bluuebunny/crossref_metadata_2025_split huggingface dataset:
P04.02 Single-cell transcriptomic analysis reveals shifts in glioblastoma cell composition in different BMP4-treated primary tumor cultures
Authors: Verploegh I S C , Conidi A , Brouwer R W W , van IJcken W F J , Lamfers M , Leenstra S , Huylebroeck D 
Published: September 2021

Abstract

BACKGROUND
Glioblastoma (GBM) is the most aggressive primary brain tumor. The well-known cellular heterogeneity of this cancer, which includes glioma tumor-initiating cells with stem cell characteristics (GSCs), (co)influences therapy resistance and tumor recurrence. Bone Morphogenetic Protein-4 (BMP4) promotes differentiation of GSCs towards astroglial lineage while suppressing oligodendrocyte maturation. Treatment with BMP4 is associated with increased survival in mice. BMPs exert effects in cell-type and context dependent fashion, but also generate subtle heterogeneity in transcriptional response among similar cells. We studied first the cell viability of BMP4-treated primary GBM cultures followed by single-cell RNA-sequencing (scRNA-seq) on two differently responding cultures, and found correlation between their responses and therapy sensitivity.

MATERIAL AND METHODS
Cell viability, proliferation and apoptosis were assessed in 17 patient-derived BMP4-treated GBM cell cultures. We selected one culture in which this treatment induced high in vitro therapeutic efficacy, and one in which the treatment was ineffective, for analysis by scRNA-seq and then compared the results on the initial panel of 17 cultures.

RESULTS
After 7 days of treatment with BMP4, cell viability ranged from 28% (referred to as highest in vitro therapeutic efficacy) to 132% compared to untreated cells. scRNA-seq of the previously mentioned cultures in passage 7 showed that all neural cell types that are usually found in freshly resected GBM, were also present in our cultures. In the culture where BMP4 induced high in vitro therapeutic efficacy, BMP4 induces the formation of a large new cell population displaying decreased cell proliferation, increased migration and cell death, while the pro-inflammatory cells were depleted. RNA-velocity analysis revealed that, the cycling of cells was greatly diminished in the culture where therapy with BMP4 was efficacious, whereas this was enhanced in the GBM culture with the lowest cell viability after treatment. Astroglial differentiation was induced in all BMP4-treated cultures, while neuronal differentiation was reduced most in the cultures in which BMP4 induced lower or no in vitro therapeutic efficacy. In the culture without therapeutic efficacy of BMP4 cell cycle arrest was not induced anymore. In addition, OLIG1/2 mRNA and protein levels seemed predictive for BMP4-therapy efficacy, while activation of translation-associated genes (RPL27A, RPS27) was a suitable, immediate post-therapeutic marker for this.

CONCLUSION
scRNA-seq of in vitro GBM cultures provides advanced insights into the mechanism underlying therapy efficacy of BMP4. Neural differentiation status is distinctive for therapeutic efficacy of BMP4 in vitro before and after therapy.
P04.03 Different role of integrin a6 in glioblastoma proneural and mesenchymal stem-like cells
Authors: Stanzani E , Pedrosa L , Bourmeau G , Anezo O , Noguera-Castells A , Passoni L , Núria N , Seano G , Tortosa A , Martinez-Soler F 
Published: September 2021

Abstract

BACKGROUND
The plasticity of tumoral cells and the presence of cells displaying stem-like features are two interrelated traits of Glioblastoma (GBM) lesions and both concur in defining its heterogeneity. Particularly, GBM stem-like cells (GSC) can be classified according to trascriptional data in different subgroups, being the Proneural (PN-GSC) and the Mesenchymal (MES-GSC) the most consolidated clusters. GSC are responsible of most of the malignant characteristics of GBM, including therapeutic resistance and tumor recurrence. Therefore, a better understanding of the mechanisms regulating GSC responsiveness to therapy taking into account GSC molecular heterogeneity may help to improve patient’s outcome. Integrin a6 is a commonly used marker for GSC capable to enrich for GSC population and sustain stemness. We investigate the role of integrin a6 in both PN and MES GSC on stemness and radioresistance.

MATERIAL AND METHODS
The expression of integrin a6 was analyzed in GSC cultures obtained from post-surgical specimens either displaying PN or MES trascriptional traits. Using cell sorting to enrich for integrin a6 expression (integrin a6-high and a6-low) and gene silencing with lentiviral-based shRNA, integrin a6 impact on both GSC cultures was tested. Also, silenced MES-GSC were analysed by means of RNA-seq. The major pathways found altered by integrin a6 silencing were validated at functional level using gliomasphere-based clonogenic assay, extreme limiting dilution assay and gamma-H2AX to monitor DNA damage repair kinetics.

RESULTS
After sorting GSC cultures by integrin a6 expression, PN-GSC a6-low showed a significant reduction in clonogenic capability and gliomasphere size when compared to a6-high (p&lt;0.0001). On the contrary, sorted MES-GSC did not display any differences. Similar results were obtained following integrin a6 lentiviral silencing. However, RNAseq on silenced MES-GSC revealed a significant impact on cell cycle regulation and DNA damage repair pathways. Indeed, Integrin a6 trascriptional inhibition in MES-GSCs impaired the capacity to clear gamma-H2AX foci after ionizing radiation (p&lt;0.001) and significantly alters MES-GSC capacity to recover from radiation treatment in gliomasphere formation assay (p&lt;0.01). According to the interpretation of the curves with the linear quadratic model, integrin a6 silenced cells displayed higher alpha- and beta- values and lower alpha/beta ratio. The obtained values demonstrate increased radiosensitivity and impaired capacity to repair sublethal DNA damage, in addition to an enhanced sensitivity to fractionated doses.

CONCLUSION
The data obtained showed that Integrin a6 regulates proliferation and stemness-related features in PN-GSC while supports radioresistance of MES-GSCs. Altogether, we reveal that integrin a6 controls different stem-associated features in GSCs depending on the molecular subtype.
P04.05 Targeted Gene-Expression analysis during malignant transformation in primary and secondary malignant meningioma
Authors: Maier A D , Meddis A , Haslund-Vinding J , Mirian C , Areskeviciute A , Nguyen P , Westergaard C , Melchior L C , Munch T N , Skjøth-Rasmussen J , Poulsgaard L , Ziebell M , Bartek Jr J , Broholm H , Poulsen F R , Gerds T A , Scheie D , Mathiesen T 
Published: September 2021

Abstract

BACKGROUND
Malignant meningiomas comprise 2–5% of all meningiomas. The process of malignant transformation when benign meningiomas (WHO grade I-II) become malignant (WHO grade III) has not previously been investigated in sequential tumour surgeries. Upregulation of FOXM1 expression and DREAM-complex repression have shown phenotypical subgroups correlating with WHO grade and aggressiveness. We investigated the RNA expression of 30 genes central to meningioma biology and 770 genes involved in neuroinflammatory pathways in primary and secondary malignant meningioma patients who underwent one to several operations.

MATERIALS AND METHODS
We identified a cohort of consecutive malignant meningioma patients treated at Rigshospitalet, Copenhagen from 2000–2020 (n=51) and gathered their malignant tumours and previous WHO grade I/II tumours. The malignant cohort (MC) was counter matched with a benign cohort (BC) where patients had no recurrences during follow-up. RNA expression signatures from 140 samples from the MC and 51 samples from the BC were analysed with the Nanostring Neuroinflammation panel customized with 30 genes known to be relevant in meningioma phenotypes.

RESULTS
49% of MC patients had a previous grade I/II meningioma making them secondary malignant meningioma patients. Progression-free survival calculated from first malignant surgery to first recurrence or death showed no significant difference in the primary vs. secondary patients. Preliminary results of single-gene analysis of MC tumours showed FOXM1, MYBL2, TOP2A, BIRC5 expression was higher in WHO grade III samples. Gene-expression signatures in the individual patients and gene ontology enrichment analyses are in process.

CONCLUSIONS
FOXM1, MYBL2, TOP2A, BIRC5 RNA expression levels seem to rise during malignant progression across patients. Gene-expression analysis using the Nanostring technology is feasible and a potentially powerful tool to distinguish meningiomas prone to malignant transformation from truly benign meningiomas.
P04.11 10-Year Institutional Retrospective Case Series of WHO Grade II Gliomas and Correlation of Seizures, Lobar Location, Histopathological Subtype and IDH-1 Mutation (2010–2020)
Authors: Lammy S , Bridgman E , Johnson H , Taylor A , Grivas A 
Published: September 2021

Abstract

BACKGROUND
A 10-year retrospective case series was undertaken of all patients who had a tissue diagnosis of a World Health Organisation (WHO) Grade II glioma, i.e. low grade glioma (LGGM), at the Institute of Neurological Sciences (INS) between January 2010 and January 2020 (NB: pre-2016 World Health Organisation classification). The objective was to assess the correlation of World Health Organisation (WHO) Grade II gliomas to seizure symptomology, intracerebral tumour location, histopathological glioma sub-type and molecular markers including isocitrate dehydrogenase-1 (IDH-1) mutation.

MATERIAL AND METHODS
We extracted data regarding clinical, radiological, histological, molecular discriminators and functional outcomes in patients. The pre-operative symptomology was restricted to seizures, headache and focal neurological deficits.

RESULTS
84 patients underwent resection and had a mean age of 42rs (range: 21-77yrs]). Seizures (NB: pre-2017 International League against Epilepsy classification [ILAE]) occurred in 71% and of these 52% were generalised, 37% partial and 11% mixed. 31% had ongoing seizures postoperatively. Headache occurred in 38% (of these 50% had headache and seizures). Focal neurological deficits (FNDs) occurred in 21% (of these 61% had FNDs and seizures). Seizure, as an isolated pre-operative symptom occurred in 48% patients compared to isolated headache in 10% and isolated FNDs in 4%. Anatomically, 58% of lesions were frontal. The seizure spatial frequency was 60% frontal. Histologically, 60% were diffuse astrocytomas and 40% oligodendrogliomas. Furthermore, 71% of oligodendrogliomas and 49% of diffuse astrocytomas had a frontal location. IDH-1 mutation occurred in 80% patients (75% of these had seizures) and of these 66% were frontal.

CONCLUSIONS
Our analysis confirms a correlation between incidence of seizures, frontal lobar location, histopathological subtype and IDH-1 mutations (p = &lt;0.05
P05.04 Reradiation by reccurent gliomas with VMAT (Volumetric Modulated Arc Therapy) technique- survival benefit
Authors: Theodorou M , Polycarpou I 
Published: September 2021

Abstract

BACKGROUND
Patients who have been treated with reirradiation for recurrent glioma reported survival benefits. Limited data are available for the outcomes after fractionated re-irradiation.
This study aims to investigate whether re-irradiation of recurrent glioma with 45Gy dose can increase the overall survival of patients.

MATERIAL AND METHODS
A retrospective analysis of 35 patients re-irradiated for high-grade glioma recurrence between 2012 and 2020 was performed. All included patients met the following criteria: a) histopathological confirmation of primary brain cancer at initial diagnosis; b) a history of initial primary radiation; c) histological and/or imaging modality confirmation of recurrence. Outcome metrics included overall survival, prognostic factors for survival, and treatment-related toxicity.

RESULTS
After the end of re-irradiation the median overall survival was 11 months (95% confidence interval, 7–14 months). From the patients evaluated in the current study after the end of re-irradiation the progression free survival was 6 months (3.8 - 8 months) while after the end of first radiation was 13 months (8 - 17.9 months). Our findings suggest that re-irradiation might prolong survival rates.

CONCLUSION
Recurrent Glioblastoma WHO IV is associated with a median overall survival of less than a year and the majority of patients have profound tumor-related symptoms.The results of this study suggest that re-irradiation may prolong the overall survival.
P06.03 Child, parent, and clinician selection of patient-reported outcome measures to use in pediatric neuro-oncology outpatient follow-up clinics
Authors: Bull K S , Stubley S , Freeman A , Liossi C , Darlington A E , Grootenhuis M A , Hargrave D , Morris C , Walker D A , Kennedy C R 
Published: September 2021

Abstract

BACKGROUND
Survivors of childhood brain tumours are at risk of poor health-related quality of life (HRQoL). Appropriate and relevant measures can be used to monitor HRQoL so that timely interventions may be made for issues thus identified. We had previously selected patient-reported outcome measures (PROMs) with good psychometric properties that had emerged as well-suited for this use in two systematic reviews. The aim of the present study was to ascertain the views of families regarding the suitability of the selected measures for use in paediatric neuro-oncology follow-up clinics. These views were then used to inform the choice of PROMs for use on the KLIK PROM portal, a website designed to gather HRQoL information from families.

MATERIAL AND METHODS
As part of the PROMOTE study, we used a multi-centre, multi-informant, cross-sectional, qualitative methods research design. Using ‘think aloud’ audio-recorded interviews, children aged 8–17 years diagnosed within the previous five years with a brain tumour, off treatment and receiving outpatient care, and their parents, were shown a total of nine PROMs and asked to express their views on which they preferred. Detailed notes were made of all audio-recordings by two independent researchers. The final choice of PROMs to be included on the KLIK PROM portal was agreed through discussion of the PROMs selected by families with an expert panel of clinicians, researchers, and parent representatives.

RESULTS
16 children and 17 parents participated and of these 2 children and 2 parents did not express a preference. The Pediatric Quality of Life Inventory (PedsQL) Core module was the most popular among the children and parents with 7/14 (50%) of children selecting it as either their 1st or 2nd choice citing that they liked the questions and felt them to be most relevant to them, and 8/15 (53%) of parents citing that it was easy, quick and simple, the wording was easy, and they liked the questions about emotional, social, and school functioning. The least popular questionnaires, with no participants selecting them as first choices, were the Kidscreen-10 and the Health Utilities Index. The latter 2 were selected only as 2nd or lower choices by 1 child and 3 parents respectively.

CONCLUSION
The PROMs that were finally selected for the KLIK PROM portal were the parent- and child-report PedsQL-Core measures of HRQoL due to their good psychometric properties, family and clinician preference and perceived relevance to follow-up care, and for clinical utility on the KLIK PROM portal.
P09.05 Treatment strategy of MRI postcontrast non-enhanced gliomas
Authors: Kalita O , Hrabalek L , Jan V , Slachta M , Klementová Y , Dolezel M , Cechakova E , Drabek J , Hajduch M , Hok P , Hlustik P , Tuckova L , Halaj M , Vrbkova J 
Published: September 2021

Abstract

BACKGROUND
MRI postcontrast nonenhanced brain tumors are found benign biologic entities with the better prognosis. The aim of this paper is to evaluate predictive features on MRI considered definite diagnosis occurrence, tumor progression, upgrading and postcontrast enhancement evolution on follow-up serial MRI.

MATERIAL AND METHODS
We retrospectively collected patients with the initially MRI postcontrast nonenhanced brain tumors, treated in our hospital from January 2009 to June 1, 2006. All tumors were converted into WHO 2016 IDH status classifications in accordance with current recommendations. Information about surgeries, patient clinical condition, MRI, and results of histological, immunohistochemical, molecular genetic, and cytogenetic investigations were gathered. Semiautomatic segmentations were performed using FSLeyes software (part of FSL package) on preoperative and followed-up 3D T1-w MPRAGE, T2-w or FLAIR scans. We focused on residual tumor volume, and time distribution of T2/FLAIR changes and T1-w postcontrast enhancement evolution.

RESULTS
Seventy-eight patients were enrolled in this study. There were 47 gliomas grade II 22 grade III and 9 grade IV. Glioma II comprised 35 diffuse astrocytomas (23 patients had IDH1 mutation). Nine gliomas grade III and 6 gliomas grade IV had IDH1 mutation. Overall survival in glioma group grade II, grade III, grade IV was 187.9 months, 71.1 months and 25.2 months, respectively. Oncotherapy underwent 14 gliomas grade II after first surgery, 13 patients had radiotherapy a 1 patient had neoadjuvant chemotherapy. Seventeen gliomas grade III were indicated to oncotherapy, 5 patients had radiotherapy and 12 had chemoradiotherapy. All patients with glioma grade IV experienced oncotherapy. Time to progression of non-contrast enhanced brain tumor was 5.8 years. Time to up-grading of non-contrast enhanced brain tumor was 16.8 months. Detailed time relations of glioma subgroup will be displayed in tables.

CONCLUSION
Regarding MRI postcontrast non-enhanced tumors, predominantly low grade gliomas (LGG), aggressive oncotherapy are reluctant to use but they are prone to repeat surgeries. Decision making issues are age, clinical patient status, histologic and genetic tumor characteristics, residual tumor volume, published guidelines for brain tumor treatment, and patient′s willing. Generally, hyposignal on the T1 postcontrast scans strictly relate to the better prognosis, even in HGG. Longer survival expectancy increases quality of life awareness. Prior to MRI postcontrast enhanced evolution and up-grading, T2/FLAIR changes have been demonstrated. T2/FLAIR scans considered also main role in LGG follow-up strategy. Individual tailored therapy is principal strategy.
Supported by Ministry of Health of the Czech Republic, grant nr. NV19-04-00281 and grant nr. NU21-03-00195
P12.04 Body Mass Index: a possible PICC-related complications risk factor in neuro oncological patients
Authors: Simonetti G , Gaviani P , Botturi A , Redaelli V , Anghileri E , Silvani A 
Published: September 2021

Abstract

BACKGROUND
The use of central venous catheter with peripheral insertion (PICC) has increased rapidly in recent years particularly in cancer patients because they represent a stable and safe vascular access to administer irritants or vesicants therapies. However, the benefit provided may occasionally be affected by severe complications. An observational study conducted at our Institute, showed a significant increase of thromboembolic risk in neuro-oncological patients compared to general cancer population (16.3% vs 6.7% respectively). For this reason, it is essential to identify independent risk factors in order to avoid preventable harm.

MATERIAL AND METHODS
Neuro-oncological patients with PICC that developed a thromboembolic event were retrospectively analyzed. We evaluated clinical data, BMI, KPS, steroid therapies and anticoagulants at the time of positioning of the PICC and at the onset of the thrombotic event.

RESULTS
A total of 90 neuro-oncological patients have been analyzed. The most common histology was represented by glioblastoma, followed by anaplastic astrocytoma, primary central nervous system lymphoma, grade II glioma. 17.6% of patients were at first diagnoses, 41.6% were at the first recurrence, and the remaining patients were at the second or third recurrence. The median KPS was 90 (range 80–100), and the median ECOG was 0 (range 0–2). Overall, 14% patients developed thromboembolic events within a median time of 34.5 days (range 5–146) after PICC implantation. Among these, 64% of patients was considered overweight. No patients were on anticoagulant therapy but all were treated with a median dose of 5.5 mg of steroids (range 3,5-12), stable between PICC insertion and onset of adverse event.

CONCLUSION
64% of patients who developed a thromboembolic event had BMI &gt;28 at the time of PICC insertion, suggesting a possible trend towards a risk of developing PICC related thrombosis in overweight/obese patients. Other independent risk factors for PICC associated complications seems to be amount of previous chemotherapies administered: 82% of patients who developed thrombotic complications had already undergone at least one line of chemotherapy before PICC placement, suggesting this condition as a possible risk factor for the onset of the event. Also failed positioning attempts could damage vascular endothelium, contributing to the onset of thrombotic complications. An accurate anamnesis and a physical evaluation with particular attention to the presence of malnutrition could help in the in the early identification of independent risk factors that could farther negatively influence the outcome of neuro-oncological patients.
P12.07 The potential of cannabinoids to improve quality of life in glioma patients: A meta-analysis in patients with neurological and oncological disease
Authors: Belgers V , Röttgering J G , Douw L , Klein M , van de Ven P M , Ket J C F , Bacher Svendsen K , Weber M , Lopez-Sendon J , Olde Rikkert M G , Chagas M H N , van Linde M E , Kouwenhoven M C M , de Witt Hamer P C 
Published: September 2021

Abstract

BACKGROUND
Gliomas are primary brain tumors with a dismal prognosis. Reducing symptoms and maintaining quality of life (QoL) are main treatment aims in glioma patients. Mental well-being is an important subdomain of QoL. Cannabinoids have been suggested to alleviate frequently experienced symptoms of reduced mental well-being such as anxiety or depression. Glioma patients frequently report unprescribed cannabinoid use for these reasons. We performed a meta-analysis of the current evidence on cannabinoid efficacy on QoL and mental well-being to identify its added value in treatment of glioma patients.

MATERIAL AND METHODS
We performed a systematic PubMed, Embase and Web of Science search according to the PRISMA guidelines on September 22nd and 23rd, 2020. The effects of any dose of tetrahydrocannabinol (THC) or cannabidiol (CBD) on both general QoL and mental well-being were evaluated. The intervention had to be given for at least a week to establish a steady-state concentration. Effect size was calculated using Hedges g. Risk of bias of included studies was assessed using Cochrane’s Risk of Bias tool 2.0.

RESULTS
We retrieved no publications on cannabinoids use and QoL in glioma and, therefore, we expanded the search to cannabinoid use in other cancer types and chronic central nervous system (CNS) diseases. Sixteen studies were identified: four in cancer and twelve in CNS disease. Meta-analysis showed no effect of cannabinoids on general QoL (twelve studies in 1,740 patients; g = -0.02, 95% CI -0.11 to 0.07, p = 0.65) and mental well-being (twelve studies in 1,587 patients; g = -0.00, 95% CI -0.15 to 0.14, p = 0.96). Risk of bias was low in five studies, raised some concern in one study and was high in ten studies, mainly due to possible unblinding of patients after psychoactive adverse effects.

CONCLUSION
No studies on the effects of cannabinoids on QoL in glioma patients have been reported. A pooled analysis of studies in oncological patients and patients with CNS disease showed no effect of cannabinoids on QoL or mental well-being. However, studies were clinically heterogeneous and only one small study investigated monotherapy CBD with undecided results. As many glioma patients currently use cannabinoids, and monotherapy CBD has not been sufficiently investigated, future studies are necessary to evaluate its value in this specific population.

SUPPORT/DISCLOSURE
This meta-analysis has been funded by The Anita Veldman Foundation (CCA-2019-2-21).