bluuebunny/crossref_metadata_2025_split huggingface dataset:
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

Abstract

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

Abstract

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

Abstract

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

Abstract

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

Abstract

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

Abstract

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 &lt;-1.645 was denoted decline and RCI &gt;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

Abstract

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 &lt; 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 &lt; 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

Abstract

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.