bluuebunny/crossref_metadata_2025 huggingface dataset:
OS02.5.A DEVELOPMENT OF A PATIENT DECISION AID FOR PATIENTS WITH RECURRENT HIGH-GRADE GLIOMA - A CO-CREATION PROCESS
Authors: Sørensen von Essen H , Rom Poulsen F , Hedegaard Dahlrot R , Piil K , Dahl Steffensen K
Published: September 2023

BACKGROUND

Patients with high-grade gliomas (HGG) face a difficult decision when the tumor recurs. There are no curable treatments, and all palliative treatment options include risks of complications and adverse effects. In this situation, support is needed for patients to navigate between these trade-offs and make preference-sensitive decisions. Shared decision making (SDM) is an approach where a decision is made in collaboration between a clinician and a patient by combining the clinician’s scientific evidence and knowledge with the patient’s subjective values and preferences. SDM aims to make quality decisions congruent with the individual patient’s informed preferences and to support patients in the decisional process. Patient decision aids (PtDA’s) have proven to be an efficient tool for facilitating SDM. However, there are no PtDA’s available for patients with recurrent HGG. This study aimed to develop a PtDA in a co-creation process with patients with recurrent HGG and family caregivers

MATERIAL AND METHODS

Based on the International Patient Decision Aids Standards, our team developed a PtDA through an iterative process of drafting and re-drafting. Patients and family caregivers were involved throughout the process as active team members. The PtDA was alpha-tested using structured interviews and the Preparation for Decision Making Scale questionnaire to assess the understandability, acceptability, and perceived usefulness of the PtDA. Data were analyzed using descriptive statistics and a directed content-analysis approach.

RESULTS

The final draft of the PtDA contained six treatment and care options, including the option of doing nothing. A balanced presentation of benefits and disadvantages was described for each option. In the alpha test, 31 patients with HGG, family caregivers, and clinicians assessed the final draft of the PtDA and found it to be understandable and acceptable. Patients and family caregivers perceived the PtDA to have a higher level of usefulness in supporting and preparing for decision making than did the clinicians (p=0.05). Ten of 11 clinicians were willing to use the PtDA in future consultations.

CONCLUSION

The PtDA was assessed to be understandable and acceptable by patients, family caregivers, and clinicians. It was perceived to support and prepare patients with recurrent HGG for decision making, and the clinicians were willing to use it in consultations. The involvement of patients and family caregivers as team members added value to the development process and the PtDA. However, the most applicable model of patient involvement in neurooncological research must be further explored to identify the benefits and limitations of approaches.
OS05.6.A TELEMEDICINE IN NEURO-ONCOLOGY - AN EVALUATION OF REMOTE CONSULTATIONS DURING THE COVID-19 PANDEMIC
Authors: Feldheim J , Schmidt T , Oster C , Feldheim J , Sure U , Kleinschnitz C , Lazaridis L , Kebir S , Glas M
Published: September 2023

BACKGROUND

To minimize the risk of infections during the Covid-19 pandemic, remote video consultations (VC) experienced an upswing in most medical fields. However, despite its multiple benefits, telemedicine in neuro-oncology comprises unique challenges and opportunities: Comprehensive neurological examinations that might not translate sufficiently to VC are very relevant for neuro-oncological patients. Also, communication in neuro-oncology can be highly emotional and challenging on a personal level, and VC have been accused of creating emotional distance between the patients and doctors. So far, evidence-based insights to evaluate and potentially customize current concepts of VC in neuro-oncology are scarce.

MATERIAL AND METHODS

We analyzed >3.700 neuro-oncological consultations conducted at our institution between the 1st of April 2020 and the 30th of June 2021, of which >300 were conducted as VC by patients' preference. Then we collected patients' basic demographic and clinical data and compared how the collective of patients that chose to participate in VC distinguished from those who did not. Also, we examined the reasons, suitable/less suitable encounters, VC's benefits and disadvantages and future opportunities by conducting an anonymized survey in the VC collective.

RESULTS

The ratio of VC participation correlated with the incidence of SARS-CoV-2 infections (r=0.5, p=0.03). Patients that participated in VC had worse clinical conditions and higher grades of malignancy, were more often diagnosed with glioblastoma, and had a longer travel distance (all p<0.01). VC were considered a fully adequate alternative to face-to-face consultations for almost all encounters that patients chose to participate in (>70%), except initial consultations. Most participants preferred to alternate between both modalities rather than participate in one alone but preferred VC over telephone consultation. Patients stated that VC made them feel safer. Participants also expressed interest in implementing other telemedicine modalities (e.g. apps) into neuro-oncology.

CONCLUSION

VC are a promising addition to patient care in neuro-oncology. However, patients and encounters should be selected individually. Patient subgroups that might be especially suitable for VC are patients with long travel distances seeking an expert opinion, patients in poor clinical condition, glioblastoma patients and patients requiring frequent consultations in person. A strength of face-to-face consultations is the more intense personal contact, whereas VC convince with a lower expense. VC made patients feel safer, and participants expressed their interest in expanding the offer of telemedicine in neuro-oncology further.
OS06.6.A FLAIR-SIGNAL INTENSITY CHANGE AS A PREDICTOR OF PROGRESSIVE GLIOBLASTOMA IN THE EORTC CENTRIC AND CORE STUDIES
Authors: Flies C M , Friedrich M , Lohmann P , van Garderen K , Smits M , Tonn J C , Weller M , Gatson N N , Galldiks N , Snijders T J
Published: September 2023

BACKGROUND

In patients with glioblastoma, radiological recurrence of enhancing tissue after chemoradiotherapy can originate from progressive disease (PD) or pseudoprogression/treatment-associated changes. In earlier studies, a change of the FLAIR-signal intensity (SI) predicted PD with 18-84% sensitivity and 71-100% specificity, both with quantitative resection cavity to ventricle SI ratio of 7.3. We assessed the rate of FLAIR-signal intensity change in patients with O6-methylguanine DNA methyltransferase (MGMT) promoter-methylated or -unmethylated glioblastoma from the randomised CENTRIC and CORE studies (NCT00689221, NCT00813943). These patients were treated with chemoradiotherapy or chemoradiotherapy with cilengitide, an integrin inhibitor.

METHODS

Patients from both studies with a gross total resection and ≥3 follow-up MRIs were included. The outcome was determined by the modified RANO criteria of 2017. Two researchers evaluated the FLAIR-SI of the resection cavity. A positive SI change was scored qualitatively in case of a visually brighter signal intensity than on the previous MRI. Quantitative analysis was based on a ratio of SI in the resection cavity compared to SI of the ventricles.

RESULTS

Follow-up was available for 307 patients. Median time from RT to (preliminary) progressive disease was 6.2 months for MGMT promoter-methylated (interquartile range, (iqr)=2.5-14.7) and 6.0 for MGMT promoter-unmethylated glioblastoma (iqr=2.7-8.9). Of the 307 patients, 142 patients showed stable disease, response, or treatment-associated changes and 165 (preliminary) PD at the end of follow-up. A qualitative FLAIR-SI change was found in 61 patients (19.9%) and 44 of these developed (preliminary) PD, with a positive predictive value of 72.1% (95%-CI 59.2-82.9%); positive predictive value was 88.9% for MGMT promoter-unmethylated and 67.4% for MGMT promoter-methylated glioblastoma. We found an overall sensitivity of the FLAIR-SI-change for PD of 26.7% (95%-CI 20.1-34.1%), with ranges of 22.9 to 39.2% depending on MGMT promoter methylation status and treatment allocation; specificity ranged from 88 to 91.3%, with an overall specificity of 88.0% (95%-CI 81.5-92.9%). Median time from first FLAIR-SI to progression was 0 months (iqr=0-2.7) with a range of 0 to 13, and from the brightest signal was 0 months (iqr=0-1.0). The average signal intensity ratio was 10.2 at the time of the brightest signal; further quantitative analyses will be presented.

CONCLUSION

We confirmed the positive predictive value of a change in FLAIR-signal intensity of the resection cavity for concurrent or subsequent progressive disease in resected glioblastoma. Patients with such a change of the signal intensity should be worked up further on (e.g. PET imaging, biopsy, any clinical change) or else undergo another MRI closely.
OS09.1.AIN VIVOTWO-PHOTON TUMOR IMAGING IN AN ORTHOTOPIC MEDULLOBLASTOMA MOUSE MODEL
Authors: Teske N , Kutlu N N , Herold J J , Dengler L , Eberle C , Nikolaishvili E , Karschnia P , Blobner J , Müller K , Langer S , Buschinger V , Warmuth L , Busch D H , Buchholz V R , Thon N , Tonn J , Feuchtinger T , von Baumgarten L
Published: September 2023

BACKGROUND

Medulloblastoma represents the most common primary brain malignancy in pediatric patients and is associated with neuro-cognitive impairment and frequent relapses after aggressive multimodal therapy. Adoptive immunotherapies such as CAR T-cell therapy are currently being investigated, showing promising results in preclinical models but lacking efficacy in first-in-human trials. Refined in vivo models to investigate reasons for treatment failures are therefore urgently needed.

METHODS

We developed a xenogeneic orthotopic medulloblastoma (MB) model in mice by combining a chronic cerebellar window with repetitive intravital two-photon laser scanning microscopy. Red tdTomato-fluorescent DAOY (SHH MB) tumor cells expressing EphA2 were implanted intracranially into the cerebellum of immunodeficient mice (n = 7), and tumor cell formation was followed by in vivo-microscopy. Intravenous fluorescein isothiocyanate (FITC)-dextran was used for intravascular plasma staining. EphA-directed CAR T-cells were injected into the adjacent brain parenchyma.

RESULTS

Chronic cranial window implantation was well tolerated and allowed repetitive visualization of the mouse cerebellum. After intracranial tumor cell implantation, continuous tumor growth could be evaluated with epifluorescence as well as 2-photon laser scanning microscopy. Tumor formation was identified as early as day 5 in every mouse and could continuously be followed up to 35 days until mice succumbed due to tumor burden. Window quality and fluorescence intensity remained high until the end of the experiments. Studies on GFP-expressing CAR T-cell injection directed against EphA2 are currently ongoing.

CONCLUSIONS

We herein establish a robust orthotopic medulloblastoma mouse model that allows repetitive in vivo tracking of fluorescence-expressing tumor cells, CAR T-cells and blood vessels over weeks. Such models may be used to study medulloblastoma tumor growth under the influence of different immunotherapies and reveal interactions between tumor cells and CAR T-cell therapies on a single-cell level.
OS09.4.A RANO 2.0: UPDATE TO THE RESPONSE ASSESSMENT IN NEURO-ONCOLOGY (RANO) CRITERIA FOR HIGH- AND LOW-GRADE GLIOMAS IN ADULTS
Authors: Wen P , Van Den Bent M , Youssef G , Cloughesy T , Ellingson B , Weller M , Galanis E , Barboriak D , DeGroot J , Gilbert M , Huang R , Lassman A , Mehta M , Molinaro A , Preusser M , Rahman R , Shankar L , Stupp R , Sul J , Villanueva-Meyer J , Wick W , Macdonald D , Reardon D , Vogelbaum M , Chang S
Published: September 2023

BACKGROUND

The Response Assessment in Neuro-Oncology (RANO) criteria for high-grade gliomas (RANO-HGG) and low-grade gliomas (RANO-LGG) were developed to improve reliability of response assessment in glioma trials. Over time some limitations of these criteria were identified, and uncertainty emerged regarding integrating features of the modified RANO (mRANO) or the immunotherapy RANO (iRANO) criteria.

MATERIAL AND METHODS

Informed by data from a cohort of glioblastoma patients and other evaluations of RANO criteria that allowed evaluation of features of the different criteria, the RANO working group developed updates to the RANO criteria (RANO 2.0).

RESULTS

Based on the 2021 WHO classification of gliomas, we recommend a standard set of criteria for both high and low-grade gliomas, to be used for all trials regardless of the treatment modalities being evaluated. In the newly diagnosed setting, the post-radiotherapy MRI, rather than the post-surgical MRI, will be used as the baseline for future comparison. Since the incidence of pseudoprogression is high in the 12 weeks following radiotherapy, continuation of treatment and confirmation of progression during this period with a repeat MRI, or histopathologic evidence of unequivocal recurrent tumor, is required to define tumor progression. However, confirmation scans are not mandatory after this period nor for recurrent tumors. For treatments with a high likelihood of pseudoprogression, mandatory confirmation of progression with a repeat MRI is highly recommended. The primary measurement remains the maximum cross-sectional area of tumor (2-dimensional) but volumetric measurements are an option. For IDH-wildtype glioblastoma, the non-enhancing disease will no longer be evaluated. In IDH-mutated tumors with a significant non-enhancing component, clinical trials may require evaluating both the enhancing and non-enhancing tumor components for response assessment.

CONCLUSION

These criteria represent a work in progress that will hopefully improve the assessment of response in glioma trials. Future updates will incorporate novel developments, advanced imaging techniques, and endpoints as they become validated.
OS09.5.A BREAKING DOWN BARRIERS: THE IMPACT OF BLOOD-BRAIN BARRIER DISRUPTION ON THE GLIOMA METABOLIC MICROENVIRONMENT, IN SITU
Authors: Riviere-Cazaux C , Carlstrom L , Rajani K , Munoz-Casabella A , Rahman M , Gharibi-Loron A , Brown D , Miller K , White J , Himes B , Jusue-Torres I , Ikram S , Ransom S , Hirte R , Oh J , Elmquist W , Sarkaria J , Vaubel R , Rodriguez M , Warrington A , Kizilbash S , Burns T
Published: September 2023

BACKGROUND

The microenvironment of glioblastoma is complex and defined in part by protumorigenic metabolic changes. Within this microenvironment, blood-brain barrier disruption is often associated with the most aggressive portions of the tumor. To date, the metabolic tumor microenvironments of enhancing, blood-brain barrier (BBB) disrupted portions of gliomas, as compared to BBB-intact tumor, remain poorly understood. Specifically, it is unclear if the associated blood-brain barrier disruption merely reflects or functionally supports tumor aggressiveness.

METHODS

Intra-operative high-molecular weight microdialysis was utilized under an investigational device exemption (NCT NCT04047264) to sample the extracellular metabolome of radiographically diverse regions during fifteen neurosurgical resections. The global extracellular metabolome of recovered microdialysate from contrast-enhancing and non-enhancing tumor, as well as brain adjacent to tumor, was evaluated via ultra-performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS) on the Metabolon platform and assessed using enrichment and correlation analyses.

RESULTS

Among 162 named metabolites identified via ultra-performance liquid chromatography tandem mass spectrometry, a novel glioma-associated metabolite, guanidinoacetate (GAA), was 126.32x higher in enhancing tumor than in adjacent brain and 13.63x higher in non-enhancing tumor than brain. Forty-eight additional metabolites were 2.05-10.18x more abundant in enhancing tumor than brain, including carnitine family members and all nine large neutral amino acids. Except for GAA and 2-hydroxyglutarate in IDH-mutant gliomas, differences between non-enhancing tumor and brain microdialysate were comparatively modest and less consistent, suggesting heterogeneity in the glioma metabolic microenvironment of blood-brain barrier (BBB) intact areas as compared to BBB-disrupted portions of gliomas. Interestingly, the enhancing but not the non-enhancing glioma metabolome was significantly enriched for plasma-associated metabolites, largely comprising amino acids and carnitines.

CONCLUSION

Our patient-derived data suggest that the BBB-disrupted metabolome of high-grade gliomas is characterized by metabolite diffusion from circulation into the tumor microenvironment. Further studies are ongoing to determine how this alteration in the glioma extracellular metabolome impacts glioma behavior and how it could be therapeutically targeted via BBB-modulating drugs.
OS10.8.A APPLICATIONS OF NOVEL FFPE BASED TECHNOLOGIES FOR THE DIAGNOSTICS OF GLIOMAS
Authors: Ritter M , Blume C , Patel B , Tang Y , Patel A , Berghaus N , Seferbekova Z , Sievers P , Herold-Mende C , Wick W , Gerstung M , von Deimling A , Sahm F
Published: September 2023

BACKGROUND

Due to the lack of consistent tumour-cell specific markers, the diffuse brain invasion of glioblastoma (GB) presents a significant diagnostic challenge, especially for specimens with a low tumour cell fraction or scarce tissue. The only common alteration found in most GB is the gain of chromosome 7 and loss of chromosome 10. The emergence of new technologies such as spatial and single nucleus transcriptomics that allow for detection of copy number alterations (CNVs) may allow us to push the diagnostic boundaries.

MATERIAL AND METHODS

We performed 10x Visium spatial transcriptomic analysis of FFPE tissue from bulk resections of 14 FFPE GB and stereotactic biopsies of 6 GB, 7 IDH mutant astrocytomas, 4 oligodendrogliomas and 1 diffuse glioma NOS. Visium tissue spots were then deconvolved using data from single nucleus transcriptomic data from nuclei isolated from FFPE tissue. Fresh frozen and FFPE single nucleus transcriptomic libraries were also generated from 4 GB with matching fresh-frozen and FFPE tissue available.

RESULTS

The infiltration zone, the tumour core and healthy brain tissue could be differentiated using the inferred CNVs of chromosome 7 and chromosome 10. Additionally, inferred CNVs of tissue fragments smaller than 1 mm2 were in accordance with Infinium MethylationEPIC array analysis (a well-established method for CNV detection) from the same tumour tissue. Using the spatial transcriptomics approach, the loss of chromosome 1p and 19q, which is characteristic for oligodendroglioma was also detected. To overcome the low resolution of Visium, deconvolution approaches using a single cell dataset can be used to determine the tumour content of a given tissue more precisely. To test if the single nuclei data from FFPE samples is suitable for deconvolution of spatial transcriptomics, we compared fresh-frozen and FFPE single nuclei data from matching tumours. As expected, FFPE and fresh frozen nuclei clustered together according to cell types and tumours in the UMAP space.

CONCLUSION

Spatial transcriptomics can be useful for brain tumour diagnostic workup, especially in cases where a limited amount of tissue prevents analysis by standard molecular diagnostic

METHODS

. Additionally, CNVs inferred from the spatial data as well as the spatial expression of marker genes help to better distinguish tumour infiltration zones from the core tumour and healthy brain tissue in the case of GB. This analysis can be further supported by deconvolution with a reference set generated from single nucleus transcriptomic analysis of FFPE tissue.
OS12.7.A IMPLEMENTATION OF A NATIONAL AYA MOLECULAR TUMOR BOARD: REPORT FROM THE CANADIAN AYA NEURO-ONCOLOGY NETWORK
Authors: Lim-Fat M , Bennett J , Al-Bati R , Climans S , Chan A , Massey N , Tsang D S , Hawkins C , Tabori U , Das S
Published: September 2023

BACKGROUND

The adolescent and young adult (AYA) population (15-39 years) is a unique and understudied population within neuro-oncology, and their care requires expertise across pediatric and adult-type brain tumors. Current challenges in AYA neuro-oncology include fragmented care across pediatric and adult hospitals, low inclusion in clinical trials, unique survivorship considerations and a lack of standard-of-care therapies for this population.

MATERIAL AND METHODS

We report on a two-year national effort from the Canadian AYA Neuro-Oncology Network (CANON) to implement national AYA rounds. The aims of the rounds are to discuss challenging cases, encourage and review the utility standardized molecular testing, and provide point-of-care multidisciplinary recommendations benefiting from the expertise of pediatric and adult providers across several tertiary and community centers.

RESULTS

Since April 2021, the Canadian national AYA rounds have occurred biweekly on a virtual secure platform. Over 2 years, 138 cases have been discussed; 23% of patients were 15-20 years old, 33% were 21-30 years old and 26% were 31-40 years old. Cases discussed included low grade gliomas (39%), followed by high grade gliomas (33%), ependymomas (6.5%), medulloblastomas (6.5%) and others (9.4%). A total of 240 participants across 25 institutions across Canada have attended the rounds, spanning adult and pediatric neurosurgery, neuro-pathology, neuro-oncology, radiation oncology and radiology. A prospective database of cases presented at our AYA rounds, matching molecular characterization, choice of therapies and relevant clinical outcomes has been initiated and interim data will be presented at the meeting.

CONCLUSION

Virtual national AYA-neuro-oncology multi-disciplinary rounds have raised awareness of current gaps and possible nation-wide solutions to improve the care of AYA brain tumors. Leveraging this network, our group has published guidelines for molecular testing in AYA brain tumors and is employing this platform for ongoing research and clinical collaborations.
P01.03.B COGNITIVE REHABILITATION IN PRIMARY BRAIN CANCER: BASELINE PATIENT CHARACTERISTICS AND NEUROPSYCHOLOGICAL ASSESSMENTS
Authors: Smith E , Weyer-Jamora C , Luks T L , Bracci P M , Brie M , Hervey-Jumper S L , Almomen R , Phan S , Rottgering J G , Chang S M , Taylor J W
Published: September 2023

BACKGROUND

Cognitive impairments are a common issue for individuals with primary brain tumors. Cognitive rehabilitation is a known effective treatment in other neurologic diseases, with emerging data in adults with brain tumors. However, there is a limited understanding of the clinical characteristics of the patients referred to cognitive rehabilitation in this population.

MATERIAL AND METHODS

We identified a cohort of adult primary brain tumor patients who were clinically referred for consideration of cognitive rehabilitation by their treating neuro-oncologist at the University of California San Francisco (UCSF) between 05/2018 - 07/2022. Baseline neurocognitive impairments were assessed both at the individual test and domain levels. We analyzed absolute impairments and incorporated relative impairments for a subset of patients using a word reading task (WTAR) for pre-morbid estimates. Absolute impairments were defined as a Z-score of -1.5 or below. Relative impairments were defined as a Z-score at least 1.5 standard deviations below the pre-morbid estimate. A two-sample test was used to assess differences between relative and absolute impairments.

RESULTS

We evaluated 136 patients with primary brain tumors. The median age was 53 years (range 21-78), with majority male (62.5%), white (61.8%), and at least 16 years of education (79.4%). Astrocytomas (36.0%) and oligodendrogliomas (27.2%) were the most common diagnoses with most tumors located in the frontal lobe (54.4%) and in the left hemisphere (52.2%). The mean time from pathologic diagnosis to testing was 3.12 years (range: -0.83 to 24.18) with 73.5% having prior radiation. Neuropsychological evaluation identified several impaired domains, with significantly more relative impairments based on premorbid estimates versus absolute (p=.01). The most commonly impaired domains for both relative and absolute impairments were processing speed at 90.6% and 43.4%; verbal learning and memory at 67.6% and 38.2%; and executive/frontal systems at 53.3% and 25%. Relative and absolute impairments for auditory attention/concentration at 46.8% and 14.1%; language abilities at 44.1% and 15.2%; and visuospatial learning and memory at 33. 3% and 21.2% were somewhat less common.

CONCLUSION

These results provide a landscape for baseline patient characteristics and cognitive function in a large cohort of primary brain tumor patients who were clinically referred for cognitive rehabilitation. Processing speed and verbal learning and memory were the most relatively affected cognitive domains in this population. We also highlight the importance of incorporating premorbid estimates in determining levels of impairment. Updated data assessing correlations among patient, tumor, treatment characteristics, and cognitive function will be presented.
P01.06.B EVOLUTION OF NEUROCOGNITIVE FUNCTIONING AFTER RADIOTHERAPY IN PATIENTS WITH BRAIN METASTASES
Authors: van Grinsven E E , Gmelich Meijling Y A , Cialdella F , Verhoeff J J C , Philippens M E P , van Zandvoort M J E
Published: September 2023

BACKGROUND

Brain metastases (BMs) occur in ten to thirty percent of the adult population. They present a heterogeneous population, with almost half already experiencing cognitive impairment prior to brain radiotherapy (RT). While RT aims to improve or stabilize the neurologic deficit(s), neurocognitive decline is often reported after treatment. To better understand cognitive performance after RT, we assessed the individual cognitive performance before, three months and at least eleven months after RT.

METHODS

The study population consisted of 32 adult patients with BMs that were referred for brain RT. An elaborate battery of neuropsychological tests was used to assess objective cognitive performance. Additionally, the Cognitive Failures Questionnaire (CFQ) and a semi-structured interview measured subjective cognitive performance and the EORTC QLQ-C30 and EQ-5D-3L were used to assess quality of life (QoL). The reliable change index (RCI) as formulated by Maassen et al. (2009) represented clinically significant change in cognitive performance at the follow-up time points, whereby RCI <-1.645 was denoted decline and RCI >1.645 improvement. This RCI takes into account test-retest reliability and practice effects.

RESULTS

Three months post-RT, 83% of the patients showed declines in at least one cognitive domain, with declines most frequent in memory (58%) and processing speed (36%). On the other hand, improvements were also found, especially for attention (92%) and fine motor coordination (46%). 50-60% of patients showed further decline in cognitive performance at task-level from three to eleven month follow-up, while 40% of patients showed further improvement. Multinomial logistic regressions indicated that a higher number of BMs was predictive of declined cognitive performance three months post-RT, specifically regarding executive functioning, processing speed and fine motor coordination. Additionally, patients without symptoms at the moment of BMs diagnosis more often showed declines in processing speed. BMs growth and age were not related to cognitive change. The change in cognitive performance was not related to either subjective cognitive performance or self-reported QoL.

CONCLUSION

Using a stringent RCI, we found patients who benefited from RT, but also patients who showed a clinical relevant cognitive decline three months post-RT. In most patients, this trend continued until at least eleven months after RT. Patients with multiple brain metastases may be particularly vulnerable to cognitive decline and death caused by tumour growth. However, life-extending RT also has its costs and thus requires careful consideration in shared decision-making regarding treatment options.

GRANT INFORMATION

The APRICOT study described in the current abstract as well as EG, were supported by funding from the Dutch Cancer Society “Koningin Wilhelmina Fonds (KWF)” (#11110).
P01.08.B MENTAL FATIGUE IN PATIENTS WITH LOW-GRADE GLIOMA: ASSOCIATIONS WITH NEUROCOGNITIVE FUNCTIONING AND TUMOR CHARACTERISTICS
Authors: Buunk A M , Siebenga F F , Kramer M C A , Gelens F , Gelmers F , Rakers S E , Bosma I , Enting R H , van der Hoorn A , van der Weide H L , Spikman J M
Published: September 2023

BACKGROUND

Fatigue is a frequent consequence of low-grade glioma (LGG), but the causes are still barely understood. Specifically mental fatigue might be related to cognitive impairment such as mental slowness and decreased attention. Also, patients with greater tumor volumes or tumors in certain locations (such as the frontal cortex) might have more cognitive impairments and experience more fatigue. The aim of the present study was twofold: (1) to examine the relationship between mental fatigue and information processing speed and complex attention and (2) to investigate the associations between mental fatigue and tumor volume and location in patients with LGG.

MATERIAL AND METHODS

124 patients with LGG (IDH mutated astrocytoma and oligodendroglioma grade 2 and 3) were included before the start of proton therapy. Different facets of fatigue, including mental fatigue, were measured after surgery, with a multidimensional fatigue scale, the Dutch Multifactor Fatigue Scale (DMFS). The Vienna Test System was used to examine simple information processing speed, response inhibition, and divided attention. Tumor location and tumor volume (radiation target volume) were scored on the pre-radiotherapy MRI scan. Descriptive statistics, Spearman’s correlations, and between group comparisons were performed.

RESULTS

41% of patients with LGG reported severe mental fatigue. No significant differences were found in mean performance on simple information processing speed, response inhibition and divided attention between severely mental fatigued patients and non-severely mental fatigued patients. However, the percentage of patients with impaired divided attention was significantly higher in the severely mental fatigued group (39%) compared to the non-severely mental fatigued group (16.2%), χ2 = 7.6, p < 0.05. No significant relationships were found between mental fatigue and tumor volume and location. Also, tumor location was not related to neurocognitive functioning, but larger tumor volume was significantly associated with poorer performance on divided attention (r = -0.19, p < 0.05).

CONCLUSION

A high rate of mental fatigue was found in patients with LGG. Furthermore, a relationship between impaired divided attention and severe mental fatigue was found. This implies that patients may develop mental fatigue due to increased cognitive efforts to compensate for attentional deficits. This might be especially important in patients with larger tumors, considering the relationship between tumor volume and divided attention. The results stress the importance of neuropsychological assessment in this patient group before the start of adjuvant treatment, to timely offer individual rehabilitation.
P02.04.B TARGETING METABOLIC VULNERABILITIES IN GLIOBLASTOMA
Authors: Burban A , Sharanek A , Bikfalvi A , Daubon T
Published: September 2023

BACKGROUND

Glioblastoma is the most common and aggressive primary brain cancer, with a median survival of 16 months. A subset of cells within these tumours, termed glioblastoma stem cells (GSCs), displays high tumourigenic capacity and resistance to conventional therapies, and are responsible for tumour recurrence. Glioblastomas have been initially shown to mainly rely on glycolysis as a source of energy. However, a growing body of literature reports that GSCs are less glycolytic than their differentiated progeny and can thrive on oxidative phosphorylation (OXPHOS) to survive, sustain stemness and fuel tumourigenic potential. Thus, targeting OXPHOS could be a promising strategy to halt energy production and starve GSCs to death. However, under metabolic stress, GSCs can also switch to a more glycolytic phenotype, suggesting a metabolic plasticity in GSCs, and thus adding a layer of complexity to target GSC metabolism. In the current study, we have investigated the impact of compound X (CX), recently shown to impair mitochondrial respiration, on the fate and tumourigenesis of GSCs.

MATERIAL AND METHODS

Multiple patient-derived and murine GSC models were used to test the impact of CX on GSCs in vitro. The effect of CX on glioblastoma tumors was evaluated using patient-derived xenografts and syngeneic mouse models.

RESULTS

We have established that CX inhibits GSC proliferation and impairs stemness-related pathways in vitro. CX delays glioblastoma tumourigenesis in vivo. While a drastic decrease in cell proliferation was observed, cell death assays revealed that CX does not induce cell death. This suggests that GSCs gain a slow-cycling phenotype to resist energy depletion. Mechanistically, we have established that CX targets complex I of the mitochondrial respiratory chain, leading to an impairment of OXPHOS. Interestingly, inhibition of OXPHOS by CX was associated with an extensive production of extracellular lactate, indicating that at least, a subset of GSCs gain metabolic adaptability by co-opting glycolysis to survive. Thus, to tackle this metabolic plasticity in GSCs, we adopted a new strategy that involves sequestration of the lactic acid intracellularly via disruption of lactate transporters. Treatment of GSCs with monocarboxylate transporter inhibitors, AZD3965 and syrosingopine, alone did not significantly impact GSC growth and viability. Strikingly, combined CX treatment with either AZD3965 or syrosingopine resulted in high intracellular lactate buildup, increased reactive oxygen species, and led to drastic cell lethality in multiple GSC models.

CONCLUSION

This study highlights that re-routing the OXPHOS-dependent GSCs to glycolysis offers a vulnerability to sensitize GSCs to cell death. Dual inhibition of OXPHOS and lactate export could be a promising therapeutic approach to deplete malignant GSCs and suppress glioblastoma tumourigenesis.
P02.12.B UNDERSTANDING THE ROLES OF EPHRIN A5 IN GLIOBLASTOMA AND ITS POTENTIAL AS A THERAPEUTIC TARGET
Authors: Skarne N , D'Souza R , Harris L , Baumgartner U , Offenhauser C , Akgül S , Beckett K , Boyd A , Day B
Published: September 2023

BACKGROUND

Glioblastoma (GBM) is the most common and aggressive malignant primary brain cancer and is associated with very poor patient outcomes. GBM has been classified into three cell subtypes (proneural (PN), classical (CL), and mesenchymal (MES)), which have been further defined into four plastic cell states (neural-progenitor-like (NPC-like), oligodendrocyte-progenitor-like (OPC-like), astrocyte-like (AC-like), and mesenchymal-like (MES-like)). Existing treatment options have had limited success in improving overall survival, with the extreme heterogeneity present in GBM presenting a major barrier to effective therapy. Thus, there is an urgent need to develop more effective therapeutic strategies which better capture heterogeneity and delay tumour relapse. Several erythropoietin-producing human hepatocellular (Eph) receptors and ephrin ligands have been shown to be functionally overexpressed in cancer and have become attractive therapeutic targets. EphA3 has previously been shown to be a functional, tumour-specific target, frequently elevated in the MES subtype. We identified ephrin A5, the high-affinity ligand of EphA3, to be frequently co-expressed with EphA3 in GBM tumours. However, unlike EphA3, the mechanisms of ephrin A5 in GBM remain understudied. We therefore believe that ephrin A5 serves as an attractive synergistic target for the treatment of GBM.

MATERIAL AND METHODS

We examined the expression of ephrin A5 in a panel of GBM patient specimens. A panel of GBM tumours were also selected for immunohistochemical and spatial transcriptomics analysis. For in vitro functional studies, ephrin A5 was overexpressed in several GBM primary cell lines. Assays examining proliferation, stemness and differentiation were performed.

RESULTS

Expression of ephrin A5 was comparable to EphA3 in GBM. 64% of GBM tumours analysed showed higher levels of ephrin A5, relative to the highest normal brain specimen. Initial immunohistochemistry analysis suggests EphA3 and ephrin A5 to be expressed discretely on over 75% of the total tumour mass. Spatial transcriptomics analysis suggests ephrin A5 to be enriched in cells of the AC-like cell state. In vitro overexpression of ephrin A5 was shown to reduce neurosphere formation and induce differentiation of GBM cells.

CONCLUSION

EphA3 and ephrin A5 are overexpressed in a portion of GBM tumours. Critically, there was a strong mutually exclusive expression to different compartments of the GBM tumour, covering the vast majority of the total tumour mass. Our data suggests that ephrin A5 overexpression drives a less aggressive, more differentiated AC-like tumour phenotype. Thus, dual targeting of EphA3 and ephrin A5 in GBM could provide an opportunity to better capture tumour heterogeneity and achieve more durable therapeutic responses.
P02.22.B CELLULAR COMPOSITION DETERMINED BY STEMNESS MARKERS IN MONOLAYER GLIOBLASTOMA CULTURES IS TUMOR SPECIFIC, HIGHLY DYNAMIC AND RELATED TO TMZ SENSITIVITY
Authors: Verploegh I S C , de Kroon A , Verhoeven F A M , Loriaux S , e. Hassnaoui H , Lamfers M , Huylebroeck D , Leenstra S
Published: September 2023

BACKGROUND

Different models are used to study pathophysiology and potential new therapeutic strategies of glioblastoma (GBM) in vitro. Generally, monolayer cultures are chosen because of their high reproducibility, while spheroid cultures are preferred to better recapitulate tumor heterogeneity and effects of the micro-environment. A common assumption is that monolayer cultures display less plasticity than spheroid cultures. In this study we examine the plasticity of stem cell-like cells in monolayer cultures and their relationship to temozolomide (TMZ) sensitivity.

MATERIAL AND METHODS

Three patient-derived GBM cultures: one TMZ sensitive, one induced TMZ-resistant and one naturally TMZ-resistant were used. All cultures were sorted in four subpopulations (CD133+/CD44+, CD133+/CD44-, CD133-/CD44+ and CD133-/CD44-) and subsequently cultured. Cellular composition was determined at multiple timepoints by immunofluorescent imaging and FACS-analysis. The effect of seeding density on cellular composition was assessed. Furthermore the effect of original culture composition on sphere forming capacity and TMZ sensitivity was assessed.

RESULTS

Culture composition was tumor-specific and the pre-sorting composition was acquired within two passages after sorting, irrespective of original subpopulation or sorting density. Even the CD133-/CD44- subpopulation was able to rapidly re-acquire the initial tumor composition. Furthermore, sphere-forming capacity was restored four passages after sorting. Interestingly, cells that were inherently resistant to TMZ expressed higher levels of CD44 than TMZ-sensitive cells. There was no relationship between expression of CD133 and sensitivity to TMZ. Sensitivity to TMZ was similar in all subpopulations four passages after sorting.

CONCLUSION

Monolayer cultures display rapid plasticity with regard to the expression of the stemness markers CD133 and CD44. Culture composition is tumor specific and inherently programmed in each tumor cell. TMZ sensitivity seems to be mostly related to CD44 expression, and not to CD133 expression. Sphere forming capacity and TMZ sensitivity are restored soon after sorting, even in initially differentiated GBM cells.
P02.24.B A DRUG DISCOVERY PLATFORM FOR COMBINATORIAL TARGETING OF CELL STATES AND ENTITIES
Authors: Jiang B , Schmitt M , Gargiulo G
Published: September 2023

Glioblastoma (GBM) is a lethal brain tumor with limited therapeutic options. Therapeutic resistance arises from the collaboration among heterogeneous and highly plastic cellular entities and states conserved across GBM patients and the tumor microenvironment.Tumor cells adapt in response to the current standard of care and infiltration of innate immune cells, recurrently acquiring a mesenchymal state that drives therapeutic resistance.Moreover, the blood-brain barrier (BBB) poses challenges to the effectiveness and bioavailability of approved therapeutics, as well as the discovery of new ones.Our lab has developed synthetic locus control regions (sLCRs) as transcriptional reporters for glioblastoma subtypes, enabling the study of cell identity and state transitions in vitro and in vivo. We have combined this tool with validated cellular models for glioblastoma mesenchymal transition and therapeutic resistance to establish an in vitro phenotypic screening platform. Currently, we are utilizing this platform to identify treatment combinations and dosing schemes that aim to overcome innate immunity-driven resistance and synergize with the standard of care. As a proof-of-concept for a new generation of brain tumor target discovery platforms, we will present the setup of our platform and preliminary results for a class of BBB-penetrant drugs.
P03.02.B VIABLE TUMOR RECURRENCE IS A MAJOR CAUSE OF LOCAL FAILURE AFTER BEVACIZUMAB THERAPY FOR RADIATION NECROSIS IN BRAIN METASTASES TREATED WITH STEREOTACTIC RADIOSURGERY
Authors: Cho Y , Yoon K , Lee D , Song S , Kim Y , Hong C , Kim J
Published: September 2023

BACKGROUND

Bevacizumab (BVZ) is known to be effective to control radiation necrosis (RN) following stereotactic radiosurgery (SRS) for brain metastases (BMs), although treatment failure may occur. Here, we investigated the incidence and pattern of local failure after BVZ therapy for RN and its underlying biological mechanism.

MATERIAL AND METHODS

We conducted a retrospective analysis on 17 patients who had been treated with BVZ for RN following SRS for BMs between 2016 and 2021. In each patient, the diagnosis of RN was made based on the conventional and advanced MR with or without positron emission tomography. Median 5 cycles (range, 2-10 cycles) of BVZ (5 mg/kg) were administered at 2-week intervals. Treatment response was assessed by volumetric changes of the lesions on MR and patients’ neurological status.

RESULTS

Treatment response was typically brisk and substantial. Best MR response was seen at median 13 weeks (range, 3-56 weeks) after the start of BVZ with a median volume decrease of 84.5% (range, 38.7-100%) of perilesional brain edema on T2WI and of 54% (range, 2.9-100%) of contrast enhancing lesions on T1WI. Patients’ neurological status improved in 16 patients (94.1%) and was stationary in 1 (5.9%). During the median follow-up of 12 months (range, 2-60 months), delayed local failure was observed in 6 patients (35.3%) at median 10 months (range, 6-14 months) after starting BVZ treatment, where viable tumor recurrence was demonstrated in all of them. No reconstitution of RN without viable tumor was observed during the follow-up.

CONCLUSION

Although BVZ was highly effective to control RN following SRS for BMs, delayed local failure frequently occurs owing to viable tumor recurrence. This may imply that much predominant vascular stabilizing effect of BVZ over anti-tumor effect transiently obscures the presence of potential viable tumor cells but does not prevent them from eventual recurrence.
P03.04.B EFFICACY OF NEOADJUVANT STEREOTACTIC RADIOSURGERY IN SOLID CANCER BRAIN METASTASES: A SYSTEMATIC REVIEW AND METANALYSIS
Authors: Gagliardi F , De Domenico P , Snider S , Nizzola M , Mortini P
Published: September 2023

BACKGROUND

Neoadjuvant stereotactic radiosurgery (NaSRS) is a novel strategy for brain metastasis (BMs) management, promising to achieve lower rates of toxicity, leptomeningeal progression, and high percentage of local control.

MATERIAL AND METHODS

An extensive systematic literature review and meta-analysis of proportions were performed. A total of 8 papers were eligible for final analysis after searching MEDLINE via PubMed, Web-of-science, Cochrane Wiley, and Embase databases.

RESULTS

A total of 551 patients undergoing NaSRS to treat 583 lesions were included. Median age was 57.7 [56.5-61.1] years, with a median tumor volume of 9.1 [8.3-14.4] cc. The most frequent histology was non-small cell lung cancer (40.7%), followed by breast (20.5%), and melanoma (15.6%). Most of the lesions had a supratentorial location (77.6%). Treatment parameters were homogenous across the studies and showed a median dose of 16 [14.9-20.5] Gy at 80% isodose.Surgery was performed after a median of 1 [1-2] day and achieved gross-total extent in 92.4% of cases. Median follow-up was 12.9 [9.9-18.9] months.Pooled proportion of patients showed an overall mortality rate of 50% (CI 37-63; I2=87%), local failure of 15% (CI 12-20%; I2=12.1%) and a rate of distant brain failure of 42% (CI 35-49%; I2=55.3%). The median local progression-free survival (PFS) was 10.4 months, while median survival without distant failure was 8 months.Rate of radionecrosis (RN) and leptomeningeal dissemination (LMD) were 4% respectively. Median overall survival (OS) was 14.4 months.

CONCLUSION

Existing data suggest that NaSRS achieves good local control on BMs with relatively lower dose than adjuvant treatment and low incidence of RN and other complications. These results need to be confirmed by larger studies with higher level of evidence to address formal comparisons with other regimens.