of 48 months (range 6–156), despite CR, there were still abnormal values in 17% of patients on overall efficiency, 17–55% of patients on executive function tests, 45–55% of patients on memory tests. No significant impaired values were found for visuo-spatial and language tests. Splenial location and age ≥ 60 years were significantly associated with worse episodic memory scores throughout the follow-up.

CONCLUSION
PCNSL-CC are associated with frequent cognitive dysfunctions, especially memory impairment, which may recover only partially despite CR, that warrant specific rehabilitation. Older age (≥ 60) and splenial location have worse neurocognition outcome.