bluuebunny/crossref_metadata_2025_split huggingface dataset:
P01.09.A Prevalence and predictors of cognitive impairment in adult glioma survivors after multimodal therapy
Authors: De Roeck L , Spiessens P , Vermeulen H , Clement P , Daisne J , De Vleeschouwer S , Sleurs C , Lambrecht M 
Published: September 2022

Abstract

Background
Long-term survival can be achieved in an increasing number of glioma patients after treatment. Therefore, safeguarding these survivors’ quality of life (QoL) is essential. Neurocognitive decline arises in many young patients, placing a heavy burden on the social and economic aspects of the patients’ lives. A lot of debate is currently ongoing regarding the prevalence of neurocognitive impairment and individual predictors of whom is susceptible for such side effect.

Material and Methods
In this cross-sectional study, 37 WHO grade 2-3 adult glioma survivors, at least one year after multimodal therapy, were tested using a comprehensive neurocognitive test battery covering multiple cognitive domains. Neurocognitive test scores were converted into z-scores using country-specific normative data. Cognitive impairment was defined as a z-score lower or equal to -1.50 for each subtest. Age, time since multimodal therapy, radiotherapy treatment and tumour location were included as predictors in a linear regression model per outcome (n=12).

Results
In this cohort, 29 patients (78%) showed a test score below the predefined cutoff on at least one cognitive test. The percentage of patients who showed test-specific cognitive impairment ranged from 8.1% to 56.76% per test. Fine motor skills, verbal memory, processing speed and executive functioning were the most commonly affected cognitive domains. In this study, the variability in processing speed performance was associated with age (TMT A, p=0.03), time since therapy (WAIS-IV coding, p=0.02) and tumour location. In these measures, poorer outcomes were observed with increasing age, longer time since therapy and in patients with gliomas located in the left frontal lobe. Moreover, age showed to be a significant predictor of verbal memory, with poorer outcomes on the HVLT-R delayed recall task with increasing age (p=0.04). Tumour location predicted working memory performance, as patients with right parietal tumours (p=0.03) showed significantly worse on the WAIS-IV digit span task.

Conclusion
These preliminary data underline the various alterations of neurocognitive functioning in glioma survivors after multimodal therapy. Therefore, future research needs to shift towards a patient-tailored approach. The next step in this study will be to link these neurocognitive data to advanced neuroimaging data to explore the potential predictive value of imaging markers for neural damage and cognitive outcomes, paving the path to innovative treatment planning techniques.
P01.11.A Perioperative executive functioning in patients with low-grade gliomas near the Frontal Aslant Tract
Authors: Landers M J F , Butterbrod E , De Baene W , Sitskoorn M M , Rutten G M 
Published: September 2022

Abstract

Background
A tract potentially involved in important executive cognitive processes is the Frontal Aslant Tract (FAT). In particular the right FAT has been associated with executive functioning (EF). In neurosurgery, it remains unclear if patients with tumors near the FAT demonstrate EF impairments after resection. This study investigated whether low grade gliomas (LGG) that affect the core white matter and/or structural integrity of the FAT predict preoperative and 3 months postoperative EF, when controlled for tumor volume and the integrity of other nearby tracts (SLF II and SLF III).

Material and Methods
Data was analyzed from patients with frontal and parietal LGG who underwent surgery between 2010-2021. Probabilistic tractography was performed prior to surgery to generate preoperative tracts of the FAT, SLF II and SLF III. The core of the FAT was defined as the white matter between the seed and the target region. Average mean diffusivity for each tract was taken as a measure of structural integrity. EF was assessed one day before and 3 months post-surgery with the following tests: Stroop test, symbol digit coding test (SDC), shifting attention test (SAT), and letter fluency test (LF). We performed linear mixed models and linear regression analyses to investigate the relationship between presurgical tumor overlap with the core of the FAT and FAT integrity with pre- and postsurgical executive test performances.

Results
Seventy-five patients were included (left tumor N=39, right tumor N=36). Mean pre-surgical Z-scores were within 0.5 standard deviation from a healthy control group for all tests, but with substantial variance between patients (Z-score range:-3.59 to 2.4). The results demonstrated that core overlap of the right FAT predicted preoperative performance on the SAT (p&lt;.01, β= -.473), Stroop (p&lt;.01, β= -.519), and SDC (p&lt;.01, β= -.519). Right or left core overlap did not significantly predict performance three months after surgery. FAT integrity did not predict preoperative EF performance, whereas it did predict SAT performance at three months post-surgical (p&lt;.01, β= -.694) when controlled for SLF II, III integrity and tumor volume.

Conclusion
Although patients with frontal or parietal LGG showed no dysfunction on tests of EF before surgery on group level, they demonstrated large variability between patients. Tumor overlap with the core of the right FAT predicted worse presurgical EF performances, but not short-term post-surgical performances. Right FAT integrity predicted short-term post-surgical performance on cognitive flexibility. These results are in line with previous findings that the right FAT is involved in EF and indicate that preoperative FAT integrity might predict which patients will perform worse after surgery.
P01.13.A The effect of musicality on language recovery after awake glioma surgery
Authors: Kappen P R , van den Brink J , Jeekel J , Dirven C M F , Klimek M , Kamphuis M , Docter-Kerkhof C S , Mooijman S A , Nandoe Tewarie R D S , Broekman M L D , Vincent A J P E , Satoer D 
Published: September 2022

Abstract

Background
Awake craniotomy is used to resect tumor while preserving language. However, differences between patients in post-operative speech/language outcome are observed despite careful intra-operative monitoring. Literature describes improved performance in language tasks during cognitive tests in musicians. Moreover increased white matter connectivity properties in the corpus callosum are described in musicians compared to non-musicians. We hypothesize better recovery of language in musical patients after awake glioma surgery, caused by higher connectivity properties from the corpus callosum.

Material and Methods
Adult patients undergoing resection for glioma with an awake resection procedure at two neurosurgical centers were prospectively included. Patients without standardized language tests at pre- and post-operative level, with a glioblastoma multiforme (WHO grade 4) or undergoing re-resection were excluded. Language was assessed with the Diagnostic Instrument for Mild Aphasia (DIMA) and corrected for age and education years from a healthy population. The patients’ musical skill was assessed through questionnaires, and divided in groups based on the Musical Expertise Criterion (MEC) which defines musicality based the duration and intensity of musical training. Volumetric measures of the corpus callosum, corrected for total brain volumes, was calculated of each included patient based on the pre-operative structural MRI.

Results
Forty-six patients, enrolled between June 2015 and September 2019, were followed-up (mean/SD; 240/174 days after craniotomy) and divided in: non-musician (41.3%, n = 19), amateur-musician (34.8%, n=16) and trained-musician (23.9%, n = 11). Overall a decrease in language was observed after craniotomy (mean/SD) of -0.361/0.771. Musical abilities correlated with less decrease in language (mean/SD) when comparing non-musicians (-0.543/0.683) to amateur (-0.272/0.910) and trained (-0.176/0.693) musicians. An increased but non-significant trend (p=0.28) between musicality and corpus callosum / brain ratio (mean/SD) was observed in non-musicians (0.763, 0.718;0.808), amateur musicians (0.792, 0.745;0.838) and trained musicians (0.835, 0.778;0.891).

Conclusion
Musicality seemed to improve language outcome after awake glioma surgery, possibly attributed due to a higher white matter connectivity in the corpus callosum. Future studies with larger sample sizes are needed to confirm our findings.
P01.17.A Role of preoperative assessment in predicting tumor induced plasticity in patients with diffuse gliomas
Authors: Latini F , Axelson H , Fahlström M , Jemstedt M , Alberius Munkhammar Å , Zetterling M , Ryttlefors M 
Published: September 2022

Abstract

Background
When diffuse gliomas (DG) affect the brain′s potential to reorganize functional networks, patients can exhibit seizures and/or language/cognitive impairment. The tumor-brain interaction and the individual connectomic organization cannot be predicted preoperatively. We aimed to, first, investigate the relationship between preoperative assessment and intraoperative findings of eloquent tumors in 36 DG operated with awake surgery. Second, we also studied possible mechanisms of tumor-induced brain reorganisation in these patients.

Material and Methods
FLAIR-MRI sequences were used for tumor volume segmentation and the Brain-Grid system (BG). This standardized radiological tool was used as an overlay for infiltration analysis. Neuropsychological (NPS) and/or language preoperative assessments were performed in all patients before the direct cortical/subcortical brain mapping. The distance between eloquent spots and tumor margins was registered and measured on the neuronavigation system. Tumours containing eloquent points within hyperintense area on FLAIR sequences (cortical or subcortical) were considered eloquent. Eloquent points within 5-10 mm from the FLAIR signal margin were considered peritumoral, while beyond 10 mm from the FLAIR signal were considered outside the tumour area. Pre and postoperative images (3 months after the operation) were merged to detect eventual residual tumour. Clinical, radiological, and topographical variables and intraoperative findings were used for correlation and logistic regression analyses.

Results
84.6% of our patients displayed neuropsychological symptoms at the preoperative assessment. Eloquent tumors were detected in 75% of the cases. Impaired NPS functions were correlated with more invasive tumors, crucial location (A4C2S2/A3C2S2-voxels, left opercular-insular/sub-insular region) and higher risk of eloquent tumors. Epilepsy was correlated with larger tumor volumes and infiltrated A4C2S2 /A3C2S2 voxels. Language impairment was correlated with infiltrated A3C2S2 voxel. Group comparison between younger and older patients (cut-off at 38 years old based on ROC curves) showed a significative difference in the number of intratumoral cortical eloquent spots (p &lt; .05) and the number of peritumoral cortical eloquent spots (p &lt; .001).

Conclusion
Preoperative NPS impairment was linked with high risk of eloquent tumors. Epilepsy and language impairment were linked with specific tumor locations while peritumoral cortical eloquent spots reflected an early compensative mechanism with age as possible influencing factor. A systematic integration of extensive cognitive assessment and advanced neuroimaging can improve our comprehension of the connectomic brain organization at the individual scale and lead to a better oncological/functional balance.
P01.20.B Peroperative cognitive monitoring in patients with aphasia
Authors: Hartung S L , Huenges Wajer I M C , van Zandvoort M J E , Robe P A J T 
Published: September 2022

Abstract

Background
Cognitive monitoring during awake glioma surgery provides the opportunity to increase the extent of resection while preserving cognitive functions. Preoperative language functioning often determines whether awake surgery can be performed since some form of communication with the patient is essential. However, as complex as it may be to perform intraoperative monitoring in patients with severe preoperative language disturbances, it is risky to assume that language disturbances are definite without functional perspectives. In addition, there are other cognitive functions that should be preserved. This study investigates to what extent cognitive functions can be monitored during awake surgery in the presence of preoperative language disturbances.

Material and Methods
Glioma data were collected in a single-centre consecutive study cohort of 186 patients who underwent awake brain surgery for either low-grade (WHO grade 1-2) glioma (40 percent) or high-grade (WHO grade 3-4) glioma (60 percent). Preoperative language disturbances were evidenced during preoperative neuropsychological assessment based on performances on the Boston Naming Test (N= 27) and Token Test (N=25). Intraoperative procedures were performed as part of clinical care.

Results
Preliminary results on the Boston Naming Test show that intraoperative testing with the use of at least one language test (picture-naming) is feasible in 80 percent of all patients with language disturbances. In those cases, a functional boundary of language functions is found in 85 percent during awake surgery. Monitoring of other non-language functions, such as working memory, inhibition, speech, motor functions and social cognition, provided functional boundaries in 25 up to 85 percent of patients with language disturbances. Postoperatively, cognitive functioning was improved in a significant number of patients.

Conclusion
Based on these preliminary results we conclude that preoperative language disturbances do not prevent from monitoring language functions as well as other cognitive functions during awake glioma surgery. In a larger cohort, more in-depth analyses will be performed on additional outcome measures (Token test, survival rate, post-surgery treatment) and postoperative functioning will be compared to a control group of patients without preoperative language disturbances. By investigating the potential of awake surgery in patients who are severely cognitively affected, we aim to increase the applicability of this method to improve neuro-oncological treatments and optimally maintain quality of life.
P01.21.A Testing Semantic Verbal Fluency (SVFT) in patients with headache suspicious of cancer helps predict those with tumour on imaging
Authors: Zienius K , Hewins W , Summers D , McKinlay L , Brennan P , Porteous L , Grant R 
Published: September 2022

Abstract

Background
Differentiating secondary headache from primary headache on history alone can sometimes be difficult. Headache “plus” other subtle cognitive features improves prediction. Patients and relatives may attribute subtle cognitive or behavioural changes to other causes (e.g. anxiety, low mood). Sematic verbal fluency - “how many animals can you think of in a minute” is commonly impaired on admission in patients with headache harbouring a tumour. We were interested whether SVFT at point of referral for scan would help predict a tumour and requested GPs report the SVFT on electronic referral for direct access scanning in cases with a history of headache suspicious of cancer. The aim of the pilot study was to establish if the SVFT was a “red flag” for secondary causes of headache. We report the results of a 20-month audit of cases.

Material and Methods
An electronic Protocol Based Referral (PBR) was developed for Headache Suspicious of Cancer to expedite scanning. The PBR sat alongside the routine e-DACI system that had been in use for some years. The GP was asked to complete the SVFT at the time of referral for scanning. Other data were gathered: PMH cancer; other symptoms/signs; co-morbid conditions and medications.

Results
GPs submitted requests for ePBR scanning in 669 cases over 20 months (62% females; Mean age 53: 60% &lt;60 years). SVFT was completed on the request form in 381 (57%) cases. In these cases median SVFT was 17 animals. 11/381 cases were found to have cancer on scanning (2.9%): 10/188 cases with intracranial tumours had a SVFT &lt;17 (5.32%) compared with one with a SVFT &gt;=17. The median SVFT in cases with cancer was 10 animals. Other possible causes of SVFT &lt;17 were - 53 psychiatric or chronic pain conditions on multiple drugs;12 were not native English speakers; 19 had co-existing dementia; 5 had small vessel disease; 4 cysts; 4 Giant Cell Arteritis ; 2 Chiari 1 malformation; PMH - encephalitis (1).

Conclusion
A SVFT result &lt;17, at the point of referral for brain imaging, in patients with headache suspicious of cancer was associated with intracranial cancer in more than 1:20 cases, whereas a SVFT of &gt;=17 was associated with cancer in 1:200 cases. SVFT may be an additional useful “red flag”. The most appropriate SVFT cut-off requires more research in a larger study. Low SVFT in headache patients may inform Cancer Referral Guidelines, improve the identification of secondary headache and help expedite cases.
P02.01.B The telomere maintenance mechanism spectrum and its dynamics in gliomas
Authors: Kim S , Chowdhury T , Yu H , Choi S , Kim K , Kang H , Lee J , Lee S , Won J , Kim K , Kim K , Kim M , Lee J , Kim J , Kim Y , Kim T , Choi S , Phi J , Shin Y , Ku J , Lee S , Yun H , Lee H , Kim D , Kim K , Hur J K , Park S , Kim S , Park C 
Published: September 2022

Abstract
The activation of the telomere maintenance mechanism (TMM) is one of the critical drivers of cancer cell immortality. In gliomas, TERT expression and TERT promoter mutation are considered to reliably indicate telomerase activation, while ATRX mutation indicates alternative lengthening of telomeres (ALT). However, these relationships have not been extensively validated in tumor tissues. Here, we show through the direct measurement of telomerase activity and ALT in a large set of glioma samples that the TMM in glioma cannot be defined in the dichotomy of telomerase activity and ALT, regardless of TERT expression, TERT promoter mutation and ATRX mutation. Moreover, we observed that a considerable proportion of gliomas lack both telomerase activity and ALT (Neither group). And this Neither group exhibited evidence of slow growth potential. From a set of longitudinal samples from a separate cohort of glioma patients, we discovered that the TMM is not fixed but changes with glioma progression. Collectively, these results suggest that the TMM is a dynamic entity and that reflects the plasticity of the oncogenic biological status of tumor cells and that the TMM should be defined by the direct measurement of telomerase enzyme activity and evidence of ALT.
P02.02.A Next-generation sequencing (NGS) for identifying actionable molecular alterations in newly diagnosed and recurrent IDHwt-glioblastoma (GBM) patients: a large mono institutional experience
Authors: Padovan M , Maccari M , Bosio A , Vizzaccaro S , Cestonaro I , Corrà M , Caccese M , Cerretti G , Fassan M , Zagonel V , Lombardi G 
Published: September 2022

Abstract

Background
NGS panels allow the identification of alterations within hundreds of cancer-related genes and can guide a personalized strategy in glioma treatment.

Material and Methods
From Nov 2019 to Jan 2022 at Veneto Institute of Oncology, Padua, Italy, a large cohort of IDHwt-GBM tissues was analyzed by NGS (FoundationOne®CDx). We identified all potential actionable molecular alterations at diagnosis and/or at recurrence. High tumor mutational burden (TMB) was defined as ≥10 mutations/megabase.

Results
We analyzed 429 IDHwt-GBM samples: NGS profile was available for 419 samples (97.7%); sample failures in 10 cases (2.3%). 351 (84%) and 68 (16%) GBM samples derived from surgery at diagnosis and recurrence, respectively. All patients received radiotherapy and/or temozolomide as first line therapy. Among all the analyzed samples, the most frequent actionable molecular alterations were: CDKN2A (57%), CDKN2B (53%), EGFR amplification (39%), EGFR mutation (24%), PTEN loss (27%), RB1 (23%), NF1 (18%), PIK3CA (18%), CDK4 (15%), MDM2 (10%), PDGFRA (8%), BRCA1-2 (7%), FGFR1-3 (7%), Myc (6%), JAK (6%), ROS1 (5%), METmut (2%), METampl (2%), BRAF V600E (2%). No NTRK1/2/3 druggable alterations were observed. High TMB was found in 18 samples. The incidence of alteration of EGFR (ampl/mut), RB1, PIK3CA was statistically different between the two subgroups of samples (Fisher test). To date, 10% of patients received a personalized treatment as compassionate use, off-label use or in clinical trials (9 Dabrafenib/Trametinib, 8 Alpelisib, 3 Erdafitinib, 2 Ipatasertib, 1 Alectinib, 1 Capmatinib, 1 Palbociclib, 1 Entrectinib, 1 Pamiparib). Activity analysis is still ongoing.

Conclusion
NGS is feasible in GBM samples. Potentially, a high rate of patients could receive a personalized treatment. The activity analysis is ongoing. However, the incidence of actionable molecular alterations may differ between diagnosis and recurrent GBM samples.
P02.03.B Drug repurposing screen reveals glioblastoma cell line susceptibility to statins
Authors: Harwood D S L , Michaelsen S R , Anand A , Mundt F , Kristensen B W 
Published: September 2022

Abstract

Background
The standard therapy for glioblastoma patients is tumor resection followed by radiotherapy and temozolomide chemotherapy. Although glioblastoma has been extensively molecularly profiled along with other cancers, this knowledge has not yet been translated into improved survival outcomes. We used a bioinformatics approach to identify potential novel therapeutic strategies for glioblastoma. Objectives: Comprehensive online datasets which have assessed up to 1376 cancer cell lines in multiple ways were interrogated to identify potential drug candidates for glioblastoma.

Material and Methods
Datasets included were from the cancer cell line encyclopedia (mRNA expression), the Achillies project (cell viability following Crispr-Cas9 knockout) and PRISM (drug treatment). A t-test comparing cell viability of glioblastoma cell lines versus other cancers was used to identify potential drug candidates, followed by the use of multiple statistical tools to investigate potential mechanism of action and status of biomarkers.

Results
Fluvastatin and pitavastatin were amongst the drugs with the most significant effects against glioblastoma cell lines while also being FDA approved. These effects were found in both glioblastoma cells and other cancer types with a mesenchymal-like expression phenotype. The anti-cancer properties of statins have previously been attributed to the inhibition of HMG-Coa reductase. Here, we found their effects correlated with the gene knockout of UBIAD1. We tested the effects of statins on patient-derived glioblastoma cell lines with a mesenchymal (n = 2) and non-mesenchymal phenotype (n=2). Mesenchymal-like glioblastoma cells lines were found to be more susceptible to statins.

Conclusion
Statins appeared to be especially effective against glioblastoma lines and the effect could be linked to the direct or indirect inhibition of UBIAD1. In vitro validation of this finding is ongoing.